Title of Invention	A PROCESS FOR THE MANUFATURE OF AN OPTIONALLY PROTECTED 4,8,8-TRIMETHYL-1-OXASPIRO (2.5) OCT-4-EN-6-01
Abstract	: A process for the manufacture of 4,8,8-trimethyl-l-(67) Abstract oxaspiro[2.5]oct-4-en-6-ol (I) by reacting the protected compound (II) with halogenated methyllithium and, if desired, cleaving off the protecting group from the thus-obtained -protected 4,8,8-trimethyl-l-oxaspiro {2.5] oet-4-en-6-ol. Both the starting material (II) and the end product (I) of the process in accordance with the invention are known, valuable intermediate for the manufacture of carotenoids.

Title of Invention

A PROCESS FOR THE MANUFATURE OF AN OPTIONALLY PROTECTED 4,8,8-TRIMETHYL-1-OXASPIRO (2.5) OCT-4-EN-6-01

Abstract

: A process for the manufacture of 4,8,8-trimethyl-l-(67) Abstract oxaspiro[2.5]oct-4-en-6-ol (I) by reacting the protected compound (II) with halogenated methyllithium and, if desired, cleaving off the protecting group from the thus-obtained -protected 4,8,8-trimethyl-l-oxaspiro {2.5] oet-4-en-6-ol. Both the starting material (II) and the end product (I) of the process in accordance with the invention are known, valuable intermediate for the manufacture of carotenoids.

Full Text	The present invention is concerned with a process for the conversion of a protected 4-hydroxy-2,6,6-trimethyl-2-cyclohexen-l-one (protected "phorenol") into the corresponding protected allylic epoxide 4,8,8-trimethyI-l-oxaspiro[2.5]octa-4-en-6-ol using a reagent which has never previously been used for this purpose. Both the starting material and the end product are known valuable intermediates for the manufacture of carotenoids. The method hitherto used for the aforementioned conversion (a "Ci-homologisation") involved dimethylsulphonium methylide as the reagent [see, for example, Pure & Appl. Chem. 51, 535-564 (1979), especially pages 546-547: 52 + 53 -> 54; as well as Helv. Chim. Acta 63,1451-1455 (1980), especially page 1452: 5. —> 6]. This reagent is, however, troublesome to produce and yields as a byproduct the olfactorily annoying dimethyl sulphide, which are serious disadvantages. The object of the present invention is to develop a process for the manufacture of the optionally protected 4,8,8-trimethyl-l-oxaspiro[2.5]octa-4-en-6-ol starting from a protected phorenol using an alternative reagent, and thereby to avoid the aforementioned disadvantages associated"with the use of dimethylsulphonium methylide. This object is achieved by using a halogenated methyllithium as the reagent in the Ci-homologisation. Compared with the previously used reagent the use of the halogenated methyllithium also saves costs. Accordingly the present, invention provides a process for the manufacture of an optionally protected 4,8,8-trimethyl-1-oxaspirof 2 . 5] oot-4~en-6~nl of the general formula I wherein R signifies hydrogen or a known protecting group for hydroxy, comprising the Rteps of reacting a protected 4-hydroxy 2,R,B~trimethyl-2-oyolohexen-1 nnf of the general formula Tl with halogenated methyllithium and if deBired, cleaving off Raid protecting group R from the thus obtained protected 4,8,8-trimethy1-1-oxaBpiro \2.5loot-en-6-ol by known means and isolating said oxaepiro [2.51 oct-en-6-ol from the reaction mixture by known methods1. The term "protecting group for hydroxy" used above embraces usual protecting groups for hydroxy groups situated in the respective structural environment, especially protecting groups familiar from the carotenoid field. Etherified hydroxy groups especially come into consideration as respective protected hydroxy groups. These are, for example, Ci-5-alkoxy groups, preferably methoxy and ethoxy; mono and dialkoxyalkoxy groups containing up to 16 carbon atoms, preferably 1 -methoxy- 1-methylethoxy [hydroxy having the so-called isopropenyl methyl ether ("IPM") protecting group] or dimethoxymethoxy; arylalkoxy groups, preferably benzyloxy; tetrahydropyranyloxy; and silyloxy groups, preferably trimethylsilyloxy and phenyldimethylsilyloxy. Where not further qualified above, the term "alkyl" embraces straight-chain and branched groups, preferably with 1-5 carbon atoms, such as, for example, methyl, ethyl, n-propyl, isopropyl, tert.butyl and the like. This also applies to the alkyl moiety of each "alkoxy". Where an aryl group is present, this is preferably phenyl, which is optionally substituted, e.g. with one or more Ci_5-alkyl and/or nitro groups. As a rule, however, unsubstituted phenyl is preferred. The IPM and the trimethylsilyl ("TMS") protecting groups are especially preferred protecting groups. Formulae I and II above are presented neutrally with respect to the isomeric form (configuration), but embrace all isomeric (especially optically isomeric) forms. In accordance with one embodiment of the process in accordance with the invention protected (S)-phorenol of formula II' is converted into protected (3S,6S)-4,8,8-trimethyl-l-oxaspiro[2.5]oct-4-en-6-ol of formula I' using the halogenated methyllithium: The Ci-homologisation according to the process in accordance with the invention is conveniently effected with halogenated methyllithium produced in situ, with the protected phorenol of formula II being reacted with a halogenated methane and with a lower alkyllithium. Fluorine, chlorine, bromine or iodine is suitable as the halogen for the dihalogenated methane [Hal in CH2(Hal)2] , with the two halogen atoms being the same or iifferent. Bromochloromethane is especially preferred in this case. As 'lower alkyl" of the lower alkyllithium there comes into consideration sspecially straight-chain or branched alkyl with up to 8 carbon atoms, such as, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.butyl, tert.butyl, pentyl, hexyl, heptyl and octyl. Ci-4-Alkyl is especially preferred, with n-butyl- or hexyllithium being a particularly preferred lower alkyllithium. This is usually used in solution in a lower alkane, preferably ftexane. The reaction of the dihalogenated methane with the lower alkyllithium produces the halogenated methyllithium, which thereupon reacts with the protected phorenol in the same reaction medium. For 3xample, chloromethyllithium is produced from bromochloromethane and n-butyllithium, with n-butyl bromide being produced as the byproduct. The Ci-homologisation (and the in situ production of the halogenated methyllithium) is, moreover, conveniently carried out in an aliphatic or cyclic ether as the solvent at temperatures of about -20°C to about -120°C, preferably of about -60°C to about -80°C. The solvent is, for example, diethyl sther or tert.butyl methyl ether or, respectively, tetrahydrofuran or dioxan. The reaction is preferably carried out in tetrahydrofuran. Conveniently, about 1 to 2, preferably about 1.1, equivalents of the dihalogenated methane as well as conveniently about 1 to 2, preferably about 1.5, equivalents of the lower alkyllithium are used per equivalent of protected phorenol. After completion of the epoxidation, which normally takes about 30 to about 60 minutes, the working up of the mixture conveniently comprises leaving it to warm, for example to the temperature range of about -70 to about -30°C, diluting with water or aqueous sodium chloride solution and extracting with a suitable organic solvent, conveniently that used for the reaction. After evaporation of the solvent and optional crystallization and/or other purification methods the product of formula I in which R signifies the protecting group R' is obtained in good purity. The protecting group present in the product obtained can, if desired, be cleaved off according to methods known per se, e.g. by hydrolysis with acid or base. Thereby, the 4,8,8-trimethyl-l-oxaspiro[2.5]oct-4-en-6-ol itself (compound of formula I in which R signifies hydrogen) is obtained. The product of formula I can be converted according to methods known per se in several reaction steps into useful end products, e.g. carotenoids and pharmaceuticals [see, for example, Pure & Appl. Chem. 51, 535-564 (1951)]. The invention is illustrated by the following Examples. Example 1 Preparation of acetone methvir(3S.6S)-4.8.8-trimethvl-l-oxaspirof2.51oct-4-en-6-yll acetal A solution of 2.00 g of (S)-4-(l-methoxy-l-methylethoxy)-2,6,6-trimethyl-2-cyclohexen-l-one and 1.25 g of bromoehloromethane in 20 ml of tetrahydrofuran, cooled to -80°C, was treated within 30 minutes with 8.3 ml of a 1.6 molar solution of n-butyllithium in hexane. The reaction mixture was then warmed to -35°C and treated with 15 ml of semi-saturated sodium chloride solution. The organic phase was separated, dried over anhydrous sodium sulphate and concentrated under reduced pressure. This gave 2.1 g i of acetone methyl[(3S,6S)-4,8,8-trimethyl-l-oxaspiro[2.5]oct-4-en-6-yl] acetal as a white solid, m.p. 53-59°C; after recrystallization from methanol, m.p. 65.2 cc Qnn Example 2 Preparation of (3R.6S)- and (3S.6S)-trimethvl-(4.8.8-trimethyl-l-oxaspiro-f2.51octa-4-en-6-yloxy)-silane starting from (4S)-4-hydroxv-2.6.6-trimethvl-2-cvclohexen-1-one via its TMS-protected form (one pot process) A solution of 22.1 g of (4S)-4-hydroxy-2,6,6-trimethyl-2-cyclohexen-l-one in 200 ml of tetrahydrofuran, cooled to -80°C, was treated within 40 minutes with 90 ml of a 1.6 molar solution of n-butyllithium in hexane and thereafter treated within 10 minutes with 20 ml of chlorotrimethylsilane. Then, 10.5 ml of bromochloromethane were added dropwise during 10 minutes and 134.5 ml of the 1.6 molar solution of n-butyllithium in hexane were added dropwise during one hour at -80°C, and the mixture was stirred for 20 minutes. The reaction mixture was warmed to -30°C and treated with 200 ml of semi-saturated sodium chloride solution. Then, the organic phase was separated, dried over anhydrous sodium sulphate and concentrated under reduced pressure. In this manner there were obtained 33.6 g of a thin-layer chromatographically pure mixture of (3R,6S)- and (3S,6S)-trimethyl-(4,8,8-trimethyl-l-oxaspiro[2.5]oct-4-en-6-yloxy)-silane. Mass spectrum: 240/3, M+; tic (SiC>2, hexane/ethyl acetate 1:1): Rf = 0.70. WE CLAIM: 1. A process for the manufacture of an optionally protected 4,8,8-trimethyl-l-oxaspiro[2.5] oct-4-en-6-ol of the general formula I wherein R signifies hydrogen or a known protecting group for hydroxy, comprising the steps of reacting a protected 4-hydroxy-2,6,6-trimethyl-2-cyclohexen-l one of the general formula II with halogenated methyllithium and if desired cleaving off said protecting group R from the thus obtained protected 4,8,8-trimethyl-1-oxaspiro [2.5]oct-en-6-ol by known means and isolating said oxaspiro [2.5] oet-en-6-ol from the reaction mixture by known methods. 2. The process as claimed in claim 1, wherein halogenated methyl 1ithium is produced in situ by adding dihalogenated methane and a lower alkyl lithium to the reaction mixture. 3. The process as claimed in claim 2, wherein the dihaloqenated methane is bromochloromethane. 4. The process as claimed in claim 2 or 3, wherein the lower alkyllithium is n-tauty or hexyl lithium. 5. The process as claimed in any one of claims i to 4, wherein the reaction is carried out in an aliphatic or cyclic ether as the solvent. 6. The process as claimed in claim 5, wherein tetrahydrofuran is used as the solvent. 7. The process as claimed in any one of claims 1 to 6, wherein the reaction is carried out at temperatures of about 20DC to about -120De, preferably of about -60°C to about -80°C. 8. The process as claimed in any one of claims 1 to 7, wherein the protecting group (R) for hydroxy is the isopropenyl methyl ether or trimethylsily1 protecting group. 9. The process as claimed in any one of claims 1 to 8, wherein the protected 4-hydroxy-2,6,6-trimethyl-2-cyclohexene -1- one is the optical isomer (S) 4-hydroxy-2,6,6~trimethyl-2- cyclohexen-1-one and is convertedd into protected optical isomer represented by (3S,6S)-4,8,8-trimethyl-l-oxaspiro [2,5] oct-4- en-6-ol. 10. A process for the manufacture of an optionally protected 4,8,8-trimethyl-l-oxaspiro [2.5] oct-4-en-8-01 substantially as herein described and exemplified.

Full Text

The present invention is concerned with a process for the conversion of a protected 4-hydroxy-2,6,6-trimethyl-2-cyclohexen-l-one (protected "phorenol") into the corresponding protected allylic epoxide 4,8,8-trimethyI-l-oxaspiro[2.5]octa-4-en-6-ol using a reagent which has never previously been used for this purpose. Both the starting material and the end product are known valuable intermediates for the manufacture of carotenoids.
The method hitherto used for the aforementioned conversion (a "Ci-homologisation") involved dimethylsulphonium methylide as the reagent [see, for example, Pure & Appl. Chem. 51, 535-564 (1979), especially pages 546-547: 52 + 53 -> 54; as well as Helv. Chim. Acta 63,1451-1455 (1980), especially page 1452: 5. —> 6]. This reagent is, however, troublesome to produce and yields as a byproduct the olfactorily annoying dimethyl sulphide, which are serious disadvantages.
The object of the present invention is to develop a process for the manufacture of the optionally protected 4,8,8-trimethyl-l-oxaspiro[2.5]octa-4-en-6-ol starting from a protected phorenol using an alternative reagent, and thereby to avoid the aforementioned disadvantages associated"with the use of dimethylsulphonium methylide. This object is achieved by using a halogenated methyllithium as the reagent in the Ci-homologisation. Compared with the previously used reagent the use of the halogenated methyllithium also saves costs.

Accordingly the present, invention provides a process for the manufacture of an optionally protected 4,8,8-trimethyl-1-oxaspirof 2 . 5] oot-4~en-6~nl of the general formula I

wherein R signifies hydrogen or a known protecting group for hydroxy, comprising the Rteps of reacting a protected 4-hydroxy 2,R,B~trimethyl-2-oyolohexen-1 nnf of the general formula Tl

with halogenated methyllithium and if deBired, cleaving off Raid protecting group R from the thus obtained protected 4,8,8-trimethy1-1-oxaBpiro \2.5loot-en-6-ol by known means and isolating said oxaepiro [2.51 oct-en-6-ol from the reaction mixture by known methods1.

The term "protecting group for hydroxy" used above embraces usual protecting groups for hydroxy groups situated in the respective structural environment, especially protecting groups familiar from the carotenoid field. Etherified hydroxy groups especially come into consideration as respective protected hydroxy groups. These are, for example, Ci-5-alkoxy groups, preferably methoxy and ethoxy; mono and dialkoxyalkoxy groups containing up to 16 carbon atoms, preferably 1 -methoxy- 1-methylethoxy [hydroxy having the so-called isopropenyl methyl ether ("IPM") protecting group] or dimethoxymethoxy; arylalkoxy groups, preferably benzyloxy; tetrahydropyranyloxy; and silyloxy groups, preferably trimethylsilyloxy and phenyldimethylsilyloxy.
Where not further qualified above, the term "alkyl" embraces straight-chain and branched groups, preferably with 1-5 carbon atoms, such as, for example, methyl, ethyl, n-propyl, isopropyl, tert.butyl and the like. This also applies to the alkyl moiety of each "alkoxy". Where an aryl group is present, this is preferably phenyl, which is optionally substituted, e.g. with one or more Ci_5-alkyl and/or nitro groups. As a rule, however, unsubstituted phenyl is preferred.
The IPM and the trimethylsilyl ("TMS") protecting groups are especially preferred protecting groups.
Formulae I and II above are presented neutrally with respect to the isomeric form (configuration), but embrace all isomeric (especially optically isomeric) forms. In accordance with one embodiment of the process in

accordance with the invention protected (S)-phorenol of formula II' is converted into protected (3S,6S)-4,8,8-trimethyl-l-oxaspiro[2.5]oct-4-en-6-ol of formula I' using the halogenated methyllithium:

The Ci-homologisation according to the process in accordance with the invention is conveniently effected with halogenated methyllithium produced in situ, with the protected phorenol of formula II being reacted with a halogenated methane and with a lower alkyllithium. Fluorine, chlorine, bromine or iodine is suitable as the halogen for the dihalogenated methane [Hal in CH2(Hal)2] , with the two halogen atoms being the same or iifferent. Bromochloromethane is especially preferred in this case. As 'lower alkyl" of the lower alkyllithium there comes into consideration sspecially straight-chain or branched alkyl with up to 8 carbon atoms, such as, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.butyl, tert.butyl, pentyl, hexyl, heptyl and octyl. Ci-4-Alkyl is especially preferred, with n-butyl- or hexyllithium being a particularly preferred lower alkyllithium. This is usually used in solution in a lower alkane, preferably ftexane. The reaction of the dihalogenated methane with the lower alkyllithium produces the halogenated methyllithium, which thereupon reacts with the protected phorenol in the same reaction medium. For 3xample, chloromethyllithium is produced from bromochloromethane and n-butyllithium, with n-butyl bromide being produced as the byproduct.
The Ci-homologisation (and the in situ production of the halogenated methyllithium) is, moreover, conveniently carried out in an aliphatic or cyclic ether as the solvent at temperatures of about -20°C to about -120°C, preferably of about -60°C to about -80°C. The solvent is, for example, diethyl sther or tert.butyl methyl ether or, respectively, tetrahydrofuran or dioxan. The reaction is preferably carried out in tetrahydrofuran.
Conveniently, about 1 to 2, preferably about 1.1, equivalents of the dihalogenated methane as well as conveniently about 1 to 2, preferably about

1.5, equivalents of the lower alkyllithium are used per equivalent of protected phorenol.
After completion of the epoxidation, which normally takes about 30 to about 60 minutes, the working up of the mixture conveniently comprises leaving it to warm, for example to the temperature range of about -70 to about -30°C, diluting with water or aqueous sodium chloride solution and extracting with a suitable organic solvent, conveniently that used for the reaction. After evaporation of the solvent and optional crystallization and/or other purification methods the product of formula I in which R signifies the protecting group R' is obtained in good purity.
The protecting group present in the product obtained can, if desired, be cleaved off according to methods known per se, e.g. by hydrolysis with acid or base. Thereby, the 4,8,8-trimethyl-l-oxaspiro[2.5]oct-4-en-6-ol itself (compound of formula I in which R signifies hydrogen) is obtained.
The product of formula I can be converted according to methods known per se in several reaction steps into useful end products, e.g. carotenoids and pharmaceuticals [see, for example, Pure & Appl. Chem. 51, 535-564 (1951)].

The invention is illustrated by the following Examples.
Example 1
Preparation of acetone methvir(3S.6S)-4.8.8-trimethvl-l-oxaspirof2.51oct-4-en-6-yll acetal
A solution of 2.00 g of (S)-4-(l-methoxy-l-methylethoxy)-2,6,6-trimethyl-2-cyclohexen-l-one and 1.25 g of bromoehloromethane in 20 ml of tetrahydrofuran, cooled to -80°C, was treated within 30 minutes with 8.3 ml of a 1.6 molar solution of n-butyllithium in hexane. The reaction mixture was then warmed to -35°C and treated with 15 ml of semi-saturated sodium chloride solution. The organic phase was separated, dried over anhydrous sodium sulphate and concentrated under reduced pressure. This gave 2.1 g i of acetone methyl[(3S,6S)-4,8,8-trimethyl-l-oxaspiro[2.5]oct-4-en-6-yl] acetal as a white solid, m.p. 53-59°C; after recrystallization from methanol, m.p. 65.2 cc Qnn

Example 2
Preparation of (3R.6S)- and (3S.6S)-trimethvl-(4.8.8-trimethyl-l-oxaspiro-f2.51octa-4-en-6-yloxy)-silane starting from (4S)-4-hydroxv-2.6.6-trimethvl-2-cvclohexen-1-one via its TMS-protected form (one pot process)
A solution of 22.1 g of (4S)-4-hydroxy-2,6,6-trimethyl-2-cyclohexen-l-one in 200 ml of tetrahydrofuran, cooled to -80°C, was treated within 40 minutes with 90 ml of a 1.6 molar solution of n-butyllithium in hexane and thereafter treated within 10 minutes with 20 ml of chlorotrimethylsilane. Then, 10.5 ml of bromochloromethane were added dropwise during 10 minutes and 134.5 ml of the 1.6 molar solution of n-butyllithium in hexane were added dropwise during one hour at -80°C, and the mixture was stirred for 20 minutes. The reaction mixture was warmed to -30°C and treated with 200 ml of semi-saturated sodium chloride solution. Then, the organic phase was separated, dried over anhydrous sodium sulphate and concentrated under reduced pressure. In this manner there were obtained 33.6 g of a thin-layer chromatographically pure mixture of (3R,6S)- and (3S,6S)-trimethyl-(4,8,8-trimethyl-l-oxaspiro[2.5]oct-4-en-6-yloxy)-silane. Mass spectrum: 240/3, M+; tic (SiC>2, hexane/ethyl acetate 1:1): Rf = 0.70.

WE CLAIM:
1. A process for the manufacture of an optionally protected 4,8,8-trimethyl-l-oxaspiro[2.5] oct-4-en-6-ol of the general formula I

wherein R signifies hydrogen or a known protecting group for hydroxy, comprising the steps of reacting a protected 4-hydroxy-2,6,6-trimethyl-2-cyclohexen-l one of the general formula II

with halogenated methyllithium and if desired cleaving off said protecting group R from the thus obtained protected 4,8,8-trimethyl-1-oxaspiro [2.5]oct-en-6-ol by known means and isolating said oxaspiro [2.5] oet-en-6-ol from the reaction mixture by known methods.

2. The process as claimed in claim 1, wherein halogenated
methyl 1ithium is produced in situ by adding dihalogenated methane and a lower alkyl lithium to the reaction mixture.
3. The process as claimed in claim 2, wherein the dihaloqenated methane is bromochloromethane.
4. The process as claimed in claim 2 or 3, wherein the lower alkyllithium is n-tauty or hexyl lithium.
5. The process as claimed in any one of claims i to 4, wherein the reaction is carried out in an aliphatic or cyclic ether as the solvent.
6. The process as claimed in claim 5, wherein
tetrahydrofuran is used as the solvent.
7. The process as claimed in any one of claims 1 to 6,
wherein the reaction is carried out at temperatures of about
20DC to about -120De, preferably of about -60°C to about -80°C.
8. The process as claimed in any one of claims 1 to 7,
wherein the protecting group (R) for hydroxy is the isopropenyl
methyl ether or trimethylsily1 protecting group.

9. The process as claimed in any one of claims 1 to 8,
wherein the protected 4-hydroxy-2,6,6-trimethyl-2-cyclohexene -1-
one is the optical isomer (S) 4-hydroxy-2,6,6~trimethyl-2-
cyclohexen-1-one and is convertedd into protected optical isomer
represented by (3S,6S)-4,8,8-trimethyl-l-oxaspiro [2,5] oct-4-
en-6-ol.
10. A process for the manufacture of an optionally
protected 4,8,8-trimethyl-l-oxaspiro [2.5] oct-4-en-8-01
substantially as herein described and exemplified.

Documents:

1743-mas-1997 abstract.pdf

1743-mas-1997 claims.pdf

1743-mas-1997 correspondence others.pdf

1743-mas-1997 correspondence po.pdf

1743-mas-1997 description (complete).pdf

1743-mas-1997 form-1.pdf

1743-mas-1997 form-13.pdf

1743-mas-1997 form-26.pdf

1743-mas-1997 form-4.pdf

1743-mas-1997 petition.pdf

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Patent Number

183388

Indian Patent Application Number

1743/MAS/1997

PG Journal Number

30/2009

Publication Date

24-Jul-2009

Grant Date

09-Jun-2000

Date of Filing

04-Aug-1997

Name of Patentee

M/S. F HOFFMANN-LA ROCHE AG

Applicant Address

124 GRENZACHERSTRASSE, CH 4070 BASLE

Inventors:

#	Inventor's Name	Inventor's Address
1	HANS HILPERT,	12 FASANENSTRASSE, CH-4153 REINACH,
2	ERICH WIDMER,	47 MITTELWEG, CH-4142 MUNCHENSTEIN,

PCT International Classification Number

C07D 303/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA