The present invention provides a process for the preparation of carbapenems.
(4R,5S,6S)-3-[[(3S,5S)-5-(Dimethylcarbamoyl)-3-pyrrolidinyl]thio]-6-[(1R)-1-hydroxy-ethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, commonly known as meropenem of Formula I is synthetic, broad-spectrum, carbapenem antibiotic.
(Formula Removed)
US Patent No 4,943,569 provides a process for the preparation of meropenem, which involves the reaction between enolphosphate of Formula II,
(Formula Removed)
and thiol side chain of Formula III in the presence of diisopropylethylamine,
(Formula Removed)
to provide a protected meropenem of Formula IV.
(Formula Removed)
The compound of Formula IV is then deprotected by using palladium catalyst to get meropenem.
The thiol side chain of Formula III is prepared by S-deacylation of the compound of Formula V in the presence of aqueous sodium hydroxide and hydrochloric acid.
(Formula Removed)
Similar processes for the preparation of meropenem have also been provided in US 4,888,344, US 5,122,604, Sunagawa M., et al., J. Antibiot (Tokyo), 1990, 43(5), 519-532 and Haruki M., et al., Heterocycles, 1995, 36, 145-159.
All the processes reported in the prior-art for the preparation of meropenem involves the isolation of the thiol side chain of Formula III, which in turn reacts with enol phosphate. Further the preparation of thiol side chain of Formula III by S-deacylation involves a strong base such as sodium hydroxide. The prior art processes also involve the isolation of the protected meropenem of Formula IV prior to deprotection.
The present inventors have developed a process for the preparation of meropenem, wherein the isolation of S-deprotected thiol side chain as well as the protected meropenem intermediate is not required. The present inventors have also found that the S-deprotection of the thiol side chain can be carried out in the presence of pyrrolidine. Thus the present process reduces the steps involved in the preparation of meropenem and shortens the process cycle. By avoiding the use of strong basic conditions, the process provides meropenem with high purity and good yield.
The term "protecting group" in the present invention refers to those used in the art and serve the function of blocking the carboxyl, amino or hydroxyl groups while the reactions are carried out at other sites of the molecule. Examples of a carboxyl protecting group include, but not limited to, optionally substituted C1-C8 alkyl, optionally substituted C3-C8 alkenyl, optionally substituted C7-C19 aralkyi, optionally substituted C6-C12 aryl, optionally substituted C1-C12 amino, optionally substituted C3-C12 hydrocarbonated silyl, optionally substituted C3-C12 hydrocarbonated stannyl, and a pharmaceutically active ester forming group. Examples of hydroxyl and amino protecting groups include, but not limited to, lower alkylsilyl groups, lower alkoxymethyl groups, aralkyi groups, acyl groups, lower alkoxycarbonyl groups, alkenyloxycarbonyl groups and aralkyloxycarbonyl groups.
A first aspect of the present invention provides a process for the preparation of the compound of Formula la,
(Formula Removed)
wherein P1 represents hydrogen or an amino protecting group, P2 represents hydrogen or a carboxyl protecting group and P3 represents hydrogen or a hydroxyl protecting group, wherein the said process comprises a) deprotecting the thiol group of the compound of Formula Va,
(Formula Removed)
wherein P1 is as defined above, R1 is a thiol protecting group selected from a group comprising of acetyl and benzoyl to get the compound of formula Ilia
(Formula Removed)
wherein P1 is as defined above,
b) reacting the compound of Formula Illa with a compound of Formula lla,
(Formula Removed)
wherein P2 and P3 are as defined above and X represents OP(O)(OR)2 or OSO2R, wherein R represents substituted or unsubstituted C1-6 alkyl, aralkyl or aryl, to get the compound of Formula la,
c) isolating the compound of Formula la from the reaction mass thereof, characterized by the fact that the compound of formula Ilia is not isolated from the reaction mixture.

A second aspect of the present invention provides a process for the preparation of the compound of Formula la,

fFORMULA la
wherein P1 represents hydrogen or an amino protecting group, P2 represents hydrogen or a carboxyl protecting group and P3 represents hydrogen or a hydroxyl protecting group wherein the said process comprises a) treating the compound of Formula Va with pyrrolidine,
(Formula Removed)
wherein P1 is as defined above, R1 is a thiol protecting group selected from a group comprising of acetyl and benzoyl to get the compound of formula Ilia
(Formula Removed)
wherein P1 is as defined above,
b) reacting the compound of Formula Illa with a compound of Formula lla,
(Formula Removed)
wherein P2 and P3 are as defined above and X represents OP(O)(OR)2 or OSO2R, wherein R represents substituted or unsubstituted C1-6 alkyl, aralkyl or aryl, to get the compound of Formula la, c) isolating the compound of Formula la from the reaction mass thereof.

A third aspect of the present invention provides a process for the preparation of meropenem of Formula I,
(Formula Removed)
wherein the said process comprises
a) deprotecting the thiol group of the compound of Formula Vb,

(Formula Removed)
wherein P1 is an amino protecting group, R1 is a thiol protecting group selected from a group comprising of acetyl and benzoyl to get the compound of formula lllb
(Formula Removed)
wherein P1 is as defined above,
b) reacting the compound of Formula lllb with a compound of Formula llb,
(Formula Removed)
wherein P2 is a carboxyl protecting group, P3 is hydrogen or a hydroxyl protecting group and X represents OP(O)(OR)2 or OSO2R, wherein R represents substituted or unsubstituted C1-6 alkyl, aralkyl or aryl, to get the compound of Formula lb,
(Formula Removed)
wherein P1, P2 and P3 are as defined above,
c) deprotecting the compound of Formula lb to get meropenem of Formula I
d) isolating meropenem of Formula I from the reaction mass thereof,

characterized by the fact that the compound of Formula lb is not isolated from the reaction mixture.

Enol-phosphate of Formula lla and thiol side chain of Formula Va can be prepared by processes reported in the prior-art as mentioned earlier. Thiol side chain is dissolved in an organic solvent and cooled to a temperature of 25°C or less. Pyrrolidine is added to the reaction mixture and stirred for sufficient time to effect deprotection of the thiol group. The reaction mixture so obtained can optionally be treated with an aqueous mineral acid solution. To the organic layer of the reaction mixture, enolphosphate is added at a temperature of 0°C or less. The reaction mixture is stirred in the presence of a base for sufficient time at the same temperature to effect the coupling reaction. The reaction mixture is subsequently hydrogenated using a palladium catalyst in presence of a non nucleophilic buffer selected from a group comprising of morpholinopropanesulphonic acid and morpholinoethanesulphonic acid or an aqueous buffer comprising N-methylmorpholine.

After completion of the reaction, the solid product is isolated from the aqueous layer, washed with an organic solvent and dried to get meropenem.

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLE 1
PREPARATION OF MEROPENEM:
4-Nitrobenzyl (2S,4S)-4-(acetylthio)-2-[(dimethylamino)carbonyl]pyrrolidine-1-carboxylate (50 g) was dissolved in N,N-dimethylformamide (500 ml) and cooled to -5° to 0°C, followed by the drop-wise addition of pyrrolidine (13.5 g) at the same temperature. The reaction mixture was stirred at -5° to 0°C for 30 minutes and cooled to -40° to -35°C. Enolphosphate (50 g) was added to the reaction mixture, followed by the addition of diisopropylethylamine (14.0 g) and stirring for 60 minutes at the same temperature. The reaction mixture was then poured into a mixture of ethyl acetate and water (500 : 500 ml). The ethyl acetate layer was separated and mixed with buffer containing N-methylmorpholine in water (500 ml) at a pH of 7.0. Hydrogenation of the reaction mixture so obtained was carried out at ambient temperature over palladium-carbon and the aqueous layer was separated after hydrogenation. Acetone (2 L) was added at 0° - 5°C to the aqueous layer of the reaction mixture to obtain the title compound in crystalline form.
Yield: 20 g
HPLC Purity: 98%
EXAMPLE 2
PREPARATION OF MEROPENEM:
4-Nitrobenzyl (2S,4S)-4-(acetylthio)-2-[(dimethylamino)carbonyl]pyrrolidine-1-carboxylate (30 g) was dissolved in dichloromethane (90 ml) and cooled to -10° to 0°C, followed by the drop-wise addition of pyrrolidine (8.0 g) at the same temperature. The reaction mixture was stirred at -5° to 0°C for 30 minutes and poured into 5% hydrochloric acid (150 ml), followed by the separation of the organic layer. Enolphosphate (30 g) was dissolved in dimethylformamide (150 ml) and cooled to -40° to -50°C, followed by the addition of the dichloromethane solution containing 4-nitrobenzyl (2S,4S)-2-[(dimethylamino)carbonyl]-4-mercaptopyrrolidine-1-carboxylate. Diisopropylethylamine (8.4 g) was added drop-wise to the reaction mixture so obtained and stirred for 60 minutes at -40° to -30°C. The reaction mixture was then poured into a mixture of ethyl acetate and water (300 : 300 ml). The ethyl acetate layer was separated and hydrogenated at pH 7.0 over palladium-carbon and
the aqueous layer was separated after hydrogenation, followed by treatment with activated carbon. The solution so obtained was filtered and acetone (2 L) was added at 0° - 5°C and stirred for 3 h at the same temperature. The reaction mixture was filtered, washed with acetone and dried to obtain the title compound.
Yield: 11 g
HPLC Purity: 98%

WE CLAIM:

1. A process for the preparation of the compound of Formula la,
(Formula Removed)
wherein P1 represents hydrogen or an amino protecting group, P2 represents hydrogen or a carboxyl protecting group and P3 represents hydrogen or a hydroxyl protecting group, wherein the said process comprises a) deprotecting the thiol group of the compound of Formula Va,
(Formula Removed)
wherein P1 is as defined above, R1 is a thiol protecting group selected from a group comprising of acetyl and benzoyl to get the compound of formula Ilia
(Formula Removed)
wherein P1 is as defined above,
b) reacting the compound of Formula Illa with a compound of Formula Ila,
(Formula Removed)
wherein P2 and P3 are as defined above and X represents OP(O)(OR)2 or OSO2R, wherein R represents substituted or unsubstituted C1-6 alkyl, aralkyl or aryl, to get the compound of Formula la,
c) isolating the compound of Formula la from the reaction mass thereof, characterized by the fact that the compound of formula Ilia is not isolated from the reaction mixture.
2. A process as claimed in claim 1, wherein step b) is carried out in presence of an
organic base.
3. A process as claimed in claim 2, wherein the organic base is diisopropylethylamine.
4. A process as claimed in claim 1, wherein step b) is carried out at a temperature of 0°C
or less.
5. A process for the preparation of the compound of Formula la,
(Formula Removed)
wherein P1 represents hydrogen or an amino protecting group, P2 represents hydrogen or a carboxyl protecting group and P3 represents hydrogen or a hydroxyl protecting group wherein the said process comprises a) treating the compound of Formula Va with pyrrolidine,
(Formula Removed)
wherein P1 is as defined above, R1 is a thiol protecting group selected from a group comprising of acetyl and benzoyl to get the compound of formula Illa
(Formula Removed)
wherein P1 is as defined above,
b) reacting the compound of Formula Ilia with a compound of Formula lla,

(Formula Removed)
wherein P2 and P3 are as defined above and X represents OP(O)(OR)2 or OSO2R, wherein R represents substituted or unsubstituted C1-6 alkyl, aralkyi or aryl, to get the compound of Formula la, c) isolating the compound of Formula la from the reaction mass thereof.
6. A process as claimed in claim 5, wherein step a) is carried out at a temperature of 25°C
or less.
7. A process as claimed in claim 5, wherein step a) comprises acidification of the reaction
mixture with a mineral acid.

8. A process for the preparation of meropenem of Formula I

(Formula Removed)
wherein the said process comprises
a) deprotecting the thiol group of the compound of Formula Vb,
(Formula Removed)
wherein P1 is an amino protecting group, R1 is a thiol protecting group selected from a group comprising of acetyl and benzoyl to get the compound of formula lllb
(Formula Removed)
wherein Pi is as defined above,
b) reacting the compound of Formula lllb with a compound of Formula lib,
(Formula Removed)
wherein P2 is a carboxyl protecting group, P3 is hydrogen or a hydroxyl protecting group and X represents OP(O)(OR)2 or OSO2R, wherein R represents substituted or unsubstituted C1-6 alkyl, aralkyl or aryl, to get the compound of Formula lb,
(Formula Removed)
wherein P1, P2 and P3 are as defined above,
c) deprotecting the compound of Formula lb to get meropenem of Formula I
d) isolating meropenem of Formula I from the reaction mass thereof,
characterized by the fact that the compound of Formula lb is not isolated from the reaction mixture.
9. A process as claimed in claim 8, wherein step c) is carried out in the presence of a
palladium catalyst.
10. A process as claimed in claim 8, wherein step c) is carried out in the presence of an aqueous buffer.
11. A process as claimed in claim 8, wherein step c) is carried out in the presence of non-nucleophilic buffer and in biphasic solvent system.
12. A process as claimed in claim 11, wherein the non-nucleophilic buffer is selected from a group comprising of morpholinopropanesulphonic acid and morpholinoethanesulphonic acid.