Indian Patents
Title of Invention

VITAMIN D RECEPTOR MODULATORS
Abstract The present invention relates to novel, non-secosteroidal, diaryl compounds with vitamin D receptor (VDR) modulating activity that are less hypercalcemic than la,25 dihydroxy vitamin D3. These compounds are useful for treating bone disease and psoriasis.
Full Text CROSS REFERENCE TO RELATED APPLICATIONS
This patent applicaton claims the benefit of priority under Title 35 United States
Code, section 119(e), of Provisional Patent Application No. 60/429,041 filed November
22, 2002; the disclosure of which is incorporated herein by reference.
BACKGROUND OF THE INVENTION
Vitamin D3 Receptor (VDR) is a ligand dependent transcription factor that
belongs to the superfamily of nuclear hormone receptors. The VDR protein is 427 amino
acids, with a molecular weight of ~50 kDa. The VDR ligand, 1a,25-dihydroxyvitamin D3
(the hormonally active form of Vitamin D) has its action mediated by its interaction with
the nuclear receptor known as Vitamin D receptor ("VDR"). The VDR ligand, 1a,25-
dihydroxyvitamin D3 (1a,25(OH)2D3) acts upon a wide variety of tissues and cells both
related to and unrelated to calcium and phosphate homeostasis.
The activity 1a,25-dihydroxyvitamin D3 in various systems suggests wide clinical,
applications. However, use of conventional VDR ligands is hampered by their associated
toxicity, namely hypercalcemia (elevated serum calcium). Currently, 1a,25(OH)2D3
marketed as Rocaltrol® pharmaceutical agent ( product of Hoffmann-La Roche), is
administered to kidney failure patients undergoing chronic kidney dialysis to treat
hypocalcemia and the resultant metabolic bone disease. Other therapeutic agents, such as
Calcipotriol® (synthetic analog of 1a,25(OH)2D3 ) show increased separation of binding
affinity on VDR from hypercalcemic activity.
Chemical modifications of 1a,25(OH)2D3 have yielded analogs with attenuated
calcium mobilization effects (R. Bouillon et. al, Endocrine Rev. 1995,16, 200-257). One
such analog, Dovonex ® pharmaceutical agent (product of Bristol-Meyers Squibb Co.), is
currently used in Europe and the United States as a topical treatment for mild to moderate
psoriasis (K. Kragballe et. al., Br. J. Dermatol. 1988, 119, 223-230).
Other Vitamin D3 mimics have been described in the publication, Vitamin D
Analogs: Mechanism of Action of Therapeutic Applications, by Nagpal, S.; Lu, J.;
Boehm, M. F., Cuir. Med. Chem. 2001, 8,1661-1679.
Although some degree of separation between the beneficial action and calcium
raising (calcemic) effects has been achieved with these VDR ligands, to date the
separation has been insufficient to allow for oral administration to treat conditions such as
osteoporosis, cancers, leukemias, and severe psoriasis.
One example of a major class of disorder that could benefit from VDR mediated
biological efficacy in the absence of hypercalcemia is osteoporosis. Osteoporosis is a
systemic disorder characterized by decreased bone mass and microarchitectural
deterioration of bone tissue leading to bone fragility and increased susceptibility to
fractures of the hip, spine, and wrist (World Health Organization WHO 1994).
Osteoporosis affects an estimated 75 million people in the United States, Europe, and
Japan.
Within the past few years, several antiresorptive therapies have been introduced.
These include bisphosphonates, hormone replacement therapy (HRT), a selective estrogen
receptor modulator (SERM), and calcitonins. These treatments reduce bone resorption,
bone formation, and increase bone density. However, none of these treatments increase
true bone volume nor can they restore lost bone architecture.
Another major disorder that could benefits from VDR mediated biological activity
is psoriasis. Psoriasis is one of the most common dermatologic diseases and is a chronic
inflammatory skin condition characterized by erythematous, sharply demarcated papules
and rounded plaques, covered by silvery micaceous scale.
Synthetic VDR ligands with reduced calcemic potential have been synthesized.
For example, a class of bis-phenyl compounds stated to mimic 1a, 25-dihydroxyvitamin
D3 is described in US Patent No. 6,218,430 and the article; "Novel nonsecosteroidal
vitamin D mimics exert VDR-modulating activities with less calcium mobilization than
1a, 25-Dihydroxyvitamin D3' by Marcus F. Boehm, et. al., Chemistry & Biology 1999,
Vol6,No.5,pgs.265-275.
Synthetic VDR ligands having an aryl-thiophene nucleus are described in United
States provisional patent application SN 60/384151, filed 29 May 2002.
There remains a need for improved treatments using alternative or improved
pharmaceutical agents that mimic 1a, 25-dihydroxyvitaniin D3 to stimulate bone
formation, restore bone quality, and treat other diseases without the attendant
disadvantage of hypercalcemia.
SUMMARY OF THE INVENTION
Novel compounds having a nucleus of formula "(A)" have been found effective as
Vitamin D Receptor (VDR) modulators:
The compounds of the invention with VDR modulating activities are represented by
formula (I)
wherein the variables R, R', R1, R2, Zb, and ZC are as hereinafter defined. It is a
discovery of this invention that compounds described herein display the desirable cell
differentiation and antiproliferative effects of 1,25(OH)2D3 with reduced calcium
mobilization (calcemic) effects if substituent ZC possesses a carbon atom linked group
that is directly connected (i.e., with no intervening non-carbon atom) to the aryl nucleus.
In another aspect, the present invention is directed towards pharmaceutical
compositions containing pharmaceutically effective amounts of compounds of
formulae (I) or a pharmaceutically acceptable salt or prodrug thereof, either singly or in
combination, together with pharmaceutically acceptable carriers and/or auxiliary agents.
Another aspect of the invention is a pharmaceutical, formulation for treatment or
prevention of osteoporosis containing pharmaceutically effective amounts of the vitamin
D receptor modulator compound of formula (I) alone or together with pharmaceutically
effective amounts of co-agents conventionally used for the treatment of osteoporosis.
Another aspect of the invention is a pharmaceutical formulation for treatment or
prevention of psoriasis containing pharmaceutically effective amounts of the vitamin D
receptor modulator compound of formula (I) alone or together with pharmaceutically
effective amounts of co-agents conventionally used for the treatment of psoriasis.
Another aspect of the invention is a pharmaceutical formulation for treatment or
prevention of prostate cancer containing pharmaccutically effective amounts of the
vitamin D receptor modulator compound of formula (I) alone or together with
pharmaceutically effective amounts of co-agents conventionally used for the treatment of
prostate cancer.
Another aspect of the invention is to use the compounds of the invention to treat
disease states responsive to Vitamin D receptor ligands.
Another aspect of the invention is the prevention and treatment of acne, actinic
keratosis, alopecia, Alzheimer's disease, autoimmune induced diabetes, bone fracture
healing, breast cancer, Crohn's disease, colon cancer, Type I diabetes, host-graft rejection,
hypercalcemia , Type II diabetes, leukemia, multiple sclerosis, insufficient sebum
secretion, osteomalacia, insufficient dermal firmness, insufficient dermal hydration,
myelodysplastic syndrome, psoriatic arthritis, renal osteodystrophy, rheumatoid arthritis,
scleroderma, seborrheic dermatitis, skin cancer, systemic lupus erythematosis, ulcerative
colitis and wrinkles; by administering to a mammal in need thereof a pharmaceutically
effective amount of a compound of Formula I.
DETAILED DESCRIPTION OF THE INVENTION
Definitions:
The term, "abscess" refers to adverse complications often associated with surgery,
trama, or diseases that predispose the host to abscess formation from encapsulated
bacteria lymphocytes, macrophages, and etc.
The term, "adhesion" refers to the adverse and abnormal union of surfaces
normally separate by the formation of new fibrous tissue resulting from an inflammatory
process.
The term, "Mustard" is inclusive of both sulfur mustards and nitrogen
mustards, either alone or in any combnation. Examplary of such compounds are the
vesicants; bis(2-chloroethyl) sulfide (Chemical Agent Symbol HD), C1(CH2)2S(CH2)2C1
1,2-bis(2-chloroethylthio)etbane (Chemical Agent Symbol Q),
C1(CH2)2S(CH2)2S(CH2)2Cl; bis(2-chloroethyithioethyl) ether,
C1(CH2)2S(CH2)O(CH2)2S(CH2)2C1 (Chemical Agent Symbol T); tris(2-chloroethyl)
amine (Chemical Agent Symbol HN3) N(CH2CH2Cl)3; N-methyl-2,2'-
dichlorodiethylamine (Chemical Agent Symbol NH2); and 2,2'-dichlorotriethylarriine,
CH3CH2N(CH2CH2Cl)2 (Chemical Agent Symbol NH1).
The tenn "branched C3-C5 alkyl" is an alkyl group selected from 1-methylethyl;
l-methylproijyl; 2-methylpropyl; 1,1-dimethylethyl; 1,1-dimethylpropyl; 1,2-
dimethylpropyl; or 2,2-dimethylpropyl. Preferred branched C3-C5 alkyl groups are 2-
methylpropyl and 1,1-dimethylethyl, with the 1,1-dimethyiethyl group being most
preferred.
The term, "branched alkyl terminal group" is used to identify the substituent ZB of
Formula I of the Invention. The defining characteristic of the branched alkyl terminal
group is that it is placed on the diphenyl nucleus other than on the phenyl ring bearing the
substituent Zc as shown, for example, in the structural formula (B);
The term, "carbon atom linked group" is used to identify the chemical substituent
Zc in the Formula I definition of compounds of the invention. Its defining characteristic
is a carbon atom as the first atom and point of attachment to the aryl ring to which it is
attached. For example in the structural formula (C):
the arrow identifies the carbon atom linked directly to the aryl nucleus of formula (I). All
compounds of the invention contain a carbon atom linked group as the ZC substituent.
The term "alkenyl" refers to aliphatic groups wherein the point of attachment is a
carbon-carbon double bond, for example vinyl, 1-propenyl, and 1-cyclohexenyl. Alkenyl
groups may be straight-chain, branched-chain, cyclic, or combinations thereof, and may
be optionally substituted. Suitable alkenyl groups have from 2 to about 20 carbon atoms.
The term "C1-C5 alkyl" refers to saturated aliphatic groups including straight-
chain, branched-chain, and cyclic groups and any combinations thereof. Alkyl groups
may further be divided into "primary", "secondary", and "tertiary" alkyl groups. In primary
alkyl groups, the carbon atom of attachment is substituted with zero (methyl) or one
organic radical. In secondary alkyl groups, the carbon atom of attachment is substituted
with two organic radicals. In tertiary alkyl groups, the carbon atom of attachment is
substituted with three organic radicals. Examples of C1-C5 alkyl groups are methyl,
ethyl, n-propyl, 1-methylethyl; n-butyl, 1-methylpropyl; 2-methylpropyl; 1,1-
dimethylethyl; n-amyl, 1,1-dimethylpropyl; 1,2-dimethylpropyl; and 2,2-dimethylpropyl.
The term, "bond" when used to describe a divalent Unking group indicates the
absence of a divalent atom, for example in the group
when L1 is -O-, L2 is a bond, L3 is -CH2-, and Rb is tBu the structural formula is
The term "cycloalkyl" includes organic radicals such as cyclopropyl, cyclobutyl,
cyclopentyl and cyclohexyl.
The term, "cycloalkenyl" includes organic radicals such as cyclopropenyl,
cyclobutenyl, cyclopentenyl and cyclohexenyl.
The term, "C1-C5 fluoroalkyl'is an alkyl group containing fluorine and includes
organic radicals such as -CF3, -CHF2, -CH2F, -CF2CF3, -CHFCF3, -CH2CF3, -
CH2CHF2, and -CH2CH2F, with -CF3 being preferred.
The abbreviation, "Me" means methyl.
The abbreviation, "Et" means ethyl.
The abbreviation, "iPr" means 1-methylethyl.
The abbreviation, "tBu" means 1,1-dimethylethyl.
The abbreviation, "3Me3OH44DiMe-Pentyl" means 3-methyl-3-hydroxy-4,4-
dimethylpentyl.
The abbreviation, "3Me3OH44DiMe-Pentenyl" means 3-methyl-3-hydroxy-4,4-
dimethylpentenyl.
The abbreviation, "3Me3OH44DiMe-Pentynyl" means 3-methyl-3-hydroxy-4,4-
dimethyipentyl.
The abbreviation, "3Et3OH44DiMe-Pentyl" means 3-ethyl-3-hydroxy-4,4-
dimethylpentyl.
The abbreviation, "3Et3OH44DiMe-Pentenyl" means 3-ethyl-3-hydroxy-4,4-
dimethylpentenyl.
The abbreviation, "3Et3OH44DiMe-Pentynyl" means 3-ethyl-3-hydroxy-4,4-
dimethylpentynyl.
The term, "-CH2-C(O)-N-pyrrolidine" refers to the radical represented by the
structural formula:
The term, "-CH2-N-pyrrolidin-2-one" refers to the radical represented by the
structural formula:
The term, "-CH2-(1-methylpyrrolidin-2-one-3-.yl)" refers to the organic radical
represented by the structural formula:
The term, "1,3,4-oxadiazolin-2-one-5-yl" refers to the organic radical represented
by the structural formula:
The term, "1,3,4-oxadiazolin-2-thionc-5-yl" refers to the organic radical
represented by the structural formula:
The tcrml, "imidazolidine-2,4-dione-5-yl" refers to the organic radical represented
by the structural formula:
The term, "isoxazol-3-ol-5-yl" refers to the organic radical represented by the
structural formula:
The term, "3-methyl-3-hydroxy-4,4-dimethylpentyl" refers to the radical having
the structural formula:
The term, "mammal" includes humans.
The term "ester" refers to compounds of the general formula; RO-C(O)R;
prepared for example, where a hydroxy group of an acid is replaced with an alkoxide
group. For example, a carboxylic ester is one in which the hydroxy group of a carboxylic
acid is replaced with an alkoxide. Esters may derive from any acid comprising one or
more hydroxy groups: for example, carbonic acid, carbamic acids, phosphonic acids, and
sulfonic acids.
The term "halo" refer to fluorine, chlorine, bromine, and iodine.
The term, "C1-C5 fluoroalkyl"is an alkyl group containing fluorine and includes
organic radicals such as -CF3, -CHF2, -CH2F, -CF2CF3, -CHFCF3, -CH2CF3,
-CH2CHF2, and -CH2CH2F, with -CF3 being preferred
The term, "(Acidic Group)" means a carbon atom linked organic group that acts
as a proton donor capable of hydrogen bonding. Illustrative of an (Acidic Group) is a
group selected from the following:
-C(O)OH,
-5-tetrazolyl,
Compounds of the Invention:
The compounds of the invention with vitamin receptor modulating (VDRM)
activities are represented by formula (I) or a pharmaceutically acceptable salt or a prodrug
derivative thereof:
wherein;
R and R' are independently C1-C5 alkyl, C1-C5 fluoroalkyl, or together R and R'
form a substituted or unsubstituted, saturated or unsaturated carbocyclic ring having from
3 to 8 carbon atoms;
R1 and R2 are independently selected from the group consisting of hydrogen,
halo, C1-C5 alkyl, C1-C5 fluoroalkyl, -O-C1-C5 alkyl, -S-C1-C5 alkyl, -O-C1-C5
fluoroalkyl, -CN, -NO2, acetyl, -S-C1-C5 fluoroalkyl, C2-C5 alkenyl, C3-C5 cycloalkyl,
and C3-C5 cycloalkenyl;
Zb is a group represented by the formula:
where m is 0, 1, or 2, and each R40 is independently hydrogen, C1-C5 alkyl, or C1-C5
fluoroalkyl;
Rig is a branched C3-C5 alkyl;
ZC is a carbon atom linked group selected from
-CO2H,
-CO2Me,
-CO2Et,
-C(O)CH2S(O)Me,
-C(O)CH2S(O)Bt,
-C(O)CH2S(O)2Me,
-C(O)CH2S(O)2Et,
-C(O)CH2CH2S(O)Me,
-C(O)CH2CH2S(O)Et,
-C(O)CH2CR2S(O)2Me,
-C(O)CH2CH2S(O)2Et,
-C(O)CH(MeX:H2CO2H,
-C(O)CH(Me)CH2CO2Me,
-C(O)CH(Me)CH2CO2Et,
-C(O)CH(Me)CH2CO2iPr,
-C(O)CH(Me)CH2CO2tBu,
-C(O)CH(Me)CH(Me)CO2H,
-C(O)CH(Me)CH(Me)CO2Me,
-C(O)CH(Me)CH(Me)CO2Et,
-C(O)CH(Me)CH(Me)CO2iPr,
-C(O)CH(Me)CH(Me)CO2tBu,
-C(O)CH(Me)C(Me) 2CO2H,
-C(O)CH(Me)C(Me) 2CO2Me,
-C(O)CH(Me)C(Me) 2CO2Et,
-C(O)CH(Me)C(Me) 2CO2iPrs
-C(O)CH(Me)C(Me) 2C02tBu,
-C(O)CH(Me)CH(Et)CO2H,
-C(O)CH(Me)CH(Et)CO2Me,
-C(O)CH(Me)CH(Et)CO2Et,
-C(O)CH(Me)CH(Et)CO2iPr,
-C(O)CH(Me)CH(Et)CO2tBu,
-C(O)C(O)OH,
-C(O)C(O)NH2,
-C(O)C(O)NHMe,
-C(O)C(O)NMe2,
-C(O)NH2,
-C(O)NMe2,
-C(O)NH-CH2-C(OPH,
-C(O)NH-CH2-C(O)OMe,
-C(O)NH-CH2-C(O)OEt,
-C(O)NH-CH2-C(O)OiPr,
-C(O)NH-CH2-C(O)OtBu,
-C(O)NH-CH(Me)-C(O)OH,
-C(O)NH-CH(Me)-C(O)OMe,
-C(O)NH-CH(Me>C(O)OEt,
-C(O)NH-CH(Me)-C(O)iPr,
-C(O)NH-CH(Me>C(O)tBu,
-C(O)NH-CH(Et>C(O)OH,
-C(O)NH-C(Me)2-C(O)OH,
-C(O)NH-C(Me)2-C(O)OMe,
-C(O)NH-C(Me)2--C(O)OEt,
-C(O)lsfH-C(Me)2-C(O)iPr,
-C(O)NH-C(Me)2-C(O)tBu,
-C(O)NH-CMe(Et>C(O)OH,
-C(O)NH-CH(F)-C(OPH5
-C(O)NH-CH(CF3>C(O)OH,
-C(O)NH-CH(OH)-C(O)OH,
-C(O)NH-CH(cyclopropjd)-C(O)OH,
-C(O)NH-C(Me)2-C(O)OH,
-C(O)NH-C(Me)2-C(O)OH,
-C(O)NH-CF(Me)-C(O)OH,
-C(O)NH-C(Me)(CF3)-C(O)OH,
-C(O)NH-C(Me)(OH)-C(OpH,
-C(O)NH-C(Me)(cyclopropyl)CO2H
-C(O)NMe-CH2-C(O)OH,
-C(O)NfMe-CH2-C(O)OMe5
-C(O)NMe-CH2-C(O)OEt,
-C(O)NMe-CH2-C(O)OiPr,
-C(O)NMe-CH2-C(O)tBu,
-C(O)NMe-CH2-C(O)OH,
-C(O)NMe-CH(Me)-C(O)OH,
-C(O)NMe-CH(F)-C(O)OH,
-C(O)NMe-CH(CF3)-C(O)OH,
-C(O)NMe-CH(OH)-C(O)OH,
-C(0)NMe-CH(cyclopropyl)-C(0)OH,
-C(O)NMe-C(Me)2-C(O)OH,
-C(O)NMe-CF(Me)-C(O)OH,
-C(O)NMe-C(MeXCF3)-C(O)OH,
-C(O)NMe-C(MeXOH)-C(O)OH,
-C(O)NMe-C(MeXcyclopropyl)-C(O)OH,
-C(O)NHS(O)Me,
-C(O)NHSO2Me,
-C(O)-NH-5-tetrazolyl,
-C(O)NHS(O)Me,
-C(O)NHS(O)Et,
-C(0)NHS02Me,
-C(O)NHSO2Et,
-C(O)NHS(O)iPr,
-C(0)NHS02il>r,
-C(O)NHS(O)tfiu,
-C(0)NHS02tBu,
-C(O)NHCH2S(O)Me,
-C(O)NHCH2S(O)Et,
-C(O)NHCH2SO2Me,
-C(O)NHCH2SO2Et,
-C(O)NHCH2CH2S(O)Me;
-C(O)NHCH2CH2S(O)Et,
-C(O)NHCH2CH2SO2Me,
-C(O)NHCH2CH2SO2Et,
-C(O)N(Me)S(O)Me,
-C(O)N(Me)SO2Me,
-C(O)-N(Me)-5-tetrazolyl,
-C(O)N(Me)S(O)Me,
-C(O)N(Me)S(O)Et,
-C(O)N(Me)SO2Me,
-C(O)N(Me)SO2Et,
-C(O)N(Me)S(O)iPr,
-C(O)N(Me))SO2iPr,
-C(O)N(Me))S(O)tBu,
-C(O)N(Me)SO2tBu,
-C(O)N(Me)CH2S(O)Me,
-C(O)N(Me)CH2S(O)Et,
-C(O)N(Me)CH2SO2Me,
-C(O)N(Me)CH2SO2Et)
-C(O)N(Me)CH2CH2S(O)Me,
-C(O)N(Me)CH2CH2S(O)Et,
-C(O)N(Me)CH2CH2SO2Me,
-C(O)N(Me)CH2CH2SO2Et,
-CH2CO2H,
-CH2-5-tetrazoIyl,
-CH2CO2Me,
-CH2CO2Et,
-CH2NHS(O)Me,
-CH2NHS(O)Et,
-CH2NHSO2Me,
-CH2NHSO2Et,
-CH2NHS(O)iPr,
-CH2NHSO2iPr,
-CH2NHS(O)tBu,
-CH2NHS02tBu,
-CH2NHCH2CH2SO2CH3,
-CH2NH(CH2CO2H),
-CH2N(C(O)Me)(CH2CO2H),
-CH2-N-pyrrolidin-2-one,
-CH2-(1-methylpyrrolidin-2-one-3-yl),
-CH2S(O)Me,
-CH2S(O)Et,
-CH2S(O)2Me,
-CH2S(O)2Et,
-CH2S(O)iPr,
-CH2S(O)2iPr,
-CH2S(O)tBu,
-CH2S(O)2tBu,
-CH2CO2H, CH2C(O)NH2,
-CH2C(O)NMe2,
-CH2C(O)NHMe,
-CH2C(O)-N-pyrrolidine,
-CH2S(O)2Me, CH2S(O)Me,
-CH(OH) CO2H,
-CH(OH)C(O)NH2)
-CH(OH)C(O)hFHMe,
-CH(OfI)C(O}NMe2,
-CH(OH)C(O)NEt2,
-CH2CH2CO2H,
-CH2CH2CO2Me,
-CH2CH2CO2Et,
-CH2CH2C(O)NH2,
-CH2CH2C(O)NHMe,
-CH2CH2C(O)NMe2>
-CH2CH2-5-tetrazolyl,
-CH2CH2S(O)2Me,
-CH2CH2S(O)Me,
-CH2CH2S(O)2Et,
-CH2CH2S(O) Et,
-CH2CH2S(O)iPr,
-CH2CH2S(O)2iPr,
-CH2CH2S(O)tBu,
-CH2CH2S(O)2tBu,
-CH2CH2S(O)NH2,
-CH2CH2S(O)NHMe,
-CH2CH2S(O)NMe2,
-CH2CH2S(O)2NH2,
-CH2CH2S(O)2NHMe
-CH2CH2S(O)2NMe2,
-CH2CH2CH2S(O)Me,
-CH2CH2CH2S(O)Et,
-CH2CH2CH2S(O)2Me,
-CH2CH2CH2S(O)2Et,
-C(O)OH,
-5-tetrazolyl,
-C(O)-N(Me)-5-tetrazolyl,
-1,3,4-oxadiazolin-2-orie-5-yl,
-imidazolidine-2,4-dione-5-yl,
-isoxazol-3-ol-yl, or
-1,3,4-oxadiazolin-2-thione-5-yl.
In the preceding formula (I) the divalent linking groups -(LI)- and -(L2)- and
-(L3)- are understood (in the case of those having more than one substituent) to be
oriented in either direction, for example, where divalent linker (LI) has the identity
-(CH2)m-0- > ** may ke configured:
wherein;
R and R' are independently methyl, ethyl, propyl, or 1-methylethyl;
R1 and R2 are independently selected from the group consisting of hydrogen,
fluoro, -C1, -CF3, -CH2F, -CHF2, methoxy, ethoxy, vinyl, methyl, ethyl, propyl, 1-
methylethyl, 1,1-dimethylethyl, butyl, 1-methylpropyl, 2-methylpropyl, or cyclopropyl;
Z3 is a branched alkyl terminated group represented by the formula:
RB is 1-methylethyl; 1-methylpropyl; 2-methylpropyl; 1,1-dimethylethyl; 1,1-
dimethylpropyl; 1,2-dimethylpropyl; 2,2-dimethylpropyl;
3-methyl-3-hydroxy-4,4-dimethylpentyl; 3-methyl-3-hydroxy-4,4-dimethylpentenyl;
3-methyl-3-hydroxy-4,4-dimethylpentyl; 3-ethyl-3-hydroxy-4,4-dimethylpentynyl;
3-ethyl-3-hydroxy-4,4-dimethylpentenyl; or 3-ethyl-3-hydroxy-4,4-dimethylpentynyl;
(L1) and (L2) and (L3) are independently divalent linking groups where
L1 is -O-, -CH2-, -CHOH-, -CH(Me)- , -C(O)-, or -C(Me)OH- ;
L2 is -CH2- „ -CHOH-, -CH(Me)- , -C(O)-, or -C(Me)OH- ; or
Li and L2 taken together is the group
-CH2-CH2-
-CH=CH- ,or
-C-C- ;
L3 is a bond, -CH2-, -CHOH-, -CH(Me)- -C(O)-, or -C(Me)OH-;
ZC is a group selected from
-C(O)CH2S(O)Me,
-C(O)CH2S(O)Et,
-C(O)CH2S(O)2Me,
-C(O)CH2S(O)2Et,
-C(O)CH2CH2S(O)Me,
-C(O)CH2CH2S(O)Et,
-C(O)CH2CH2S(O)2Me,
-C(O)CH2CH2S(O)2Et,
-C(O)CH(Me)CH2CO2H,
-C(O)CH(Me)CH2CO2Me,
-C(O)CH(Me)CH2CO2Et,
-C(O)CH(Me)CH2CO2iPr,
-C(O)CH(Me)CH2CO2tfiu,
-C(O)CH(Me)CH(Me)CO2H,
-C(O)CH(Me)CH(Me)CO2Me,
-C(O)CH(Me)CH(Me)CO2Et>
-C(O)CH(Me)CH(Me)CO2iPr,
-C(O)CH(Me)CH(Me)CO2tBu,
-C(O)CH(Me)C(Me) 2CO2H,
-C(O)CH(Me)C(Me) 2CO2Me,
-C(O)CH(Me)C(Me) 2CO2Et,
-C(O)CH(Me)C(Me) 2C02iPr5
-C(O)CH(Me)C(Me) 2C02tBu,
-C(O)CH(Me)CH(Et)CO2H,
-C(O)CH(Me)CH(Et)CO2Me,
-C(O)CH(Me)CH(Et)CO2Et,
-C(O)CH(Me)CH(Et)CO2iPr,
-C(O)CH(Me)CH(Et)CO2tBu,
-C(O)C(O)OH,
-C(O)C(O)NH2,
-C(O)C(O)NHMe,
-C(O)C(O)NMe2,
-C(O)NH2,
-C(O)NMe2,
-C(O)NH-CH2-C(O)OH,
-C(O)NH-CH2-C(O)OMe,
-C(O)NH-CH2-C(O)OEt,
-C(O)NH-CH2-C(O)OiPr,
-C(O)NH-CH2-C(O)OtBu,
-C(O)NH-CH(Me)-C(O)OH,
-C(O)NH-CH(Me)-C(O)OMe,
-C(O)NH-CH(Me)-C(O)OEt,
-C(O)hfH-CH(Me)-C(O)iPr,
-C(O)NH-CH(Me)-C(O)tBu,
-C(O)NH-CH(Et)-C(O)OH,
-C(O)NH-C(Me)2-C(O)OH,
-C(O)NH-C(Me)2-C(O)OMe,
-C(O)NH-C(Me)2-C(O)OEt,
-C(O)NH-C(Me)2-C(O)iPr,
-C(O)NH-C(Me)2-C(O)tBu,
-C(O)NH-CMe(Et)-C(O)OH,
-C(O)NH-CH(F)-C(O)OH,
-C(O)NH-CH(CF3)-C(O)OH,
-C(O)NH-CH(OH)-C(O)OH,
-C(O)NH-CH(cyclopropyl)-C(O)OH,
-C(O)NH-C(Me)2-C(O)OH,
-C(O)NH-C(Me)2-C(O)OH,
-C(O)NH-CF(Me)-C(O)OH,
-C(O)NH-C(Me)(CF3)-C(O)OH,
-C(O)NH-C(Me)(OH)-C(O)OH,
-C(O)NH-C(Me)(cyclopropyl)CO2H,
-C(O)NMe-CH2-C(O)OH,
-C(O)NMe-CH2-C(O)OMe,
-C(O)NMe-CH2-C(O)OEt,
-C(O)NMe-CH2-C(O)OiPr,
-C(O)NMe-CH2-C(O)tBu,
-C(O)NMe-CH(Me)-C(O)OH,
-C(O)NMe-CH(F)-C(0)0H,
-C(O)NMe-CH(CF3)-C(O)OH,
-C(O)NMe-CH(OH)-C(O)OH,
-C(O)NMe-CH(cyclopropyi>C(O)OH,
-C(O)NMe-C(Me)2-C(O)OH,
-C(O)NMe-CF(Me)-C(O)OH,
-C(O)NMe-C(Me)(CF3>C(O)OH,
-C(O)NMe-C(Me)(OH)-C(O)OH,
-C(O)NMe-C(Me)(cyclopropyl)-C(O)OH,or
-C(O)-N(Me)-5-tetrazolyl.
Other preferred compounds of the invention are those represented by formula (I)
or a pharmaceutically acceptable salt or a prodrug derivative thereof:
wherein;
R and R' are independently methyl or ethyl;
R1 and R2 are independently selected from the group consisting of hydrogen,
fluoro, -C1, -CF3, -CH2F, -CHF2, methoxy, ethoxy, vinyl, methyl, or cyclopropyl;
ZB is a branched alkyl terminated selected from the formulae:
ZC is selected from
-C(O)NH2,
-C(O)NMe2,
-C(O)NH-CHrC(O)OH,
-C(O)NH-CH2-C(O)OMe,
-C(O)NH-CH2-C(O)OEt,
-C(O)NH-CH2-C(O)OiPr,
-C(O)NH-CH2-C(O)OtBu,
-C(O)NH-CH(Me)-C(O)OH,
-C(O)NH-CH(Me)-C(O)OMe,
-C(O)NH-CH(Me)-C(O)OEt,
-C(O)NH-CH(Me)-C(O)iPr,
-C(O)NH-CH(Me)-C(O)tBu,
-C(O)NH-CH(Et)-C(O)OH,
-C(O)NH-C(Me)2-C(O)OH,
-C(O)NH-C(Me)2-C(O)OMe,
-C(O)NH-C(Me)2-C(O)OEt,
-C(O)NH-C(Me)2-C(O)iLPr,
-C(O)NH-C(Me)2-C(0)tBu,
-C(O)NH-CMe(Et)-C(O)OH,
-C(O)NH-CH(F)-C(O)OH,
-C(O)NH-CH(CF3)-C(O)OH,
-C(O)NH-CH(OH)-C(O)OH,
-C(O)NH-CH(cyclopropyl)-C(O)OH,
-C(O)NH-C(Me)2-C(O)OH,
-C(O)NH-C(Me)2-C(O)OH,
-C(0)NH-OF(Me)-C(0)OH,
-C(O)NH-C(MeXCF3)-C(O)OH,
-C(O)NH-C(MeXOH)-C(O)OH,
-C(O)NH-C(Me)(cyclopropyl)CO2H,
-C(O)NMe-CH2-C(O)OH,
-C(O)NMe-CH2-C(O)OMe,
-C(O)NMe-CH2-C(O)OEt,
-C(O)NMe-CH2-C(O)OiPr,
-C(O)NMe-CH2-C(O)tBu,
-C(O)NMe-CH(Me)-C(O)OH,
-C(O)NMe-CH(F)-C(O)OH,
-C(O)NMe-CH(CF3)-C(O)OH,
-C(O)NMe-CH(OH)-C(O)OH,
-C(O)NMe-CH(cyclopropyl)-C(O)OH,
-C(O)NMe-C(Me)2-C(O)OHs
-C(O)NMe-CF(Me)-C(O)OH,
-C(O)NMe-C(MeXCF3)-C(O)OH,
-C(O)NMe-C(Me)(OH)-C(O)OH,
-C(O)NMe-C(Me)(cyclopropyl>C(O)OH,
-C(O)-N(Me)5-tetrazolyl,
Particularly preferred is a compound or a pharmaceutically acceptable salt or ester
prodrug derivative thereof represented by structural formulae (AA) to(DB) as follows:
AA)
Other particularly preferred compounds of the invention are those shown
by the structural formulae C-1 to C-54 set out below. Pharmaceutically acceptable salts
for prodrug derivatives of these compounds are also preferred.
For all of the above compounds of the invention defined by Formula (I) the
preferred prodrug derivative is a methyl ester, ethyl ester N,N-diethylglycolamido ester or
morpholinylethyl ester. In addition, for all of the above compounds of the invention the
preferred salt is sodium or potassium.
Other specific compounds that are preferred embodiments of this invention and
are preferred for for practicing the method of treatment of the invention are set out in the
following Tables. All numbers in the Tables cells reciting chemical species are to be
understood as subscripts in chemical formulae, for example, in the first row of Table 1,
Compound No. 1, the symbol, "CO2Me" is to be understood as the conventional chemical
nomenclature, - CO2H -. Each row of the Tables 1 and 2 represents a single compound
having an identifying defining the specific substituents in the structural formula displayed
above each Tables, as follows:
Among1 other preferred compounds of the invention are those represented by the
formula:
and pharmaceutically acceptable salts thereof; wherein;
said compound is selected from a compound code numbered 1 thru 468, with each
compound having the specific selection of substituents RB, RC L1, L2, and L3 shown
in the row following the compound code number, as set out in the following Table 1 :
and phaimaceutically acceptable salts thereof;
wherein;
said compound is selected from a compound code numbered 1B thru 81B, with
each compound having the specific selection of substituents RB, RC L1L2, and L3
shown
in the row following the compound code number, as set out in the following Table 3 :
and phannaceutically acceptable salts thereof;
wherein;
said compound is selected from a compound code numbered 1C thru 162C, with
each compound having the specific selection of substituents Rb, RC L1 L2, and L3
shown
may be varied to analogous molecules to provide desired substitutions in the final reaction
product.
Definitions of symbols used in the Schemes:
(PhO)2P(O)N3 - diphenyl phosphorus azide
BBr3 - boron tribromide
BF3-OEt2 - boron trifluoride etherate
BnBr - benzyl bromide
CH3CN - acetonitrile
DMAP - 4-(dimethylamino)pyridine
DMF-N,N-dimethylformamide
DMSO - dimethylsulfoxide
DPPF - dichloro[1,1-bis(diphenylphosphino)ferrocene
DPPB— l,4-bis(diphenylphosphino)butane
EDCI- 3-Emyl-l-[3-(dimemylarnino)propyl]carbodiimide hydrochloride
Et3N - triethylamine
EtOH-ethanol
H2NCH2CO2Me - methyl glycinate
HN(OMe)Me -N-methyl-O-methyl hydroxylamine
HNMe2 - dimethyl amine
K2CO3 - potassium carbonate
KOH - potassium hydroxide
LAH - lithium aluminum hydride
LiHMDS - lithium hexamethyldisilazide
mCPBA-meta-chloroperbenzoic acid
MeI - methyl iodide
MeOH -methanol
NaBH4 - sodium borohydride
NaH - sodium hydride
NaI - sodium iodide
NMP - N-methylpyrrolidin-2-one
Na-S-R3 - sodium alkyhnercaptide
PBr3 -phosphorus tribromide
Pd(0Ac)2 - palladium (II) acetate
Pd-C - palladium on carbon
pTSA - para-toluenesulfonic acid
Pyr - pyridine
R2MgBr - alkyl magnesium bromide
R3MgBr - alkyl magnesium bromide
R5MgBr - alkyi magnesium bromide
R2S(O)2NH2 - alkylsulfonamide
tBuC(O)CH2Br - 2-bromopinacolone
Tf2O - triflic anhydride
TFA - trifluoroacetic acid
THF - tetrahydrofuran
Description of the Schemes:
Preparation of diphenyl acid and diphenyl acylaminotetrazole (Scheme 1).
A mixture of 3-substituted-4-hydroxy benzoic acid 1a and methanol is treated with HC1
(gas) to yield methyl benzoate ester 1 Methyl benzoate ester 1 is reacted with excess
alkyl magnesium bromide to produce tertiary alcohol 2. Tertiary alcohol 2 is converted to
phenol 4 by reaction with O-benzyl-2-substituted phenol 3a and BF3-Et2O. O-benzyi-2-
substituted phenol 3a is derived from the reaction of 2-substituted phenol 3 with
benzylbromide and NaH. Phenol 4 is reacted with triflic anhydride/pyridine to give
triflate 5 which is subjected to methoxycarbonylation with Pd(OAc)2, DPPF, CO (689-
6895 KPa), methanol and triethylamine in either DMF or DMSO at 80-100 °C to yield
methyl ester 6. DPPB may be used instead of DPPF for the methoxycarbonylation
reaction. Methyl ester 6 is subjected to palladium catalyzed hydrogenolysis and alkylated
with NaH/pinacolone bromide to give ketone 7. Ketone 7 is sequentially reacted with
sodium borohydride/MeOH and potassium hydroxide/EtOH/H2O/ 80 °C to produce acid
8. Acid 8 is coupled with EDCI, DMAP and 5-aminotetrazole to give acylamino tetrazole
9. Acid 8 is also coupled with EDCI, DMAP and alkylsulfonamide to give
acylsulfonamide 9a.
Preparation of functionalized sidechain analogs (Scheme 2).
Ester 6 is reduced with LAH to give benzyl alcohol 10. Benzyl alcohol 10 is converted to
benzylic bromide 11. with PBr3 and alklylated with the enolate of pinacolone to afford
ketone 12. Ketone 12 is transformed into keto-ester 14 via Pd-C catalyzed
hydrogenolysis, triflate formation with triflic anhydride/pyridine and palladium catalyzed
methoxycarbonylation. Keto-ester 14 is subjected to sodium borohydride reduction and
potassium hydroxide hydrolysis to produce alcohol-acid 15. Alcohol-acid 15 is coupled
with EDCI/Et3N/DMAP/R4NHCH2CO2Me and hydrolyzed with LiOH/EtOH/H2O to
afford amide-acid 15a.
Preparation of alkylated pinacolol sidechain (Scheme 3).
Ketone 7 is alkylated with LiHMDS/Mel and reduced with NaBH4/MeOH to give alcohol
16.. Alcohol 16 is hydrolyzed with potassium hydroxide to afford alcohol-acid 1/7.
Alcohol-acid 17 is reacted sequentially with 1) EDCI/Et3N/DMAP/R4NHCH2CO2Me;
and 2) LiOH/EtOH/H2O to give amide-acid 17a.
Preparation of alkylsulfonylmethyl sidechain analogs (Scheme 4).
Benzylic bromide 11 is reacted with sodium alkylmercaptide and oxidized with mCPBA
to give sulfone 18. Sulfone 18 is hydrogenolyzed with Pd-C/H2 and alkylated with
pinacolone chloride, potassium carbonate and sodium iodide to produce ketone sulfone
19. Ketone sulfone 19 is reduced with sodium borohydride to afford alcohol sulfone 20.
Preparation of unsymmetrical central link diphenyl scaffold (Scheme 5).
3-Substituted-4-hydroxybenzoic acid is coupled with EDCI/N-methy-N-
methoxyamine/DMAP and alkylated with benzyl bromide to give amide 2L Amide 21 is
sequentially reacted with R2MgBr and R3MgBr Grignard reagents to afford tertiary
alcohol 23. Alcohol 23 is reacted with 2-substituted phenol 3 and BF3-OEt2 to produce
diphenylalkane 24- Diphenylalkane 24 is reacted with triflic anhydride/pyridine and
methoxycarbonylated with Pd(OAc)2, (DPPF or DPPB), carbon monoxide, MeOH, and
Et3N to give ester 26. Ester 26 is hydrogenolyzed with Pd-C/H2 and alkylated with
pinacolone bromide to yield ketone ester 27. Ketone ester 22 is reduced with sodium
borohydride and hydrolyzed with potassium hydroxide to afford alcohol-acid 28.
Alcohol-acid 28 is coupled with EDCI/Et3N/DMAP/R4NHCH2CO2Me and hydrolyzed
with LiOH/EtOH/H2O to afford amide-acid 28a.
Preparation of tertiary alcohol sidechain analog (Scheme 6).
Phenol 4 is alkylated with pinacolone bromide and reacted with MeMgBr or EtMgBr to
give alcohol 29. Alcohol 29 is hydrogenolyzed with Pd-C/H2, reacted with triflic
anhydride/pyridine and methoxycarbonylated to afford ester 30. Ester 30 is hydrolyzed
with potassium hydroxide, coupled with EDCI/Et3N/DMAP/R4NHCH2CO2Me, and
hydrolyzed to produce tertiary alcohol amide-acid 3L
Preparation of direct linked tetrazole (Scheme 7).
Acid 8 is reacted with formamide and sodium methoxide to give primary amide 32.
Primary amide 32 is treated with trifluoroacetic acid and methylene chloride followed by
2-chloro-1,3-dimethyl-2-imidazoliniumhexafluorophosphate to give nitrile 33. Nitrile 33_
is reacted with sodium azide and triethylammonium hydrochloride in N-methylpyrrolidin-
2-one to afford tetrazole 34.
Preparation of amide (Scheme 8).
Acid 8 is reacted with diphenyl phosphorus azide and triethylamine followed by treatment
with dimethylamine and 4-(dimethylamino)pyridine to yield amide 35.
Preparation of esters (Scheme 9).
Acid 8 is treated with sodium iodide and N,N-dimethyl-2-chloroacetamide to give ester
36. Acid 8 is treated with sodium iodide and N-morpholinocarbonyhnethyl chloride to
give ester 37.
Alternative Synthesis of Diphenylalkyl Scaffold (Scheme 10).
Phenol 2 is heated with pTS A to give olerln 38. Olefin 38 is alkylated with 2-
chloropinacolone and reacted with a 2-substituted phenol/BF3-OEt2 to yield phenol 40.
Phenol 40 is converted to the corresponding phenolic triflate and reduced to alcohol 41..
Alcohol 41. is methoxycarbonylated to afford ester 42. Ester 42 is hydrolyzed to produce
acid 8.
Synthesis of Pentynol Phenyl alley! Phenyl Acids (Scheme 11).
Ester 26 is hydrogenolyzed with Pd-C/H2 and reacted with Tf2O/pyridine to give triflate
43. Triflate 43 is sequentially reacted with 1) TMS-acetylene, PdC12(PPh3)2, Et3N, and
DMF and 2) CsF and water to afford acetylene 44. Acetylene 44 is treated with
Zn(OTf)2/t-butyl aldehyde/chiral auxiliary (with or without) to give alcohol 46.
Alternatively, acetylene 44 is reacted with LiHMDS/ketone 45 to give alcohol 46.
Alcohol 46 is hydrolyzed with KOH/EtOH/H2O to afford acid 47. Acid £7 is
sequentially reacted with 1) EDCI/Et3N/DMAP/R4NHCH2CO2Me and 2)
LiOH/EtOH/H2O to give amide-acid 48.
Synthesis of Cis-Pentenol Phenyl alkyl Phenyl Acids (Scheme 12).
Amide-acid 48 is hydrogenated with Lindlar catalyst to afford cis-pentenol amide-acid 49.
Synthesis of trans-Pentenol Phenyl Alkyl Phenyl Acids (Scheme 13).
Triflate 25 is sequentially reacted with 1) TMS-acetylene, PdC12(PPh3)2, Et3N, and DMF
and 2) CsF and water to afford acetylene 50. Acetylene 50 is treated with Zn(OTf)2/t-
butyl aldehyde/chiral auxiliary (with or without) to give alcohol 51 Alternatively,
acetylene 50 is reacted with LiHMDS/ketone 45 to give alcohol 51 Alcohol 51 is
reduced with LAH or DiBAH to afford trans-pentenol 52. Trans-pentenol 52 is
sequentially reacted with 1) Pd-C/H2; 2) Tf2O/pyridine; 3) Pd(OAc)2, DPPF, CO,
MeOH, Et3N, DMF; 4) KOH/EtOH/H2O; 5) EDCI/Et3N/DMAP/R4NHCH2CO2Me; and
6) LiOH/EtOH/H2O to give trans-pentenol amide-acid 53. For reaction step 3, DPPB and
DMSO.
Scheme 1: Synthesis of Diphenyl Scaffold
EXAMPLES
Abbreviations:
The following examples use several standard abbreviations, for example;
"RT" is room temperature, "Rt" or tret are symbols for retention time, and "Hex"
refers to hexanes
Concentration is performed by evaporation from RT to about 70°C under vacuum (1-
10mm)
Example 1
Preparation of racemic 3'-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3'-[4-
memoxycarbonyl-3-methylphenyl]pentane.
To a mixture of o-cresol (196 g, 1.81 mol) and 3-pentanone (60 ml, 0.57 mol)
is added methanesulfonic acid (45 ml, 0.69 mol) and stirred for 3 days. The reaction
is basified to pH 8 with satd Na2CO3 and extracted with EtOAc. The organic layer is
washed with water (6 X 500 ml), Na2SO4 dried, concentrated, chromatographed (2 kg
SiO2, Hex to 80% EtOAc/Hex), and triturated with Hex to give the title compound as
a white solid (100 g, 61%).
NMR 400 mHz(DMSO): 5 0.49 (t, J = 7.3 Hz, 6H), 1.91 (q, J = 7.3 Hz, 4H), 2.02 (s,
6H), 6.61 (d, J = 8.3 Hz, 2H), 6.73 (d, J = 8.3 Hz, 2H), 6.76 (s, 2H), 8.94 (s, 2H).
High Res. EI-MS: 284.1794; calc. for C19H24O2: 284.1776
B. 3'-[4-(2-Oxo-3,3-dimethylbutoxy)-3-methylphenyl)]-3 '-[4-hydroxy-3-
methylphenyl]pentane.
To a mixture of 60% NaH disp (8.0 g, 200 mmol) and DMF (600 ml) is added
3,3-bis[4-hydroxy-3-methylphenyl]pentane (56.88 g, 200 mmol) and stirred for 2h.
To the reaction is added 3,3-dimethyl-l-bromo-2-butanone (26.93 ml, 200 mmol)
dropwise and stirred overnight. The solvent is removed in-vacuo. To the resulting
residue is added EtOAc/water (800 ml/200 ml), acidified to pH 3 with 5N HC1, and
partitioned. The organic layer is washed with water (2X), brine, Na2SO4 dried,
concentrated, and chromatographed (3 kg SiO2, hex to 15% EtOAc/hex) to give the
title compound as a white solid (35 g, 46%).
NMR (300mHz, DMSO): a 0.52 (t, J = 7.3 Hz, 6H), 1.16 (s, 9H), 1.95 (q, J = 7.3 Hz,
4H), 2.04 (s, 3H), 2.12 (s, 3H), 5.05 (s, 2H), 6.57 (d, J = 9.1 Hz, 1H), 6.63 (d, J = 8.1
Hz, 1H), 6.81 (m, 2H), 8.97 (s, 1H).
ES-MS: 400(M+NH4).
C. 3'-[4-(2-Oxo-3,3-dimethylbutoxy)-3-methylphenyl]-3'-[4-
trifluoromethylsulfonyloxy-3-methylphenyl]pentane
To a 0 °C solution of 3'-[4-(2-oxo-3,3-dimethylbutoxy)-3-methylphenyl)]-3'-
[4-hydroxy-3-methylphenyl]pentane(20 g, 52 mmol), pyridine (30 ml) is added Tf2O
(9.7 ml, 57 mmol). The mixture is wanned to RT and stirred 14 h. The reaction is
concentrated. The residue is partitioned between Et2O/1N HC1. The organic layer is
washed with water, brine, Na2SO4 dried, concentrated, and chromatographed (hex to
10% EtOAc/hex) to give the title compound as an oil (26.3 g, 98%).
NMR (300mHz, DMSO): 8 0.53 (t, J = 7.3 Hz, 6H), 1.16 (s, 9H), 2.04 (q, J = 7.3 Hz,
4H), 2.14 (s, 3H), 2.28 (s, 3H), 5.07 (s, 2H), 6.61 (d, J = 8.8 Hz, 1H), 6.86 (dd, J =
2.2, 8.8 Hz, 1H), 6.91 (d, J = 1.8 Hz, 1H), 7.10 (dd, J = 2.2, 8.8 Hz, 1H), 7.25 (m,
2H).
ES-MS: 532.5 (M+NH4).
D. 3'-[4-(2-Hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3'-[4-
trifluoromethylsulfonyloxy-3-methylphenyl]pentane.
To a 0 °C mixture of 3'-[4-(2-oxo-3,3-dimethylbutoxy)-3-methylphenyl]-3'-[4-
trifluoromethy!sulfonyloxy-3-methylphenyl]pentane (25.5 g, 49.5 mmol) and MeOH (200
ml) is added NaBH4 (2.63 g, 59.4 mol) in portions. After stirring for 15 m, the reaction is
allowed to warm to RT and stirred for 16 h. The reaction is concentrated and partitioned
between Et2O/lN HCl. The organic layer is washed with water, Na2SO4 dried, and
concentrated to give the title compound as an oil(26.0 g, quant).
NMR (300mHz, DMSO): 6 0.55 (t, J = 7.3 Hz, 6H), 0.92 (s, 9H), 2.04 (q, J = 7.3 Hz,
4H), 2.11 (s, 3H), 2.28 (s, 3H), 3.46 (m, 1H), 3.76 (m, 1H), 4.03 (m, 1H), 4.78 (d, J =
5.5 Hz, 1H), 6.89 (m, 3H), 7.10 (dd, J = 1.8, 8.8 Hz, 1H), 7.23 (m, 2H).
High Res. EI-MS, m/e: 516.2171; calc. for C26H35F3O5S: 516.2157.
E. 3 '-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-memylphenyl3-3'-[4-
methoxycarbonyl-3-methylphenyl]peintane.
A mixture of 3'-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3'-[4-
trifluoromethylsulfonyloxy-3-methylphenyl]pentane (27 g, 52.2 mmol), Pd(OAc)2 (1.2
g, 5.22 mmol), Dppf (5.8 g, 10.4 mmol), MeOH (21 ml, 522.mmol), Et3N (22 ml, 157
mmol), and DMF (100 ml) is pressurized with carbon monoxide (1000 psi) and heated
to 110 °C for 48 h. After cooling, the reaction is filtered through diatomaceous earth
with EtOAc wash. The filtrate is diluted with 1:1 Et2O:EtOAc, washed with 1N HCl,
and filtered through diatomaceous earth, Na2SO4 dried, concentrated, and
chromatographed (hex to 10% EtOAc/hex) to give the title compound (14 g, 63%).
NMR 300 MHz(DMSO): 5 0.54 (t, J = 7.3 Hz, 6H), 0.92 (s, 9H), 2.04 (q, J = 7.3 Hz,
4H), 2.09 (s, 3H), 2.46 (s, 3H), 3.45 (m, 1H), 3.76 (m, 4H), 4.02 (m, 1H), 4.78 (d, J = 5.5
Hz, 1H), 6.83 (m, 2H), 6.92 (dd, J = 2.2, 8.4 Hz, 1H), 7.07 (m, 2H), 7.74 (d, J = 8.1 Hz,
1H).
High Res. FAB-MS: 426.2750; calc. for C27H38O4: 426.2770.
Preparation of racemic3'-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3'-[4-
carboxyl-3-methylphenyl]pentane.
A mixture of 3'-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3'-[4-
methoxycarbonyl-3-methylphenyl]pentane (8.3 g, 19.4 mmol), EtOH (100 ml), water
(100 ml) is added KOH (10.8 g, 97 mmol) and heated to 75 °C for 8 h. The reaction
is concentrated with a stream of nitrogen and the residue is partitioned between 1:1
Et2O:EtOAc and 1N HCl. The organic layer is washed with water, Na2SO4 dried,
concentrated, and chromatographed (gradient 20% EtOAc/MeCb to 30%
EtOAc/CHCl3) to give the title compound as a white foam (7.85 g, 95%).
NMR mHz(DMSO): 8 0.54 (t, J = 7.3 Hz, 6H), 0.92 (s, 9H), 2.05 (q, J = 7.3 Hz, 4H),
2.10 (s, 3H), 2.47 (s, 3H), 3.45 (m, 1H), 3.76 (m, 1H), 4.02 (dd, J = 3.3, 9.9 Hz, 1H),
4.78 (d, J = 5.1 Hz, 1H), 6.83 (m, 2H), 6.92 (dd, J = 1.8, 8.4 Hz, 1H), 7.05 (m, 2H),
7.72 (d, J = 8.1 Hz, 1H), 12.60 (br s, 1H).
High Res. ES-MS: 435.2498; calc. for C26H36O4+Na: 435.2511
Example 3A and Example 3B
Preparation of enantiomers of 3'-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3'-
t4-carboxyl-3-methylphenyl)]pentane.
A mixture of racemic 3'-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3'-
[4-carboxyl-3-methylphenyl)]pentane, Example 3, is chromatographed with a ChiralPak
AD column to give enantiomer 1, Example 3A (110 mg, 37%) and enantiomer 2,
Example 3B (110 mg, 37%).
Enantiomer 1, Example 3 A
HPLC: ChiralPak AD (4.6X250 mm); 0.1% TFA/20% EPA/80% heptane; 1 ml/m
(flow rate); Rt = 6.2 m
NMR eq. To Example 2.
High Res. ES-MS: 411.2521; calc. for C26H36O4-H: 411.2535
Enantiomer 2, Example 3B
HPLC: ChiralPak AD (4.6X250 mm); 0.1% TFA/20% IPA/80% heptane; 1 ml/m
(flow rate); Rt = 7.3 m
NMR eq. To Example 2.
High Res. ES-MS: 413.2728; calc. for C26H36O4+H: 413.2692
Example 3A Alternate method
Preparation of enantiomer 1 of 3'-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-
3'-[4-carboxyl-3-methylphenyl]pentane from enantiomer 1 of 3'-[4-(2-hydroxy-3,3-
dimethylbutoxy)-3-methylphenyl]-3'-[4-methoxycarbonyl-3-methylphenyl]pentane.
Using a procedure analogous to Example 2, enantiomer 1 of 3'-[4-(2-hydroxy-3,3-
dimethylbutoxy)-3-methylphenyl]-3'-[4-methoxycarbonyl-3-methylphenyl]pentane,
Example 4A, gave the title compound as a glassy solid (1.3 g, quant).
Enantiomer 1, Example 3 A
HPLC: ChiralPak AD (4.6X250 mm); 0.1% TFA/20% IPA/80% heptane; 1 ml/m
(flow rate); Rt = 7.0 m
NMR eq. To Example 2.
High Res. ES-MS: 435.2533; calc. for C26H36O4+Na: 435.2511
High Res. ES-MS: 430.2943; calc. for C26H36O4+NH4: 430.2943
HPLC correlation of Example 3 A (derived from chiral HPLC of 2) and 3 A (derived from
the hydrolysis of 4A):
A mixture of Example 3 A (1 mg) (derived from chiral HPLC of 2) and 3 A (1 mg)(derived
from the hydrolysis of 4A) is dissolved in TFA/20% IPA/80% and analyzed by HPLC;
ChiralPak AD (4.6X250 mm); 0.1% TFA/20% IPA/80% heptane; 1 ml/m (flow rate); to
give a single peak with Rt = 7.0 m.
Example 3B alternate method
Preparation of enantiomer 2 of 3'-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-
3'-[4-carboxyl-3-methylphenyl]pentane from enantiomer 2 of 3'-[4-(2-hydroxy-3,3-
dimethylbutoxy)-3-methylphenyl]-3 '-[4-methoxycarbonyl-3-methylphenyl]pentane.
Using a procedure analogous to Example 2, enantiomer 2 of 3'-[4-(2-hydroxy-3,3-
dimethylbutoxy)-3-methylphenyl]-3'-[4-memoxycarbonyl-3-methylphenyl]pentane)
Example 4B, gave the title compound as a glassy solid (1.3 g, quant).
Enantiomer 2, Example 3B
HPLC: ChiralPak AD (4.6X250 mm); 0.1% TFA/20% IPA/80% heptane; 1 ml/m
(flow rate); Rt = 8.0 m
NMR eq. To Example 2.
High Res. ES-MS: 435.2536; calc. for C26H36O4+Na: 435.2511
HPLC correlation of Example 3B (derived from chiral HPLC of 2) and 3B (derived from
the hydrolysis of 4B):
A mixture of Example 3B (1 mg) (derived from chiral HPLC of 2) and 3B (1 mg)(derived
from the hydrolysis of 4B) is dissolved in TFA/20% IPA/80% and analyzed by HPLC;
ChiralPak AD (4.6X250 mm); 0.1% TFA/20% IPA/80% heptane; 1 ml/m (flow rate); to
give a single peak with Rt = 8.16 m.
Example 4A and 4B
Preparation of enantiomers of 3'-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3'-
[4-methoxycarbonyl-3-methylphenyl]pentane.
A mixture of racemic 3'-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3'-
[4-methoxycarbonyl-3-methylphenyl]pentane, Example 1, is chromatographed with a
ChiralPak AD column to give enantiomer 1, Example 4A (1.72 g, 49%) and enantiomer 2,
Example 4B (1.72 g, 49%).
Enantiomer 1, Example 4A
HPLC: ChiralPak AD (4.6X250 mm); 15% IPA/80% heptane; 1 ml/m (flow rate); Rt
= 5.4m
NMR eq. To Example 1.
High Res. ES-MS: 444.3130; calc. for C27H38O4+NH4: 444.3114
Enantiomer 2, Example 4B
HPLC: ChiralPak AD (4.6X250 mm); 15% IPA/80% heptane; 1 ml/m (flow rate); Rt
= 8.0 m
NMR eq. To Example 1.
High Res. ES-MS: 444.3134; calc. for C27H38O4+NH4: 444.3114
Preparation of 3'-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3'-[4-
methylsulfonylaminocarbonyl-3-methylphenyl)]pentane.
To a mixture of methane sulfonamide (92 mg, 0.97 mmol), EDCI (186 mg, 0.97
mmol), DMAP (118 mg, 0.97 mmol) and CH2C12 (7 ml) is added 3'-[4-(2-hydroxy-3,3-
dimethylbutoxy)-3-methylphenyl]-3 '-[4-carboxyl-3-methylphenyl]pentane, Example 1,
(400 mg, 0.97 mmol) and stirred overnight. The reaction is diluted with CH2Cl2, washed
with IN HC1 (4 X 20 ml), Na2SO4 dried, concentrated, and chromatographed (gradient
CHCI3 to 10% CH3CN/CHCI3) to give the title compound as a solid (240 mg, 51%).
NMR mHz(DMSO): 8 0.60 (t, J = 7.3 Hz, 6H), 1.01 (s, 9H), 2.06 (q, J = 7.3 Hz, 4H),
2.17 (s, 3H), 2.42 (d, J = 2.9 Hz, 1H), 2.49 (s, 3H), 3.43 (s, 3H), 3.70 (d, J = 8.8 Hz,
1H), 3.86 (t, J = 8.8 Hz, 1H), 4.09 (dd, J = 2.4, 9.3 Hz, 1H), 6.71 (d, 8.8 Hz, 1H), 6.82
(d, J = 2.0 Hz, 1H), 6.91 (dd, J = 2.4, 8.8 Hz, 1H), 7.09 (m, 2H), 7.37 (d, J = 7.8 Hz,
1H), 12.30 (s,lH).
High Res. ES-MS: 490.2633; calc. for C27H39NO5S+H: 490.2627
Example 6
Preparation of 3'-[4-(2-oxo-3,3-dimethylbutoxy)-3-methylphenyl]-3'-[4-(2-
carboxylethyi)-3-methylphenyl]pentane.
To a solution of 3,3-bis[4-hydroxy-3-methylphenyl]pentane (10 g, 35.2 mmol) and
DMF (180 ml) is added 60% NaH disp (1.4 g, 35.2 mmol). After stirring for 30 m, to the
reaction is added benzyl bromide (4.2 ml, 35.2 mmol). The mixture is stirred for 14 h and
concentrated in vacuo. The residue is partitioned between Et2O/water. The organic layer
is washed with IN HC1, water, brine, Na2SO4 dried, concentrated, and chromatographed
(MeCk) to give the title compound as an oil (6.5 g, 49%).
NMR 300 MHz(DMSO): 5 0.52 (t, J - 7.3 Hz, 6H), 1.96 (q, J = 7.3 Hz, 4H), 2.04 (s, 3H),
2.12 (s, 3H), 5.05 (s, 2H), 6.63 (d, J = 8.1 Hz, 1H), 6.75 (dd, J = 2.2, 8.1 Hz, 1H), 6.79 (s,
1H), 6.89 (m, 3H), 7.44 (m, 5H), 8.96 (s, 1H).
High Res. FAB-MS: 374.2237; calc. for C26H30O2: 374.2246
B. 3 '-[4-Benzyloxy-3-methylphenyl]-3 '-[4-trifluoromethylsulfonyloxy-3-
methylphenyl]pentane.
Using a procedure analogous to Example 1C, 3'-[4-benzyloxy-3-methylphenyl]-
3'-[4-hydroxy-3-methylphenyl]pentane gives the title compound as an oil (21.5 g, 91%).
NMR 300 MHz(DMSO): 8 0.54 (t, J = 7.3 Hz, 6H), 2.05 (q, J = 7.3 Hz, 4H), 2.14 (s, 3H),
2.28 (s, 3H), 5.06 (s, 2H), 7.10 (dd, J = 2.2, 8.8 Hz, 1H), 7.26 (m, 2H), 7.34 (d, J = 7.0
Hz, 1H), 7.39 (m, 4H).
High Res. FAB-MS: 506.1743; calc. for C27H29F3O4S: 506.1739
C. 3 '-[4-Benzyloxy-3-methylphenylJ-3 '-[4-(2-ethoxycarbonylethyl)-3-
methylphenyl]pentane.
To a mixture of 3'-[4-benzyloxy-3-methylphenyl]-3'-[4-
trifluoromethylsulfonyloxy-3-methylphenyl]pentane (5.3 g, 10.5 mmol) and THF (5 ml) is
sequentially added Pd(dppf)Cl2 (860 mg, 1.05 mmol), LiCl (1.78 g, 42 mmol), and 0.5 M
BrZnCH2CH2CO2Et in THF (63 ml, 31.4 mmol). The mixture is heated to 60 °C for 18 h.
After cooling to RT, the mixture is concentrated in-vacuo, partitioned between
Et2O/EtOAc/lN HC1. The organic layer is washed with IN HC1, water, Na2SO4 dried,
concentrated, and chromatographed (hex to 10% EtOAc/hex) to give the title compound
(2.5 g, 52%).
NMR 400 MHz(DMSO): 8 0.51 (t, J = 7.3 Hz, 6H), 1.14 (t, J = 7.1 Hz, 3H), 2.00 (q, J =
7.3 Hz, 4H), 2.10 (s, 3H), 2.18 (s, 3H), 2.52 (t, J = 8.1 Hz, 2H), 2.75 (t, J = 8.1 Hz, 2H),
4.01 (q, J = 7.1 Hz, 2H), 5.03 (s, 2H), 6.87 (m, 5H), 6.98 (d, J = 7.8 Hz, 1H), 7.31 (d, J =
7.3 Hz, 1H), 7.37 (m, 2H), 7.43 (d, J = 7.1 Hz, 2H).
High Res. ES-MS: 476.3178; calc. for C31H38O3+NH4: 476.3165
D. 3'-[4-Hydroxy-3-methylphenyl]-3'-[4-(2-ethoxycarbonylethyl)-3-
methyiphenyl]pentane
A mixture of 3'-[4-benzyloxy-3-methylphenyl]-3'-[4-(2-ethoxycarbonyl
ethyl)-3-methylphenyl]pentane (2.4 g, 5.45 mmol), EtOH (20 ml), and 10% Pd/C (250
mg) is hydrogenated at atmospheric pressure for 18 h. The reaction is filtered through
diatomaceous earth with EtOAc wash. The filtrate is concentrated to give the title
compound (2 g, quant).
NMR 400 MHz(DMSO): 8 0.49 (t, J = 7.3 Hz, 6H), 1.12 (t, J = 7.1 Hz, 3H), 1.95 (q, J =
7.3 Hz, 4H), 2.01 (s, 3H), 2.18 (s, 3H), 2.52 (t, J = 7.7 Hz, 2H), 2.75 (t, J = 7.7 Hz, 2H),
4.01 (q, J = 7.1 Hz, 2H), 6.61 (d, J = 8.3 Hz, 1H), 6.73 (d, J = 8.3 Hz, 1H), 6.77 (s, 1H),
6.86 (m, 2H), 6.97 (d, J = 7.8 Hz, 1H), 8.98 (s, 1H).
High Res. ES-MS: 391.2218; calc. for C24H32O3+Na: 391.2249
E. 3'-[4-(2-Oxo-3,3-dimethylbutoxy)-3-methylphenyl]-3'-[4-(2-
ethoxycarbonylethyl)-3-methylphenyl]pentane
Using a procedure analogous to Example 1B, 3'-[4-hydroxy-3-methylphenyl]-3'-
[4-(2-ethoxycarbonylethyl)-3-methylphenyl]pentane and l-bromo-3,3-dimethyl-2-
butanone gave the title compound (2.1 g, 83%).
1HNMR 400 MHz(DMSO-d6): 50.50(t, J = 7.3Hz, 6H), 1.05-1.14(m, 12H), 1.98 (q, J
= 7.3 Hz, 4H), 2.10 (s, 3H), 2.18 (s, 3H), 2.52 (t, J = 7.7, 2H), 2.75 (t, J = 7.7, 2H), 4.02
(q, J = 7.2 Hz, 2H), 5.04 (s, 2H), 6.55 (d, J = 8.3 Hz, 1H), 6.82-6.89 (m, 4H), 6.98 (d, J =
8.1,1H).
High Res. ES-MS: 489.2990; calc. for C30H42O4+Na: 489.2981
F. 3'-[4-(2-oxo-3,3-dimethylbutoxy)-3-methylphenyl]-3'-[4-carboxylethyd-3-
methylphenyl]pentane
Using a procedure analogous to Example 2, 3'-[4-(2-oxo-3,3-dimethylbutoxy)-3-
methylphenyl]-3'-[4-(2-ethoxycarbonyiethyl)-3-methylphenyl]pentane gives the title
compound (1.8 g3 95%).
1H NMR 300 MHz (DMSO-d6): 8 0.52 (t, J = 7.3 Hz, 6H), 1.16 (s, 9H), 2.01 (q, J = 7.32
Hz, 4H), 2.13 (s, 3H), 2.20 (s, 3H), 2.46 (t, J = 7.3 Hz, 2H), 2.74 (t, J = 7.3 Hz, 2H), 5.06
(s, 2H), 6.58 (d, J = 8.4 Hz, 1H), 6.89 (m, 4H), 7.01 (d, J = 7.7 Hz, 1H).
High Res. ES-MS: 461.2669; calc. for C28H38O4+Na: 461.2668
Example 7
Preparation of 3'-[4-(2-oxo-3,3-dimethylbutoxy)-3-methylphenyl]-3'-[4-(2-
dimethylcarbamoylethyl)-3-methylphenyl]pentane.
To a 0 °C mixture of 3'-[4-(2-oxo-3,3-dimethylbutoxy)-3-methylphenyl]-3'-
[4-(2-carboxyleihyl)-3-methylphenyl]pentane (500 mg, 1.14 mmol), pyridine (101 ul,
1.25 mmol), DMF (4.4 ul, 0.057 mmol) and MeCl2 (4 ml) is added oxalyl chloride
(104 ul, 1.2 mmol). After stirring for 10 m, to the mixture is added 2M Me2NH/THF
(2.3 ml, 4.56 mmol). To the reaction is added MeCl2 (4 ml) and stirred at RT for 2 h.
The mixture is concentrated and partitioned between Et2O/lN HC1. The organic layer
is washed with water, Na2SO4 dried, concentrated, and chromatographed (hex to
CH2C12 to 15% EtOAc/MeCl2) to give the title compound as a solid (85 mg, 16%).
1H NMR 400 MHz (DMSO-d6): 5 0.51 (t, J = 7.3 Hz, 6H), 1.14 (s, 9H), 1.96 (q, J = 7.3
Hz, 4H), 2.11 (s, 3H), 2.19 (s, 3H), 2.48 (t, J = 7.2, J = 8.8 Hz, 2H, under DMSO peak),
2.69 (t, J = 7.2, J = 8.8 Hz, 2H), 2.79 (s, 3H), 2.88 (s, 3H), 5.05 (s, 2H), 6.55 (d, J = 8.8
Hz, 1H), 6.84-6.87 (m, 4H), 6.99 (d, J = 8.3 Hz, 1H).
ES-MS: 466.2 (M+H)
Example 8
Preparation of 3'-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3'-[4-(2-
dimethylcarbamoylethyl)-3-methylphenyl]pentane.
Using a procedure analogous to Example 1D, 3'-[4-(2-oxo-3,3-
dimethylbutoxy)-3-methylphenyl]-3 '-[4-(2-dimethylcarbamoylethyl)-3-
methylphenyl]pentane gives the title compound as a white glassy solid (65 mg, quant).
1H NMR 300 MHz (DMSO-d6): d 0.53 (t, J = 7.0 Hz, 6H), 0.92 (s, 9H), 6.96 (q., J =
6.96 Hz, 4H), 2.10 (s, 3H), 2.20 (s, 3H), 2.50 (t, J = 6.9, J = 8.4 Hz, 2H, under DMSO
peak), 2.71 (t, J = 6.9, J = 8.4 Hz, 2H), 2.80 (s, 3H), 2.90 (s, 3H), 3.45 (m, 1H), 3.75
(m, 1H), 4.01(dd, J = 2.9, J = 6.9 Hz, 1H), 6.80 (d, J = 8.4,1H), 6.89 (m, 4H), 7.01 (d,
J = 8.0 Hz, 1H).
High Res. ES-MS: 490.3301; calc. for C30H45NO3+Na: 490.3297
Preparation of 3'-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3'-[4-(2-
dimethylcarbamoyl-t-ethylidene)-3-methylphenyl]pentane.
To a mixture of 3'-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3'-[4-
trifluoromethylsulfonyloxy-3-methylphenyl]pentane (640 mg, 1.24 mmol), Pd(OAc)2
(14 mg, 0.062), DPPP (51 mg, 0.124 mmol), and DMF (2.5 ml) is added Et3N (0.69
ml, 4.96 mmol). The mixture is purged with N2 and N,N-dimethylacrylamide (0.39
ml, 3.71 mmol) is added. The reaction is heated to 80 °C for 14 h and then cooled.
The mixture is partitioned between EtOAc/water. The organic layer is washed with
IN HCl, water, brine, Na2SO4 dried, concentrated, and chromatographed (MeCl2 to
60% EtOAc/MeCl2) to give the title compound as a white foam (90 mg, 16%).
1H NMR 300 MHz (DMSO-d6): d 0.55 (t, J = 7.0 Hz, 6H), 0.92 (s, 9H), 2.04 (q, J =
7.0 Hz, 4H), 2.10 (s, 3H), 2.31 (s, 3H), 2.92 (s, 3H), 3.13 (s, 3H), 3.45 (m, 1H), 3.75
(dd, J = 7.4,9.9 Hz, 1H), 4.02 (dd, J = 3.3,9.9 Hz, 1H), 4.78 (d, J = 5.1 Hz, 1H), 6.81
(d, J = 8.8 Hz, 1H), 6.87 (s, 1H), 6.96 (m, 3H), 7.01 (s, 1H), 7.62 (m, 2H).
High Res. ES-MS: 466.3328; calc. for C30H44NO3+H: 466.3321
Preparation of enantiomers of 3'-[4-(2-hydroxy-l,3,3-trimethylbutoxy)-3-methylphenyl]-
3'-[4-methoxycarbonyl-3-methylphenyl]pentane.
JB5-A03275-45-1
(enantiomer 2) Example 10Db
A. 3'-[4-(2-oxo-3,3-dimethylbutoxy)-3-methylphenyl]-3'-[4-methoxycarbonyl-3-
methylphenyl]pentane.
Using a procedure analogous to Example 1B, 3'-[4-hydroxy)-3-methylphenyi]-3'-
[4-methoxycarbonyl-3-methylphenyl]pentane gave the title compound as a white solid
(19.5 g, 88%).
NMR 300 mHz(DMSO): d 0.54 (t, J = 7.3 Hz, 6H), 1.16 (s, 9H), 2.05 (q, J = 7.3 Hz, 4H),
2.13 (s, 3H), 2.47 (s, 3H), 3.79 (s, 3H), 5.07 (s, 2H), 6.59 (d, J = 9.1 Hz, 1H), 6.86 (m,
2H), 7.06 (d, J = 8.1 Hz, 1H), 7.11 (s, 1H), 7.72 (d, J = 8.1 Hz, 1H).
High Res. ES-MS: 442.2953; calc. for C27H36O4+NH4: 442.2957.
B. 3'-[4-(2-oxo-l,3,3-trimethylbutoxy)-3-me1hylphenyl]-3'-[4-methoxycarbonyl-3-
methylphenyl]pentane.
To a-78 °C mixture of 3'-[4-(2-oxo-3,3-dimethylbutoxy)-3-methylphenyl]-3'-[4-
(2-methoxycarbonyl-3-methylphenyl)]pentane (2.0 g, 4.7 mmol) in THF (10 ml) is added
1M LiHMDS/THF (5.2 ml, 5.2 mmol). The reaction is warmed to -45 °C, stirred for 1.25
h, added Mel (351 ul, 5.6 mmol). After warming to RT and stirred overnight, the reaction
is diluted with Et20, washed with 1N HCl, water, and Na2SO4 dried. The organic
solution is concentrated and chromatographed (50% CHC13/hex) to give the title
compound (1.75 g, 85%).
NMR 300 mHz(DMSO): 8 0.53 (t, J = 7.3 Hz, 6H), 1.10 (s, 9H), 1.34 (d, J = 6.6 Hz, 3H),
2.04 (q, J = 7.3 Hz, 4H), 2.10 ( s, 3H), 2.46 (s, 3H), 3.79 (s, 3H), 5.32 (q, J = 6.6 Hz, 1H),
6.88 (m, 3H), 7.05 (d, J - 8.4 Hz, 1H), 7.10 (s, 1H), 7.71 (d, J = 8.1 Hz, 1H).
High Res. ES-MS: 456.3107; calc. for C28H38O4+NH4: 456.3114
C. 3'-[4-(2-hydroxy-1,3,3-trimethylbutoxy)-3-methylphenyl]-3'-[4-methoxycarbonyl-3-
methylphenyl]pentane.
Using a procedure analogous to Example 1D, 3'-[4-(2-oxo-1,3,3-trimethylbutoxy)-
3-methylphenyl]-3'-[4-methoxycarbonyl-3-methylphenyl]pentane gives the title
compound (1.6 g, 100%).
NMR 300 mHz(DMSO): 5 0.54 (t, J = 7.3 Hz, 6H), 0.91 (s, 9H), 1.19 (d, J = 5.9 Hz, 3H),
2.07 (m, 7H), 2.48 (s, 3H), 3.08 (dd, J = 1.1,7.7 Hz, 1H), 3.79 (s, 3H), 4.35 (d, J = 7.7
Hz, 1H), 4.57 (br q, J = 5.9 Hz, 1H), 6.84 (m, 3H), 7.06 (br d, J = 8.4 Hz, 1H), 7.14 (s,
1H), 7.72 (d, J = 8.4 Hz, 1H).
High Res. ES-MS: 456.3107; calc. for C28H38O4+NH4: 456.3114.
D. Enantiomers of 3'-[4-(2-hydroxy-l,3,3-trimethylbutoxy)-3-methylphenyl]-3'-[4-
methoxycarbonyl-3-melhvlphenyl]pentane.
Using a procedure analogous to Example ID, 3'-[4-(2-oxo-l,3,3-trimethylbutoxy)-
3-methylphenyl]-3'-[4-methoxycarbonyl-3-methylphenyl]pentane gave a racemic mixture
of the title compound. The mixture is chromatographed (Chiralpak AD) to give
enantiomer 1 (543 mg, 36%, Rt =) and enantiomer 2 (822 mg, 55%, Rt = ).
Enantiomer 1 Example 10Da
NMR 300 mHz (DMSO): 8 0.54 (t, J = 7.3 Hz, 6H), 0.91 (s, 9H), 1.20 (d, J = 6.2 Hz, 3H),
2.07 (m, 7H), 2.48 (s, 3H), 3.08 (dd, J = 1.5, 7.7 Hz, 1H), 3.79 (s, 3H), 4.35 (d, J = 7.7
Hz, 1H), 4.57 (m, 1H), 6.84 (m, 3H), 7.06 (dd, J = 1.1, 8.4 Hz, 1H), 7.14 (s, 1H), 7.72 (d,
J = 8.4Hz, 1H).
High Res. ES-MS: 458.3257; calc. for C28H40O4+NH4: 458.3270.
Enantiomer 2 Example 10Db
NMR 300 mHz (DMSO): eq. to enantiomer 1.
MS: 440.29 (M+).
High Res. ES-MS:; calc. for C27H39NO5S+H:
Example 11
Preparation of enantiomer 1 of 3'-[4-(2-hydroxy-l,3,3-trimethylbutoxy)-3-methylphenyl]-
3'-[4-carboxyl-3-methylphenyl]pentane.
Using a procedure analogous to Example 2, enantiomer 1 of 3'-[4-(l-methyl-2-
hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3'-[4-methoxycarbonyl-3-
methylphenyl]pentane, Example 10Da, gave the title compound (420 mg, 96%).
HPLC: ChiralPak AD (4.6X250 mm); 0.1% TFA/20% IPA/80% heptane; 1 ml/m (flow
rate); Rt = m
NMR 300 mHz (DMSO): 8 0.54 (t, J = 7.3 Hz, 6H), 0.91 (s, 9H), d, J = 5.9 Hz, 3H), 2.07
(m, 7H), 2.48 (s, 3H), 3.08 (dd, J = 1.1,7.7 Hz, 1H), 4.35 (d, J = 7.7 Hz, 1H), 4.57 ( m,
1H), 6.84 (m, 3H), 7.04 (d, J = 8.1 Hz, 1H), 7.10 (s, 1H), 7.72 (d, J = 8.1 Hz, 1H), 12.60
(brs, 1H).
High Res. ES-MS: 875.5439; calc. for [C27H38O4+Na] + C27H38O4: 875.5438.
Example 12
Preparation of enantiomer 2 of 3'-[4-(2-hydroxy-3,3-trimethylbutoxy)-3-methylphenyl]-
3 '-[4-carboxyl-3-methylphenyl)]@@@pentane.
Using a procedure analogous to Example 2, enantiomer 2 of 3'-[4-(2-hydroxy-
13,3-trimethylbutoxy)-3-methylphenyl]-3'-[4-methoxycarbonyl-3-methylphenyl]pentane,
Example 10Db, gave the title compound (680 mg, 94%).
HPLC: ChiralPak AD (4.6X250 mm); 0.1% TFA/20% IPA/80% heptane; 1 ml/m (flow
rate); Rt = m
NMR 300 mHz (DMSO): eq. to enantiomer 1.
High Res. ES-MS: 449.2657; calc. for C27H38O4+Na: 449,2668.
Example 12a
Preparation enanriomer 1 of 3'-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3'-
[4-(tetrazol-5-ylaminocarbonyi)-3-methylphenyl]pentane.
Using a procedure analogous to Example 5, enantiomer 1 of 3'-[4-(2-hydroxy-3,3-
dimethyibutoxy)-3-methylphenyl]-3'-[4-carboxyl-3-methylphenyl3pentane, Example 3A,
and 5-aminotetrazole give the title compound (440 mg, 95%).
NMR 300 mHz (DMSO): 0.57 (t, J = 7.3 Hz, 6H), 0.92 (s, 9H), 2.09 (m, 7H), 2.40 (s,
3H), 3.46 (m, 1H), 3.76 (dd, J = 7.3, 10.2 Hz, 1H), 4.03 (dd, J = 3.3,10.2 Hz, 1H),
4.79 (d, J = 5.5 Hz, 1H), 6.83 (d, J = 8.4 Hz, 1H), 6.89 (s, 1H), 6.95 (d, J = 8.4 Hz,
1H), 7.08 (d, J = 8.1 Hz, 1H), 7.12 (s, 1H), 7.52 (d, J = 8.1 Hz, 1H), 12.23 (s, 1H),
16.00 (brs, 1H).
High Res. ES-MS: 480.2983; calc. for C27H37N5O3+H: 480.2975.
Example 12b
Preparation enantiomer 2 of 3'-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3'-
[4-(tetrazol-5-ylaminocarbonyl)-3-methylphenyl]pentane.
Using a procedure analogous to Example 5, enantiomer 2 of 3'-[4-(2-hydroxy-3,3-
dimethylbutoxy)-3-methylphenyl]-3 '-[4-carboxyl-3-methylphenyl]pentane, Example 3B,
and 5-aminotetrazole gives the title compound (385 mg, 83%).
NMR 300 mHz (DMSO): eq. to enantiomer of 1.
High Res. ES-MS: 480.2968; calc. for C27H37N5O3+H: 480.2975.
Example 13
Preparation of l-[4-(l-ethyl-l-{4-[(2-memanesulfonyl-ethylamino)-methyl]-3-methyl-
phenyl}-propyl)-2-methyl-phenoxy]-3,3-dimethyl-butan-2-one.
A. Methyl 4-(l-{4-[2-(tert-Butyldimethylsilanyloxy)-3,3-dimethyl-butoxy]-3-
methylphenyl}-1-ethylpropyl)-2-methyl-benzoate.
To a solution of the methyl 4-(l-{4-[2-(hydroxy)-3,3-dimethyl-butoxy]-3-
methylphenyl}-1-ethylpropyl)-2-methylbenzoate (4.79 g, 11.24 mmol), Example 1, in
DMF (40 mL) is added imidazole (1.14 g, 16.87 mmol) followed by the addition of
TBSC1 (1.78 g, 11.80 mmol). The mixture is stirred at RT overnight and concentrated.
The mixture is partitioned between 0.1 M HC1 (100 mL) and EtOAc (100 mL). The
aqueous layer is extracted with EtOAC. The combined organic layers is MgSO4 dried,
concentrated, and chromatographed (10% EtOAc/Hex) to give the title compound (4.37 g,
72%).
1H NMR (CDCl3): 8 0.04 (s, 3H), 0.10 (s, 3H), 0.60 (t, J= 7.0 Hz, 6H), 0.89 (s, 9H), 0.96
(s, 9H), 2.04-2.09 (m, 4H), 2.16 (s, 3H), 2.55 (s, 3H), 3.66 (dd, J = 5.6, 3.6 Hz, 1H), 3.82-
3.86 (m, 4H), 3.97 (dd, J= 10.0,3.2 Hz, 1H), 6.65 (d, J= 8.4 Hz, 1H), 6.83-7.06 (m, 4H),
7.79 (d, /= 7.6 Hz, 1H). ES-MS (m/z): calcd for C33H52O4Si (M+): 540.9; found: 541.2.
B. [4-(l-{4-[2-(tert-Butyldimemylsilanvloxy)-3,3-dimethylbutoxy]-3-methylphenyl}-l-
ethylpropyl)-2-methylphenyl]-methanol.
To a 0 °C solution of the methyl 4-(l-{4-[2-(t-butyldimethylsilanyloxy)-3,3-
dmemyl-butoxy]-3-memylphenyl}-1-efliylpropyl)-2-methyl-benzoate (4.37 g, 8.09 mmol)
in THF (50 mL) is added LiAlH4 (0.31 g, 8.09 mmol). The reaction is stirred for 10 m and
allowed to warm to RT overnight The mixture is cooled to 0 °C and quenched
successively with H2O (0.3 mL), 15 % NaOH (0.3 mL) and H2O (0.9 mL). The mixture is
stirred for 10 m, warmed to RT, stirred for 20 m, filtered through celite with EtOAc (100
mL) wash, and concentrated to give the title compound (4.14 g, 8.08 mmol, 99%).
1H NMR (CDCl3): 8 0.04 (s, 3H), 0.10 (s, 3H), 0.59 (t, J= 7.1 Hz, 6H), 0.89 (s, 9H), 0.94
(s, 9H), 2.05 (q, J= 7.1 Hz, 4H), 2.17 (s, 3H), 2.31 (s, 3H), 3.66 (dd, J = 6.0, 3.6 Hz, 1H),
3.70(t,J=5.6Hz, lH),3.84(dd,J=9.8,5.2 Hz, 1H), 3.97 (dd, .7=9.8, 3.6 Hz, 1H),
4.67 (s, 2H), 6.65 (d, J= 8.4 Hz, 1H), 6.88-7.02 (m, 4H), 7.21 (d, J= 8.0 Hz, 1H). ES-
MS (m/z): calcd for C32H56NO3Si (M+NH4)+: 530.9; found: 530.2.
C. 4-(l-{4-[2-(t-Butyldimethylsilanyloxy)-3,3-dimethylbutoxy]-3-methylphenyl}-1-
ethylpropyl)-2-methylbenzaldehyde.
To a solution of [4-(l-{4-[2-(t-butyidimethylsilanyloxy)-3,3-dimethylbutoxy]-3-
methylphenyl}-1-ethylpropyl)-2-methylphenyl]methanol (0.25 g, 0.48 mmol) in CH2C12
(4 mL) is added powdered 4A molecular sieves (250 mg) followed by the addition of
NMO (84 mg, 0.72 mmol), and TPAP (8.4 mg, 0.02 mmol). The resulting mixture is
stirred at RT for 5 m, filtered through silica gel, washed with EtOAc, and the combined
filtrate is concentrated to give the title compound (0.20 g, 83%).
!H NMR (CDC13): 8 0.04 (s, 3H), 0.10 (s, 3H), 0.61 (t, J= 7.2 Hz, 6H), 0.89 (s, 9H), 0.96
(s, 9H), 2.09 (q, J= 7.2 Hz, 4H), 2.17 (s, 3H), 2.62 (s, 3H), 3.67 (dd, J= 5.4, 3.4 Hz, 1H),
3.85 (dd, J= 9.8, 5.4 Hz, 1H), 3.97 (dd, J= 9.8, 3.4 Hz, 1H), 6.67 (d, J= 8.4 Hz, 1H),
6.84-6.92 (m, 2H), 7.08 (s, 1H), 7.17 (d, J= 8.0 Hz, 1H), 7.67 (d, J= 8.4 Hz, 1H), 10.21
(s, 1H). ES-MS (m/z): calcd for C32H5103Si (M+H)+: 511.8; found: 511.2.
D. [4-(l-{4-[2-(t-Butyldimethylsilanyloxy)-3,3-dimethylbutoxy]-3-methylphenyl}-l-
ethylpropyl)-2-methylbenzylJ-(2-methanesulfonylethyl)amine.
To a mixture of 4-(l-{4-[2-(t-butyldimethylsilanyloxy)-3,3-dimethylbutoxy]-3-
methylphenyl}-l-ethylpropyl)-2~methylbenzaldehyde (2.40 g, 4.71 mmol), Et3N (0.9 ml,
6.12 mmol), and 2-aminoethylmethylsulfone hydrochloride (0.78 g, 5.18 mmol) is treated
with Ti(OiPr)4 (1.8 ml, 6.12 mmol). The mixture is stirred for 1 h, diluted with CH3OH
(20 mL), then NaBCNH3 (0.33 g, 5.18 mmol) is added The mixture is stirred overnight,
quenched with H2O (3 mL), stirred for 1 h., and filtered through SiO2 with EtOAc (100
mL) wash. The filtrate is concentrated and chromatographed (75-80%EtOAc) to give the
title compound (1.47 g, 2.38 mmol, 51%).
1HNMR (CDCl3), 5 0.05 (s, 3H), 0.12 (s, 3H), 0.61 (t, 7= 7.4 Hz, 6H), 0.91 (s, 9H)5 0.97
(s, 9H), 2.05 (q, J= 7.4 Hz, 4H), 2.19 (s, 3H), 2.33 (s, 3H), 2.99 (s, 3H), 3.21-3.27 (m, 3.5
H), 3.66-3.72 (m, 1.5 H), 3.83 (s, 2H), 3.86 (t, J= 5.9 Hz, 1H), 3.98 (dd,J= 9.8, 3.4 Hz,
1H), 6.65 (d, J= 8.3 Hz, 1H), 6.86-6.88 (m, 1H), 6.92 (dd, J= 8.3,2.4 Hz, 1H), 6.99 (s,
1H), 7.00 (bs, 1H), 7.14 (d, J= 8.2 Hz, 1H). ES-MS (m/z): calcd for C35H60O4SSi
(M+H)+: 619.0; found: 619.6.
E. l-[4-(l-Ethyl-l-{4-[(2-methanesulfonylethylamino)methyl]-3-methylphenyl}propyl)-
2-methylphenoxy]-3,3-dimethylbutan-2-ol.
To a mixture of [4-(l-{4-[2-(t-butyldimethylsilanyloxy)-3,3-dimethylbutoxy]-3-
methylphenyl}-l-ethylpropyl)-2-methylbenzyl]-(2-methanesulfonylethyl)amine (1.47 g,
2.43 mmol) in THF (30 mL) is added 1M TBAF (2.7 mL, 2.7 mmol), and refluxed for 2
h. After cooling to RT, the mixture is diluted with H2O (20 mL) and extracted with
EtOAc (3 x 30 mL). The combined organic layers are MgSO4 dried, concentrated, and
chromatographed (80% EtOAc/Hex) to give the title compound (0.97 g, 1.93 mmol,
79%).
1H NMR (CDCl3), 8 0.60 (t, J= 7.4 Hz, 6H), 1.02 (s, 9H), 2.05 (q, J= 7.4 Hz, 4H), 2.18
(s, 3H), 2.34 (s, 3H), 3.01 (s, 3H), 3.32 (bs, 4H), 3.71 (dd, J= 8.8, 2.4 Hz, 1H), 3.86 (t, J
= 9.3 Hz, 1H), 3.88 (s, 2H), 4.09 (dd, J= 9.3,2.4 Hz, 1H), 6.70 (d, /= 8.3 Hz, 1H), 6.89
(bs, 1H), 6.90-6.96 (m, 1H), 6.98 (s, 1H), 7.00 (s, 1H), 7.13 (d, J= 7.5 Hz, 1H). ES-MS
(m/z): calcd for C29H46O4S (M+H)+: 504.8; found: 504.4.
F. t-Butyl (4- {1-ethyl-1-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-propyl}-2-
methylbenzyl)-(2-methancsulfonylethyl)carbamate.
To a mixture of of l-[4-(l-ethyl-l-{4-[(2-methanesulfonyIethyl-amino)methyl]-3-
mettiylphenyl}propyl)-2-methylphenoxy]-3,3-dimethyibutan.-2-ol (0.97 g, 1.92 mmol),
NaHCO3 (0.32 g, 3.84 mmol), H2O(10 mL), and THF (5 mL), is added (Boc)20 (0.46 g,
2.11 mmol). The reaction is stirred overnight, diluted with H2O (10 mL), and extracted
with EtOAc ( 2 x 20 mL). The combined organic layers are washed with 0.1M HC1 (15
mL), brine (10 mL); MgSO4 dried, and chromatographed (40% EtOAc/Hex) to give the
title compound (0.86 g, 1.43 mmol, 74%).
1HNMR (CDCl3), 5 0.61 (t, J= 7.3 Hz, 6H), 1.02 (s, 9H), 1.45 (bs, 9H), 2.05 (q, J= 7.3
Hz, 4H), 2.19 (s, 3H), 2.24 (s, 3H), 2,44 (bs, 1H), 2.70-3.20 (b, 5H), 3.58 (bs, 2H), 3.71
(dd, J= 8.8,2.9 Hz, 1H), 3.86 (t, J = 8.8 Hz, 1H), 4.10 (dd, J = 8.8, 2.9 Hz, 1H), 4.47 (s,
2H), 6.71 (d, J= 8.4 Hz, 1H), 6.80-7.01 (m, 5H). ES-MS (m/z): calcd for C34H57N2O6S
(M+NH4): 621.9; found: 621.3.
G. t-Butyl (4- {1-[4-(3,3-dimethyl-2-oxobutoxy)-3-methylphenyl]-1-ethylpropyl} -2-
methylbenzyl)-(2-methanesulfonylethyl)carbamate.
Using a procedure analogous to Example 13C, from t-butyl (4-{1-ethyl-1-[4-(2-
hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-propyl}-2-methyIbenzyl)-(2-
methanesulfonylethyl)carbamate (0.26 g, 0.43 mmol) to give the title compound (0.25 g,
0.42 mmol, 95%).
1H NMR (CDCU), 5 0.60 (t, J= 7.5 Hz, 6H), 1.26 (s, 9H), 1.48 (bs, 9H), 2.05 (q, 7-7.5
Hz, 4H), 2.23 (s, 3H), 2.25 (s, 3H), 2.60-3.20 (m, 5H), 3.57 (bs, 2H), 4.46 (s, 2H), 4.84 (s,
2H), 6.50 (d, J= 8.1 Hz, 1H), 6.80-7.01 (m, 5H). ES-MS (m/z): calcd for C34H51O6S:
60L9; found: 602.2.
H. 1-[4-(l -Ethyl-1 - {4-[(2-methanesulfonylethylamino)-methyl]-3 -methylphenyl} propyl)-
2-methyiphenoxy]-3,3-dimethylbutan-2-one.
To a mixture of t-butyl (4- {1 -[4-(3,3-dimethyl-2-oxobutoxy)-3-mpthylphenyl]-1-
ethylpropyl}-2-methylbenzyl)-(2-mettianesulfonylethyl)carbamate (0.25, g, 0.41 mmol)
and CH2Cl2 (5 mL) is added TFA (5 mL,), stirred for 10 m, and concentrated. The
residue is diluted with EtOAc (100 mL), washed with satd NaHCO3 (2 x 30 mL); MgSO4
dried, and chromatographed (90% EtOAc) to give the title compound (0.19 g, 0.39 mmol,
95%).
1HNMR(CDCl3).d0.61 (t, 7=7.2 Hz, 6H), 1.27 (s, 9H), 2.05 (q,J= 7.2 Hz, 4H), 2.25
(s, 3H), 2.32 (s, 3H), 2.99 (s, 3H), 3.25 (s, 4H), 3.81 (s, 2H), 4.84 (s, 2H), 6.49 (d, J = 8.3
Hz, 1H), 6.85-7.00 (m, 4H), 7.13 (d, J= 7.7 Hz, 1H). ES-MS (m/z): calcd for
C29H44NO4S (M+H)+: 502.7; found: 502.2.
Example 14
Preparation of 4- {1 -ethyl-1 -[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl] propyl} -
N-(2-methanesulfonylethyl)-2-methylbenzamide.
To a mixture of 4-(l-{4-[2-(hydroxy)-3,3-dimethyl-butoxy]-3-methylphenyl}-l-
ethylpropyl)-2-methylbenzoic acid, Example 1, (0.53 g, 1.29 mmol), 2-
aminoethylmethylsulfone hydrochloride (0.21 g, 1.29 mmol), HOBt (0.19 g, 1.43 mmol),
Et3N (0.72 mL, 5.19 mmol) and CH2Cl2 (10 mL) is added EDCI (0.249 g, 1.29 mmol) and
stirred overnight. The reaction is diluted with CH2Cl2 (50 mL), washed with 1M HC1 (2 x
30 mL), H2O (20 mL), satd NaHCO3 (2 x 20 mL), and brine (20 mL). The organic layer
is MgSO4 dried, concentrated, and chromatographed (75% EtOAc/Hex) to give the title
compound (0.51 g, 76%).
1H NMR (CDC13), 8 0.59 (t, J= 7.8 Hz, 6H), 1.01 (s, 9H), 2.00-2.28 (m, 4H), 2.17 (s,
3H), 2.41 (s, 3H), 3.00 (s, 3H), 3.35 (t, J= 5.6 Hz, 1H), 3.70 (bd, J= 8.6 Hz, 1H), 3.85 (t,
J= 9.1 Hz, 1H), 3.97 (dd, J= 12.3, 5.6 Hz, 2H), 4.09 (dd, J= 9.1, 3.0 Hz, 1H), 6.53 (t, J
= 5.9 Hz, 1H), 6.69 (d, J= 7.8 Hz, 1H), 6.85 (s, 1H), 6.91-7.01 (m, 2H), 7.25-7.29 (m,
2H). ES-MS (m/z): calcd for C29H44NO5S (M + H)+: 518.7; found: 518.3.
Example 15A&15B
Preparation of enantiomer 1 and 2 of 4-{l-ethyl-l-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-
methylphenyl]propyl}-N-(2-methanesulfonyiethyl)-2-methylbenzamide.
A racemic mixture of 4-{l-ethyl-l-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-
methylphenyl]propyl}-A'-(2-methanesulfonylethyl)-2-methylbenzamide (0.34 g), Example
14, is chromatographed (HPLC: ChiralPak AD, 60% EtOH/Hept) to give enantiomer 1
(0.10 g, 29%, rt = 4.9 m) and enantiomer 2 (0.125 g, 37%, rt = 6.3 m).
Example 15A, 2071445 (enantiomer 1):
HPLC: ChiralPak AD (4.6 X 250 mm); 60% EtOH/Hept; 1.0 mL/m (flow rate); rt = 4.9
m; @ 240 nm.
NMR & LC/MS: equivalent to the racemate, Example 14.
Example 15B, 2071447 (enantiomer 2):
HPLC: ChiralPak AD (4.6 X 250 mm); 60% EtOH/Hept; 1.0 mL/m (flow rate); rt = 6.3
m; @ 240 nm.
NMR & LC/MS: equivalent to the racemate, Example 14.
Example 16
Preparation of 4-{1-[4-(3,3-dimethyl-2-oxobutoxy)-3-methylphenyl]-1-ethylpropyl}-N-(2-
methanesulfonylethyl)-2-methylbenzamide.
Using a procedure analogous to Example 13C, from 4-{l-ethyl-l-[4-(2-hydroxy-
3,3-dimethylbutoxy)-3-methylphenyl]propyl}-N:-(2-methanesulfonylethyl)-2-
methylbenzamide, Example 14, (0.08 g, 0.16 mmol), NMO (27 mg, 0.24 mmol), and
TPAP (2.8 mg, 0.08 mmol) are reacted for 1 h to give the title compound (0.06g, 76%).
1H NMR (CDCl3): 8 0.60 (t, J= 7.4 Hz, 6H), 1.27 (s, 9H), 2.05 (q, J = 7.4 Hz, 4H), 2.24
(s, 3H), 2.42 (s, 3H), 3.01 (s, 3H), 3.36 (t, J = 6.0 Hz, 2H), 3.94-4.02, (m, 2H), 4.82 (s,
2H), 6.46-6.57 (m, 2H), 6.82-7.23 (m, 5H). ES-MS (m/z): calcd for C29H42NO5S (M +
H)+: 516.7; found: 516.4.
Example 17
Preparation of 4-{l-[4-(3,3-dimethyl-2-oxobutoxy)-3-meth.ylphenyl]-1-ethylpropyl}-2-
methylbenzoic acid.
To a mixture of 4-{1-[4-(3,3-dimethyl-2-hydroxybutoxy)-3-methylphenyl]-l-
ethylpropyl}-2-methylbenzoic acid, Example 1, (0.50 g, 1.22 mmol) in CH2CI2 (10 mL)
is added a solution of the Dess-Martin reagent (0.57 g, 1.34 mmol) in CH2CL2 (10 mL)
dropwise and stirred for 2 h. The reaction is diluted with EtOAc (100 mL), washed with
10% Na2SO3 (2 x 20 ml), 0.1 MHCl (20 ml), and H2O (20 ml). The organic layer is
MgSO4 dried, and concentrated to give the title compound (0.48 g, 1.17 mmol, 95%).
1H NMR (CDCl3), 5 0.62 (t, J= 7.2 Hz, 6H), 1.27 (s, 9H), 2.09 (q, J = 7.2 Hz, 4H), 2.25
(s, 3H), 2.61 (s, 3H), 4.85 (s, 2H), 6.51 (d, J= 8.8 Hz, 1H), 6.85-6.91 (m, 2H), 7.05-7.10
(m, 2H), 7.93 (d, J= 9.0 Hz, 1H). ES-MS (m/z): calcd for C26H38NO4 (M + NH4)+:
428.6; found: 428.3.
Example 18
Preparation of enantiomer 1 of [(4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-
methyl-phenyl]-propyl} -2-methyl-benzoyl)-methyl-amino]-acetic acid.
A. Enantiomer 1 of [(4-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimemyl-butoxy)-3-methyl-
phenyl]-propyl}-2-methyl-benzoyl)-methyl-amino]-acetic acid methyl ester.
Using a procedure analogous to Example 5, from enantiomer 1 of 4-(l-{4-[2-
(hydroxy)-3,3-dimethyl-butoxy]-3-methylphenyl} -1 -ethylpropyl)-2-methylbenzoic acid,
Example 3A, (1.28 g, 3.17 mmol) and Af-methyl glycine methyl ester hydrochloride (0.48
g, 3.41 mmol) to give the title compound (1.43 g, 2.88 mmol, 93%). 1H NMR (CDCl3), d
0.57-0.65 (m, 6H), 1.02 (s, 9H), 2.00-2.11 (m, 4H), 2.18 (s, 3H), 2.25 (s, 0.80H), 2.32 (s,
2.20H), 2.89 (s, 2.20H), 3.15 (s, 0.80H), 3.70 (s, 0.8H), 3.72 (d, J= 2.6 Hz, 1H), 3.79 (s,
2.2H), 3.86 (t, J = 8.8 Hz, 1H), 3.91 (s, 0.52H), 4.09 (dd, J = 7.0,2.6 Hz, 1H), 4.32 (bs,
1.48H), 6.70 (d, J= 8.3 Hz, 1H), 6.85-7.11 (m, 5H). ES-MS (m/z): calcd for C30H44NO5
(M + H)+: 498.7; found: 498.3.
B. Enantiomer 1 of [(4-{l-ethyl-l-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-
phenyl]-propyl}-2-methyl-benzoyl)-methyl-amino]-aceticacid
(Enantiomer 1)
Using a procedure analogous to Example 2, from enantiomer 1 of [(4-{1-ethyl-1-
[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyi]-propyl}-2-methyl-benzoyl)-
methyl-amino]-acetic acid methyl ester (1.43 g, 2.88 mmol) to give the title compound
(1.24 g, 2.57 mmol, 90%). 1H NMR (CDCl3), 5 0.56-0.63 (m, 6H), 1.02 (s, 9H), 2.01-
2.09 (m, 4H), 2.11 (s, 0.7H), 2.18 (s, 2.3H), 2.23 (s, 0.70H), 2.29 (s, 2.30H), 2.91 (s,
2.30H), 3.14 (s, 0.70H), 3.71 (dd,J= 8.8,2.6 Hz, 1H), 3.86 (t,7= 8.8 Hz, 1H), 3.92(s,
OATH), 4.09 (dd, 7= 8.8,2.6 Hz, 1H), 4.33 (bs, 1.53H), 6.69 (d, J= 8.8 Hz, 0.23H), 6.70
(d, J= 8.3 Hz, 0.77H), 6.85-7.11 (m, 5H). ES-MS (m/z): calcd for C29H40NO5 (M - H)':
482.7; found: 482.3.
Example 19
Enantiomer 2 of [(4- {1 -Ethyl-1 -[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-
propyl} -2-methyl-benzoyl)-methyl-amino]-acetic acid.
(Enantiomer 2)
Using a procedure analogous to Example 5, from enantiomer 2 of 4-(l-{4-[2-
(hydroxy)-3,3-dimethyl-butoxy]-3-methylphenyl}-l-ethylpropyl)-2-methylbenzoicacid,
Example 3B, (1.08 g, 2.62 mmol) to give the title compound (1.16 g, 2.33 mmol, 89%).
1H NMR & LC/MS: equivalent to Example 18A.
B. Enantiomer 2 of [(4-{1-Ethyi-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-
phenyl]-propyI}-2-methyl-benzoyl)-methyl-amino]-aceticacid.
Using a procedure analogous to Example 2, from enantiomer 2 of [(4-{1-ethyl-1-
[4-(2-hydroxy-3)3-dimelhyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoyl)-
methyi-amino]-acetic acid methyl ester (0.58 g, 1.16 mmol) givesthe title compound (0.53
g, 1.10 mmol, 95%). 1HNMR & LC/MS: equivalent to Example 18B,
Example 20
A. 2-(4-{l-Emyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-
methyl-benzoylamino)-2-methyl-propionic acid methyl ester.
Using the procedure analogous to Example 5, from enantiomer 1 of 4-{1-ethyl-1-
[4-(2-hydroxy-3,3-1imethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-ben2oic acid,
Example 3A, (0.40 g, 0.97 mmol) and 2-aminoisobutyric acid methyl ester hydrochloride
(0.15 g, 1.07 mmol) to furnish the title compound (0.36 g, 0.70 mmol, 72 %). 1HNMR
(CDCl3), 8 0.60 (t, J=7.6 Hz, 6H), 1.01 (s, 9H), 1.64 (s, 6H), 2.01-2.09 (m, 4H)S 2.17 (s,
3H), 2.40 (s, 3H), 2.70 (d, J=9.0 Hz, 1H), 3.77 (s, 3H), 3.85 (t, J=9.1 Hz, 1H), 4.09 (d,
J= 9.6 Hz, 1H), 6.28 (s, 1H), 6.70 (dd, J= 8.9,2.6 Hz, 1H), 6.85 (s, 1H), 6.93 (d, J= 8.6
Hz, 1H), 6.95-7.02 (m, 2H), 7.27 (dd,J= 7.9,2.6 Hz, 1H). ES-MS (m/z): calcd. for
C31H46NO5 (M+H)+: 512.3; found: 512.3.
B. 2-(4-{1-Ethyl-1-[4-(2-hydroxy-3,3-dmiethyl-butoxy)-3-methyl-phenyl3-propyl}-2-
methyl-benzoylamino)-2-methyl-propionicacid.
(Enantiomer 1)
Using a procedure analogous to Example 2, from enantiomer 1 of 2-(4-{1-eithyl-1-
[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-memyl-phenyl]-propyl}-2-methyl-benzoylamino)-
2-methyl-propionic acid methyl ester (0.36 g, 0.70 mmol) to furnish the titled compound
(0.35 g, 0.70 mmol, 92%). 1H NMR (CDCl3), 8 0.59 (t, J= 7.3 Hz, 6H), 1.01 (s, 9H), 1.67
(s, 6H), 2.05 (q, J= 7.3 Hz, 4H), 2.17 (s, 3H), 2.40 (s, 3H), 3.70 (dd, J= 8.7, 2.7 Hz, 1H),
3.86 (t, J = 8.9 Hz, 1H), 4.09 (dd, J= 9.1,2.7 Hz, 1H), 6.28 (s, 1H), 6.70 (d, J= 8.5 Hz,
1H), 6.85 (d,J= 2.3 Hz, 1H), 6.93 (dd,J= 8.5,2.3 Hz, 1H), 6.98-7.03 (m, 2H), 7.26 (d,7
= 7.9 Hz, 1H). ES-MS (m/z): calcd. for C30H44NO5 (M+H)+: 498.3; found: 498.3.
Example 21
Preparation of 4-{l-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-l-ethyl-propyl}-
benzoic acid.
To a mixture of 4-(Z/E-2-penten-3-yl)phenol (7.45 g, 45.9 mmol), CH2Cl2
(150 mL), and Tf2O (13.4 g, 47.5 mmol) is added DIPEA (6.13 g, 47.5 mol) drop
wise. After stirring overnight, the reaction is poured into ice water (100 mL) and
separated. The organic layer is washed with cold water (2 x 50 mL), Na2SO4 dried,
filtered and concentrated to give the title compound as an oil (10.5 g, 78%) which is
used as is.
B. 4-[(l-Ethyl-1-(3-methyl-4-hydroxyphenyl)propyl]-O-
trifluoromethylsulfonylphenol.
To 4-(Z/E-2-penten-3-yl)-O-trifluoromethylsuifonyl-phenol (5.25 g, 17.8
mmol) and O-cresol (7.7 g, 71.4 mmol) in CH2C12 (20 mL) at -20 °C is added
BF3.Et2O (240 µL, 1.9 mmol), and the mixture is allowed to come to RT and stirred
16 h. To the reaction is added ethylene glycol (5 mL), and the CH2Cl2 is evaporated
under vaccum. The residue is vacuum distilled up to 70 °C at 0.116 mm to remove the
excess phenol and ethylene glycol. The residue is partitioned between Et2O (50 mL)
and water (50 mL). The organic layer is washed with water (3 x 50 mL), saturated
brine, Na2SO4 dried, filtered and concentrated. The residue is chromatographed to
give the title compound (3.9 g, 54%).
H-NMR ppm in CDCl3: 7.24 (2H, d, J= 9.0 Hz); 7.14 (2H, d, J= 9.2 Hz); 6.84 (1H,
s); 6.83 (1H, d, J = 8.0 Hz); 6.66 (1H, d, J= 8.0 Hz); 4.70 (1H, s); 2.20 (3H, s); 2.05
(4H, q, J = 7.2 Hz); 0.61 (6H, t, J= 7.2 Hz). LC-MS: 401.1 (M-1).
C. 4-[(1-Ethyl-l-(3-methyl-4-hydroxyphenyl)propyi]-benzoic acid, methyl ester.
Using a procedure analogous to Example IE, from 4-[(l-ethyl-l-(3-methyl-4-
hydroxyphenyl)propyl]-0-trifluoromethylsulfonylphenol (2.5 g, 6.2 mmol) gives the
title compound (1.08 g, 56%).
H-NMR ppm in CDCl3: 7.89 (2H, d, J= 8.0 Hz); 7.23 (2H, d, 7= 8.0 Hz); 6.84 (1H,
s); 6.83 (1H, d,J= 8.2 Hz); 6.65 (1H, d,J= 8.2 Hz); 4.58 (1H, s); 3.89 (3H, s); 2.18
(3H, s); 2.08 (4H, q, J= 7.2 Hz); 0.61 (6H, t, J= 7.2 Hz). LC/MS: 313.1 (M+1), 311.1
(M-1).
Using a procedure analogous to Example 1B, from 4-[(1-ethyl-l-(3-methyl-4-
hydroxyphenyl)propyl]-benzoic acid, methyl ester (0.88 g, 2.81 mmol) gives the title
compound (0.95 g, 2.32 mmol, 95%). 1H NMR (CDCL,), 5 0.61 (t, J= 7.4 Hz, 6H), 1.26
(s, 9H), 2.09 (q, J = 7.4 Hz, 4H), 2.24 (s, 3H), 3.89 (s, 3H), 4.84 (s, 2H), 6.49 (d, 7= 8.8
Hz, 1H), 6.85-6.89 (m, 2H), 7.24 (d, J= 8.4 Hz, 2H), 7.91 (d, J= 9.4 Hz, 2H). ES-MS
(m/z): calcd for C26H38NO4 (M+NH4): 428.6; found: 428.3.
E. 4- {1 -Ethyl-1 -[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl} -benzoic
acid methyl ester.
Using a procedure analogous to Example 1D, from 4-{l-[4-(3,3-dimethyl-2-
oxo-butoxy)-3-methyl-phenyl]-l-ethyl-propyl}-benzoic acid methyl ester (0.94 g, 2.29
mmol) to give the title compound (0.93 g, 2.26 mmol, 99%). 1H NMR (CDCl3), 8
0.62 (t, J= 7.6 Hz, 6H), 1.02 (s, 9H), 2.10 (q, J= 7.6 Hz, 4H), 2.17 (s, 3H), 3.71 (dd,
J= 8.8, 2.9 Hz, 1H), 3.86 (t, J= 8,6 Hz, 1H), 3.90 (s, 3H), 4.09 (dd, J= 9.3, 2.9 Hz,
1H), 6.71 (d, J= 8.3 Hz, 1H), 6.86 (d, J= 2.1 Hz, 1H), 6.92 (d, J= 2.4 Hz, 1H), 6.94
(d, J= 2.6 Hz, 1H), 7.25 (d, J= 8.3 Hz, 1H), 7.91 (d, 7= 8.6 Hz, 2H). ES-MS (m/z):
calcd for C26H37O4 (M+H)+: 413.6; found: 413.3.
F. 4-{l-Ethyl-1-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-propyl}benzoic
acid.
Using a procedure analogous to Example 2, from 4-{l-ethyl-l-[4-(2-hydroxy-
3,3-dimethyl-butoxy)-3-methyl-phenyl3-propyl}-benzoic acid methyl ester (0.93 g,
2.25 mmol) givesthe title compound (0.81 mmol, 2.02 mmol, 90%). 1H NMR
(CDC13), 8 0.63 (t, J= 7.2 Hz, 6H), 1.02 (s, 9H), 2.12 (q, J = 7.2 Hz, 4H), 2.18 (s,
3H), 3.71 (dd, J = 8.7, 2.4 Hz, 1H), 3.86 (t, J= 9.3 Hz, 1H), 4.09 (dd, J= 9.3, 2.4 Hz,
1H), 6.71 (d, J= 8.3 Hz, 1H), 6.87 (d, J= 1.9 Hz, 1H), 6.93 (d, J= 2.4 Hz, 1H), 6.95
(d, J = 2.0 Hz, 1H), 7.28 (d, J= 8.4 Hz, 1H), 7.97 (d, J= 8.8 Hz, 2H). ES-MS (m/z):
calcd for C25H33O4 (M-M) 397.6; found: 397.2.
G. 4-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzoic
acid.
Using a procedure analogous to Example 17, from 4-{1-ethyl-1-[4-(2-hydroxy-
3,3-dimethylbutoxy)-3-methylphenyl]-propyl}benzoic acid (0.31 g, 0.79 mmol) and
Dess-Martin reagent (366 mg, 0.86 mmol) gives the title compound (0.27 g, 0.69
mmol, 88%). %). 1H NMR (CDCl3), 8 0.62 (t, J = 7.0 Hz, 6H), 1.27 (s, 9H), 2.10 (q, J
= 7.0 Hz, 4H), 2.24 (s, 3H), 4.85 (s, 2H), 6.50 (4 J= 9.1 Hz, 1H), 6.85-6.90 (m, 2H),
7.28 (d, J = 8.1 Hz, 2H), 7.96 (d, J= 8.2 Hz, 2H). ES-MS (m/z): calcd for C25H31O4
(M-H)": 395.6; found: 395.2.
Example 22 and 23
Preparation of enantiomer 1 and 2 of 4-{l-Ethyl-l-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-
methylphenyl]-propyl}benzoic acid.
A racemic mixture of 4-{l-ethyl-1-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-
methylphenyl]-propyl}benzoic acid (500 mg) is chromatographed (CHIRALPAK AD
column, Heptane, 90 %; EtOH, 9.5%, CH3OH, 0.5%, TFA, 0.1%) to give enantiomer 1 (rt
= 7.4 m), Example 22 (231 mg, 46%) and enantiomer 2 (rt = 9.4 m), Example 23 (230
mg, 46%).
Example 22, (Enantiomer 1):
rt = 7.4 m
NMR & LC/MS: Identical to the racemic material, Example 21F.
Example 23, (Enantiomer 2)
rt = 9.4m
NMR & LC/MS: Identical to the racemic material, Example 21F.
Example 24
Preparation of (4- {1-ethyl-1-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-
propyl}-2-methylbenzoylamino)acetic acid.
A. Methyl (4-{l-emyl-l-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl] propyl}-2-
methylbenzoylamino)acetate.
Using a procedure analogous to Example 5, from 4-(1-{4-[2-(hydroxy)-3,3-
dimethyl-butoxy]-3-meth5iphenyl}-1-ethylpropyl)-2-methylbenzoic acid (0.50 g, 1.22
mmol) and glycine methyl ester hydrochloride (0.15 g, 1.22 mmol) give the title
compound (0.587 g, 1.21 mmol, 99%).
1H NMR (CDC13), 5 0.62 (t, 7= 7.5 Hz, 6H), 1.03 (s, 9H), 2.07 (q, 7= 7.5 Hz, 4H), 2.19
(s, 3H), 2.43 (s, 3H), 3.71 (dd, 7= 8.8, 2.9 Hz, 1H), 3.80 (s, 3H), 3.87 (t, 7= 8.8 Hz, 1H),
4.08-4.12(m, 1H), 4.24 (d, 7= 5.4 Hz, 1H), 6.26(t,7= 5.4Hz, 1H), 6.71 (d,7=8.8 Hz,
1H), 6.88 (d, 7= 2.0 Hz, 1H), 6.94 (dd, 7= 8.5,2.5 Hz, 1H), 6.99-7.04 (m, 2H), 7.32 (d, 7
= 7.8 Hz, 1H). ES-MS (m/z): calcd for C29H42NO5 (M + H)+: 484.7; found: 484.2.
B. (4-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-propyl}-2-
methylbenzoylamino)acetic acid.
A mixture of methyl (4-{l-ethyl-l-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-
methylphenyl]propyl}-2-methylbenzoylamino)acetate (0.43 g, 0.89 mmol), CH3OH (10
ml), NaOH (0.18 g, 4.46 mmol), and H2O (1mL) is refluxed for 2 h. The reaction is
concentrated, diluted with H2O (5 ml), acidified (pH 3-4) with 0.1 M HC1 and extracted
with EtOAc (3x15 mL). The combined organic layers are MgSO4 dried, and
concentrated to give the title compound (0.29 g, 71%).
1H NMR (CD3OD), 5 0.66 (t, 7= 7.2 Hz, 6H), 1.05 (s, 9H), 2.15 (q, J= 7.2 Hz, 4H), 2.20
(s, 3H), 2.42 (s, 3H), 3.63-3.68 (m, 1H), 3.91 (dd, 7= 10.0, 7.8 Hz, 1H), 4.09 (s, 2H), 4.16
(dd,J= 10.0,2.9 Hz, 1H), 6.81 (d, J= 9.3 Hz, 1H), 6.86 (d, J= 2.1 Hz, 1H), 7.02 (dd, J=
8.4,2.1 Hz, 1H), 7.09 (s, 1H), 7.11 (s, 1H), 7.37 (d,7= 8.1 Hz, 1H). ES-MS (m/z): calcd
for C28H40NO5 (M + H)+: 470.6; found: 470.2.
Example 25A and Example 25B
Preparation of enantiomer 1 and 2 of (4-{l-ethyi-l-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-
methyIphenyl]-propyI}-2-methylbenzoylamino)acetic acid.
(Enantiomer 1)
(Enantiomer 2)
A racemic mixture of (4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-
methylphenyl]-propyi}-2-methyibenzoylamino)acetic acid (0.217 g), Example 24, is
chromatographed (HPLC: CbiralPak AD, 0.1% TFA in 0.75:14.25:85
CH3OH:EtOH:Hept) to give enantiomer 1 (80.6 mg, 37%, rt = 8.0 m) and enantiomer 2
(81.1 mg, 37%, rt= 10.1m).
(Enantiomer 1), Example 25A:
HPLC: ChiralPak AD (4.6 X 250 mm); 0.1% TFA in 0.75:14.25:85 CH3OH:EtOH:Hept;
1.0 mL/m (flow rate); rt = 8.0 m; @ 280 nm; 97.8% ee.
NMR & LC/MS: equivalent to the racemate, Example 24.
(Enantiomer 2), Example 25B:
HPLC: ChiralPac AD (4.6 X 250 mm); 0.1% TFA in 0.75:14.25:85 CH3OH:EtOH:Hept;
1.0 mL/m (flow rate); rt = 10.1 m; @ 280 nm; 95.2% ee.
NMR & LC/MS: equivalent to the racemate,^Example 24.
Example 26
Preparation enantiomer 1 of 3'-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3'-
[4-(tetrazol-5-ylaminocarbonyl)-3-methylphenyl]pentane.
Using a procedure analogous to Example 5, enantiomer 1 of 3'-[4-(2-hydroxy-3,3-
dimethylbutoxy)-3-methylphenyl]-3'-[4-carboxyl-3-methylphenyl]pentane and 5-
aminotetrazole give the title compound (440 mg, 95%).
NMR 300 mHz (DMSO): 0.57 (t, J = 7.3 Hz, 6H), 0.92 (s, 9H), 2.09 (m, 7H), 2.40 (s,
3H), 3.46 (m, 1H), 3.76 (dd, J = 7.3,10.2 Hz, 1H), 4.03 (dd, J = 3.3,10.2 Hz, 1H),
4.79 (d, J = 5.5 Hz, 1H), 6.83 (d, J = 8.4 Hz, 1H), 6.89 (s, 1H), 6.95 (d, J = 8.4 Hz,
1H), 7.08 (d, J = 8.1 Hz, 1H), 7.12 (s, 1H), 7.52 (d, J = 8.1 Hz, 1H), 12.23 (s, 1H),
16.00 (brs, 1H).
High Res. ES-MS: 480.2983; calc. for C27H37N5O3+H: 480.2975.
Example 27
Preparation enantiomer 2 of 3'-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3'-
[4-(tetrazol-5-ylaminocarbonyl)-3-methylphenyl]pentane.
(enantiomer 2)
Using a procedure analogous to Example 5, enantiomer 2 of 3'-[4-(2-hydroxy-3,3-
dimethylbutoxy)-3-methylphenyl]-3 '-[4-carboxyl-3-methylphenyl]pentane and 5-
aminotetrazole gives the title compound (385 mg, 83%).
NMR 300 mHz (DMSO): eq. to enantiomer of 1.
High Res. ES-MS: 480.2968; calc. for C27H37N5O3+H: 480.2975.
Preparation of 4- {1 -Ethyl-1 -[4-(2-hydroxy-1,3,3-trimethyl-butoxy)-3-methyl-phenyl]-
propyl}-2-methyl-benzoic acid.
Using a procedure analogous to Example 2, from racemic 4-{l-ethyl-l-[4-(2-
hydroxy-1,3,3-trimethyl-butoxy)-3-methyl-phenyl]-propyl} -2-methyl-benzoic acid methyl
ester, Example 10C, (4.70 g, 10.68 mmol) gives the title compound (2.93 g, 6.87 mmol,
64%).
1H NMR and ES-MS: equivalent to the pure enantiomer 1, Example 11.
Example 29
Preparation enantiomer 1 of 3'-[4-(2-hydroxy-l,3,3-trimethylbutoxy)-3-methylphenyl]-3'-
[4-(tetrazol-5-ylaminocarbonyl)-3-methylphenyi]pentane.
Using a procedure analogous to Example 5, enantiomer 1 of 3'-[4-(2-hydroxy-
1,3,3-trimethylbutoxy)-.3-methylphenyl]-3'-[4-arboxyl-3-methylphenyl]pentane,
Example 11, and 5-aminotetrazole give the title compound (125 mg, 72%).
1H NMR 400 MHz (DMSO-d6): 5 0.57 (t, J = 7.3 Hz, 6H), 0.91 (s, 9H), 1.20 (d, J = 6.3
Hz, 3H), 2.07 (m, 7H), 2.41 (s, 3H), 3.07 (br s, 1H), 4.37 (br s, 1H), 4.57 (q, J = 5.8,1H),
6.87 (m, 3H), 7.06 (d, J = 7.8 Hz, lH), 7.15 (s, 1H), 7.50 (d, J = 7.8 Hz, 1H), 12.24 (s,
1H), 16.0 (s, 1H).
High Res ES(+)MS m/z: 494.3127; calc. for C28H39N5O3 + H: 494.3131
Example 30
Preparation enantiomer 2 of 3'-[4-(2-hydroxy-l,3,3-trimethylbutoxy)-3-methylphenyl]-3'-
[4-(tetrazol-5-ylaminocarbonyl)-3-methylphenyl]pentane.
Using a procedure analogous to Example 5, enantiomer 2 of 3'-[4-(2-hydroxy-
1,3,3-trimethylbutoxy)-3-methylphenyl]-3'-[4-carboxyl-3-methylphenyl]pentane,
Example 12, and 5-aminotetrazole give the title compound (150 mg, 74%).
High Res ES(+)MS m/z: 494.3144; calc. for C28H39N5O3 + H: 494.3131
Example 31
Preparation enantiomer 1 of 3'-[4-(2-hydroxy-l,3.3-trimethylbutoxy>3-methylphenyl]-3'-
[4-(carboxymethylarminocarbonyl)-3-methylphenyl]peotane.
A. Enantiomer 1 of 3'-[4-(2-hydroxy-1,3,3-trimethylbutoxy)-3-methylphenyl]-3'-[4-
(methoxycarbonylmethylaminocarbonyl)-3-methylphenyl]pentane.
Using a procedure analogous to Example 5, enantiomer 1 of 3'-[4-(2-hydroxy-
1,3,3-trimethylbutoxy)-3-methylphenyl]-3'-[4-carboxyi-3-methylphenyl]pentane, methyl
glycinate hydrochloride, and DMAP (2.5 eq) give the title compound (150 mg, 86%).
1H NMR 400 MHz (DMSO-d6): 8 0.55 (t, J = 7.3 Hz, 6H), 0.91 (s, 9H), 1.20 (d, J = 5.9
Hz, 3H), 1.98-2.07 (m, 7H), 2.32 (s, 3H), 3.07 (s, 1H), 3.65 (s, 3H), 3.93(d, J = 6.3 Hz,
2H), 4.36 (br s, 1H), 4.55 (q, J = 7.2 Hz, 1H), 6.80-6.84 (m, 2H), 6.89 (d, J = 8.3 Hz, 1H),
7.00 (d, J = 7.8 Hz, 1H), 7.05 (s, 1H), 7.24 (d, J = 8.3 Hz, 1H), 8.61 (t, J = 5.9 Hz, 1H).
High Res ES(+)MS m/z: 498.3224; calc. for C30H43NO5 + H: 498.3219.
B. Enantiomer 1 of 3'-[4-(2-hydroxy-1,3,3-trimethylbutoxy)-3-methylphenyl]-3'-[4-
(carboxymethylaminocarbonyl)-3-metbylphenyl]pentane.
Using a procedure analogous to Example 2 but reacted at RT, enantiomer 1 of 3'-
[4-(2-hydroxy-1,3,3-trimethylbutoxy)-3-methylphenyl]-3'-[4-
(methoxycaxbonylmethyiaminocarbonyl)-3-methylphenyl]pentane gives the title
compound (130 mg, 99%).
1H NMR 400 MHz (DMSO-d6): d 0.55 (t, J = 7.3 Hz, 6H), 0.91 (s, 9H), 1.20 (d, J = 5.9
Hz, 3H), 1.98-2.07 (m, 7H), 2.32 (s, 3H), 3.07 (s, 1H), 3.84 (d, J = 5.8 Hz, 2H), 4.37 (br s,
1H), 4.56(q, J = 6.3 Hz, 1H), 6.80-6.84 (m, 2H), 6.89 (dd, J = 2.4, J = 8.3 Hz, 1H), 7.00
(d, J = 8.3 Hz, 1H), 7.04 (s, 1H), 7.25 (d, J = 7.8 Hz, 1H), 8.48 (t, J = 5.9 Hz, 1H)
High Res ES(+)MS m/z: 484.3041; calc. for C29H41NO5 + H: 484.3063
Example 32
Preparation enantiomer 2 of 3'-[4-(2-hydroxy-l,3,3-trimethylbutoxy)-3-methylphenyl]-3'-
[4-(carboxymethylaminocarbonyl)-3-methylphenyl]pentane.
A. Enantiomer 2 of 3'-[4-(2-hydroxy-1,3,3-trimethylbutoxy)-3-methylphenyl]-3'-[4-
(methoxycarbonylmethylaminocarbonyl)-3-methylphenyl]pentane.
Using a procedure analogous to Example 5, enantiomer 2 of 3'-[4-(2-hydroxy-
1,3,3-trimethylbutoxy)-3-methylphenyl]-3'-[4rcarboxyl-3-methylphenyl]pentane, methyl
glycinate hydrochloride, and DMAP (2.5 eq) give the title compound (160 mg, 78%).
NMR equivalent to Example 31A.
High Res ES(+)MS m/z: 498.3200; calc. for C30H43NO5 + H: 498.3219
B. Enantiomer 2 of 3'-[4-(2-hydroxy-l,3,3-trimethylbutoxy)-3-methylphenyl]-3'-[4-
(carboxymemylaminocarbonyl)-3-methyiphenyl]pentane.
Using a procedure analogous to Example 2 but reacted at RT, enantiomer 2 of 3'-
[4-(2-hydroxy-l,3,3-trimethylbutoxy)-3-methylphenyl]-3'-[4-
(methoxycarbonylmethylanimocarbonyl)-3-methylphenyl]pentane gives the title
compound (145 mg, quant).
NMR equivalent to Example 31B.
High Res ES(+)MS m/z: 484.3080; calc. for C29H41NO5 + H: 484.3063
Example 33
Preparation of enantiomer 1 of (4-{l-ethyi-l-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-
methyl-phenyl]-propyl}-2-methyl-benzyloxy)-acetic acid.
A. Enantiomer 1 of 4(1-{4-[2-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-butoxy]-3-
methyl-phenyl}-1-ethyl-propyl)-2-methyl-benzoic acid methyl ester.
(enantiomer 1)
Using a procedure analogous to Example 13 A, from enantiomer 1 of 4-{1-ethyl-1-
[4-(2-hydroxy-33-dimethyl-butoxy)-3-metfayl-phenyl]-propyl}-2-methyl-benzoic acid
methyl ester (1.90 g, 4.45 mmol to furnish the title compound (2.40 g, 4.45 mmol, >99%).
1H NMR & ES-MS: equivalent to (Example 13A).
B. Enantiomer 1 of [4-(l-{4-[2-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-butoxy]-3-
methyl-phenyl}-1-ethyl-propyl)-2-methyl-phenyl]-methanol.
Using a procedure analogous to 13B, from enantiomer 1 of 4-(l-{4-[2-(tert-butyl-
dimethyl-silanyloxy)-3,3-dimethyl-butoxy]-3-methyl-phenyl}-l-ethyl-propyl)-2-methyl-
benzoic acid methyl ester (2.40 g, 4.45 mmol) to furnish the title compound (2.10 g, 4.09
mmol, 91%).
1H NMR & ES-MS: equivalent to (Example 13B).
C. [4-(l-{4-[2-(tert-Butyl-dimethyl-silanyioxy)-3,3-dimethyl-butoxy]-3-methyl-phenyl}-
1-ethyl-propyl)-2-methyl-benzyloxy]-acetic acid methyl ester.
To a solution of enantiomer 1 of [4-(l-{4-[2-(tert-butyl-dimethyl-silanyloxy)-3,3-
dimethyl-butoxy]-3-methyl-phenyl}-1-ethyl-propyl)-2-memyl-phenyl]-methanol, (2.10 g,
4.10 mmol) and PhCH3 (10 mL) is added methyl glycolate (6.5 mL, 81.89 mmol) and
MeReO3 (0.02 g, 0.082 mmol). The solution is heated at a reflux for 2 hours with the use
of a Dean-Stark trap. The solution is concentrated and chromatographed to give the title
compound (0.96 g, 1.64 mmol, 40%).
1H NMR (CDCl3), 8 0.06 (s, 3H), 0.11 (s, 3H), 0.61 (t, J= 7.3 Hz, 6H), 0.90 (s, 9H), 0.97
(s, 9H), 2.05 (q, J= 7.3 Hz, 4H), 2.18 (s, 3H), 2.33 (s, 3H), 3.67 (dd, J= 5.7, 3.2 Hz, 1H),
3.77 (s, 3H), 3.85 (dd, J= 9.7, 5.7 Hz, 1H), 3.98 (dd, J= 9.7, 3.5 Hz, 1H), 4.12 (s, 2H),
4.60 (s, 2H), 6.65 (d, J= 8.4 Hz, 1H), 6.87 (d, J= 2.1 Hz, 1H), 6.92 (dd, J= 8.4, 2.6 Hz,
1H), 6.97-7.01 (m, 2H), 7.17 (d, J= 8.4 Hz, 1H). ).
D. Enantiomer 1 of (4-{l-ethyl-l-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-
propyl} -2-methyl-benzyloxy)-acetic acid.
To a solution of enantiomer 1 of [4-(l-{4-[2-(tert-butyl-dimethyl-silanyloxy)-3,3-
dimethyl-butoxy]-3-methyl-phenyl}-l-ethyl-propyl)-2-methyl-benzyloxy]-acetic acid
methyl ester (0.96 g, 1.64 mmol) and THF (10 mL) is added 1M TBAF (3.3 mL, 3.28
mmol). The solution is heated at a reflux overnight and concentrated. The residue is
dissolved in MeOH (5 mL) and water (1 mL), NaOH (0.33 g, 8.21 mmol) is added and the
solution is heated at reflux for 3 hours. The solution is concentration, dissolved in EtOAc
(20 mL), washed with 1M HC1 (15 mL), water (15 mL), brine (15 mL), dried over
MgSO4, and concentrated. The residue is chromatographed to furnish the title compound
(0.45 g, 0.99 mmol, 60%).
1H NMR (CDCl3), 8 0.60 (t, J= 7.3 Hz, 6H), 1.02 (s, 9H), 2.05 (q, J= 7.3 Hz, 4H), 2.17
(s, 3H), 2.31 (s, 3H), 3.71 (dd, J= 8.8, 2.6 Hz, 1H), 3.86 (t, J = 8.8 Hz, 1H), 4.09 (dd, J =
8.8,2.6 Hz, 1H), 4.13 (s, 2H), 4.62 (s, 2H), 6.70 (d, J= 8.3 Hz, 1H), 6.90-7.02 (m, 4H),
7.16 (d, J=7.5 Hz, 1H).
ES-MS (m/z): calcd. for C28H41O6 (M-H)-: 455.6; found: 455.2.
Example 34
Preparation of epimer 1 of D-2-(4-{1-ethyl-l-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-
methyl-phenyl]-propyl} -2-methyl-benzoylamino)-propionic acid.
A. Epimer 1 of D-2-(4-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-
propyl}-2-methyl-benzoylamino)-propionic acid methyl ester.
(D-Epimer 1)
Using a procedure analogous to Example 5, from enantiomer 1 of 4-{1-ethyl-1-[4-
(2-hydroxy-3,3-dimethyl-butoxy)-3-methyi-phenyl]-propyl} -2-methyl-benzoic acid (0.40
g, 0.97 mmol) and D-alanine methyl ester hydrochloride (0.15 g, 1.07 mmol) to furnish
the title compound (0.36 g, 0.72 mmol, 75%).
1H NMR (CDCl3), 8 0.60 (t, J= 7.2 Hz, 6H), 1.00 (s, 9H), 1.49 (d, J= 7.1 Hz, 3H), 2.05
(q, J= 7.2 Hz, 4H), 2.17 (s, 3H), 2.40 (s, 3H), 3.69 (dd, J= 8.5, 2.7 Hz, 1H), 3.76 (s, 3H),
3.84 (t,J= 9.1 Hz, 1H),4.07 (dd, J= 9.1,2.5 Hz, 1H), 4.72-4.81 (m, 1H), 6.42 (d, J= 7.9
Hz, 1H), 6.68 (d, J= 8.4 Hz, lH)i 6.84 (d, J= 2.4 Hz, 1H), 6.92 (dd, J = 8.4, 2.4 Hz, 1H),
6.96-7.01 (m, 2H), 7.28 (d, J= 8.1 Hz, 1H).
ES-MS (m/z): calcd. for C30H44NO5 (M+H)+: 498.3; found: 498.3.
B. Epimer 1 of Z)-2-(4-{l-Ethyl-l-[4-(2-hydroxy-3,3-dimefliyl-butoxy)-3-methyl-phenyl]-
propyl} -2-methyl-benzoylamino)-propionic acid.
Using a procedure analogous to Example 2, from epimer 1 of D-2-(4-{l-ethyl-l-
[4-(2-hydroxy-3,3-dimemyl-butoxy)-3-memyl-phenyl]-propyl}-2-memyl-beriz»ylainino)-
propionic acid methyl ester (0.36 g, 0.72 mmol) to furnish the titled compound (0.31 g,
0.64 mmol, 89 %).
1H NMR (CDCl3), 8 0.60 (t, J= 7.5 Hz, 6H), 1.01 (s, 9H), 1.50 (d, J = 7.3 Hz, 3H), 2.05
(q, J= 7.5 Hz, 4H), 2.17 (s, 3H), 2.41 (s, 3H), 3.71 (dd,J= 8.4,2.5 Hz, 1H), 3.85 (t, J =
8.9 Hz, 1H), 4.09 (dd, J = 9.3,2.7 Hz, 1H), 4.74-4.83 (m, 1H), 6.33 (d, J= 7.8 Hz, 1H),
6.70 (d, J = 8.5 Hz, 1H), 6.85 (d, J= 2.2 Hz, 1H), 6.93 (dd, J= 8.2, 2.2 Hz), 6.98-7.03 (m,
1H), 7.01 (s, 1H), 7.30 (d, J= 8.0 Hz, 1H).
ES-MS (m/z): calcd for C29H42NO5 (M+H)+: 484.3; found: 484.3.
Example 35.
Preparation of racemic 3'-[3-chloro-4-(2-hydroxy-3,3-dimethylbutoxy)phenyl]-3'-[4-
carboxyphenyl]pentane.
To a solution of methyl 3-chloro-4-hydroxybenzoate (25.0 g, 133 mmol) in THF
(250 mL) is added dropwise 1.0 M ethylmagnesium bromide/THF (442 mL, 442 mmol) at
a rate maintaining the temperature below 27 °C. The brownish grey reaction is stirred for
72 h. The reaction mixture is cooled in an ice bath and quenched with satd ammonium
chloride (1 ml portions) until evolution of ethane subsides. Additional satd NH4C1
solution is added (total of 50mL) and the mixture is concentrated to remove most of the
THF. The residue is added to water and ether, filtered through diatomaceous earth, and
partitioned. The organic layer is washed with brine (3 X), MgSO4 dried, and
concentrated to give the title compound (28.6 g, 99%).
H-NMR (300 mHz, CDC13): 8 7.38 (1H, d, J = 1.6 Hz), 7.07 (1H, dd, J = 8.4 Hz, J = 1.6
Hz), 6.95 (1H, d, J = 8.4 Hz), 5.53 (1H, br s), 1.80 (4H, m), 0.76 (6H, t, J = 7.6 Hz).
IR (CHC13): 3600 cm-1,3540 cm-1.
El (+) TOF MS: Observed m/z 214.076; Calc. m/z. 214.0761
B. [E, Z]-3-(3-Chloro-4-hydroxyphenyl)-3-pentene
A mixture of 3-(3-chloro-4-hydroxyphenyl)-3-pentanol (10.0 g, 46.5 mmol),
pTSA monohydrate (20 mg, catalytic amount), and toluene (300 mL) is heated on a
steam bath for 3 h. Analysis by TLC indicates the loss of starting material and
formation of a much less polar compound. The toluene solution is cooled to RT,
washed with satd sodium carbonate solution (25 mL), MgSO4 dried, and concentrated
to give the title compounds as a [E:Z] isomeric mixture of [85:15] (9.2 g, quant).
TLC (CHC13): Rf-0.7
H-NMR (300 mHz, DMSO-d6): 6 6.85-7.30 (3H, m), 5.65 (0.85H, q, J = 6.8 Hz),
5.43 (0.15H, q, J = 6.8 Hz), 2.43( (1.7H, q, J = 7.6 Hz), 2.28 (0.3H, q, J = 7.6 Hz),
1.72 (2.55H, d, J = 7.6 Hz), 1.52 (0.45H, d, J = 7.6 Hz), 0.90 (2.55H, t, J = 7.6 Hz)
0.85 (0.45H, t, J = 7.6 Hz)
C. [E,Z]-3-[3-Chloro-4-(2-oxo-3,3-dimethylbutoxy)phenyl]-3-pentene
A mixture of [E,Z]-3-(3-chloro-4-hydroxyphenyl)-3-pentene (4.00 g, 20.3 mmol)
and 1-chloropinacolone (2.73 g, 20.3 mmol), anhydrous KI (0.17 g, 1.0 mmol), K2CO3
(14.0 g, 102 mmol) and acetonitrile (80 mL) is refluxed for 3 h. The reaction is cooled
to RT and concentrated. The residue is partitioned between methylene chloride ( 50 mL)
and ice water (50 mL). The organic layer is MgSO4 dried, concentrated, and
chromatographed (40% to 70% chloroform in hexane) to give the title compounds as an
85 : 15 [E. Z] mixture (5.07 g, 85%).
H-NMR (300 mHz, DMSO-d6): d 7.37 (0.85H, d, J = 2.1 Hz), 7.22 (0.85H, dd, J=2.1, J =
8.6 Hz), 7.18 (0.15H, d, J = 2.1 Hz), 7.03 (0.15H, dd, J = 2.0 Hz, J = 8.4 Hz), 6.88
(0.15H, d, J = 8.4 Hz), 6.85 (0.85H, d, J = 8.6 Hz), 5.71 (0.85H, m), 5.52 (0.15H, m), 5.25
(2H, s), 2.45 (1.70H, q, J = 7.6 Hz), 2.30 (0.30H, q, J = 7.6 Hz), 1.75 (2.55H, d, J = 7.6
Hz), 1.53 (0.45H, d, J = 7.6 Hz), 1.17 (9H, s), 0.91 (2.55H, t, J = 7.6 Hz), ,0.88 (0.45H, t,
J = 7.6Hz).
El (+) TOF MS: Observed m/z 294.139; Calc. m/z 294.1387.
D. 3 '-[3-ChIoro-4-(2-oxo-3.3-dimethylbutoxy)phenyl]-3 '-(4-hydroxyphenyl)pentane.
A -20 °C solution of [E,Z]-3-[3-chloro-4-(2-oxo-3,3-dimethylbutoxy)phenyl]-3-
pentene ( 4.5 g, 15.2 mrnol), phenol (17.2 g, 183 mmol) and methylene chloride (30 mL)
is treated with BF3-etherate (0.863 g, 6.1 mmol) and stirred for 30 m while maintaining
the temperature near -20 °C. The resulting light reddish brown solution is allowed to
warm to 0 °C and kept at that temperature for 16 h. The reaction is distilled at 45 °C/0.04
mm to remove most of the excess phenol. The residue is treated with powderized
NaHCO3 (600 mg), ethylene glycol (15 ml), and distilled to remove the last of the phenol
and almost all of the glycol. The resulting viscous tan oily residue is cooled to RT and
distributed between sat NaHCO3 (25 mL) and ethyl acetate ( 200 mL). The organic layer
is separated, washed with water (5 x 50 mL), Na2SO4 dried, and concentrated to give the
title compound as an oil (5.8 g, 98%).
H-NMR (300 mHz, CDC13): 7.21 (1H, d, J = 2.3 Hz), 6.99 (2H, d, J = 8.7 Hz), 6.95 (1H,
dd, J = 2.3 Hz, J = 8.6 Hz), 6.75 (2H, d, J = 8.7 Hz), 6.62 (1H, d, J = 8.6 Hz), 4.91 (2H,
s), 4.86 (1H, s), 2.02 (4H, q, J = 7.3 Hz), 1.28 (9H, s), 0.62 (6H, t, J = 7.3 Hz).
ES(+) MS m/z: 389.3 [M+H]; calc. m/z 389.1883 [M+H].
E. 3'-[3-chloro-4-(2-oxo-3.3-dimethylbutoxy)]-3 '-(4-
trifluoromethylsulfonyloxyphenyl)pentane.
Using a procedure analogous to Example 1C with isopropyldiethylamine as the base,
allowing the reaction to warm from 0 to RT overnight, and with potassium phosphate
monobasic/sodium hydroxide buffer quench, 3'-[3-chloro-4-(2-oxo-3.3-
dimethylbutoxy)phenyl]-3'-(4-hydroxyphenyl)pentane and triflic anhydride give the
title compound as a colorless oil (3.7g, 69%).
H-NMR (300 mHz, DMSO-D6): 8 7.40 (2H, d, J = 8.7 Hz), 7.33 (2H, d, J = 8.7 Hz), 7.15
(1H, d, J = 2.1 Hz), 6.98 (1H, dd, J = 2.1 Hz, J = 8.6 Hz), 6.78 (2H, d, J = 8.6 Hz), 5.22
(2H, s), 2.07 (4H, q, J = 7.3 Hz), 1.17 (9H, s), 0.55 (6H, t, J = 7.3 Hz).
FAB+ MS m/z: 521.0 [M+H]; calc. 521.1376 [M+H].
ES MS: 521.3 [M+1], 538.3 [M+NH4], 543.2 [M+Na].
F. 3'-[4-(2-oxo-3,3-trimethylbutoxy)-3-chloro-phenyl]-3'-4-carbomethoxyphenyl)-
pentane.
To 3 '-[4-(2-oxo-3,3-dimethylbutoxy)-3-chlorophenyl]-3'-(4-trifluoromethyl-
sulfonyloxy-phenyl)-pentane (3.7 g 7.1 mmol), palladium acetate (64 mg, 0.28 mmol),
dppf (315 mg, 0.28 mmol), and triethylamine (4 mL) are heated in the absence of air
under an atmosphere of carbon monoxide (initial 100 psig) in DMF (20 mL) and
methanol (2 mL) at 110 °C for 48 h. The reaction mixture is cooled to room temperature,
vented, and filtered. The filtrate is partitioned between EtOAc and water. The organic
phase is washed 3 times with water, once with sat brine, dried over anhydrous Na2SO4,
and concentrated under vacuum. The residue is chromatographed on 10 g silica gel with
8% EtOAc in hexanes to give the title compound (1.12 g, 37%).
H-NMR (400 mHz, CDC13): 8 7.91 (2H, d, J = 8.8 Hz), 7.21 (2H, d, J = 8.8 Hz), 7.16
(1H, s), 6.88 (1H, d, J = 8.8 Hz), 6.59 (1H, d, J = 8.8 Hz), 4.90 (2H, s), 3.89 (3H, s), 2.07
(4H, q, J = 7.2 Hz), 1.25 (9H, s), 0.61 (6H, t, J = 7.2 Hz).
FAB(+) MS m/z [M]: 431.1; calc. m/z431.3.
ES (+) MS: m/z 431.3 [M+H], 448.3 [M+NH4].
G. Racemic 3'-[3-chloro-4-(2-hydroxy-3,3-dimethylbutoxy)phenyl]-3'-[4-
carbomethoxyphenyl]pentane.
A solution of 3'-[4-(2-oxo-3,3-trimethylbutoxy)-3-chloro-phenyl]-3'-(4-
methoxycarbonyl-phenyi)-pentane (0.825 g, 1.91 mmol) in MeOH (10 mL) under a N2
atmosphere is cooled to 0°C. Sodium borohydride (0.076g, 2.01 mmol) is added in one
portion and the reaction mixture is stirred for 15 minutes. Acetone (1 mL) followed by
potassium phosphate monobasic/sodium hydroxide buffer (3 mL) are added and the
resulting mixture is concentrated to remove most of the MeOH. The residue is distributed
into water and CH2C12 and the organic layer is separated and dried over anhydrous
MgSO4. The desired product is obtained as a colorless oil, (0.816 g, 98.5%).
H-NMR (300 mHz, CDC13): 8 7.92 (2H, d, J = 8.8 Hz), 7.22 (2H, m), 7.15 (1H, d, J =
2.3), 6.93 (1H, dd, J = 2.3 Hz, J = 8.8 Hz), 6.84 (1H, d, J = 8.8 Hz), 4.17 (1H, dd, J = 2.6
Hz, J = 9.0 Hz), 3.89 (s, 3H), 3.87 (t, J = 8.9 Hz,), 3.62 (1H, dt, J = 2.6, J = 8.9, J = 3.0),
2.60, (1H, d, J = 3.0 Hz), 2.09 (4H, q, J = 7.3 Hz), 1.01 (9H, s), 0.61 (6H, t, J = 7.3 Hz).
FAB(+) MS m/z [M]: 432.2; calc. for C25H33ClO4: m/z 432.2.
IR(CHC13): 1718 cm-1
H. Racemic 3'-[3-chloro-4-(2-hydroxy-3,3-dimethylbutoxy)phenyl]-3'-[4-
carboxyphenyl]pentane, sodium salt
The methyl ester of 3'-[3-chloro-4-(2-hydroxy-3,3-dimethyl-butoxy)phenyl]-
3'-[4-(carboxy)phenyl]pentane (0.600 g, 1.38 mmol) and 2N NaOH (3.46 mL, 6.93
mmol) are refluxed in EtOH (15mL) under a N2 atmosphere for 1 h. TLC (SiO2;
CHC13) shows the loss of the starting material and appearance of a more polar
compound spot near the origin. The reaction is allowed to cool to near RT and
subsequently it is concentrated under reduced pressure to remove EtOH and provide a
white residue. The residue is dissolved in a minimum amount of hot water (approx.
20 mL) and cooled and scratched to provide the desired sodium salt as white crystals
(0.582 g, 96%).
H-NMR (300 mHz, DMSO): 8 7.73 (2H, d, J = 8.7 Hz), 7.00 to 7.06 (5H, m), 4.88 (1H, d,
J = 5.1 Hz), 4.10 (1H, dd, J = 3.0 Hz, J = 10.2 Hz), 3.86 (1H, dd, J = 3.1 Hz, J = 10.2
Hz), 3.47 (1H, m), 2.04 (4H, q, J = 7.3 Hz), 0.92 (9H, s), 0.55 (6H, t, J = 7.3 Hz).
ES (+) MS m/z 436.2 [M+NH4], 441.1 [M+Na]
ES (-) MS m/z 417.2 [M-H].
IR(CHC13):1601 cm-1.
I. Racemic 3'-[3-chloro-4-(2-hydroxy-3,3-dimethylbutoxy)phenyl]-3'-[4-
carboxyphenyl]pentane.
A portion of the above 3'-t3-chloro-4-(2-hydroxy-3,3-dimethyl-
butoxy)phenyl]-3 '-[4-(carboxy)phenyl]pentane, sodium salt (0.182 g, 0.413 mmol) is
dissolved in 50 ml of hot water. After the solution is allowed to cool to near to RT it
is acidified with dropwise addition of 5N HCl. The resulting white precipitate is
collected and washed with ice water and subsequently vacuum dried to provide the
desired free acid (0.169 g, 98%).
H-NMR (300 mHz, DMSO): 5 7.85 (2H, d, J = 8.3 Hz), 7.27 (2H, d, J = 8.3) 7.00 to
7.12 (3H, m), 4.85 (1H, d, J = 5.1 Hz), 4.11 (1H, dd, J = 3.0 Hz, J = 10.2 Hz), 3.87
(1H, dd, J = 3.1 Hz, J = 10.2 Hz), 3.47 (1H, m), 2.08 (4H, q, J = 7.3 Hz), 0.94 (9H, s),
0.56(6H,t,J = 7.3Hz).
ES (+) MS: 436.2 [M+MH4], 441.1 [M+Na]
ES (-) MS: 417.2 [M-1].
IR(CHC13): 1691 cm-1.
Example 36 and 37
Separation of optical isomers of 3'-[3-chloro-4-(2-hydroxy-3,3-
dimethylbutoxy)phenyl]-3'-[4-carboxyphenyl]pentane.
A racemic mixture of the Na salt of 3'-[3-chloro-4-(2-hydroxy-3,3-
dimethyIbutoxy)phenyl]-3'-4-carboxyphenyl)pentane (350 mg) is chromatographed
with a Chiralpak AD column to give enantiomer 1, Example 36 (120 mg, 36%) and
enantiomer 2, Example 37 (117 mg, 35%).
Example 36, Enantiomer 1
HPLC: Chiralpak AD (4.6 X 150 mm); 100% 3A Alcohol; 0.6 mL/m (flow rate); rt =
7.3 m; 240 nm; ee 99.7% by HPLC.
H-NMR (300 mHz, DMSO): 8 7.85 (2H, d, J = 8.3 Hz), 7.27 (2H, d, J = 8.3) 7.00 to
7.12 (3H, m), 4.85 (1H, d, J = 5.1 Hz), 4.11 (1H, dd, J = 3.0 Hz, J = 10.2 Hz), 3.87
(1H, dd, J = 3.1 Hz, J = 10.2 Hz), 3.47 (1H, m), 2.08 (4H, q, J = 7.3 Hz), 0.94 (9H, s),
0.56(6H,t,J = 7.3 Hz).
ES (+) MS: 436.2 [M+NH4], 441.1 [M+Na]
ES(-) MS: 417.2 [M-1].
Example 37, Enantiomer 2
HPLC: Chiralpak AD (4.6 X 150 mm); 100% 3A Alcohol; 0.6 mL/m (flow rate); rt =
10.5 m; 240 nm; ee 99.0% by HPLC.
H-NMR (300 mHz, DMSO): 5 7.85 (2H, d, J = 8.3 Hz), 7.27 (2H, d, J = 8.3) 7.00 to
7.12 (3H, m), 4.85 (1H, d, J = 5.1 Hz),4.11 (1H, dd, J = 3.0 Hz, J= 10.2 Hz), 3.87
(1H, dd, J = 3.1 Hz, J = 10.2 Hz), 3.47 (1H, m), 2.08 (4H, q, J = 7.3 Hz), 0.94 (9H, s),
0.56(6H,t,J = 7.3Hz).
ES (+) MS: 436.2 [M+NH4], 441.1 [M+Na]
ES(-) MS: 417.2 [M-1].
Example 38
Preparation of racemic 3'-[3-chloro-4-(2-hydroxy-3,3-dimethylbutoxy)phenyl]-3'-[3-
mcthyl-4-(carboxy)phenyl]pentane.
Using a procedure analogous to Example 1C, [E, Z]-3-(3-chloro-4-
hydroxyphenyl)-3-pentene, triflic anhydride, and diisopropylethylamine are reacted at
RT for 3 h to give the title compound as a yellow oil in a [E:Z] ratio of 9:1 (16.7 g,
98%). Chromatography over silica gel using 10% chloroform in hexane as the eluent
provided 11.72 g (71.%) of purified material.
H-NMR (300 mHz, CDC13): d 7.01-7.39 (3H, m), 5.70 (0.9H, q, J = 6.9 Hz), 5.53
(0.1H, q, J = 6.9 Hz), 2.41( (1.8H, q, J = 7.6 Hz), 2.24 (0.2H, q, J = 7.6 Hz), 1.74
(2.7H, d, J = 7.6 Hz), 1.48 (0.3H, d, J = 7.6 Hz), 0.91 (2.7H, t, J = 7.6 Hz) ), 0.89
(0.3H,t,J = 7.6Hz).
ES GC MSm/z 328.0; Calc. for C12H12C1F3O3S m/z 328.0148.
B. 3'-(4-hydroxy-3-methylphenyl)-3'-[3-chloro-4-(trifluoromethylsulfonyloxy)-
phenyl]pentane.
Using a procedure analogous to Example 35D, [E,Z]-3-[3-chloro-4-
(trifluoromethylsulfonyIoxy)phenyl]-3-pentene and o-cresol are reacted at RT overnight to
give the title compound as a pale tan oil (4.29g, 38%).
H-NMR (300 mHz, CDC13): 6.5 to 7.3 (6H, m) 4.57 (lH,s), 2.21 (3H, s), 2.05 (4H, q, J =
7.3Hz),0.62(6H,t,J=7.3Hz).
ES (-) MS m/z 435.1 [M-H].
C. 3'-[3-chloro-4-(2-oxo-3.3-dimethylbutoxy)-phenyl]-3'-[3-meihyl-4-
(trifluoromethylsulfonyloxy)phenyl]pentane.
Triflate Rearrangement Procedure.
Using a procedure analogous to Example 35C, 3'-(!3-chloro-4-hydroxyphenyl)-3'-
[3-methyl-4-(trifluoromethylsulfonyloxy)phenyl]pentane, 1 -chloropinacolone, anhydrous
KI, and K2CO3 are reacted in acetonitrile to give the title compound (2.61 g, 53%)
following chromatographies (30% to 50% chloroform/Hex; Hex to 10% EtOAc/Hex).
H-NMR (300 mHz, CDC13): 5 7.15 (1H, d, J = 2.3 Hz), 7.11 (1H, d, J= 8.4 Hz), 7.04 (1H,
d, J = 2.3 Hz), 7.02 (1H, dd, J = 2.3 Hzr J = 8.4 Hz), 6.89 (1H, dd, J = 8.6 Hz, J = 2.3 Hz),
6.62 (1H, d, J = 8.6 Hz), 4.91 (2H, s), 2.32 (3H, s), 2.03 (4H, q, J = 7.2 Hz), 1.26 (9H, s),
0.60 (6H, t, J = 7.2 Hz).
ES (+) MS m/z, [M+NH4]: 552.2.
Further NMR data: COSY data allowed the spin systems of the two aromatic rmgs to be
grouped together. When the OCH2 was selectively excited, a NOE is observed with a
resonance at 6.62 8 which is ortho only coupled. When the aromatic methyl (at 2.32 5)
was excited, a NOE is observed to a meta coupled proton at 7.04 8. These resonances are
not part of the same spin system, requiring the OCH2 and aromatic methyl to be on
different rings. Therefore the triflate has migrated during the reaction and the isolated
product has the structure shown above. (HMBC data also supports this conclusion.)
D. 3'-[3-chloro-4-(2-oxo-3.3-dimethylbutoxy)phenyl]-3'-[3-methyl-4-
(carbomethoxy)phenyl]pentane.
Using a procedure analogous to Example 35F, 3'-[3-chloro-4-(2-oxo-3.3-
dimethylbutoxy)-phenyl]-3'-[3-methyl-4-(trifluoromethylsulfonyl-
oxy)phenyl]pentane, MeOH, dppb, DMSO, Et3N, and Pd(OAc)2 under an atmosphere
of CO are reacted to provide the title compound as a colorless oil (938 mg, 73%).
H-NMR (300 mHz, CDC13): 8 7.82 (1H, d, J = 8.8 Hz), 7.20 (1H, d, J= 2.3 Hz), 7.03 -
7.05 (2H, m), 6.92 (1H, dd, J = 2.3 Hz, J = 8.6 Hz), 6.63 (1H, d, J = 8.6 Hz), 4.92 (2H, s),
3.89 (3H, s), 2.57 (3H, s), 2.08 (4H, q, J = 7.3 Hz), 1.27 (9H, s), 0.63 (6H, t, J = 7.3 Hz).
ES (+) MS m/z: 462.4 [M+NH4].
FAB (+) MS m/z [M+H]: 445.2; calc. m/z 445.1.
E. Racemic 3'-[3-chloro-4-(2-hydroxy-3.3-dimethylbutoxy)phenyl]-3'-[3-methyl-4-
(carbomethoxy)phenyl]pentane.
Using a procedure analogous to Example 35G, 3'-[3-chloro-4-(2-oxo-3.3-
dimethylbutoxy)phenyl]-3'-[3-methyl-4-(carbomethoxy)phenyl]pentane was reduced
by NaBH4 to provide the title compound as a colorless oil (735 mg, 98%).
H-NMR (300 mHz, CDC13): 8 7.89 (1H, d, J = 8.8 Hz), 7.13 (1H, d, J = 1.78 Hz), 7.00
(2H, m), 6.93 (1H, dd, J = 2.2 Hz, J = 8.8 Hz), 6.80 (1H, d, J = 8.8 Hz), (4.17 (1H, dd, J
= 2.6 Hz, J = 9.0 Hz), 3.86 (1H, m), 3.85 (3H, s), 3.74 (1H, m), 2.60, (1H, d, J = 3.0 Hz),
2.54 (3H, s), 2.06 (4H, q, J = 7.3 Hz), 1.01 (9H, s), 0.61 (6H, t, J = 7.3 Hz).
FAB (+) MS m/z [M+H]: 447.1; calc m/z 447.2.
IR (CHC13): 1717 cm"1
F. Racemic 3'-[3-chloro-4-(2-hydroxy-3,3-dimethylbutoxy)phenyl]-3'-[3-methyl-4-
(carboxy)phenyl]pentane.
Using a procedure analogous to Example 35 H&I, racemic 3'-[3-chloro-4-(2-
hydroxy-3.3-dimethylbutoxy)phenyl]-3'-[3-methyl-4-(carbomethoxy)-phenyl]pentane
was saponified by aqueous NaOH in EtOH to form the Na salt corresponding to the
desired compound. After removal of the EtOH under reduced pressure, the residue
containing the Na salt was dissolved in water and acidified in a manner analogous to
the procedure of Example CDJ-3 to provide the title compound as a white solid (470
mg, 97%).
H-NMR (300 mHz, DMSO): 8 7.72 (1H, d, J = 8.0 Hz), 7.00 to 7.10 (5H, m), 4.84 (1H, d,
J = 5.6 Hz), 4.09 (1H, dd, J = 2.8 Hz, J = 10.4 Hz), 3.85 (1H, dd, J = 7.0 Hz, J = 10.4
Hz), 3.45 (1H, m), 2.47 (3H, s), 2.06 (4H, q, J = 7.3 Hz), 0.91 (9H, s), 0.55 (6H, t, J = 7.3
Hz).
ES (+) MS m/z 450.2 [M+NH4], 455.2 [M+Na].
ES(-)MS m/z 431.1 [M-1].
IR(CHC13): 1689 cm-1.
Example 39
Preparation of Racemic 3 '-[3-methyl-4-(2-hydroxy-3,3-dimethylbutoxy)phenyl]-3 '-(3-
chloro-4-carboxyphenyl)pentane.
Using a procedure similar to Example 35F, a mixture of [E,Z]-3-[3-chloro-4-
(trifiuoromethylsulfonyloxy)phenyl)-3-pentene, MeOH, dppb, DMSO (instead of
DMF), Et3N, and Pd(OAc)2 under an atmosphere of CO at 80 °C for 4 h are reacted
to provide the title compound as a colorless liquid in a [E:Z] ratio of 9:1 (1.99 g,
92%).
H-NMR (300 mHz, CDCl3): 8 7.06-7.85 (3H, m), 5.85 (0.9H, q, J = 6.9 Hz), 5.60
(0.1H, q, J = 6.9 Hz), 3.94 (0.3H, s), 3.93 (2.7H, s), 2.50 (1.8H, q, J = 7.6 Hz), 2.32
(0.2H, q, J = 7.6 Hz), 1.82 (2.7H, d, J = 7.6 Hz), 1.53 (0.3H, d, J = 7.6 Hz), 0.97
(2.7H, t, J = 7.6 Hz), 0.94 (0.3H, t, J = 7.6 Hz).
IR (CHC13): 1726 cm-1
ES GC MS m/z 238.1, M+; Calc. C13H15ClO2 m/z 238.1
B. 3'-(4-hydroxy-3-methylphenyl)-3 '-[3-chloro-4-caxbomethoxyphenyl]pentane.
Using a procedure analogous to Example 35D, [E,Z]-3-[3-chloro-4-
carbomethoxyphenyl)-3-pentene and o-cresol are reacted at RT overnight to give the title
compound as a thick, pale yellow oil (3.54g, 99%).
H-NMR (300 mHz, CDC13): 8 7,74 (1H, d, J = 8.2 Hz), 7.29 (1H, d, J= 1.7 Hz), 7.08 (1H,
dd, J = 1.7 Hz, J = 8.2 Hz), 6.81 (2H, m), 6.63 (1H, d, J = 8.9 Hz), 3.91 (3H, s), 2.20 (3H,
s), 2.09 (4H, q, J = 7.3 Hz), 1.27 (9H, s), 0.70 (6H, t, J = 7.3 Hz).
ES(+)MS m/z 347.1 [M+1].
IR(CHC13): 1725 cm-1.
C. 3'-[4-(2-oxo-3,3-trimethylbutoxy)-3-methyl-phenyl]-3'-(3-chloro-4-
carbomethoxyphenyl)-pentane.
Using a procedure analogous to Example 35C, 3'-(4-hydroxy-3-methylphenyl)-3'-
[3-chloro-4-carbomethoxyphenyl]pentane, 1-chloropinacolone, anhydrous KI, and
K2CO3 are reacted in acetonitrile to give the title compound as a clear colorless oil
(3.46g, 90%).
H-NMR (300 mHz, CDC13): 5 7.70 (1H, d, J = 8.2 Hz), 7.28 (1H, d, J= 1.8 Hz), 7.07 (1H,
dd, J =1.8, J =8.2), 6.858 - 6.87 (2H, m), 6.50 (1H, d, J = 9.2 Hz), 4.84 (2H, s), 3.91
(3H, s), 2.23 (3H, s), 2.05 (4H, q, J = 7.3 Hz), 1.53 (9H, s), 0.61 (6H, t, J = 7.3 Hz).
FAB(+) MS m/z [M+H]: 445.2 Calc. m/z 445.2.
IR(CHC13): 1725 cm-1.
D. Racemic 3'-[3-methyl-4-(2-hydroxy-3,3-dimethyibutoxy)phenyl]-3'-(3-chloro-4-
carbomethoxyoxyphenyl)pentane.
Using a procedure analogous to Example 35G, 3'-[4-(2-oxo-3,3-
trimethylbutoxy)-3-methyl-phenyl]-3'-(3-chloro-4-carbomethoxyphenyl)-pentane was
reduced by NaBH4 to provide the title compound as a colorless oil (2.75 g, 91%).
H-NMR (300 mHz, CDC13): 8 7.75 (1H, d, J = 8.8 Hz), 7.27 (1H, d, J= 1.8 Hz), 7.16
(1H3 d, J =2.0 Hz), 7.07 (1H, dd, J = 1.8 Hz, J = 8.8 Hz), 6.94 (1H, dd, J = 2.0 Hz, J =
8.8 Hz), 6.83 (1H, d, J = 8.8 Hz), 4.18 (1H, dd, J = 2.6 Hz, J = 9.0 Hz), 3.92 (3H, s), 3.89
(1H, m), 3.74 (1H, m), 2.60, (1H, broad s), 2.06 (4H, q, J = 7.3 Hz), 1.04 (9H, s), 0.63
(6H,t,J = 7.3 Hz).
FAB(+) MS m/z [M+H]: 447.3; calc. m/z 447.2
IR(CHC13): 1733 cm-1
E. Racemic 3'-[3-methyl-4-(2-hydroxy-3,3-dimethylbutoxy)phenyl]-3'-(3-chloro-4-
carboxyphenyl)pentane..
Using a procedure analogous to Example 35H, racemic 3'-[3-methyl-4-(2-
hydroxy-3,3-dimethylbutoxy)phenyl]-3'-(3-chloro-4-carbometb.oxyoxyphenyl)pentane
was saponified by aqueous NaOH in EtOH to form the Na salt corresponding to the
desired compound. After removal of the EtOH under reduced pressure, the residue
containing the Na salt was dissolved in water and acidified in a manner analogous to
the procedure of Example 391 to provide the title compound as a white solid (1.84 g,
93%).
H-NMR (300 mHz, DMSO): d 7.69 (1H, d, J = 8.0 Hz), 7.10 to 7.20 (2H, m), 6.80 to 6.95
(3H, m),4.78 (1H, d, J = 5.6 Hz), 4.02 (1H, dd, J = 2.8 Hz, J = 10.4 Hz), 3.76 (1H, dd, J =
7.0 Hz, J = 10.4 Hz), 3.44 (1H, m), 2.10 (3H, s), 2.04 (4H, q, J = 7.3 Hz), 0.93 (9H, s),
0.56 (6H, t, J = 7.3 Hz).
ES (+) MS m/z 433.2 [M+H], 450.1 [M+NH4], 455.1 [M+Na].
ES(-)MS m/z 431.2 [M-H].
IR(CHC13): 1701cm-1.
Example 40
Preparation of raccmic 3'-[3-chloro-4-(2-bydroxy-3,3-dimcthylbutoxy)phenyl]-3'-(3-
chloro-4-carboxyphenyl)pentane.
Using a procedure analogous to Example 35D, [E,Z]-3-[3-chloro-4-
carbomethoxyphenyl]-3-pentene and o-chlorophcnol are reacted (initially at RT overnight,
then at 70 °C for 20 h, and finally at 90 °C overnight) to give the title compound as an oil
(886 mg, 58%).
H-NMR (300 mHz, CDC13): 6.90 to 7.76 (6H, m), 5.45 (lH.s), 3.93 (3H, s), 2.06
(4H, q, J - 7.3 Hz), 0.64 (6II, t, J =7.3 Hz).
ES (+) MS m/z 367.0 [M+H].
IR(CHCD): 1726 cm-1
B. 3'-[4-(2-oxo-3,3-trimetliyIbutoxy)-3-chlorophenyl]-3'-(3-chloro-4-
carbomethoxyphenyl)-pentane.
Using a procedure analogous to Example 35C, 3'-(4-hydroxy-3-chlorophenyl)-
3'-(3-chloro-4-carbomethoxy-phenyl)pentane, 1-chloropinacolone, anhydrous KI, and
K2CO3 are reacted in acetonitrile to give the title compound as a clear, nearly
colorless oil (919 mg, 89%).
H-NMR (300 mHz, CDCl3): 8 7.72 (1H, d, J = 8.2 Hz), 7.26 (1H, m), 7.17 (1H, d, J =2.3,
7.06 (1H, dd, J = 1.8 Hz, J = 8.2 Hz), 6.90 (1H, dd, J = 8.7 Hz, J = 2.3 Hz), 4.91 (2H, s),
3.92 (3H, s), 2.05 (4H, q, J = 7.3 Hz), 1.26 (9H, s), 0.62 (6H, t, J = 7.3 Hz).
ES (+) MS m/z 465.1 [M+H], 482.1 [M+NH4].
C. Racemic 3'-[3-chloro-4-(2-hydroxy-3,3-dimethylbutoxy)phenyl]-3'-(3-chloro-4-
carbomethoxyphenyl)pentane.
Using a procedure analogous to Example 35G, 3'-[4-(2-oxo-3,3-
trimethylbutoxy)-3-chlorophenyl]-3'-(3-chloro-4-carbomethoxyphenyl)-pentane was
reduced by NaBH4 to provide the title compound as a colorless oil (738 mg, 98%).
H-NMR (300 mHz, CDC13): 8 7.89 (1H, d, J = 8.8 Hz), 7.13 (1H, d, J = 1.78 Hz),
7.00 (2H, m), 6.93 (1H, dd, J = 2.2 Hz, J = 8.8 Hz), 6.80 (1H, d, J = 8.8 Hz), (4.17
(1H, dd, J = 2.6 Hz, J = 9.0 Hz), 3.86 (1H, m), 3.85 (3H, s), 3.74 (1H, m), 2.60, (1H,
d, J = 3.0 Hz), 2.06 (4H, q, J = 7.3 Hz), 1.01 (9H, s), 0.61 (6H, t, J = 7.3 Hz).
ES (+) MS m/z 489.2 (M+Na).
IR(CHC13): 1717 cm-1
D. Racemic 3'-[3-chloro-4-(2-hydroxy-3,3-dimethylbutoxy)phenyl]-3'-(3-chloro-4-
carboxyphenyl)pentane.
Using a procedure analogous to Example 35H, racemic 3'-[3-methyl-4-(2-
hydroxy-3,3-dimethylbutoxy)phenyl]-3'-(3-chloro-4-carbomethoxy-phenyl)pentane
was saponified by aqueous NaOH in EtOH to form the Na salt corresponding to the
desired compound. After removal of the EtOH under reduced pressure, the residue
containing the Na salt was dissolved in water and acidified in a manner analogous to
the procedure of Example 391 to provide the title compound as a white solid (517 mg,
94%).
H-NMR (300 mHz, DMSO): 8 7.74 (1H, d, J = 8.0 Hz), 7.04 to 7.30 (5H, m), 4.88 (1H, d,
J = 5.6 Hz), 4.14 (1H, dd, J = 2.8 Hz, J = 10.4 Hz), 3.89 (1H, dd, J = 7.0 Hz, J = 10.4
Hz), 3.49 (1H, m), 2.04 (4H, q, J = 7.3 Hz), 0.95 (9H, s), 0.58 (6H, t, J = 7.3 Hz).
ES (+) MS m/z 475.2 [M+Na].
IR(CHC13):1701 cm-1.
Example 41 and Example 42
Separation of optical isomers of 3'-[3-chloro-4-(2-hydroxy-3,3-dimethyl-
butoxy)phenyl] -3' -(3 -chloro-4-carboxyphenyl)pentane.
A racemic mixture 3'-[3-chloro-4-(2-hydroxy-3,3-dimethylbutoxy)-phenyl]-3'-
(3-chloro-4-carboxyphenyl)pentane. (490 mg) is chromatographed with a
ChiralpakAD column to give enantiomer 1, Example 41 (192 mg, 39%) and
enantiomer 2, Example 42 (185 mg, 38%).
Enantiomer 1, Example 41
HPLC: Chiralpak AD (4.6 X 250 mm); 3:2 heptane: isopropyl alcohol with 0.1%
TFA; 1.0 mL/m (flow rate); rt = 7.8 m; 270 nm; ee 99.9% by HPLC.
H-NMR (300 mHz, DMSO): 5 7.74 (1H, d, J = 8.0 Hz), 7.04 to 7.30 (5H, m), 4.88 (1H5 d,
J = 5.6 Hz), 4.14 (1H, dd, J = 2.8 Hz, J = 10.4 Hz), 3.89 (1H, dd, J = 7.0 Hz, J = 10.4
Hz), 3.49 (1H, m), 2.04 (4H, q, J = 7.3 Hz), 0.95 (9H, s), 0.58 (6H, t, J = 7.3 Hz).
ES (+) MS m/z 475.2 [M+Na].
Enantiomer 2, Example 42
HPLC: Chiralpak AD (4.6 X 250 mm); 3:2 heptane: isopropyl alcohol with 0.1%
TFA; 1.0 mL/m (flow rate); rt = 10.6 m; 270 nm; ee 99.5% by HPLC.
H-NMR (300) mllz, DMSO): 8 7.74 (1H, d, J = 8.0 Hz), 7.04 to 7.30 (5H, m), 4.88 (1H, d,
J = 5.6 Hz): 4.14 (1H, dd, J = 2.8 Hz, J = 10.4 Hz), 3.89 (1H, dd, J = 7.0 Hz, J = 10.4
Hz), 3.49 , m), 2.04 (4H, q, J = 7.3 Hz), 0.95 (9H, s), 0.58 (6H, t, J = 7.3 Hz).
ES(+)MF -'7.475.1 [M+Na].
Example 43
Preparation of raccmic l-(4-{l-Ethyl-l-[4-(lH-tetrazol-5-yl)-phenyl]-propyl}-2-methyl-
phenoxy)-22 dimethyl-butan-2-ol.
To elyl, p-iodobenzoate (11.04 g, 40 mmol) in diethylether (100 mL) at -20° C.
under nitrogen is added 1M ethyhnagnesium bromide (91 mL, 91 mmol) dropwise
with mechanical stirring, and the mixture is allowed to come to R.T. and stirred over
night. The mixture is quenched with satd. sodium bicarbonate and triturated with
diethylether six times. The organic layers are combined; washed with water; dried
over anhydrous sodium sulfate; and evaporated under vacuum to give the title
compound as an oil (10.4 g, 90%) which is used as is.
1H NMR (400 mHz, CDCl3), 8 7.64 (d, J = 8.8 Hz, 2H), 7.11 (d, J = 8.8 Hz, 2H),
1.7-5-1 :5 (m, 411), 0.75 (t, J = 7.4 Hz, 6h).
B. 1 -,14 [1-Ethyl-1-(4-iodophenyl)-propyl]}-2-methyl-phenol.
T,22-(4-iodophcnyl)-3'-pentanol (10.4 g, 36 mmol) and o-cresol (15.5 g, 143
mmol in methylene chloride (5 mL) is added borontrifluoride etherate (0.96 mL, 7.2
mmol and the mixture is allowed to stir at room temperature overnight. The mixture
is quar hed with satd. sodium bicarbonate, and extracted into diethylether. The
organic phase is washed with water; dried over anhydrous sodium sulfate; and
eval and under vacuum. The residue is vacuum distilled (0.5 mm) to 80 °C. to
remoexcess o-crcsol, and the residue is partitioned between diethylether and water.
The organic layer is dried over anhydrous sodium sulfate, and evaporated under
vacant to give the title compound as an oil (13 g, 95%) which is used as is.
1H NMR (400 ml-Iz, CDC13), 6 7.53 (d, J = 8.8 Hz, 2H), 6.90 (d, J = 8.8 Hz, 2H), 6.84
(s, 83 (d. J = S.9 Hz, 1H), 6.64 (d, J = 8.9 Hz, 1H), 4.50 (s, 1H), 2.20 (s, 3H),
201 J = 7.2 Hz, 411), 0.60 (t, J = 7.2 Hz, 6H).
C.-Etliy:-l-(4-iodophenyl)-propyl]-2-methyl-phenoxy}-3,3-dimethyl-butan-2-
In a procedure analogous to Example 35C, l-{4-[l-Ethyl-l-(4-iodophenyl)-
propyl]}-2-methyl-phenor(13 g, 34 mmol) gave the title compound as an oil (13.9 g,
85%) which is used as is.
1H NMR (400 mHz, CDC13), 8 7.53 (d, J = 8.4 hz, 2H), 6.90 (d, J = 8.4 Hz, 2H), 6.87
(s, 1H), 6.86 (d, J = 8.8 hz, 1H), 6.48 (d, J = 8.8 Hz, 1H), 4.83 (s, 2H), 2.23 (s, 3H),
2.01 (q, J = 7.2 Hz, 4H), 1.25 (s, 9H).
D. 4-{l-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzonitrile.
To a mixture of l-{4-[l-ethyl-1-(4-iodo-phenyl)-propyl]-2-methyl-phenoxy}-3,3-
dimethyl-butan-2-one (3.0 g 6.27 mmol) and DMF (30 mL) is added Zn(CN)2 (0.44 g,
3.76 mmol), Pd2(dba)3 (0.29 g, 0.31 mmol), and DPPF (0.42 g, 0.75 mmol). The
solution is heated at 100 °C overnight,-diluted with Et2O (200 mL), washed with 4:1:4
sat NH4Cl:Conc. NH4OH:water (100 mL), water (100 mL), brine (100 mL), dried
MgSO4, filtered and concentrated. The residue is purified by ISCO (10%-2-% EtOAc
gradient) to furnish the title compound (1.1 g, 2.91 mmol, 46%).
1H NMR (CDCl3), 8 0.52-0.63 (m, 6H), 1.26 (s, 9H), 2.03-2.10 (m, 4H), 2.24 (s, 3H),
4.85 (s, 2H), 6.50 (d, J= 9.4 Hz, 1H), 6.82-6.86 (m, 2H), 7.27 (d, J= 8.4 Hz, 2H),
7.53(d, J=8.9 Hz,2H).
LC/MS (m/z): calcd. for C25H31NO2 (M+H)+: 378.6; found: 395.3.
E1-(4-{1-Ethyl-1-[4-(lH-tetrazol-5-yl)-phenyl]-propyl}-2-methyl-phenoxy)-3,3-
dimethyl-butan-2-one.
To a mixture of 4-{1-[4-(3,3-dimemyl-2-oxo-butoxy)-3-memyl-phenyl]-1-ethyl-
propyl}-benzonitrile (0.50 g, 1.32 ramol), and DMF (5 mL) is added NaN3 (0.26 g,
3.95 mmol) and Et3N·HCl (0.54 g, 3.95 mmol). The slurry is heated at 110 °C
overnight. The slurry is diluted with EtOAc (50 mL), washed with 1M HC1 (40 mL)
water (40 mL), brine (40 mL), dried over MgSO4, filtered and concentrated. The
residue is purified by ISCO (20%- 40% [89% EtOAc: 10% MeOH: 1% AcOH]
gradient) to furnish the title compound (0.37g, 0.88 mmol, 66%).
'H NMR (CDC13), 8 0.57-0.62 (m, 6H), 1.27 (s, 9H), 2.02-2.11 (m, 4H), 2.17 (s, 3H),
4.87 (s, 2H), 6.50 (d, J= 9.4 Hz, 1H), 6.82-6.88 (m, 2H), 7.22-7.28 (m, 3H), 7.94 (d, J
= 7.9 Hz, 2H).
LC/MS (m/z): calcd. for C25H32N4O2 (M+H)+: 421.7; found: 421.2.
F. l-(4-{l-Ethyl-l-[4-(lH-tetrazol-5-yl)-phenyl]-propyl}-2-methyl-phenoxy)-3,3-
dimethyl-butan-2-ol.
To a mixture of l-(4-{l-Ethyl-l-[4-(lH-tetrazol-5-yl)-phenyl]-propyl}-2-methyl-
phenoxy)-3,3-dimethyl-butan-2-one (0.37 g, 0.88 mmol) and EtOH (5 mL) was added
NaBH4 (0.037 g, 0.97 mmol) and the solution stirred for 1 hour. The solids were
removed by filtration and the solution concentrated. The residue was purified by
ISCO (10- 30 [89% EtOAc:10% MeOH: 1% AcOH] gradient) to furnish the title
compound (0.32 g, 0.76 mmol, 86%).
1HNMR (CDCl3), 8 0.59-0.64 (m, 6H), 1.02 (s, 9H), 2.05-2.12 (m, 4H), 2.13 (s, 3H),
3.75 (dd, J = 2.8, 8.8 Hz, 1H), 3.89 (t, J= 8.8 Hz, 1H), 4.10 (dd, J= 2.8, 8.8 Hz, 1H),
6.68 (d,J= 8.2 Hz, 1H), 6.85 (d, J= 2.2 Hz, 1H), 6.92 (dd, J= 2.2, 8.7 Hz, 1H), 7.31
(d, J = 8.4 Hz, 2H), 8.01 (d, J = 8.4 Hz, 2H).
LC/MS (m/z): calcd. for C25H34N4O2 (M+H)+: 423.7; found: 423.2.
Example 44 and Example 45
Separation of enantiomers of l-(4-{l-Ethyl-l-[4-(lH-tetrazol-5-yl)-phenyl]-propyl}-
2-methyl-phenoxy)-3,3-dimethyl-butan-2-ol.
A racemic mixture of l-(4-{l-Ethyl-l-[4-(1H-tetrazol-5-yl)-phenyl]-propyl}-2-
methyl-phenoxy)-3,3-dimethyl-butan-2-ol (0.32 g) is chromatographed (CHIRALPAK
ADH column, 0.1% TFA, 20% /-PrOH/Hept) to give enantiomer 1, (0.168 g, 0.40 mmol,
45 %) and enantiomer 2, (0.150 g, 0.35 mmol, 41 %).
Example 44, enantiomer 1
Rt = 7.7m
1H NMR (CDCl3), 8 0.57-0.67 (m, 6H), 1.02 (s, 9H), 2.05-2.12 (m, 4H), 2.14 (s, 3H),
3.74 (dd, J = 2.2, 8.8 Hz, 1H), 3.89 (t, J= 8.8 Hz, 1H), 4.10 (dd, J= 2.2, 8.8 Hz, 1H),
6.69 (d,J= 8.8 Hz, 1H), 6.86 (s, 1H), 6.93 (d, J= 8.8 Hz, 1H), 7.31 (d, J= 8.0 Hz, 2H),
7.99 (d, J= 8.0 Hz, 2H). LC/MS (m/z): calcd. for C25H34N4O2 (M+H)+: 423.7; found:
423.3.
Example 45, enantiomer 2
Rt = 11.6m
1H NMR (CDCl3), 8 0.59-0.66 (m, 6H), 1.01 (s, 9H), 2.05-2.15 (m, 4H), 2.16 (s, 3H),
3.71 (dd, J = 2.5, 8.7 Hz, 1H), 3.87 (t, J= 9.0 Hz, 1H), 4.09 (dd, J = 2.5, 9.0 Hz, 1H),
6.71 (d, J= 8.8 Hz, 1H), 6.87 (d,J= 1.7 Hz, 1H), 6.95 (dd, J= 2.2, 8.5 Hz, 1H), 7.31 (d,
J = 8.2 Hz, 2H), 8.01 (d, J= 8.2 Hz, 2H). LC/MS (m/z): calcd. for C25H34O2 (M+H)+:
423.7; found: 423.3.
Example 46
Preparation of epimer 1 of P)-2-(4-{1-ethyl-l-[4-(2-hydroxy-l,3,3-trimethyl-butoxy)-3-
methyl-phenyl]-propyl}-2-methyl-benzoylamino)-propionic acid
Using a procedure analogous to Example 5, isomer 1 of 4-{l-ethyl-l-[4-(2-
hydroxy-1,3,3-triraethyl-butoxy)-3-methyl-phen3d]-pnopyl}-2-methyl-benzoic acid (0.55
g, 1.29 mmbl). (D)-alananine methyl ester hydrochloride (198 rug, 1.42 mmol), EDCI
(276 mg, 1.44 mmol), and 1-hydroxybenzotriazole hydrate (195 mg, 1.44 mmol) furnish
the title compound (0.42 g, 0.82 mmol, 63%).
1H NMR (CDC13), 8 0.62 (t, J= 7.3 Hz, 6H), 0.97 (S, 9H), 1.35 (d, J= 6.3 Hz, 3H), 1.51
(d, J= 7.5 Hz, 3H), 2.06 (q, J= 7.3 Hz, 4H), 2.14 (s, 3H), 2.43 (s, 3H), 3.18 (bs, 1H),
3.79 (s, 3H), 4.58 (q, J= 6.3 Hz, 1H), 4.79 (m, 1H), 6.32 (d, J= 8.1 Hz, 1H), 6.69 (d, J =
8.3 Hz, 1H), 6.84-7.05 (m, 4H), 7.30 (d, J= 8.3 Hz, 1H).
ES-MS (m/z): calcd. for C31H46NO5 (M+H)+: 511.7; found: 512.3.
B. Preparation of epimer 1 of (D)-2-(4-{1-ethyl-l-[4-(2-hydroxy-l,3,3-trimethyl-butoxy)-
3-methyl-phenyl]-propyl} -2-methyl-benzoylamuio)-propionic acid.
Using a procedure analogous to Example 2, epimer 1 of (D)-2-(4-{1 -ethyl-1-[4-(2-
hydroxy-l,3,3-trimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoylamino)-
propionic acid methyl ester (0.42 g, 0.82 mmol) and LiOH give the title compound (0.41
g, 0.82 mmol, 100%).
1H NMR (CDCl3), 8 0.62 (t, J= 7.5 Hz, 6H), 0.97 (S, 9H), 1.36 (d, J= 6.2 Hz, 3H), 1.57
(d, J= 7.0 Hz, 3H), 2.06 (q, J= 7.5 Hz, 4H), 2.14 (s, 3H), 2.44 (s, 3H), 3.19 (d, J= 0.9
Hz, 1H), 4.58 (dq, J= 6.2, 0.9 Hz, 1H), 4.74-4.82 (m, 1H), 6.28 (d, J= 7.0 Hz, 1H), 6.69
(d, J= 8.8 Hz, 1H), 6.84-7.06 (m, 4H), 7.31 (d, J= 7.9 Hz, 1H). ES-MS (m/z): calcd. for
C31H46NO5 (M+H)+: 511.7; found: 512.3.).
ES-MS (m/z): calcd for C30H42NO5 (M-H)-: 496.7; found: 496.3.
Example 47
Preparation of epimer 1 of (L)-2-(4-{1-Ethyl-l-[4-(2-hydroxy-l,3,3-trimethyl-butoxy)-3-
methyl-phenyl]-propyl}-2-methyl-benzoylamino)-propionic acid.
Using the procedure analogous to Example 46A, isomer 1 of 4-{l-ethyl-l-[4-(2-
hydroxy-l,3,3-trimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoic acid (0.55
g, 1.29 mmol) and (L)-alananine methyl ester hydrochloride (198 mg, 1.42 mmol) furnish
the title compound (0.56 g, 1.09 mmol, 85%).
1H NMR (CDCl3), 5 0.62 (t, J= 7.2 Hz, 6H), 0.97 (S, 9H), 1.36 (d, J= 6.1 Hz, 3H), 1.51
(d, J= 7.4 Hz, 3H), 2.06 (q, J = 7.2 Hz, 4H), 2.15 (s, 3H), 2.43 (s, 3H), 3.18 (bs, 1H),
3.79 (s, 3H), 4.58 (dq, J= 6.1, 0.9 Hz, 1H), 4.79 (m, 1H), 6.32 (d, J = 7.3 Hz, 1H), 6.69
(d, J= 8.5 Hz, 1H), 6.84-7.05 (m, 4H), 7.30 (d, J= 8.3 Hz, 1H).
ES-MS (m/z): calcd. for C31H46NO5 (M+H)+: 511.7; found: 512.3.
B. Preparation of epimer 1 of (Z,)-2-(4-{1-Ethyl-1-[4-(2-hydroxy-l,3,3-trimethyl-butoxy)-
3-methyl-phenyl]-propyl} -2-methyl-benzoylamino)-propionic acid.
Using a procedure analogous to Example 46B, epimer 1 of (D)-2-(4-{1-ethyl-1-[4-
(2-hydroxy-1,3,3-trimemyl-butoxy)-3-memyl-phenyl]-propyl}-2-memyl-benzoylarnino)-
propionic acid methyl ester (0.56 g, 1.09 mmol) gives the title compound (0.54 g, 1.09
mmol, 100%).
1H NMR (CDCl3), 5 0.62 (t, J 7.0 Hz, 6H), 0.97 (S, 9H), 1.36 (d, J= 6.1 Hz, 3H), 1.57
(d, J= 7.4 Hz, 3H), 2.06 (q, J= 7.0 Hz, 4H), 2.14 (s, 3H), 2.44 (s, 3H), 3.19 (d, J= 1.3
Hz, 1H), 4.59 (q, J= 6.1, Hz, 1H), 4.74-4.82 (m, 1H), 6.29 (d, J= 7.0 Hz, 1H), 6.69 (d, J
= 8.8 Hz, 1H), 6.84-7.07 (m, 4H), 7.31 (d, J= 8.4 Hz, 1H).
ES-MS (m/z): calcd for C30H42NO5 (M-H)': 496.7; found: 496.3.
Example 48
Preparation of epimer 2 of (D)-2-(4-{l-ethyl-l-[4-(2-hydroxy-l,3,3-trimethyl-butoxy)-3-
methyl-phenyl]-propyl} -2-methyl-benzoylamino)-propionic acid.
A. Preparation of epimer 2 of (D)-2-(4-{1-emyl-1-[4-(2-hydroxy-l,3,3-trimethyl-butoxy)-
3-methyl-phenyl]-propyl}-2-methyl-benzoylamino)-propionic acid methyl ester.
Using the procedure analogous to Example 46A, isomer 2 of 4-{1-ethyl-1-[4-(2-
hydroxy-1,3,3-trimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-ben2oic acid (0.50
g, 1.17 mmol) and (D)-alananine methyl ester hydrocbloride (180 mg, 1.29 mmol)
furnish the title compound (0.47 g, 0.92 mmol, 79%). 1H NMR) & ES-MS (m/z):
identical to that of Example 47 A.
B. Preparation of epimer 2 of (D)-2-(4-{1-emyl-l-[4-(2-hydroxy-l,3,3-trimethyl-butoxy)-
3-methyl-phenyl]-propyl}-2-methyl-benzoylamino)-propionicacid.
Using a procedure analogous to Example 46B, from epimer 2 of (D)-2-(4-{1-
emyl-1-[4-(2-hydroxy-133-trimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-
benzoylamino)-propionic acid methyl ester (0.47 g, 0.92 mmol) to give the title
compound (0.39 g, 0.79 mmol, 86%). !H NMR & ES-MS : identical to that of Example
47B.
Example 49
Preparation of epimer 2 of (L)-2-(4-{l-Ethyl-l-[4-(2-hydroxy-l,3,3-trimethyl-butoxy)-3-
methyl-phenyl]-propyl}-2-methyl-benzoylammo)-propionic acid.
A. Preparation of epimer 2 of (L)-2-(4-{1-ethyl-l-[4-(2-hydroxy-1,3,3-trimethyl-butoxy)-
3-methyl-phenyl]-propyl}-2-methyl-benzoylamino)-propionic acid methyl ester.
Using the procedure analogous to Example 46A, isomer 2 of 4-{l-ethyl-l-[4-(2-
hydroxy-1,3,3-trimethyl-butoxy)-3-methyl-phenyl]-propyl} -2-methyl-benzoic acid (0.50
g, 1.17 mmol) and (L)-alananine methyl ester hydrochloride (180 mg, 1.29 mmol) furnish
the title compound (0.47 g, 0.92 mmol, 79%). 1H NMR) & ES-MS (m/z): identical to
that of Example 46A.
B. Preparation of epimer 2 of (L)-2-(4-{l-ethyl-l-[4-(2-hydroxy-l,3,3-trimethyl-butoxy)-
3-methyl-phenyl]-propyl}-2-methyl-benzoylamino)-propionicacid.
Using a procedure analogous to Example 24B, epimer 2 of (Z,)-2-(4-{l-ethyl-l-[4-
(2-hydroxy-l,3,3-trimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoylamino)-
propionic acid methyl ester (0.47 g, 0.92 mmol) give the title compound (0.44 g, 0.88
mmol, 96%). 1H NMR & ES-MS: identical to that of Example 46B.
Example 50
Preparation of enantiomer 1 of 5-(4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-
methyl-phenyl]-propyl}-2-methyl-ben2yl)-thiazolidine-2,4-dione.
To a mixture of enantiomer 1 of 4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-
butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoic acid (1.11 g, 2.69 mmol) and DMF
(5 mL) is added hydroxylamine hydrochloride (0.29 g, 2.96 mmol), EDCI ( 0.57 g, 2.96
mmol), HOBt (0.40 g, 2.96 mmol), and NEt3 (1.65 mL, 11.84 mmol). The mixture is
stirred at ambient temperature overnight, diluted with EtOAc (40 mL), washed with 1M
HC1 (40 mL), water (40 mL), brine (40 mL), dried over MgSO4, filtered and concentrated.
The residue is purified by ISCO (10%-40% EtOAc gradient) to furnish the title compound
(1.0g, 2.19mmol,81%).
1HNMR (CDCl3), 8 0.57-0.64 (m, 6H), 1.02 (s, 9H), 2.02-2.10 (m, 4H), 2.17 (s, 3H),
2.29 (s, 3H), 3.28 (bs, 3H), 3.53 (bs, 1H), 3.71 (dd, J= 2.7, 8.8 Hz, 1H), 3.86 (t, J= 8.8
Hz, 1H), 4.10 (dd, J= 2.7, 8.8 Hz, 1H), 6.70 (d, J = 8.6 Hz, 1H), 6.86 (d, 7- 2.0 Hz, 1H),
6.94 (dd, 7= 2.2, 8.1 Hz, 1H), 6.97-7.02 (m, 3H), 7.14 (d, 7= 8.4 Hz, 1H). LC/MS (m/z):
calcd. for C28H41NO4 (M+H)+: 456.7; found: 456.2.
B. Enantiomer 1 of 4-{l-ethyl-l-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-
propyl} -2-methyl-benzaldehyde.
To a mixture of enantiomer 1 of 4-{1-ethyl-l-[4-(2-hydroxy-3,3-dimethyl-
butoxy)-3-methyl-phenyl]-propyl}-N-methoxy-2,N-dimethyl-benzamide (1.0 g, 2.42
mmol) and THF (10 mL) is added 1M in THF LAH ( 2.5 mL, 2.55 mmol) with cooling.
THF (5 mL) was added and the solution stirred for 1 hour. The solution is diluted with
Et2O (100 mL) and washed with 1M HCl (50 mL). The aqueous phase is extracted with
Et2O (50 mL). The combined organic layers are washed with 1M HC1 (50 mL), brine (50
mL), dried over MgSO4, filtered and concentrated to furnish the title compound (0.64 g,
1.61 mmol, 67%).
'H NMR (CDC13), 8 0.59-0.66 (m, 6H), 1.02 (s, 9H), 2.05-2.15 (m, 4H), 2.18 (s, 3H),
2.62 (s,3H), 3.71 (dd, J= 1.9,9.1 Hz, 1H), 3.86 (t,J= 9.1 Hz, 1H), 4.10 (dd,J= 1.9,9.1
Hz, 1H), 6.72 (d,y= 8.2 Hz, 1H), 6.87 (s, 1H), 6.93 (d, J= 8.7 Hz, 1H), 7.06 (s, 1H), 7.17
(d,J= 8.2 Hz, 1H) 7.67 (dd, J= 1.7, 8.0,1H), 10.20 (s, 1H).
LC/MS (m/z): calcd. for C26H36O3 (M+H)+: 397.7.; found: N/A.
C.Enantiomer 1 of 5-(4- {1 -ethyl-1 -[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-
phenyl]-propyl}-2-methyl-benzylidene)-thiazoIidine-2,4-dione.
To a mixture of enantiomer 1 of 4-{1-Ethyl-l-[4-(2-hydroxy-3,3-dimethyl-
butoxy)-3-methyi-phenyl]-propyl}-2-methyl-benzaldehyde (0.64 g, 1.61 mmol) and
toluene (20 mL) is added 90 % 2,4-thiazolidinedione (0.25 g, 1.94 mmol), and piperdine
acetate (0.04 g, 0.24 mmol). The solution is heated to a reflux overnight and the water
removed by a Dean-Stark trap. The solution is diluted with EtOAc (60 mL), washed with
water (50 mL), saturated NaHCO3 (50 mL), dried over MgSO4, filtered and concentrated.
Purified by ISCO (20% -50% EtOAc gradient) to furnish the title compound (0.75 g, 1.51
mmol, 94%).
1HNMR (CDC13), 5 0.60-0.67 (m, 6H), 1.03 (s, 9H), 2.04-2.13 (m, 4H), 2.19 (s, 3H),
2.42 (s, 3H), 2.50 (d,7=2.0 Hz, 1H), 3.72 (d, J= 8.8 Hz, 1H), 3.86 (t, J= 8.9 Hz, 1H),
4.10 (dd,7= 2.7, 9.4 Hz, 1H), 6.72 (d,7= 8.1 Hz, 1H), 6.88 (d, J= 1.7 Hz, 1H), 6.94 (dd,
J= 2.3, 8.7 Hz, 1H), 7.08 (s, 1H), 7.11 (dd,7= 1.8,8.4 Hz, 1H), 7.33 (d,J= 8.4, IE),
8.06 (s,1H), 8.97 (bs, 1H).
LC/MS (m/z): calcd. for C29H37NO4S (M+H)+: 494.5; found: 494.2.
D. Enantiomer 1 of 5-(4-{l-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-
phenyl]-propyl}-2-methyl-benzyl)-thiazolidine-2,4-dione.
To a mixture of enantiomer 1 of 5-(4-{1-Ethyl- l-[4-(2-hydroxy-3,3-dimethyl-
butoxy)-3-methyl-phenyl]-propyI}-2-methyl-benzylidene)-thiazolidine-2,4-dione(0.35 g,
0.71 mmol) and MeOH (10 mL) is added Mg (0.17 g, 7.1 mmol). The solution is heated
at a reflux for 4 hours. The solution is filtered thru celite®, rinsed with MeOH (2 mL),
and the solution concentrated. The residue is purified by ISCO (15%-30% EtOAc
gradient) to furnish the title compound (0.13 g, 0.26 mmol, 37%).
1H NMR (CDCb), 5 0.57-0.65 (m, 6H), 1.02 (s, 9H), 2.01-2.10 (m, 4H), 2.19 (s, 3H),
2.31 (s,3H),2.50(d,.J= 2.6 Hz, 1H), 2.97-3.06 (m, 1H), 3.65 (dd, J= 3.8,14.5 Hz, 1H),
3.69-3.75 (m, 1H), 3.87 (t, J= 8.8 Hz, 1H), 4.10 (dd,J= 2.7, 9.3 Hz, 1H), 4.52 (dd, J =
3.8,11.2 Hz, 1H), 6.70 (dd, J= 2.3, 8.5 Hz, 1H), 6.87-7.04 (m, 5H), 8.56 (bs, 1H).
LC/MS (m/z): calcd. for C29H39NO4S (M+H)+: 496.6; found: 496.2.
Example 51
Preparation of enantiomer 2 of 5-(4-{1-ethyl-l-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-
methyl-phenyl]-propyl}-2-methyl-benzyl)-thiazolidine-2,4-dione.
A. Enantiomer 2 of 4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-
propyl}-N-methoxy-2,N-dimethyl-benzamide.
To mixture of enantiomer 2 of 4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-
3-methyl-phenyl]-propyl}-2-methyl-benzoic acid (0.70 g, 1.70 mmol) and DMF (5 mL) is
added hydroxylamine hydrochloride (0.18 g, 1.87 mmol), EDCI (0.33 g, 1.87 mmol),
HOBt (0.23 g, 1.87 mmol), and NEt3 (0.95 mL, 6.79 mmol). The mixture is stirred at
ambient temperature overnight, diluted with EtOAc (40 mL), washed with 1M HC1 (40
mL), water (40 mL), brine (40 mL), dried over MgSO4, filtered and concentrated to
furnish the title compound (0.76 g, 2.19 mmol, 81%).
1H NMR (CDCI3), 8 0.57-0.64 (m, 6H), 1.02 (s, 9H), 2.01-2.10 (m, 4H), 2.17 (s, 3H),
2.28 (s, 3H), 3.28 (bs, 3H), 3.54 (bs, 1H), 3.71 (dd, J = 2.6, 8.8 Hz, 1H), 3.86 (t,7= 8.8
Hz, 1H), 4.10 (dd, J= 2.6, 8.8 Hz, 1H), 6.70 (d, J= 8.3 Hz, 1H), 6.86 (d, J= 2.2 Hz, 1H),
6.94 (dd,J= 2.2, 8.6 Hz, 1H), 6.97-7.02 (m, 3H), 7.13 (d, J= 8.3 Hz, 1H). LC/MS (m/z):
calcd. for C28H41NO4 (M+H)+: 456.7; found: 456.3.
B. Enantiomer 2 of 4-{l-Ethyl-l-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-
propyl}-2-methyl-benzaldehyde.
To a mixture of enantiomer 2 of 4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-
butoxy)-3-methyl-phenyl]-propyl}-N-methoxy-2,N-dimethyl-benzamide (0.76 g, 1.75
mmol) and THF (20 mL) is added 1M LAH in THF (1.75mL, 1.75 mmol) with cooling,
and the solution stirred for 1 hour. The solution is diluted with Et2O (100 mL) and
washed with 1M HC1 (50 mL). The aqueous phase is extracted with Et2O (50 mL). The
combined organic layers are washed with 1M HC1 (50 mL), brine (50 mL), dried over
MgSO4, filtered and concentrated to furnish the title compound (0.48 g, 1.21 mmol, 73%).
1HNMR (CDCl3), 8 0.60-0.65 (m, 6H), 1.02 (s, 9H), 2.07-2.14 (m, 4H), 2.18 (s, 3H),
2.62 (s, 3H), 3.58-3.74 (m, 1H), 3.87 (t, J= 8.9 Hz, 1H), 4.10 (dd, J= 2.6, 9.2 Hz, 1H),
6.72 (d, 7= 8.6 Hz, 1H), 6.87 (d, J= 2.5, 8.6,1H), 7.06 (s, 1H), 7.17 (dd, J= 1.8, 8.2 Hz,
1H), 7.67 (d, J= 8.4,1H), 10.20 (s, 1H).
LC/MS (m/z): calcd. for C26H36O3 (M+H)+: 397.7.; found: 397.3.
C. Enantiomer 2_of 5-(4-{l-Ethyl-l-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-
phenyl]-propyl}-2-methyl-benzylidene)-thiazolidine-2,4-dione.
To a mixture of enantiomer 2 of 4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-
butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzaldehyde (048 g, 1.21 mmol) and
toluene (15 mL) is added 90 % 2,4-thiazolidinedione (0.19 g, 1.45 mmol), and piperdine
acetate (0.03 g, 0.18 mmol). The solution is heated to a reflux overnight and the water
removed by a Dean-Stark trap. The solution is diluted with EtOAc (60 mL), washed with
water (50 mL), brine (50 mL), dried over MgSO4, filtered and concentrated. Purified by
ISCO (20% -40% EtOAc gradient) to furnish the title compound (0.50 g, 1.00 mmol,
83%).
1HNMR (CDCl3), 5 0.60-0.67 (m, 6H), 1.03 (s, 9H), 2.05-2.12 (m, 4H), 2.19 (s, 3H),
2.42 (s, 3H), 2.51 (d, J= 2.5 Hz, 1H), 3.70-3.75 (m, 1H), 3.88 (t, J= 8.8 Hz, 1H), 4.10
(dd, 7= 2.7,9.2 Hz, 1H), 6.72 (d, J= 8.3 Hz, 1H), 6.88 (d, J= 1.8 Hz, 1H), 6.94 (dd, J=
2.2, 8.6 Hz, 1H), 7.08 (s, 1H), 7.11 (dd, J= 1.8, 8.0 Hz, 1H), 7.33 (d, J = 8.0, 1H), 8.06
(s, 1H),9.02(bs, 1H).
LC/MS (m/z): calcd. for C29H37NO4S (M+H)+: 494.5; found: 494.2.
D. Enantiomer 2 of 5-(4-{l-Ethyl-l-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-
phenyl]-propyl} -2-methyl-benzyl)-thiazolidine-2,4-dione.
To a mixture of enantiomer 2 of 5-(4-{l-Ethyl-l-[4-(2-hydroxy-3,3-dimethyl-
butoxy)-3-methyl-phenyl]-propyl}-2-methyi-benzylidene)-thiazolidine-2,4-dione
(example Rupp-7) (0.25 g, 0.50 mmol) and MeOH (10 mL) is added Mg (0.12 g, 5.04
mmol). The solution is heated at a reflux for 4 hours. The solution is filtered thru celite®,
rinsed with MeOH (2 mL), and the solution concentrated. The residue is purified by
ISCO (15%-30% EtOAc gradient) to furnish the title compound (0.084 g, 0.17 mmol,
34%).
'H NMR (CDCI3), 5 0.56-0.63 (m, 6H), 1.02 (s, 9H), 2.00-2.10 (m, 4H), 2.18 (s, 3H),
2.31 (s, 3H), 2.51 (d, J= 2.1 Hz, 1H), 2.97-3.06 (m, 1H), 3.65 (dd, J= 3.9,14.7 Hz, 1H),
3.69-3.75 (m, 1H), 3.86 (t, J= 8.9 Hz, 1H), 4.09 (dd, J= 2.7, 9.4 Hz, 1H), 4.52 (dd, / =
3.8,11.2 Hz, 1H), 6.70 (d, J= 8.5 Hz, 1H), 6.86-7.03 (m, 5H), 8.56 (bs, 1H). LC/MS
(m/z): calcd. for C29H39NO4S (M+H)+: 496.6.; found: 496.2.
Example 52 and 53
Enantiomer 1 and 2 of [(4-{l-Ethyl-l-[4-(2-hydroxy-l,3,3-trimethyl-butoxy)-3-methyl-
phenyl]-propyl}-2-methyl-benzoyl)-methyl-amino]-acetic acid.
(Enantiomer 1)
(Enantiomer 2)
A. Racemic [(4- {1 -Ethyl-1 -[4-(2-hydroxy-1,3,3-trimethyl-butoxy)-3-methyl-phenyl]-
propyl}-2-methyl-benzoyl)-methyl-amino]-acetic acid methyl ester.
Using a procedure analogous to Example 46A, from racemic 4-{1-ethyl-1-[4-(2-
hydroxy-l,3,3-trimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoic acid (1.46
g, 3.43 mmol) and sascoine methyl ester hydrochloride (0.52 g, 3.76 mmol) to give the
title compound (1.74 g, 3.40 mmol, 99%).
1HNMR(CDCl3), 8 0.58-0.65 (m,6H), 0.97 (s,6H), 1.02 (s,3H), 1.33 (d,J=6.2 Hz,
1H), 1.36 (d, J= 6.2 Hz, 2H), 2.00-2.10 (m, 4H), 2.14 (s, 3H), 2.25 (s, 1H), 2.33 (s, 2H),
2.57 (d, J= 9.6 Hz, 0.33H), 2.58 (d, J = 9.6 Hz, 0.66H), 2.89 (s, 3H), 3.18 (dd, J= 9.6,
1.3 Hz, 1H), 3.69 (s, 1H), 3.79 (s, 2H), 3.91 (s, 0.66H), 4.32 (bs, 1.34H), 4.59 (dq, J=
6.2,1.3 Hz, 1H), 6.69 (d, J= 8.3 Hz, 1H), 6.84-7.11 (m, 5H).
ES-MS (m/z): calcd for C31H45NO5 (M+H)+: 512.7; found: 512.3.
B. Separation of enantiomers of [(4-{1-ethyl-1-[4-(2-hydroxy-l,3,3-trimethyl-butoxy)-3-
methyl-phenyl]-propyl}-2-methyl-benzoyl)-methyl-amino]-acetic acid methyl ester.
A racemic mixture of [(4-{1-ethyl-1-[4-(2-hydroxy-l,3,3-trimethyl-butoxy)-3-
methyl-phenyl]-propyl}-2-methyl-benzoyl)-methyl-amino]-acetic acid methyl ester (1.73
g), is chromatographed (HPLC: ChiralPak AD, 0.1% TFA in zPrOH:Hept = 5 : 95) to give
enantiomer 1 (0.636 g, 38%, rt = 21.8 m) and enantiomer 2 (0.72 g, 42%, rt = 26.7 m).
(Enantiomer 1)
HPLC: ChiralPak AD, 0.1% TFA in /PrOH:Hept = 5 : 95; 0.6 mL/m (flow rate); rt = 21.8
m; @ 240 nm;
NMR & LC/MS: equivalent to the racemate.
(Enantioraer 2)
HPLC: ChiralPak AD, 0.1% TFA in iPrOH:Hept = 5 : 95; 0.60 mL/m (flow rate); rt =
26.7 m; @ 240 run;
NMR & LC/MS: equivalent to the racemate
C. Enantioraer 1 of [(4-{1-Ethvl-1-[4-(2-hydroxy-1,3,3-trimethyl-butoxy)-3-rnethyl-
phenyl]-propyl}-2-methyl-benzoyl)methyl-amino]-acetic acid.
Using a procedure analogous to Example 46B, enantiomer 1 of [(4- {1 -ethyl-1-[4-
(2-hydroxy-1,3,3-trimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoyl)-methyl-
amino]-acetic acid methyl ester (0.63 g, 1.24 rrunol) gives the title compound (0.58 g,
1.16mmol,93%).
1H NMR (CDCl3), 5 0.58-0.65 (m, 6H), 0.98 (s, 9H), 1.36 (d, J = 6.2 Hz, 3H), 2.06 (q, J -
7.1 Hz, 4H), 2.14 (s, 3H), 2.25 (s, 0.9H), 2.31 (s, 2.1H), 2.93 (s, 3H), 3.16 (bs, 1H), 3.18
(d,7= 1.3 Hz, 1H), 3.95 (s, 1H),4.35 (s, 1H),4.59 (q, J=6.2 Hz, 1H), 6.68-7.11 (m,
6H).
ES-MS (m/z): calcd for C30H42NO5 (M-H): 496.7; found: 496.3.
D. Enantiomer 2 of [(4-{ 1-Ethyl-1-[4-(2-hydroxy-1,3,3-trimethyl-butoxy)-3-raethyl-
phenyl]-propyl} -2-methyl-benzoyl)-methyi-amino]-acetic acid.
Using a procedure analogous to Example 46B, enantiomer 2 of [(4-{1-ethyl-1-[4-
(2-hydroxy-1,3,3-trimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoyl)-methyl-
amino]-acetic acid methyl ester (0.72 g, 1.41 mmol) gives the title compound (0.64 g,
1.28 mmol, 91%). 1H NMR & ES-MS (m/z): identical to enantiomer 1 of [(4-{1-Ethyl-1-
[4-(2-hydroxy-1,3,3 -trimethyl-butoxy)-3 -methyl -phenyl]-propyi} -2-methyl-benzoyl)-
mcthyl-amino]-acetic acid.
Example 54
Preparation of 3'-[4-(3-oxo-4,4-dimethylpentyl)-3-methylphenyl]-3'-[4-carboxyl-3-
methylphenyl]pentane.
Using a procedure analogous to Example 1E, 3'-[4-benzyloxy-3-methylphenyl]-
3'-[4-trifluoromethanesulfonyloxy-3-methylphenyl]pentane gives the title compound (30
g, 77%).
1H NMR 300 MHz (DMSO-d6): 8 0.54 (t, J = 6.9 Hz, 6H), 2.05 (q, J = 6.9 Hz, 4H), 2.12
(s, 3H), 2.47 (s, 3H), 3.78 (s, 3H), 5.06 (s, 2H), 6.91 (m, 3H), 7.05 (d, J = 8.41 Hz, 1H),
7.11 (s, 1H), 7.29-7.47 (m, 5H), 7.72 (d, J = 8.05,1H)
B. 3'-[4-benzyloxy-3-methylphenyl]-3'-[4-hydroxymethyl-3-methylphenyl]pentane.
Using a procedure analogous to Example 13B, 3'-[4-benzyloxy-3-methylphenyl]-
3'-[4-methoxycarbonyl-3-methylphenyl]pentane gives the title compound (6.0 g, quant).
]H NMR 400 MHz (DMSO-d6): 8 0.54 (t, J = 7.2 Hz, 6H), 2.02 (q, J = 7.2 Hz, 4H), 2.12
(s, 3H), 2.17 (s, 3H), 4.42 (d, J = 6.0 Hz, 2H), 4.94 (t, J = 5.6 Hz, 1H), 5.05 (s, 2H), 6.87-
6.94 (m, 5H), 7.19 (d, J = 8.0 Hz, 1H), 7.31 (d, J = 7.6, 1H), 7.38 (t, J = 7.2 Hz, 2H),
7.44(d, J = 7.2 Hz, 2H)
High Res. FAB-MS: 388.2397; calc. for C27H32O2: 388.2402.
C. 3'-[4-(3-oxo-4,4-dimethylpentyl)-3-methylphenyl]-3 '-[4-benzyloxy-3-
methylphenyl]pentane.
To a 0 °C mixture of 3'-[4-benzyloxy-3-methylphcnyl]-3'-(4-hydroxymcthyl-3-
methyiphcnyi]pentanc (6.0 g, 15.4 mmol) and Et2O (40 ml) is added PBr3 (1.6 ml, 17.0
mmol). The reaction is stirred for 2 h and allowed to warm to RT. The reaction is diluted
with Et2O, washed with minimal amount of water, brine, Na2SO4 dried, concentrated, and
azeotrope to dryness with toluene. The resulting residue is dissolved in THF (4 ml) and
cooled to -78 °C to afford the bromidc/THF solution. In a separate flask is charged with
1M LiHMDS (31 ml, 30.8 mmol), cooled to -78 C, and added pinacolone (3.9 ml, 30.8
mmol). The reaction is stirred for 1.5 h, warmed to -55 C and transferred (via syringe) to
the -78 °C solution of bromidc/THF. The reaction is allowed to warm to RT and stirred
for 16 h. The reaction is diluted with Et2O and washed with IN HC1. The organic layer
is Na2SO4 dried and chromatographed (70% CHC13/Hex) to give the title compound (5.2
g, 71%).
1H NMR 400 MHz (DMSO-d6): 5 0.48 (t, J = 7.6 Hz, 6H), 0.97 (s, 9H), 1.93 (q , J - 7.2
Hz, 4H), 2.05 (s, 3H), 2.13 (s, 3H), 2.60 (t, J - 8.0 Hz, 2H), 2.69 (t, J = 8.4 Hz, 2H), 4.98
(d, J = 4.4 Hz, 2H), 6.77-6.84 (m, 5H), 6.90(d, J = 8.0 Hz, 1H), 7.24-7.26 (m, 1H), 7.32 (t,
J = 7.2 Hz, 2H), 7.38 (d, J - 7.2 Hz, 2H).
D. 3'-[4-(3-oxo-4,4-dimethylpenty])-3-mcthylphenyl]-3'-[4-hydroxy-3-
methylphenyljpentanc.
Using a procedure analogous to Example 6D, 3'-f4-(3-oxo-4,4-dimethylpcntyl)-3-
methylphenyl]-3'-f4-benzyloxy-3-methylphcnyl]pentanc gives the title compound (3.1 g.
74%).
1H NMR 400 MHz (DMSO-d6): d 0.51 (t, J = 6.8 Hz, 6H), 1.03 (s, 9H), 1.96 (q, J = 7.2
Hz, 4H), 2.03 (s, 3H), 2.19 (s, 3H), 2.66 (t, J = 6.4 Hz, 2H), 2.74 (t, J = 6.4 Hz, 2H), 6.61
(d, J = 8.0 Hz, 1H), 6.73 (dd, J = 2.0 Hz, J = 8.0 Hz, 2H), 6.83-6.86 (m, 2H), 6.95(d, J =
8.0 Hz, 1H), 8.97 (s, J = 8.0 Hz, 1H).
E. 3'-[4-(3-oxo-4,4-dimethylpentyl)-3-methylphenyl]-3'-[4-(trifluromethylsulfonyloxy)-
3 -methylphenyl]pentane.
Using a procedure analogous to Example 1C, 3'-[4-(3-oxo-4,4-dimethylpentyl)-3-
methylphenyl]-3'-[4-hydroxy-3-methylphenyl]pentane gives the title compound (4.2 g,
quant).
1H NMR 400 MHz (DMSO-d6): 8 0.53 (t, J = 7.2 Hz, 6H), 1.03 (s, 9H), 2.05 (q , J = 7.2
Hz, 4H), 2.21 (s, 3H), 2.27 (s, 3H), 2.66 (t, J = 8.4 Hz, 2H), 2.74 (t, J = 8.0 Hz, 2H), 6.84
(dd, J = 1.6 Hz, J = 6.4 Hz, 1H), 6.91 (s, 1H), 7.00(d, J = 7.6 Hz, 1H), 7.07 (dd, J = 2.0
Hz, J = 6.4 Hz, 1H), 7.21-7.24 (m, 2H).
ES-MS: 530.25 (M+NH4).
F. 3'-[4-(3-oxo-4,4-dimethylpentyl)-3-methylphenyl]-3'-[4-(methoxycarboxyl)-3-
methylphenyl]pentane.
Using a procedure analogous to Example 1E, 3'-[4-(3-oxo-4,4-dimethylpentyl)-3-
methylphenyl]-3'-[4-(trifluoromethylsulfonyloxy)-3-methylphenyl]pentane-gives the title
compound as a white foam (2.1 g, 67%).
1H NMR 400 MHz (DMSO-d6): 5 0.53 (t, J = 7.2 Hz, 6H), 1.03 (s, 9H), 2.07 (q, J = 7.2
Hz, 4H), 2.20 (s, 3H), 2.46 (s, 3H), 2.69 (t, J = 7.6 Hz, 2H), 2.75 (t, J = 6.4 Hz, 2H), 3.78
(s, 3H), 6.84 (d, J = 8.4 Hz, 1H), 6.88 (s, 1H), 6.98(d, J = 8.0 Hz, 1H), 7.03 (dd, J = 1.6
Hz, J = 6.8 Hz, 1H), 7.08 (s, 1H), 7.70 (d, J = 8.4 Hz, 1H).
High Res ES(+)MS m/z: 440.3167; calc. for C28H38O3 + NH4: 440.3165
G. 3'-[4-(3-oxo-4,4-dimethylpentyl)-3-methylphenyi]-3'-[4-carboxyl-3-
methylphenyl]pentane.
Using a procedure analogous to Example 2, 3'-[4-(3-oxo-4,4-dimethylpentyl)-3-
methylphenyl]-3'-[4-(methoxycarboxyl)-3-methylphenyl]pentane gives the title
compound as a white foam (1.5 g, 97%).
1H NMR 300 MHz (DMSO-d6): 8 0.54 (t, J = 7.0 Hz, 6H), 1.03 (s, 9H), 2.07 (q, J = 6.6
Hz, 4H), 2.20 (s, 3H), 2.46 (s, 3H), 2.68 (d, J = 7.0 Hz, 2H), 2.73 (d, J = 5.9, 2H), 6.85-
6.90 (m, 2H), 6.99-7.06 (m, 3H), 7.72 (d, J = 8.4 Hz, 1H).
High Res ES(+)MS m/z: 426.3003; calc. for C27H36O3 + NH4: 426.3008
Example 55
Preparation of racemic 3'-[4-(3-hydroxy-4,4-dimethylpentyl)-3-methylphenyl]-3'-[4-
carboxyl-3-methylphenyl]pentane.
Using a procedure analogous to Example 1D, 3'-[4-(3-oxo-4,4-dimethylpentyl)-3-
methylphenyl]-3'-[4-carboxyl-3-methylphenyl]pentane gives the title compound as a
white foam (1.5 g, quant).
1H NMR 300 MHz (DMSO-d6): d 0.54 (t, J = 7.3 Hz, 6H), 0.80 (s, 9H), 1.30-1.36 (m,
1H), 1.58-1.64 (m,-lH), 2.07 (q , J = 6.9 Hz, 4H), 2.20 (s, 3H), 2.47 (s, 3H), 2.74-2.82 (m,
1H), 2.99-3.04 (m, 1H), 4.41 (d, J = 6.2, 1H), 6.85-6.89 (m, 2H), 7.02-7.08 (m, 3H), 7.72
(d,J = 8.0 Hz, 1H),
High Res ES(+)MS m/z: 428.3145; calc. for C27H38O3 + NH4: 428.3165
Compounds of the Invention - Salts. Stereoisomers. & Prodrups:
Salts of the compounds represented by formulae (I) are an additional aspect of the
invention. The skilled artisan will also appreciate that the family of compounds of
formulae I include acidic and basic members and that the present invention includes
pharmaceutically acceptable salts thereof.
In those instances where the compounds of the invention possess acidic or basic
functional groups various salts may be formed which are more water soluble and
physiologically suitable than the parent compound. Representative pharmaceutically
acceptable salts, include but are not limited to, the alkali and alkaline earth salts such as
lithium, sodium, potassium, ammonium, calcium, magnesium, aluminum, zinc, and the
like. Salts are conveniently prepared from the free acid by treating the acid in solution
with a base or by exposing the acid to an ion exchange resin. For example, a carboxylic
acid substituent on the compound of Formula I may be selected as -CO2H and salts may
be formed by reaction with appropriate bases (e.g., NaOH, KOH) to yield the
corresponding sodium and potassium salt.
Included within the definition of pharmaceutically acceptable salts are the
relatively non-toxic, inorganic and organic base addition salts of compounds of the
present invention, for example, ammonium, quaternary ammonium, and amine cations,
derived from nitrogenous bases of sufficient basicity to form salts with the compounds of
this invention (sec, for example, S. M. Berge, et al, "Pharmaceutical Salts," J. Phar. Sci..
66: 1-19 (1977)). Moreover, the basic group(s) of the compound of the invention may be
reacted with suitable organic or inorganic acids to form salts such as acetate,
benzenesulfonate, benzoate, bicarbonate, bisulfatc, bitartrate, boratc, bromide, camsylate,
carbonate, chloride, choline, clavulanate, citrate, chloride, chloroprocaine, choline,
dicthanolamine, dihydrochloride, diphosphate, edetate, cdisylate, estolate, esylate,
ethylencdiamine, fluoride, fumaratc, gluceptate, gluconate, glutamate, glycolylarsanilate,
hcxylresorcinatc, hydrabamine, bromide, chloride, hydrobromidc, hydrochloride,
hydroxynaphthoate, iodide, isothionatc, lactate, lactobionate, laurate, malate, maleate.
malscate, mandelatc, meglumine, mcsylatc, mesviate, methylbromde, methylnitrate,
methylsulfate, mucate, napsylate, nitrale, oleate, oxalate, palmitate, pamoate.
pantothenate, phosphate, polygalacturonate, procane, salicylate, stearate, subacetate,
succinate, sulfate, tannate, tartrate, teoclate, tosylate, trifluoroacetate, trifluoromethane
sulfonate, and valerate.
Certain compounds of the invention may possess one or more chiral centers and
may thus exist in optically active forms. Likewise, when the compounds contain an
alkenyl or alkenylene group there exists the possibility of cis- and trans- isomeric forms of
the compounds. The R- and S- isomers and mixtures thereof, including racemic mixtures
as well as mixtures of cis- and trans- isomers, are contemplated by this invention.
Additional asymmetric carbon atoms can be present in a substituent group such as an
alkyl group. All such isomers as well as the mixtures thereof are intended to be included
in the invention. If a particular stereoisomer is desired, it can be prepared by methods
well known in the art by using stereospecific reactions with starting materials which
contain the asymmetric centers and are already resolved or, alternatively by methods
which lead to mixtures of the stereoisomers and subsequent resolution by known
methods. For example, a chiral column may be used such as those sold by Daicel
Chemical Industries identified by the trademarks:
CHIRALPAK AD, CHIRALPAK AS, CHIRALPAK OD, CHIRALPAK OJ,
CHIRALPAK OA, CHIRALPAK OB, CHIRALPAK OC, CHIRALPAK OF,
CHIRALPAK OG, CHIRALPAK OK, and
CHIRALPAK CA-1.
By another conventional method, a racemic mixture may be reacted with a single
enantiomer of some other compound. This changes the racemic form into a mixture of
diastereomers. These diastereomers, because they have different melting points, different
boiling points, and different solubilities can be separated by conventional means, such as
crystallization.
Compounds of the Invention- Salts. Stereoisomers. & Prodrugs:
Salts of the compounds represented by formulae (I) are an additional aspect of the
invention. The skilled artisan will also appreciate that the family of compounds of
formulae I include acidic and basic members and that the present invention includes
. pharmaceutically acceptable salts thereof.
In those instances where the compounds of the invention possess acidic or basic
functional groups various salts may be formed which are more water soluble and
physiologically suitable than the parent compound. Representative pharmaceutically
acceptable salts, include but are not limited to, the alkali and alkaline earth salts such as
lithium, sodium, potassium, ammonium, calcium, magnesium, aluminum, zinc, and the
like. Salts are conveniently prepared from the free acid by treating the acid in solution
with a base or by exposing the acid to an ion exchange resin. For example, a carboxylic
acid substituent on the compound of Formula I may be selected as -CO2H and salts may
be formed by reaction with appropriate bases (e.g., NaOH, KOH) to yield the
corresponding sodium and potassium salt.
Included within the definition of pharmaceutically acceptable salts are the
relatively non-toxic, inorganic and organic base addition salts of compounds of the
present invention, for example, ammonium, quaternary ammonium, and aminc cations,
derived from nitrogenous bases of sufficient basicity to form salts with the compounds of
this invention (see, for example, S. M. Berge, et al, "Pharmaceutical Salts," J. Phar. Sci..
66: 1-19 (1977)). Moreover, the basic group(s) of the compound of the invention may be
reacted with suitable organic or inorganic acids to form salts such as acetate,
benzenesulfonatc, benzoate, bicarbonate, bisulfate, bitartrate, boratc, bromide, camsylate,
carbonate, chloride, choline, clavulanate, citrate, chloride, chloroprocaine, choline,
diethanolaminc, dihydrochloride, diphosphate, cdetate, edisylatc, estolatc, esylate,
ethylenediamine, fluoride, fumarate, gluceptate, gluconate, glutamate, glycolylarsanilatc,
hexylresorcinate, hydrabamine, bromide, chloride, hydrobromide, hydrochloridc,
hydroxynaphthoate, iodide, isothionate, lactatc, lactobionate, laurate, malate, maleate,
malseatc, mandelate, meglumine, mesylate, mesviate, methylbromide, methylnitratc,
methylsulfate, mucate, napsylate, nitrate, oleatc, oxalate, palmitate, pamoate,
pantothenate, phosphate, polygalacturonate, procane, salicylate, stearatc, subacctate,
succinate, sulfate, tannate, tartrate, teoclatc, tosylate, trifluoroacetate, trifluoromethane
sulfonatc, and valerate.
Certain compounds bf the invention may possess one or more chiral centers and
may thus exist in optically active forms. Likewise, when the compounds contain an
alkenyl or alkenylene group there exists the possibility of cis- and trans- isorneric forms ot
the compounds. The R- and S- isomers and mixtures thereof, including racemic mixtures
as well as mixtures of cis- and trans- isomers, are contemplated by this invention.
Additional asymmetric carbon atoms can be present in a substituent group such as an
alkyl group. All such isomers as well as the mixtures thereof are intended to be included
in the invention. If a particular stereoisomer is desired, it can be prepared by methods
well known in the art by using stereospecific reactions with starting materials which
contain the asymmetric centers and arc already resolved or, alternatively by methods
which lead to mixtures of the stercoisomers and subsequent resolution by known
methods. For example, a chiral column may be used such as those sold by Daicel
Chemical Industries identified by the trademarks:
CHIRALPAK AD, CHIRALPAK AS, CHIRALPAK OD, CHIRALPAK OJ,
CHIRALPAK OA, CHIRALPAK OB, CHIRALPAK OC, CHIRALPAK OF,
CHIRALPAK OG, CHIRALPAK OK, and
CHIRALPAK CA-1.
By another conventional method, a racemic mixture may be reacted with a single
enantiomer of some other compound. This changes the racemic form into a mixture of
diastereomers. These diastercomers, because they have different melting points, different
boiling points, and different solubilities can be separated by conventional means, such as
crystallization.
The present invention is also embodied in mixtures of compounds of formulae I.
Prodrugs are derivatives of the compounds of the invention which have chemically
or metabolically cleavablc groups and become by solvolysis or under physiological
conditions the compounds of the invention which are pharmaccutically active in vivo.
Derivatives of the compounds of this invention have activity in both their acid and base
derivative forms, but the acid derivative form often offers advantages of solubility, tissue
compatibility, or delayed release in a mammalian organism (see, Bundgard, H., Design of
Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives
well known to practitioners of the art, such as, for example, esters prepared by reaction of
the parent acidic compound with a suitable alcohol, or amides prepared by reaction of the
parent acid compound with a suitable amine. Simple aliphatic or aromatic esters derived
from acidic groups pendent on the compounds of this invention arc preferred prodrugs. In
some cases it is desirable to prepare double ester type prodrugs such as (acyloxy) alkyl
esters or ((alkoxycarbonyl)oxy)alkyl esters. Particularly preferred esters to use as
prodrugs are; methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl,
morpholinoethyl, and N,N-diethylglycolamido.
N,N-diethylglycolamido ester prodrugs may be prepared by reaction of the sodium
salt of a compound of Formula (I) (in a medium such as dimethylformamid6) with 2-
chloro-N,N-diethylacetamide (available from Aldrich Chemical Co., Milwaukee,
Wisconsin USA; Item No.25,099-6).
Morpholinylethyl ester prodrugs may be prepared by reaction of the sodium salt of
a compound of Formula (I) (in a medium such as dimethylformamid6) 4-(2-
chloroethyl)morpholine hydrochloride (available from Aldrich Chemical Co., Milwaukee,
Wisconsin USA, Item No. C5.220-3).
Morpholinylethyl ester prodrugs may be prepared by reaction of the sodium salt of
a compound of Formula I (in a medium such as dimethytformamid6) 4-(2-
chlorocthyl)morpholinc hydrochloride (available from Aldrich Chemical Co., Milwaukee,
Wisconsin USA, Item No. C5.220-3). The prodrugs, for example, may be prepared by
reaction of the sodium salt for a compound of Formula I with;
Also, lower alkyl (viz., C1-C8) ester prodrugs may be prepared by conventional
means such as reacting the sodium or potassium salt (derived by forming the salt of any
acidic compound of the invention, viz., reaction of a base such as KOH with an acidic
group such as CO2H) of a compound of Formula 1 with an alkyl iodide such as methyl
iodide, ethyl iodide, n-propyl iodide, isopropyl iodide. Typical ester prodrug substitucnts
are
Pharmaceutical Formulations containing the Novel Compounds of the Invention:
Pharmaceutical formulations of the invention are prepared by combining (e.g.,
mixing) a thcrapeutically effective amount of the compound of the invention
(compounds of Formula I) together with a pharmaceutically acceptable carrier or
diluent. The present pharmaceutical formulations arc prepared by known procedures
using well-known and readily available ingredients.
In making the compositions of the present invention, the compounds of
Formula I will usually be admixed with a carrier, or diluted by a carrier, or enclosed
within a carrier which may be in the form of a capsule, sachet, paper or other container.
When the carrier serves as a diluent, it may be a solid, semi-solid or liquid material
which acts as a vehicle, or can be in the form of tablets, pills, powders, lozenges,
elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid
medium), or ointment, containing, for example, up to 10% by weight of the
compound. The compounds of the present invention are preferably formulated prior to
administration.
The compounds of the invention may also be delivered by suitable formulations
contained in a transderm patch. Alternatively, the compounds of the invention may be
delived to a patient by sublingual administration.
For the pharmaceutical formulations any suitable carrier known in the art can be
used. In such a formulation, the carrier may be a solid, liquid, or mixture of a solid and a
liquid. Solid form formulations include powders, tablets and capsules. A solid carrier
can be one or more substances which may also act as flavoring agents, lubricants,
solubilisers, suspending agents, binders, tablet disintegrating agents and encapsulating
material.
Tablets for oral administration may contain suitable oxcipients such as calcium
carbonate, sodium carbonate, lactose, calcium phosphate, together with disintegrating
agents, such as maize, starch, or alginic acid, and/or binding agents, for example,
gelatin or acacia, and lubricating agents such as magnesium stearate, stearic acid, or
talc.
In powders the carrier is a finely divided solid which is in admixture with the
finely divided Active ingredient. In tablets the compound of Formula I is mixed with a
carrier having the necessary binding properties in suitable proportions and compacted in
the shape and size desired. The powders and tablets preferably contain from about 1 to
about 99 weight percent of the compound which is the novel compound of this invention.
Suitable solid carriers are magnesium carbonate, magnesium stearate, talc, sugar lactose,
pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl
cellulose, low melting waxes, and cocoa butter.
Sterile liquid form formulations include suspensions, emulsions, syrups and
elixirs.
The compounds of the invention may be dissolved or suspended in a
pharmaceutically acceptable carrier, such as sterile water, sterile organic solvent or a
mixture of both. The compounds can often be dissolved in a suitable organic solvent, for
instance aqueous propylene glycol. Other compositions can be made by dispersing the
finely divided compounds of the invention in aqueous starch or sodium carboxymethyl
cellulose solution or in a suitable oil.
Methods of Usinp the Compounds of the Invention:
Generic disease states benefited by treatment with the compounds of Formula I include,
but are not limited to:
disease states characterized by abnormal calcium regulation
disease states characterized by abnormal cell proliferation
disease states characterized by abnormal cell differentiation
disease states characterized by abnormal immune response
disease states characterized by abnormal dermatological conditions
disease states characterized by neurodegenerativc condition
disease states characterized by inflammation
disease states characterized by vitamin D sensitivity
disease states characterized by hyperproliferative disorders.
Specific disease states benefited by treatment of the compounds of formula I and II
include, but are not limited to:
Acne
Actinic keratosis
Alopecia
Alzheimer's disease
Bone maintenance in zero gravity
Bone fracture healing
Breast cancer
Chemoprovention of Cancer
Crohn's disease
Colon cancer
Type I diabetes
Host-graft rejection
Hypercalcemia
Type II diabetes
Leukemia
Multiple sclerosis
Myelodysplastic syndrome
Insufficient sebum secretion
Osteomalacia
Osteoporosis
Insufficient dermal firmness
Insufficient dermal hydration
Psoriatic arthritis
Prostate cancer
Psoriasis
Renal osteodystrophy
Rheumatoid arthritis
Scleroderma
Skin cancer
Systemic lupus crythcmatosus
Skin cell protection from Mustard vesicants
Ulccrative colitis
Vitiligo
Wrinkles
Particularly preferred is the treatment of psoriasis and osteoporosis by
administration to a mammal (including a human) of a therapeutically effective amount
of compounds of Formulae I. By "pharmaceutically effective amount" it is meant that
quantity of pharmaceutical agent corresponding to formulae I which prevents, removes
or reduces the deleterious effects of a disease state in mammals, including humans.
The specific dose of a compound administered according to this invention to
obtain therapeutic or prophylactic effects will, of course, be determined by the particular
circumstances surrounding the case, including, for example, the compound administered,
the route of administration and the condition being treated. Typical daily doses will
contain a pharmaceutically effective amount typically in the range of from about 0.0001
mg/kg/day to about 50 mg/kg/day of body weight of an active compound of this
invention. Preferably the dose of compounds of the invention will be from 0.0001 to 5
mg/kg/day of body weight.
Preferably compounds of the invention (e.g., per Formula I) or pharmaceutical
formulations containing these compounds are in unit dosage form for administration to
a mammal. The unit dosage form can be a capsule or tablet itself, or the appropriate
number of any of these. The quantity of Active ingredient in a unit dose of composition
may be varied or adjusted from about 0.0001 to about 1000 milligrams or more
according to the particular treatment involved. It may be appreciated that it is
necessary to make routine variations to the dosage depending on the age and condition
of the patient. Dosage will also depend on the route of administration. The compounds
of the inventiion may be administered by a variety of routes including oral, aerosol,
rectal, transdcrmal, sublingual, subcutaneous, intravenous, intramuscular, and
mtranasal. Particularly preferred is the treatment of psoriasis with an ointment type
formulation containing the compounds of the invention. The ointment formulation
may be applied as needed, typically lrom one to 6 times daily.
Treatment of psoriasis is preferably done with topical application by a
formulation in the form of a cream, oil, emulsion, paste or ointment containing a
therapeutically effective amount of a compound defined by Formula (I), and in
particular those compounds set out in Tables 1 or 2 or those compounds identified as
"AA" to "BQ", supra. The formulation for topical treatment contains from 0.5 to
0.00005 weight percent, preferably from .05 to 0.0005 weight percent, and most
preferably from 0.025 to 0.001 of a compound defined by formula (I).
For example, two semisolid topical preparations useful as vehicles for VDR
modulators in treatment and prevention of psoriasis are as follows:
Polyethylene Glycol Ointment USP (p. 2495)
Prepare Polyethylene Glycol Ointment as follows:
Polyethylene Glycol 3350 400 g.
Polyethylene Glycol 400 600 g.
To make 1000 g.
Heat the two ingredients on a water bath to 65C. Allow to cool, and stir
until congealed. If a firmer preparation is desired, replace up to 100 g of
the polyethylene glycol 400 with an equal amount of polyethylene glycol
3350.
Hvdrophilic Ointment USP (p. 1216)
Prepare Hydrophilic Ointment as follows:
Methylparaben 0.25 g.
Propylparaben 0.15 g.
Sodium Lauryl Sulfate 10 g.
Propylene Glycol 120 g.
Stearyl Alcohol 250 g.
White Petrolatum 250 g.
Purified Water 370 g.
To make about 1000 g.
The Stearyl Alcohol and White Petrolatum are melted on a steam bath, and
wanned to about 75C. The other ingredients, previously"dissolved in the water are added,
warmed to 75C, and the mixture stirred until it congeals.
For each of the above formulations the compound of formula (I) is added during
the heating step in an amount that is from 0.5 to 0.00005 weight percent, preferably from
.05 to 0.0005 weight percent, and most preferably from 0.025 to 0.001 weight percent of
the total ointment weight. (Source: - United States Pharmacopoeia 24, United States
Pharmacopeial Convention, 1999)
Conventional therapy for osteoporosis includes; (i) estrogens, (ii) androgens, (iii)
calcium supplements, (iv) vitamin D metabolites, (v) thiazide diuretics, (vi) calcitonin,
(vii) bisphosphonates, (viii) SERMS, and (ix) fluorides (see, Harrison's Principles of
Internal Medicine, 13th edition, 1994, published by McGraw Hill Publ., ISBN 0-07-
032370-4, pgs.2172-77; the disclosure of which is incorporated herein by reference.).
Any one or combination of these conventional therapies may be used in combination with
the method of treatment using compounds of Formulae I as taught herein. For example,
in a method of treating osteoporosis, the vitamin D receptor modulator compounds of the
invention (e.g., as defined by formula I) may be administered separately or simultaneously
with a conventional therapy. Alternatively, the vitamin D receptor modulator compounds
of the invention may be combined with conventional therapeutic agents in a formulation
for treatment of osteoporosis such as set out below:
A formulation for treating osteoporosis comprising:
Ingredient (A1): a vitamin D receptor modulator represented by
formula (I), or a pharmaceutically acceptable salt or aliphatic ester
prodrug derivative thereof;
Ingredient (B1):
one or more co-agents that are conventional for treatment
osteoporosis selected from the group consistulg of:
a. estrogens,
b. androgens,
c. calcium supplements,
d. vitamin D metabolites,
e. thiazide diuretics,
f. calcitonin,
g. bisphosphonates,
h. SERMS, and
i- fluorides.
Ingredient (C1): optionally, a carrier or diluent.
Typically useful formulations are those wherein the weight ratio of (A1) to (B1) is from
10:1 to 1:1000 and preferably from 1:1 to 1:100.
Combination Therapy for Psoriasis:
Conventional therapy for psoriasis includes topical glucocorticoids, salicylic acid,
crude coal tar, ultraviolet light, and methotrexate (see, Harrison's Principles of Internal
Medicine, 13th edition, 1994, published by McGraw Hill Publ., ISBN 0-07-032370-4,
pgs.2172-77). Any one or combination of these conventional therapies may be used in
combination with the method of treatment using compounds of Formulae I as taught
herein. For example, in a method of treating osteoporosis, the vitamin D receptor
modulator compounds of the invention (e.g., as defined by formula I) may be topically
administered separately or simultaneously with a conventional therapy. Alternatively, the
vitamin D receptor modulator compounds of the invention may be combined with
conventional therapeutic agents in a topically applied formulation for treatment of
osteoporosis such as set out below:
A formulation for treating osteoporosis comprising:
Ingredient (A2): a vitamin D receptor modulator represented by
formula (I), or a pharmaceutically acceptable salt or aliphatic ester
prodrug derivative thereof;
Ingredient (B2):
one or more co-agents that are conventional for treatment
osteoporosis selected from the group consisting of:
a. topical glucocorticoids ,
b. salicylic acid, or
c. crude coal tar.
Ingredient (C2): optionally, a carrier or diluent.
Typically useful formulations are those wherein the weight ratio of (A2) to (B2) is from
1:10 to 1:100000 and preferably from 1:100 to 1:10000.
Explanation of Table 5 and 6 column numerical superscripts:
1. Test Compound numbers refer to the products of the corresponding Example
Nos. that is, compounds within the scope of the invention. For example, the number "Ex.
2" refers to the compound, 3'-[4-(2-hydroxy-3,3-dimcthylbutoxy) -3-methylphenyl]-3'-[5-
mcthoxycarbonyl-4-methylthiophen-2-yl]pcntane, prepared in Example 2. The control
experiments are done with the double letter coded compounds identified as follows:
"AA" = 1a,25-dihydroxyvitamin D3
"BB"= 3-(4-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-
propyl}-2-methyl-phenoxy)-propanc-1,2-diol
"CC" = 1 -(4- {1 -[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methy1-phenyl]-cyclohexyl} -
2-mcthyl-phenoxy)-3,3-dimethyl-butan-2-one
"DD" = compound represented by the formula:
3. The VDR CTF (Caco-2 cells) test is described in the "Assay" section of the
Description, infra.
4. The OCN Promoter test is described in the "Assay" section of the Description,
infra.
5. The Mouse Hypercalcemia test is described in the "Assay" section of the
Description, infra.
6. The keratinocyte proliferation assay is described in the "Assay" section of
the Description, infra.
7. The IL-10 induction assay is described in the "Assay" section of the
Description, infra.
Assay Methods
Use of the Assay Methods;
The evaluation of the novel compounds of the invention for osteoporosis and other
related diseases is done using a plurality of test results. The use of multiple assays is
necessary since the combined properties of (i) high activity for the vitamin D receptor,
and (ii) prevention of hypercalcemia must be achieved to have utility for the methods of
treating diseases, which are also, aspects of this invention. Some of the tests described
below arc believed related to other tests and measure related properties of compounds.
Consequently, a compound may be considered to have utility in the practice of the
invention if is meets most, if not all, of the acceptance criteria for the above described
tests.
The evaluation of the novel compounds of the invention for psoriasis is done using
the Keratinocyte Proliferation Assay in combination with other assays that measure
inhibition of II--2 production and stimulation of IL-10 production in peripheral blood
mononuclear cells (PBMCs).
Brief Description. Utility and Acceptance Criteria for the Assay Methods:
1. The RXR-VDR heterodimcrAssav:
This assay provides the VDR activity of a test compound. It is
desirable to have low EC.50 values for a compound in this assay. The lower the KC50
value, the more active the compound will be as a VDR agonist. Desired assay results
are EC50 values less than or equal to 600 nM. Preferred assay results arc less than
250 nM, and most preferably less than 150 nM.
2. The Caco-2 cell Co-transfcction Assay:
The Caco-2 cell assay is an indicator for the undesirable condition of
hypercalcernia. This co-transfection assay is a surrogate assay for in vivo calcemic
activity of VDR ligands. It is desirable to have high EC50 values for a test compound
in this assay. The higher the EC50 values for a compound the less calcemic it will be
in vivo. Desired assay results are EC50 greater than or equal to 300 nM. Preferred
assay results are greater than 1000 nM.
3. The OCN (osteocalcini Promoter Assay
The OCN Promoter Assay is an indicator and marker for osteoporosis.
Desired assay results arc EC50 less than or equal to 325 nM. Preferred assay results
are less than 50 nM.
4. The Mouse Hypercalcemia Assay
The Mouse Hypercalcemia Assay is a six day hypcrcalcemia test for toxicity
and selectivity. Acceptable test results are levels greater than 300 ng/kg/day.
Preferred assay results are levels greater than 1000 ng/kg/day.
5. The Keratinocvte Proliferation Assay
This Assay is indicative for the treatment of psoriasis. An acceptable test result
is IC50 value of less than or equal to 300 nM. Preferred assay results are IC50 values
of less than 100 nM.
6. The IL-10 induction Assay
This is an in vitro efficacy assay for psoriasis, abscess and adhesion. Psoriasis involves
both keratinocytes and immune cells. II.-10 is a unique cytokinc because it is anti-
inflammatory and immunosuppressjve. This assay tells us whether a VDRM is able to
function as an agonist in PBMCs (primary blood mononuclcar cells) or not. A lower
EC50 value is desirable in this assay since a compound with a lower EC50 value will be a
better agonist in PBMCs. An acceptable test result is an EC50 value of less than 200 nM.
Preferred assay results are EC50 values of less than 100 nM.
7. Other Compound Assay Standards
An alternative measure of the therapeutic index (bone efficacy vx. Hypervcalcemia) of
compounds of the invention for treatment of osteoporosis is a numerical ratio
calculated as follows:
Dose Threshold needed to induce hypercalcemia
divided by
Dose Threshold needed for bone efficacy
An alternative measusre of the therapeutic index (in vivo keratinocyte proliferation vs.
hypercalcemia) of compounds of the invention for treatment of psoriasis is a
numerical ratio calculated as follows:
Dose Threshold needed to induce hypercalcemia
divided by
Dose Threshold needed to induce keratinocyte proliferation
For the above ratios, Dose Thresholds are determined from dose response curve data.
Details of the Assay Methods:
(1) Materials and Method for RXR-VDR Heterodimerization Assay:
Transfection Method:
• FuGENE 6 Transfection Reagent (Roche Cat # 1 814 443 )
Growth Media:
• D-MEM High Glucose (Gibco BRL Cat # 11054-020), 10% FBS, 1% antibiotic-
antimycotic (Ab-Am)
FBS heat inactivated (Gibco BRL Cat # 10092-147 )
Ab-Am (Gibco BRL Cat # 15240-062 )
Cells:
• Grow SaOs-2 cells in T-152 cm2 culture flasks in growth media.
'• Keep the density at 5-6 x 105 cells/ml
• Passage cells 1:3 twice a week
• Add Trypsin EDTA (Gibco BRL Cat # 25300-020)and incubate
• Resuspend cells in plating media and transfer into growth media.
Wash Media:
• HBSS Low Glucose Without Phenol Red (Gibco BRL Cat U 14175-095), 1% Ab-Am
Plating Media:
• D-MEM Low Glucose Without Phenol Red (Gibco BRL Cat # 11054-020), 1% Ab-Am
D-MEM
Stripped FBS (Hyclone Cat# SH3OO68.O3 Lot#AHM9371)
Ab-Am
Transfection / Treatment Media:
• D-MEM Low Glucose Without Phenol Red only
T-152 cm2 culture flask:
• Use Corning Coastar T-152 cm2 culture flask (Cat # 430825) to grow the cells
Flat well Plates:
• Use well plate to plate cells
• Use Deep well plate sterile to make up treatment media.
Luciferase Assay Reagent:
• Use Steady-Glo Luciferase Reagent from Promega (Cat # E2550) Consists of:
a. E2533 Assay Substrate, lyopholized product and
b. E2543 Assay Buffer.
• Thaw at room temperature
• Store
DAY 1: Cell Plating:
Cell Harvesting
Aspirate media from culture flask, rinse cells with HBSS and aspirate.
Add trypsin and incubate.
When cells appear detached, resuspend cells in growth media.
Transfer into a new flask with fresh growth media for passaging the cells.
Plate well plates and two extra plates
I) Cell Count
Mix the cell suspension using pipette
Use Hematocytometer to count the cells
Load cell suspension onto the bemocytometer chamber
Count cells.
Plate seeding:
Use plating media 10 % Stripped FBS in D-MEM Low Glucose, Without Phenol Red, 1%
Ab-Am
Plate 14 plates @ 165 µl/ well.
In sterile flask add cell suspension
to plating media.
Mix.
Add cells / well.
Place the cells in the incubator.
Cells should be about 75 % confluent prior to transfection.
Step 1:DNA and Media
Add plain DMEM media to tubes for mixing the DNA
Add the Reporter gene pFR-LUC
Add the Gal4-RXR-DEF and VP16-VDR-LBD
Step 2: FuGENE and Media
Prepare plain DMEM media in a ubes for mixing FuGENE
Add FuGENE 6 Transfection Reagent
Incubate
Step 3: FuGENE , DNA and Media Complex
Add FuGENE Media complex from step 2 to DNA Media complex from step l
Incubate
Step 4: FuGENE , DNA and Media Complex to-well plate
Add FuGENE-DNA-Media complex from step 3 to each plate
Incubate.
Day 3: Dosing
Treatment preparation
Allow for transfection time
Make a stock solution of the compounds in DMSO
Vortex until all the compounds has been dissolved.
Further dilute in D-MEM (Low Glucose - With out Phenol Red)
Add compounds in quadruplicate to give final volume
Incubate.
Day 4: Luciferase Assay
Read the plates after drug treatment
Remove part of media from all the wells and leave remainder
Add Steady-Glo Luciferase Reagent mixture / wells
Incubate
Count each well using a Luminescence counter, Top Count NXT by Packard
Set a delay between plates to reduce the background.
(2) Materials and Method for The Caco-2 Cell Assay:
Caco-2 cells, grown in phenol red free, DMEM (Invitrogen, Carlsbad, CA)
containing 10 % charcoal-stripped FCS (Hyclone, Logan, UT), were transfectcd
with Fugcne 6 reagent (Roche Diagnostics, Indianapolis, IN). Cells (5000/wcll)
were plated 18 h before transfection in a 96 well plate. The Cells were transfectcd
with Gal4-responsive reporter pFRLuc (150 ng, Stratagenc, La Jolla CA) and the
receptor expression vector pGal4-VDR-LBD (10 ng), along with Fugene 6
reagent (0.2 µl/well). The DNA-Fugenc complex was formed by incubating the
mixture for 30 min at room temperature. The cells were transfected in triplicate
for 5 h, and treated with various concentrations of VDR ligands (form 0.01 nM to
10,000 nM concentration range) 18h post-transfcction. The luciferase activity
was quantified using Steady-Glo reagent kit (Promcga, Madison, Wl) as per
manufacturer's specifications.
(31 Materials and Method for The OCN Promoter Assay:
The activation of ostcocalcin by VDR ligands was evaluated in a rat
osteoblast-like cell line RG-15 (ROS 17/2.8) stably expressing rat osteocalcin
promoter fused with luciferasc reporter gene. The stable cell lines were
established as reported before (Activation of Osteocalcin Transcription involves
interaction of protein kinase A- and Protein kinase C-dependent pathways.
Boguslawski, G., Hale, L. V., Yu, X.-P., Miles, R. R., Onyia, J. E., Santerrc R.
F., Chandrasekhar, S. J Biol. Chem. 275, 999-1006,2000). Confluent RG-15
cells maintained in DMEM/F-12 medium (3:1) containing 5% FBS, 300 Gg/ml
G418 and at 37°C under 5% CO2/95% air atmosphere were trypsinized (0.25%
trypsin) and plated into white opaque 96-well cell culture plates (25000
cells/well). After 24 hr, cells (in DMEM/F-12 medium + 2% FBS) were treated
with various concentrations of compounds, dissolved in DMSO. The final
DMSO concentration remained at 0.01% (v/v). After 48 hr treatment, the
medium was removed, cells were lysed with 50 ?l of lysis buffer (From
Luciferase reporter assay system, Roche Diagnostics, Indianapolis, IN) and
assayed for luciferase activity using the Luciferase Reporter Gene Assay kit from
Boehringer Mannheim as per manufacturer's specifications.
(41 Materials and Method for The Mouse Hvpercalcemia Assay:
Weanling, virus -antibody-free, five to six weeks old female DBF mice (Harlan,
Indianapolis, IN) are used for all the studies. Animals are allowed to acclimate to local
vivarium conditions for 2 days. Mice are maintained on a 12 hr light/dark cycle at 22°C
with ad lib access to food (TD 5001 with 1.2% Ca and 0.9%P Teklad, Madison, WI) and
water. The animals then are divided into groups with 4-5 mice per group. Different doses
of test compounds prepared in 10% Ethanol and 90% sesame oil are administered to mice
orally via gavage for 6 days. 1a-25(OH)2D3 0.5µg/kg/d was also given to one group of
mice as the positive control. Serum ionized calcium is evaluated at 6 hours after the last
dosing under isoflurane anesthesia by Ciba-Coming Ca +/PH Analyzer, (Model 634,
Chiron Diagnostics Corp., Kast Walpole, MA). Raw data of group differences is assessed
by analysis of variance (ANOVA) using Fisher's protected least significant difference
(PLSD) where the significance level was P (5) The Keratinocvte Proliferation Assay:
KERtr cells (Human skin keratinocyte transformed with a retrovirus vector,
obtained from ATCC) were plated in 96-well flat-bottomed plates (3000 cells/well) in 100
?1 keratinocyte serum free medium supplemented with bovine pituitary extract in the
absence of EGF (Life Technologies, Rockville, MD) and incubated at 37°C for two days.
The cells were treated with various concentrations of VDR ligands (ten-fold serial
dilution from 10,000 nM to 0.1 nM in triplicate), dissolved in 100 Dl keratinocyte serum
free medium supplemented with bovine pituitary extract in the absence of EGF and
incubated at 37°C for 72hr. BrdU (5-bromo-2'-deoxyuridine) incorporation was analyzed
as a measure of DNA replication (Cell proliferation ELISA kit, Roche Diagnostics,
Indianapolis, IN) and absorbance was measured at 405 run. Potency values (IC50) values
were determined as the concentration (nM) of compound that elicited a half-maximal
response.
(6) Materials and Method for human IL-10 Induction Assay:
Isolation of peripheral blood mononuclear cells (PBMCs):
A. Collect 50 ml of human blood and dilute with media, RPMI-1640.
B. Prepare sterile tubes with ficol.
C. Add diluted blood to tubes.
D. Centrifuge.
E. Discard the top layer and collect the cells from middle layer.
F. Divide all cells into four tubes and add media.
G. Centrifuge.
H. Aspirate off media and resuspend.
I. Collect all cells
J. Centrifuge, at 1200 rpm for 10 minutes.
K. Resuspend in RPMI-1640 with 2% FBS and count cells
Stimulation of PBMC:
L. Prepare TPA in DMSO.
M. Dissolve PHA in water .
N. Plate TPA/PHA treated PBMCs in well plates.
O. Incubate.
Treatment:
P. Prepare all compound dilutions in plain RPMI- 1640 media.
Q. Add diluted compound.
R. Incubate.
Sample Collection and assay:
S. Remove all the cells by centrifugation and assay the supernatant for IL-10 by
immunoassay.
1) T. Perform EL-10 assay using anti-human IL-10 antibody coated beads, as
described by the manufacturer (Linco Research Inc., St. Charles, MO).
WE CLAIM:
1. A compound or a pharmaceutically acceptable salt or an ester derivative Liereof
selected from C-1 to C-55:
6. The compound of claims 1, and 2-4 wherein the ester derivative is a methyl ester,
ethyl ester N,N-diethylglycolamido ester or morpholinylethyl ester.
7. The salt derivative of a compound as claimed in any one of claims 1, and 2-5
wherein the salt is sodium or potassium.
8. A pharmaceutical formulation comprising a compound as claimed in any one of
claims 1, and 2-7 together with a pharmaceutically acceptable carrier or diluent.
9. A formulation comprising a vitamin D receptor modulator as claimed in claims 1.
and 2-7 along with one or more co-agents selected from the group comprising of
estrogens, androgens, calcium supplements, vitamin D metabolites, thazide duretics.
calcitonin, bisphosphonates SERMS, and fluorides optionally along with a carrier or
diluent.
10. The formulation of claim 9 wherein the weight ratio of vitramin D receptor
modulator and co-agent is from 10:1 to 1:1000.
The present invention relates to novel, non-secosteroidal, diaryl compounds with vitamin D receptor (VDR) modu-
lating activity that are less hypercalcemic than la,25 dihydroxy vitamin D3. These compounds are useful for treating bone disease
and psoriasis.

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Patent Number 225187
Indian Patent Application Number 01191/KOLNP/2005
PG Journal Number 45/2008
Publication Date 07-Nov-2008
Grant Date 05-Nov-2008
Date of Filing 21-Jun-2005
Name of Patentee ELI LILLY AND COMPANY
Applicant Address LILLY CORPORATE CENTER, INDIANAPOLIS, IN 46285
Inventors:
# Inventor's Name Inventor's Address
1 BUNEL, EMILIO, ENRIQUE 2991 TOPAZ LANE, CARMEL, IND 46032
2 GAJEWSKI, ROBERT, PETER 1501 FRIENDSHIP DRIVE, INDIANAPOLIS, IN 46217
3 JONES, CHARLES, DAVID 223 BRUNSWICK AVENUE, INDIANAPOLIS, IN 46227
4 LU JIANLIANG 11921 CASTLESTONE DRIVE, FISHERS, IN 46039
5 MA, TIANWEI 5676 SAPPHIRE DRIVE, CARMEL, IN 46033
6 NAGPAL, SUNIL 5258 COMANCHE TRAIL, CARMEL, IN 46033
7 YEE, YING, KWONG 5127 BRIARSTONE TRACE, CARMEL, IN 46033
PCT International Classification Number C07C 59/90, 62/24
PCT International Application Number PCT/US2003/035055
PCT International Filing date 2003-11-20
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/429,041 2002-11-22 U.S.A.