Title of Invention

PROCESS FOR PRODUCING CARBAPENEM COMPOUND FOR ORAL ADMINISTRATION.

Abstract The present invention provides a process for efficiently producing a 1B-methylcarbapenem compound for oral administration. The process, which is for producing a 1B-methylcarbapenem compound represented by general formula (2)IS CHARACSTERIZED BY reacting a B-lactam compound represented by general formula (1) as a starting material with a thiol compound (R3-SH) in the presence of a base and optionally eliminating the protective group R1. In the formula (1) and (2), R1 denotes a hydrogen atom, a trimethylsilyl group or a triethylsilyl group; R2 denotes an alkyl group hlaving a 1 to 10 carbon atoms or a cycloalkyl group having 3 to 10 carbon atoms, R3 denotes as organic group; and R4 denotes hydrogen, a trimethylsilyl group or a triethylsilyl group .
Full Text Description
PROCESS FOR PRODUCING CARBAPENEM COMPOUND FOR ORAL
ADMINISTRATION
Technical Field
The present invention relates to an efficient and
extremely useful process for producing a 1b-methylcarbapenem
compound for oral administration.
Background Art
A lP-methylcarbapenem compound is one of the
antibacterial agents attracting the most attention because
it shows an excellent antibacterial effect on a wide variety
of pathogenic organisms and is excellent in stability in vivo.
Accordingly, various research and development have been made
energetically in recent years attempting to produce the drugs
for oral administration. Processes for producing a
lP-methylcarbapenem compound for oral administration, which
are generally used at present, include the following processes.
For example, there is described a process in Japanese
Unexamined Patent Application Publication No. 8-53453 and J.
Antibiot., p. 429-439, 1997, which comprises the steps of
reacting a compound represented by formula (6):
with each of various thiol compounds (R-SH) to synthesize a
compound represented by formula (7):
wherein R denotes a thiol residue; eliminating a p-nitrobenzyl
group, a protective group, from the compound represented by
formula (7) , for example, by hydrogenolysis or reduction by
a zinc powder to convert it to a compound represented by formula
(8):
wherein R denotes a thiol residue; and subjecting the
carboxylic moiety of the resulting compound (8) to
pivaloyloxymethylation to produce a compound represented by
formula (9):
wherein R denotes a thiol residue, and But denotes a tert-butyl
group.
As the compounds represented by formula (9) , for example,
in Japanese Unexamined Patent Application Publication Nos.
8-53453 and 10-19507 6 is described a compound represented by
formula (10):
; in J. Antibiot., P. 429-439, 1997 and Japanese Unexamined
Patent Application Publication No. 10-130270 is described a
compound represented by formula (11):
; and in Japanese Unexamined Patent Application Publication
No. 10-152491 is described a compound represented by formula
(12) :
All of these compounds are synthesized by the above-described
process.
However, when 1b-methylcarbapenem compound for oral
administration is produced by these production processes, it
is necessary to exchange the protecting group of carboxylic
acid through multistep reactions, which is ineffective; and
relatively expensive thiol compounds, each of which is related
to a thiol residue in a final product, are used in the initial
stage of synthesis, which is disadvantageous in terms of
production cost. These have been regarded as problems in the
above production processes.
Furthermore, in Japanese Unexamined Patent Application
PublicationNos. 8-59663 and2000-344774 is describedaprocess
for producing a compound represented by formula (15):
wherein R5 denotes a hydroxy-protecting group; R6 denotes a
thiol residue contained in a 1b-methylcarbapenem compound,
a product; and R7 denotes an organic group,
by the steps of synthesizing a compound represented by
formula (14):
wherein R5, R6 and R7 each denote the same as described above;
and R8, R9 and Ro each denote a lower alkoxy group having 1
to 4 carbon atoms, or any one of R8, R9 and Ro denotes an alkyl
group having 1 to 4 carbon atoms and remaining two each denote
a lower alkoxy group having 1 to 4 carbon atoms,
from a compound represented by formula (13):
wherein R5, R6 and R7 each denote the same as described above,
and
cyclizing the compound represented by formula (14).
However, in this production process also, relatively
expensive thiol compounds, each of which is related to a thiol
residue in a final product, are used in the initial stage of
synthesis in the same manner as described above. Therefore,
the process is also disadvantageous in terms of production
cost, which has been regarded as a problem.
Furthermore, in J. Org. Chem., vol. 61, P. 7889-7894,
1996 and Japanese Unexamined Patent Application Publication
No. 5-279367 is described a compound represented by formula
(16):
wherein Me denotes a methyl group; and But denotes the same
as described above. It may be considered that the compound
is converted to a lP-methylcarbapenem compound by allowing
it to react with any of various thiol compounds and by
deprotection of a hydroxy group. However, since a
tert-butyldimethylsilyl group is used as the
hydroxy-protecting group in the above compound (16), it is
necessary to use a reagent that influences other functional
groups in order to perform deprotection at the hydroxylic
moiety, as illustrated in Protective Groups in Organic
Synthesis (J Wiley & Sons, New York), P. 44-46, 1981. This
is a problem in terms of yields or the like. The present
inventors have made various studies on the method of
deprotection, and have found that it is difficult to perform
deprotection easily and efficiently.
Under the circumstances as described above, the
development of a efficient process for producing a
lP-methylcarbapenem compound for oral administration,
wherein the process is advantageous in terms of production
cost, has been desired.
Summary of the Invention
In view of the above circumstances, the present inventors
have extensively studied on the development of a production
process in which a thiol compound can be introduced by one
step at the final stage of the synthesis of a
1b-methylcarbapenem compound for oral administration. As a
result of the extensive study, the present invention has been
accomplished.
Specifically, the present invention provides a process
for producing a compound represented by general formula (2) :
wherein R2 denotes an alkyl group having 1 to 10 carbon atoms
or a cycloalkyl group having 3 to 10 carbon atoms; R3 denotes
an organic group; and R4 denotes a hydrogen atom, a
trimethylsilyl group or a triethylsilyl group,
characterized by reacting a compound represented by
general formula (1):
wherein R1 denotes a hydrogen atom, a trimethylsilyl group
or a triethylsilyl group; R2 denotes the same as described
above,
with a thiol compound represented by general formula (3) :
R3-SH (3)
wherein R3 denotes the same as described above,
in the presence of a base and optionally eliminating the
protective group R1.
Detailed Disclosure of the Invention
The present invention will now be described in detail
below.
The present invention provides a process for producing
a compound represented by general formula (2):
, characterized by reacting a compound represented by general
formula (1):
with a thiol compound represented by general formula (3):
R3-SH (3)
in the presence of a base and optionally eliminating the
protective group R1.
Substituents in each compound will first be described.
The substituent R1 denotes a hydrogen atom, a trimethylsilyl
group or a triethylsilyl group. When the substituent R1 is
a hydrogen atom, there is obtained a compound (2) in which
the substituent R4 is a hydrogen atom. On the other hand,
from the compound (1) in which the substituent R1 is a
trimethylsilyl group or a triethylsilyl group, there is
produced a compound (2) in which the substituent R4 is a
trimethylsilyl group or a triethylsilyl group. In this case,
the compound (2) having the substituent R4 which is obtained
as a product is different from the conventionally known
compound represented by (16) as described above in that it
can easily deprotect the hydroxy group to obtain the compound
(2) having a hydrogen atom as the substituent R4. The
substituent R1 is selected such that, when the compound (2)
obtained as a product is subjected to deprotection reaction,
it can be eliminated under a mild condition with minimum
decomposition of other functional group moieties in the
compound to the extent possible.] In order to facilitate the
deprotection, when the substituent R1 is a hydroxy-protecting
group, it needs to be a trimethylsilyl group or a triethylsilyl
group, preferably a trimethylsilyl group.
The substituent R2 denotes an alkyl group having 1 to
10 carbon atoms or a cycloalkyl group having 3 to 10 carbon
atoms, which may be contained in the alkanoyloxymethyl group
portion of a carboxylate residue in a compound that may finally
be developed as a lp-methylcarbapenem compound for oral
administration.
Examples of the alkyl group having 1 to 10 carbon atoms
include methyl, ethyl, n-propyl, iso-propyl, n-butyl,
iso-butyl, sec-butyl, tert-butyl, n-octyl, n-decanyl and the
like.
The cycloalkyl group having carbon atoms of 3 to 10 may
have a substituent, which includes an alkyl group having carbon
atoms of 1 to 4 such as methyl and ethyl, and the like. Examples
of the cycloalkyl group having carbon atoms of 3 to 10 include
cyclopropyl, cyclohexyl, 1-methylcyclohexyl,
4-methylcyclohexyl and the like.
As the substituent R2, a tert-butyl group, which is often
used in the development of a carbapenem compound for oral
administration, is most preferred among others.
The substituent R3 denotes an organic group, which may
preferably be contained in the thiol residue in a compound
that may finally be developed as a lfi-methylcarbapenem compound
for oral administration. More preferably, examples of the
thiol residue of a thiol compound represented by general
formula (3):
R3-SH (3)
(wherein R3 denotes an organic group) include the thiol residue
of a compound which is described in Japanese Unexamined Patent
Application Publication No. 8-53453, represented by formula
(4) :
; the thiol residue of a compound which is described in J.
Antibiot., P. 429-439, 1997, represented by formula (5):
; and the thiol residue of a compound which is described in
Japanese Unexamined Patent Application Publication No.
10-152491, represented by formula (19):
The substituent R3 is preferably the thiol residue of
a compound represented by formula (4) or the thiol residue
of a compound represented by formula (5).
The substituent R4 denotes a hydrogen atom, a
trimethylsilyl group or a triethylsilyl group. As described
above, when the substituent R4 is a trimethylsilyl group or
a triethylsilyl group, a l(3-methylcarbapenem compound for oral
administration can be easily obtained by eliminating it as
necessary.
A production process of the present invention will now
be described.
The compound represented by formula (1), which is the
starting raw material to be used in the present invention,
can be derived from a compound represented by formula (17) :
wherein R" denotes an aryl group or a heteroaryl group, which
may have a substituent, examples of which are described in
detail as reference examples 1 to 4. The compound represented
by formula (17) can be easily prepared according to the
description in Chem. Pharm. Bull., vol. 42, P. 1381-1387, 1994.
The compound (1) is reacted with the thiol compound
represented by formula (3) in the presence of a base to obtain
a lP-methylcarbapenem compound represented by formula (2).
The reaction is performed in an inert solvent which does
not decompose the compound (1) . Examples of the inert solvent
include, but not limited to, ether solvents such as
tetrahydrofuran, dioxane and diethyl ether; aromatic
hydrocarbon solvents such as benzene, toluene andxylene; amide
solvents such as N,N-dimethylformamide and
N,N-dimethylacetamide; dimethyl sulfoxide, acetonitrile,
acetone, methylene chloride and mixed solvents thereof, and
the like. Most preferred are N,N-dimethylformamide,
N,N-dimethylacetamide and acetonitrile, in terms of reaction
rate.
The molar amount of the thiol compound (3) to be used
in the reaction needs to be 1.0 time or more as compared to
that of the compound (1), preferably from 1.1 to 3.0 times.
The thiol compound (3) may form a salt such as a hydrochloride.
Furthermore, the base to be usedmay include organic amines,
alkalimetal salts, alkali metal alkoxides, alkalimetal amides,
alkali metal hydrides and the like.
Examples of the organic amines include triethylamine,
diisopropylethylamine, 4-dimethylaminopyridine,
1, 8-diazabicyclo[ 5.4.0] -undec-7-ene (DBU) ,
l,5-diazabicyclo[ 4.3. 0]-non-5-ene (DBN) , and
l,4-diazabicyclo[ 2.2.2] octane (DABCO) . When organic amines
are used, the molar amount of the same to be used needs to
be 1.0 time or more as compared to that of the compound (1),
preferably from 1.1 to 3.0 times.
Examples of the alkali metal salts include alkali metal
carbonates such as sodium carbonate, potassium carbonate and
cesium carbonate; alkali metal bicarbonates such as sodium
bicarbonate and potassium bicarbonate; and the like. When
the alkali metal carbonates are used, the molar amount of the
same to be used needs to be 0.5 time or more as compared to
that of the compound (1), preferably from 1.1 to 2.0 times.
When the alkali metal bicarbonates are used, the molar amount
of the same to be used needs to be 1.0 time or more as compared
to that of the compound (1) , preferably from 1.1 to 2.0 times.
Examples of the alkali metal alkoxides include potassium
tert-butoxide, sodium tert-butoxide and the like. When the
alkali metal alkoxides are used, the molar amount of the same
to be used needs to be 1.0 time or more as compared to that
of the compound (1), preferably 1.1 to 2.0 times.
Examples of the alkali metal amides include lithium
bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide,
potassium bis(trimethylsilyl)amide and the like. When the
alkali metal amides are used, the molar amount of the same
to be used needs to be 1.0 time or more as compared to that
of the compound (1), preferably 1.1 to 2.0 times.
Examples of the alkali metal hydrides include sodium
hydride, potassiumhydride and the like. When the alkali metal
hydrides are used, the molar amount of the same to be used
needs to be 1. 0 time or more as compared to that of the compound
(1), preferably 1.1 to 2.0 times.
The above reaction is performed typically in the range
of -78°C to 60°C, preferably in the range of -40°C to 40°C in
order to inhibit decomposition of the reactants and products.
Furthermore, the reaction time is typically in the range
of 5 minutes to 40 hours, preferably in the range of one hour
to 30 hours from the above reason.
Naturally, the progress of the reaction with time can
be obtained by analytic means such as thin layer chromatography
(TLC) and high-performance liquid chromatography (HPLC).
The target compound (2) can be isolated from the mixture
after the reaction through operations such as pH-adjustment,
extraction, liquid separation, washing, concentration,
purification and the like, which are frequently used in typical
organic reactions.
When the substituent R1 of the compound (1) is a hydrogen
atom, the compound (2) having a hydrogen atom as the substituent
R4 can be obtained in the above reaction. Thus, a
1b-methylcarbapenem compound for oral administration can be
directly obtained.
On the other hand, when the substituent R1 is a
trimethylsilyl group or a triethylsilyl group, the resulting
compound (2) has a trimethylsilyl group or a triethylsilyl
group as the substituent R4, respectively. The above
hydroxy-protecting group (a trimethylsilyl group or a
triethylsilyl group) as the substituent R1 is selected as a
substituent which can be easily eliminated. Accordingly,
when pH of the mixture after the reaction is adjusted in the
operation such as extraction, washing or the like, the
deprotection of the hydroxylic moiety can be performed at the
same time as the operation by creating an acidic condition
in the mixture. Thus, the compound (2) having a trimethylsilyl
group or a triethylsilyl group as the substituent R4 can be
easily converted to the compound (2) having a hydrogen atom
as the substituent R4, thereby obtaining a 1b-methylcarbapenem
compound for oral administration.
The acidic condition to be used in the above operation
is not particularly limited as long as the pH is 7 or less,
and the pH is preferably in the range of 2 to 6. In this pH
range, the hydroxy-protecting group can be eliminated
extremely easily. In order to achieve the above acidic
condition, for example, an aqueous citric acid solution,
hydrochloric acid or the like can be added to the extract or
the like.
Furthermore, when the substituent R4 is a trimethylsilyl
group or a triethylsilyl group, the compound (2) may be once
isolated from the reaction mixture to eliminate it separately.
In addition to the above-described method, typical conditions
for eliminating silyl protecting groups, as described, for
example, in "Protective Groups in Organic Synthesis" (J Wiley
& Sons, New York), pp. 39-50, 1981, can be adopted as the
deprotection method in this case.
A 1b-methylcarbapenem compound represented by formula
(2) can be synthesized efficiently and easily in short steps
from a compound represented by formula (1) and a thiol compound
represented by formula (3) according to the present invention.
The present invention provides a preferable process as a
process in which a thiol compound represented by formula (4)
or (5) is particularly used as the thiol compound represented
by formula (3) to synthesize a lP-methylcarbapenem compound
for oral administration represented by formula (10):
Best Mode for Carrying Out the Invention
The present invention will now be described in more detail
below with reference to examples and reference examples, but
is not particularly limited at all to these descriptions. The
meaning of the abbreviations used in the following examples
and reference examples is as follows:
Me: methyl group
But: tert-butyl group
TMS: trimethylsilyl group
TES: triethylsilyl group
Reference Example 1: Production of
(3S,4S)-4-[ (1R) -l-(p-chlorophenylthiocarbonyl) ethyl] -3-[ (
1R)-1-hydroxyethyl] -1-pivaloyloxymethyloxycarbonylmethyl-
2-azetidinone
In 18 ml of dimethylformamide, was dissolved 8 .18 g (22 . 0
mmol) of
(3S,4S)-l-carboxymethyl-4-[ (1R)-1-(p-chlorophenylthiocarb
onyl) ethyl] -3-[ (1R) -1-hydroxyethyl] -2-azetidinone at room
temperature. To the resulting solution, were successively
added 5.5 ml (40.0 mmol) of pivaloyloxymethyl chloride and
5.75 g (40.3 mmol) of sodium iodide, and was added dropwise
4.2 ml (25.3 mmol) of diisopropylethylamine, followed by
stirring the mixture for 20 hours at the same temperature.
The reaction mixture was diluted with 120 ml of toluene. The
toluene solution was washed with 2.5% aqueous sodium
bicarbonate solution and water, each several times. The
resulting toluene solution was dried over sodium sulfate, and
then the solvent was removed by evaporation. The resulting
oily residue was dissolved in 60 ml of toluene at room
temperature. To the resulting solution was added 120 ml of
hexane, precipitating a crystal, which was filtered and washed
to obtain 9. 46 g of a white crystal of the title compound (yield:
92.7%).
NMR8 (CDC13) : 1.19 (9H, s) , 1.32-1.34 (6H, m) , 3.11-3.18 (2H,
m) , 3.87 (1H, d, J = 18.1 Hz) , 4.15 (1H, dd, J = 2.4, 4.4 Hz) ,
4.22-4.24 (1H, m), 4.35 (1H, d, J= 18.1 Hz), 5.7 6 (2H, s),
7.31 (2H, d, J = 8.8 Hz), 7.40 (2H, d, J = 8.8 Hz)
Reference Example 2: Production of
(4R, 5R, 6S)-6-[ (lR)-l-trimethylsilyloxyethyl] -3-diphenylph
osphoryloxy-4-methyl-7-oxo-l-azabicyclo[ 3.2.0] hept-2-ene-
2-carboxylic acid pivaloyloxymethyl ester
In 20 ml of toluene, was dissolved 1.997 g (4.1 iranol)
of
(3S,4S)-4-[ (lR)-l-(p-chlorophenylthiocarbonyl) ethyl] -3-[ (
1R)-1-hydroxyethyl] -1-pivaloyloxymethyloxycarbonylmethyl-
2-azetidinone which was synthesized in the same manner as in
Reference Example 1. To the resulting solution, was added
0.88 mL (6.4 mmol) of triethylamine and was dropwise added
0.78 mL (6.2 mmol) of trimethylsilyl chloride at room
temperature, followed by stirring the mixture for 15 hours
at the same temperature. The reaction mixture was diluted
with 5 ml of toluene. The toluene solution was washed with
water several times. The resulting toluene solution was dried
over sodium sulfate, and then the solvent was removed by
evaporation.
To 2.63 g of the resulting oily residue, was added 22.5
.ml of tetrahydrofuran to dissolve the oily residue. The
solution was cooled to -70°C, andO.956g (8.5mmol) ofpotassium
tert-butoxide was added to the cooled solution, followed by
stirring the mixture for 15 minutes. Then, 0.26mL (4.2mmol)
of methyl iodide was added to the mixture at the same temperature.
The resulting mixture was stirred for 25 minutes while
gradually raising the temperature to -35°C, followed by adding
1. 0 mL (4.9 mmol) of diphenylphosphoryl chloride to the mixture
at -35°C. The resulting mixture was stirred for 1.8 hours
while gradually raising the temperature to -9°C. The reaction
mixture was diluted with 20 ml of toluene. The toluene solution
was washed with 2.5% aqueous sodium bicarbonate solution and
water, each several times under cooling with ice. The
resulting toluene solution was dried over sodium sulf ate, and
then the solvent was removed by evaporation to obtain the title
compound.
High-performance liquid chromatography was used as the
means for tracking the progress of the reaction for the purpose
of analysis. The reaction mixture and the titled compound
obtained were analyzed by dissolving them in an eluant which
was prepared by mixing acetonitrile/water/phosphoric acid in
a ratio of 700/300/1. As a result, a compound was detected
at the same retention time as that of the product to be described
in Reference Example 3. This revealed that the trimethylsilyl
group as a hydroxy-protecting group was easily eliminated.
NMR8 (CDC13) : 0.11 (9H, s), 1.19-1.29 (15H, m) , 3.24 (1H, dd,
J = 2.9, 6.6 Hz) , 3.45-3.50 (1H, m) , 4.07-4.19 (2H, m) , 5.78
(1H, d, J = 5.5 Hz) , 5.81 (1H, d, J = 5.5 Hz) , 7.15-7.40 (12H,
m)
Reference Example 3: Production of
(4R,5R,6S)-6-[ (1R)-1-hydroxyethyl] -3-diphenylphosphorylox
y-4-methyl-7-oxo-l-azabicyclo[ 3.2.0] hept-2-ene-2-carboxyl
ic acid pivaloyloxymethyl ester
In 5 ml of toluene, was dissolved 0.97 g (2.0 mmol) of
(3S/4S)-4-[ (lR)-l-(p-chlorophenylthiocarbonyl) ethyl]-3-[ (
1R)-1-hydroxyethyl] -1-pivaloyloxymethyloxycarbonylmethyl-
2-azetidinone which was synthesized in the same manner as in
Reference Example 1. To the resulting solution, was added
0.50 g (5.0 mmol) of triethylamine and was dropwise added 0. 39
g (3.6 mmol) of trimethylsilyl chloride at room temperature,
followed by stirring the mixture for 15 hours at the same
temperature. The reaction mixture was diluted with toluene.
The toluene solution was washed with water several times. The
resulting toluene solution was dried over sodium sulfate, and
then the solvent was removed by evaporation.
To the resulting oily residue, was added 15 ml of a mixed
solvent composed of tetrahydrofuran and toluene in a volume
ratio of 1 to 2 to dissolve the oily residue. The solution
was cooled to -25°C, and 0.475 g (4.2 mmol) of potassium
tert-butoxide was added to the cooled solution, followed by
stirring the mixture for one hour. Then, 0.30 g (2.1 mmol)
of methyl iodide was added to the mixture at the same temperature.
The resulting mixture was stirred for 20 minutes, followed
by adding 0.60 g (2.2 mmol) of diphenylphosphoryl chloride
to the mixture. The resulting mixture was stirred for 2.5
hours.
To the reaction mixture, were added ethyl acetate and
water under cooling with ice. The mixed solution was adjusted
to pH 3 with aqueous IN hydrochloric acid. The ethyl acetate
solution, which was obtained by phase separation, was washed
with aqueous sodium bicarbonate solution and water, each
several times. Then, the resulting solution was dried over
sodium sulfate, and the solvent was removed by evaporation
to obtain the title compound.
NMR8 (CDC13) : 1.18-1.20 (12H, m) , 1.29 (3H, d, J = 4.9 Hz),
3.28 (1H, dd, J = 2.4, 6.3 Hz) , 3.45-3.51 (1H, m) , 4.17-4.21
(2H, m) , 5.77 (1H, d, J = 5.5 Hz) , 5.81 (1H, d, J = 5.5 Hz) ,
7.21-7.40 (12H, m)
Reference Example 4: Production of
(4R, 5R, 6S)-6-[ (lR)-l-triethylsilyloxyethyl] -3-diphenylpho
sphoryloxy-4-methyl-7-oxo-l-azabicyclo[ 3.2.0] hept-2-ene-2
-carboxylic acid pivaloyloxymethyl ester
In 10 ml of toluene, was dissolved 0.493 g (1.0 mmol)
of
(3S,4S)-4-[ (1R) -l-(p-chlorophenylthiocarbonyl) ethyl] -3-[ (
1R) -1-hydroxyethyl] -1-pivaloyloxymethyloxycarbonylmethyl-
2-azetidinone which was synthesized in the same manner as in
Reference Example 1. To the resulting solution, was added
0.17 g (1.7 mmol) of triethylamine and was dropwise added 0.24
g (1.6 mmol) of triethylsilyl chloride at room temperature,
followed by stirring the mixture for 22 hours at the same
temperature. The reaction mixture was diluted with 10 ml of
toluene. The toluene solution was washed with water several
times. The resulting toluene solution was dried over sodium
sulfate, and then the solvent was removed by evaporation.
To the resulting oily residue, was added 6 ml of
tetrahydrofuran to dissolve the oily residue. The solution
was cooled to -25°C, and 0.232 g (2.1 mmol) of potassium
tert-butoxide was added to the cooled solution, followed by
stirring the mixture for 60 minutes. Then, 0.19 g (1.05 mmol)
of benzyl bromide was added to the mixture at the same
temperature. The resulting mixture was stirred for 20 minutes,
followed by adding 0.30 g (1.1 mmol) of diphenylphosphoryl
chloride to the mixture. The resulting mixture was stirred
for 2 hours. The reaction mixture was diluted with 50 ml of
toluene. The toluene solution was washed with 2.5% aqueous
sodiumbicarbonate solution and water, each several times under
cooling with ice. The resulting toluene solution was dried
over sodium sulfate, and then the solvent was removed by
evaporation to obtain the title compound.
NMR8 (CDC13) : 0.59-0.62 (6H, m) , 0.94 (9H, t, J = 8.1 Hz),
1.19-1.28 (15H, m) , 3.23 (1H, dd, J = 2.9, 6.6 Hz) , 3.42-3.46
(1H, m) , 4.13 (1H, dd, J = 2.9, 10.3 Hz) , 4.18-4.23 (1H, m) ,
5.78 (1H, d, J = 5.5 Hz) , 5.81 (1H, d, J = 5.5 Hz) , 7.15-7.43
(12H, m)
Example 1: Production of
pivaloyloxymethyl(1R,5S,6S)-2-[ 1-(1,3-thiazolin-2-yl)azet
idin-3-yl] thio-6-[ (1R)-1-hydroxyethyl] -1-methyl-carbapen-
2-em-3-carboxylate
In 15 ml of acetonitrile, was dissolved 4 . 53 g of a yellow
oily residue containing
(4R,5R, 6S)-6-[ (lR)-l-trimethylsilyloxyethyl] -3-diphenylph
osphoryloxy-4-methyl-7-oxo-l-azabicyclo[ 3.2.0] hept-2-ene-
2-carboxylic acid pivaloyloxymethyl ester synthesized in
Reference Example 2. To the resulting solution, was added
1.10 g (5.1 mmol) of a compound represented by formula (18) :
and was dropwise added 1.8 ml (10.3 mmol) of
diisopropylethylamine under cooling with ice, followed by
stirring the mixture for 1.9 hours at the same temperature.
After the completion of the reaction, the solvent was removed
by evaporation from the mixture, followed by adding 40 ml of
ethyl acetate and 100 ml of water. The resulting solution
was washed with aqueous potassium bicarbonate solution and
aqueous sodium bicarbonate solution. To the resulting ethyl
acetate solution, was added aqueous citric acid solution to
make the solution acidic, thereby extracting the target
compound into the water phase. It was extracted again into
the ethyl acetate phase by adding 50 ml of ethyl acetate and
potassium bicarbonate. The solvent was removed by
evaporation from the solution until the weight of the solution
is reduced to 12 g. To the resulting solution, was added 25
ml of heptane to precipitate a crystal, which was filtered
and washed to obtain 1.87 g of a white crystal containing the
title compound.
NMR8 (CDC13): 1.23 (9H, s), 1.23 (3H, d, J=7.1), 1.34 (3H,
d, J = 6.4 Hz) , 3.13-3.21 (1H, m) , 3.23 (1H, dd, J = 2.7, 6.8
Hz), 3.37 (2H, t, J = 7.6 Hz), 3.94-4.03 (4H, m), 4.10-4.26
(3H, m), 4.36-4.42 (2H, m), 5.84 (1H, d, J = 5.5 Hz), 5.97
(1H, d, J = 5.5 Hz)
Example 2: Production of
pivaloyloxymethyl(1R,5S,6S)-2-[ 1-(1,3-thiazolin-2-yl)azet
idin-3-yl] thio-6-[ (1R)-1-hydroxyethyl] -1-methyl-carbapen-
2-em-3-carboxylate
In 1 ml of acetonitrile, was dissolved 0.32 g of an oily
residue containing
(4R,5R,6S)-6-[ (1R)-1-hydroxyethyl] -3-diphenylphosphorylox
y-4-methyl-7-oxo-l-azabicyclo[ 3.2.0] hept-2-ene-2-carboxyl
ic acid pivaloyloxymethyl ester synthesized and purified in
the same manner as in Reference Example 3. To the resulting
solution, was added 0. 07 g (0.33mmol) of a compound represented
by formula (18):
and was dropwise added 0.09 g (0.70 mmol) of
diisopropylethylamine at -10°C, followed by stirring the
mixture for 3 hours at the same temperature. After the
completion of the reaction, 20 ml of ethyl acetate and 20 ml
of water was added to the reaction mixture. To the resulting
solution, was added aqueous citric acid solution to extract
the target compound into the water phase. It was extracted
again into the ethyl acetate phase by adding 20 ml of ethyl
acetate and potassium bicarbonate. The resulting solution
was dried over sodium sulf ate, and then the solvent was removed
by evaporation from the solution. The production of the title
compound was confirmed by NMR analysis.
Example 3: Production of
pivaloyloxymethyl (1R, 5S, 6S) -2-[ (3R) -5-oxopyrrolidin-3-yl]
thio-6-[ (1R)-1-hydroxyethyl] -l-methyl-carbapen-2-em-3-car
boxylate
In 15 ml of acetonitrile, was dissolved 4.32 g of an oily
residue containing
(4R, 5R, 6S)-6-[ (lR)-l-trimethylsilyloxyethyl] -3-diphenylph"
osphoryloxy-4-methyl-7-oxo-l-azabicyclo[ 3.2.0] hept-2-ene-
2-carboxylic acid pivaloyloxymethyl ester synthesized in the
same manner as in Reference Example 2. To the resulting
solution, was added 0. 57 g (4.9mmol) of a compound represented
by formula (5) :
and was dropwise added 0.79 g (6.1 mmol) of
diisopropylethylamineat 5°C, followed by stirring the mixture
for 70 minutes at the same temperature. After the completion
of the reaction, acetonitrile was removed by evaporation from
the mixture, followed by dissolving the resulting mixture in
40 ml of ethyl acetate. The resulting solution was washed
several times with aqueous sodium bicarbonate solution to
remove the byproduced diphenylphosphate. To the resulting
ethyl acetate solution, was added water and then aqueous IN
hydrochloric acid, until the solution has a pH of 3. The ethyl
acetate solution, which was obtained by liquid separation
operation, was washed with aqueous sodiumbicarbonate solution
and water, and then dried over sodium sulfate. The solvent
in the resulting solution was removed by evaporation, and the
residue was dissolved in 20 mL of acetone. To the resulting
solution, was added 30 mL of toluene. Acetone was gradually
removed by evaporation from the solution, and it was observed
that the resulting solution became cloudy. The cloudy
solution was stirred for one hour at a temperature in the range
of 0 to 5°, and the resulting solution was filtered and washed
to obtain a white crystal. The crystal was dissolved in acetone
again. The resulting solution was subj ected to the operations
of toluene addition, removal of the solvent by evaporation,
stirring, filtration and washing in the same manner as
described above to obtain 0.70 g of a white crystal containing
the title compound.
NMR8 (CDCI3): 1.22 (9H, s), 1.27 (3H, d, J=7.1), 1.32 (3H,
d, J = 6.3 Hz), 2.39 (1H, dd, J = 5.1, 17.1 Hz), 2.83 (1H,
dd, J=8.1, 17.1Hz), 3.26 (1H, dd, J = 2.4, 6.8Hz), 3.31-3.36
(1H, m), 3.84 (1H, dd, J = 8.1, 10.7 Hz), 4.01-4.06 (1H, m) ,
4.22-4.28 (2H, m), 5.82 (1H, d, J = 5.5 Hz), 5.96 (1H, d, J
= 5.5 Hz)
Example 4: Production of
pivaloyloxymethyl(1R,5S,6S)-2-[ (3R) -5-oxopyrrolidin-3-yl]
thio-6-[ (1R)-1-hydroxyethyl] -l-methyl-carbapen-2-em-3-car
boxylate
In 5 ml of acetonitrile, was dissolved 0.84 g of an oily
residue containing
(4R,5R, 6S)-6-[ (lR)-l-triethylsilyloxyethyl] -3-diphenylpho
sphoryloxy-4-methyl-7-oxo-l-azabicyclo[ 3.2.0] hept-2-ene-2
-carboxylic acid pivaloyloxymethyl ester synthesized in the
same manner as in Reference Example 4. To the resulting
solution, was added 0.12 g (l.Ommol) of a compound represented
by formula (5):
and was dropwise added 0.13 g (1.0 mmol) of
diisopropylethylamine at a temperature in the range of 0 to
5°C, followed by stirring the mixture for 3 hours at the same
temperature. After the completion of the reaction, 20 ml of
toluene and 20 ml of water were added to the reaction mixture,
and then aqueous IN hydrochloric acid was added to the resulting
solution, until the solution has a pH of 2. The toluene
solution, which was obtained by liquid separation operation,
was washed with aqueous sodiumbicarbonate solution and water,
and then dried over sodium sulfate. The solvent in the
resulting solution was removedby evaporation f romthe solution.
The production of the title compound was confirmed by NMR
analysis.
Industrial Applicability
The present invention enables efficient and easy
synthesis of various lP-methylcarbapenem compounds for oral
administration on which research and development have been
actively conducted in recent years, and therefore, the present
invention is industrially useful.
CLAIMS
1. A process for producing a compound represented by general
formula (2):
wherein R2 denotes an alkyl group having 1 to 10 carbon atoms
or a cycloalkyl group having 3 to 10 carbon atoms; R3 denotes
an organic group; and R4 denotes a hydrogen atom, a
trimethylsilyl group or a triethylsilyl group,
characterized by reacting a compound represented by
general formula (1):
wherein R1 denotes a hydrogen atom, a trimethylsilyl group
or a triethylsilyl group; R2 denotes the same as described
above,
with a thiol compound represented by general formula (3) :
R3-SH (3)
wherein R3 denotes the same as described above,
in the presence of a base and optionally eliminating the
protective group R1.
2. The production process according to claim 1, wherein R2
is a tert-butyl group.
3. The production process according to claim lor 2, wherein
R3 is the thiol residue of a thiol compound represented by
formula (4):
4 . The production process according to claim 1 or 2, wherein
R3 is the thiol residue of a thiol compound represented by
formula (5):
The present invention provides a process for efficiently
producing a 1?-methylcarbapenem compound for oral
administration. The process, which is for producing a
1?-methylcarbapenem compound represented by general formula
(2), is characterized by reacting a ?-lactam compound
represented by general formula (1) as a starting material with
a thiol compound (R3-SH) in the presence of a base and optionally
eliminating the protective group R1.
In the formulae (1) and (2) , R1 denotes a hydrogen atom, a
trimethylsilyl group or a triethylsilyl group; R2 denotes an
alkyl group having 1 to 10 carbon atoms or a cycloalkyl group
having 3 to 10 carbon atoms; R3 denotes an organic group; and
R4 denotes hydrogen, a trimethylsilyl group or a triethylsilyl
group.

Documents:

00826-kolnp-2005-abstract.pdf

00826-kolnp-2005-assignment.pdf

00826-kolnp-2005-claims.pdf

00826-kolnp-2005-correspondence.pdf

00826-kolnp-2005-description (complete).pdf

00826-kolnp-2005-form 1.pdf

00826-kolnp-2005-form 18.pdf

00826-kolnp-2005-form 3.pdf

00826-kolnp-2005-form 5.pdf

00826-kolnp-2005-gpa.pdf

00826-kolnp-2005-letter patent.pdf

00826-kolnp-2005-reply first examination report.pdf

826-KOLNP-2005-FORM-27.pdf


Patent Number 216892
Indian Patent Application Number 826/KOLNP/2005
PG Journal Number 12/2008
Publication Date 21-Mar-2008
Grant Date 19-Mar-2008
Date of Filing 06-May-2005
Name of Patentee KANEKA CORPORATION
Applicant Address 2-4, NAKANOSHIMA 3-CHOME, KITA-KU, OSAKA-SHI, OSAKA 530-8288
Inventors:
# Inventor's Name Inventor's Address
1 NISHINO KEITA C/O. KANEKA CORPORATION, TAKASAGO PLANT 1-8, TAKASAGOCHO, MIYAMAECHO TAKASAGO-SHI, HYOGO 676-8688
2 KOGA TERUYOSHI C/O. KANEKA CORPORATION, TAKASAGO PLANT 1-8, TAKASAGOCHO, MIYAMAECHO TAKASAGO-SHI, HYOGO 676-8688
PCT International Classification Number C07F 7/18
PCT International Application Number PCT/JP2003/014320
PCT International Filing date 2003-11-13
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 2002-330128 2002-11-13 Japan