The present invention provides a process for the preparation of carbapenem compounds.
Carbapenem compounds are known for their broad and potent antibacterial activity. A large number of derivatives have been prepared and investigated for clinical efficacy. Meropenem, ertapenem and doripenem are some of the carbapenem antibiotics available in the market for treating various bacterial infections.
Thiol side chain compounds of Formulae I and II are important intermediates in the preparation of carbapenem compounds,
(FORMULA REMOVED)

wherein P1 represents hydrogen or an amino protecting group, and R1 and R2 are same or different and are hydrogen, C1-5 alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
The thiol side chain compounds of the above formulae are further condensed with enolphosphate of Formula III to obtain respective carbapenem antibiotics,
(FORMULA REMOVED)

wherein P2 represents hydrogen or a carboxyl protecting group, P3 represents hydrogen or hydroxyl protecting group and X represents OP(O)(OR)2 or OSO2R, wherein R represents substituted or unsubstituted C1-6 alkyl, aralkyl or aryl.
Thiol side chain compounds of Formulae I and II are in turn prepared by S-deprotection of the compounds of Formulae IV and V respectively,
(FORMULA REMOVED)

wherein P1, R1 and R2 are as defined above, and R3 is a thiol protecting group selected from a group comprising of acetyl or benzoyl.
US Patent No 4,943,569 provides a process for the preparation of meropenem, wherein the process involves the reaction between enolphosphate of Formula III, wherein P2 is p-nitrobenzyl, P3 is hydrogen and X is diphenoxyphosphoryloxy, and thiol side chain compound of Formula I, wherein Pi is p-nitrobenzyloxycarbonyl, and R1 and R2 are methyl, followed by deprotection of the protected meropenem intermediate. In this method, the thiol side chain compound of Formula I, wherein P1 is p-nitrobenzyloxycarbonyl, and R1 and R2 are methyl, is prepared by S-deacetylation of the compound of Formula IV, wherein Pi is p-nitrobenzyloxycarbonyl, R1 and R2 are methyl, and R3 is acetyl, in the presence of aqueous sodium hydroxide and hydrochloric acid.
US Patent No 5,478,820 provides a similar process for the preparation of ertapenem, wherein the thiol group of the compound of Formula IV, wherein P1 is p-nitrobenzyloxycarbonyl, R1 is hydrogen, R2 is 3-allyloxycarbonylphenyl, and R3 is acetyl, is deprotected in the presence of 1 M sodium hydroxide. Yataka Nishino et al., Org. Process Res. Dev. 2003, 7(6), 846-850, provides a process for the preparation of doripenem, wherein the thiol group of the compound of Formula V, wherein each P1 independently represents p-nitrobenzyloxycarbonyl or t-butyloxycarbonyl, and R3 is acetyl, is S-deacetylated in the presence of 98% sulfuric acid.
Similar processes for the preparation of carbapenem compounds 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, Yasuyoshi Iso et al, J. Antibiot (Tokyo), 1996, 49(2), 199-209, and Haruki M., etal., Heterocycles, 1995, 36, 145-159.
The prior art processes involve the preparation of thiol side chain compounds of Formulae I and II by S-deacylation using strong basic or acidic conditions. Such reaction conditions also require considerable quantity of strong base or acid for neutralization of the reaction mixture. Carbapenem ring system being sensitive to such acidic or basic conditions, it usually results in reduced yield and increased impurity level.
The present inventors have found that the S-deprotection of the thiol side chain compound can be carried out in the presence of acetyl chloride, silica chloride, oxalyl chloride or thionyl chloride. The present method employs only a catalytic quantity of these chloride compounds and does not require the addition of base or acid for neutralization. Thus the present process provides final carbapenem compounds with improved 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 aralkyl, 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, aralkyl groups, acyl groups, lower alkoxycarbonyl groups, alkenyloxycarbonyl groups and aralkyloxycarbonyl groups.
first aspect of the present invention provides a process for the preparation of the compound of Formula VI,
(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, R1 and R2 are same or different and are hydrogen, C1-5 alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, wherein the said process comprises
a) treating the thiol compound of Formula IV with acetyl chloride, silica chloride,
thionyl chloride or oxalyl chloride,
wherein P1, R1 and R2 are as defined above, R3 is a thiol protecting group selected from a group comprising of acetyl or benzoyl, to get the compound of
(FORMULA REMOVED)

wherein P1, R1 and R2 are as defined above,
b) reacting the compound of Formula I with a compound of Formula III,
(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 VI, c) isolating the compound of Formula VI from the reaction mass thereof.
Enol-phosphate of Formula III and thiol side chain of Formula IV can be prepared by processes reported in the prior-art as mentioned earlier. Thiol side chain of Formula IV is treated with a catalytic quantity of acetyl chloride, silica chloride, thionyl chloride or oxalyl chloride in the presence of an organic solvent selected from a group comprising of C1-5 alkanol, aromatic hydrocarbon, halogenated hydrocarbon, ketone, ester and ether. The deprotection of the thiol group is effected by heating or by stirring the reaction mixture for sufficient time. The S-deprotected thiol side chain of Formula I can optionally be isolated from the reaction mixture by layer separation. The S-deprotected thiol side chain of Formula I or a reaction mixture comprising the same, and enolphosphate of Formula III are dissolved in an organic solvent and the resultant reaction mixture is cooled to a temperature less than or equal to about 0°C. The reaction mixture is stirred in the presence of an organic 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 obtain the compound of Formula VI.
A second aspect of the present invention provides a process for the preparation of the compound of Formula VII,
(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 thiol compound of Formula V with acetyl chloride, silica chloride,
thionyl chloride or oxalyl chloride,
(FORMULA REMOVED)

wherein P1 is as defined above, R3 is a thiol protecting group selected from a group comprising of acetyl or benzoyl, to get the compound of formula II
(FORMULA REMOVED)

wherein P1 is as defined above,
b) reacting the compound of Formula II with a compound of Formula III,
(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 VII, c) isolating the compound of Formula VII from the reaction mass thereof.
Enol-phosphate of Formula III and thiol side chain of Formula V can be prepared by processes reported in the prior-art as mentioned earlier. Thiol side chain of Formula V is treated with a catalytic quantity of acetyl chloride, silica chloride, thionyl chloride or oxalyl chloride in the presence of an organic solvent selected from a group comprising of C1-5 alkanol, aromatic hydrocarbon, halogenated hydrocarbon, ketone, ester and ether. The deprotection of the thiol group is effected by heating or by stirring the reaction mixture for sufficient time. The S-deprotected thiol side chain of Formula II can optionally be isolated from the reaction mixture by layer separation. The S-deprotected thiol side chain of Formula II or a reaction mixture comprising the same, and enolphosphate of Formula III are dissolved in an organic solvent and the resultant reaction mixture is cooled to a temperature less than or equal to about 0°C. The reaction mixture is stirred in the presence of an organic 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 can be isolated from the aqueous layer, washed with an organic solvent and dried to obtain the compound of Formula VII.
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:
a) Preparation of 4-nitrobenzyl (2S,4S)-2-[(dimethylamino)carbonyl]-4-
mercaptopyrrolidine-1-carboxylate
4-Nitrobenzyl (2S,4S)-4-(acetylthio)-2-[(dimethylamino)carbonyl]pyrrolidine-1-
carboxylate (50 g) was suspended in methanol (250 ml), followed by the addition of acetyl chloride (10 g). The reaction mixture was stirred for 5 h at ambient temperature and then added to a mixture of methylene chloride (500 ml) and water (500 ml). The organic layer was collected and washed with water (250 ml). The organic layer was concentrated and the residue was recrystallized with isopropylalcohol to obtain the title compound. Yield: 80%
PMR (CDCI3) Data: 8.15 (d, 2H), 7.50 (d, 2H), 5.21 (s, 2H), 4.62 (m, 1H), 4.70 (m, 1H), 4.06 (t, 1H), 3.41 (t, 1H), 3.26 (t, 2H), 3.10 (s, 3H), 2.90 (s, 3H), 2.72 (t, 1H) and 1.88 (1H,br)
b) Preparation of 4-nitrobenzyl (2S,4S)-2-[(dimethylamino)carbonyl]-4-
mercaptopyrrolidine-1-carboxylate
4-Nitrobenzyl (2S,4S)-4-(acetylthio)-2-[(dimethylamino)carbonyl]pyrrolidine-1-
carboxylate (50 g) was suspended in methanol (250 ml), followed by the addition of acetyl chloride (5 g). The reaction mixture was refluxed for 2.5 h followed by cooling to
ambient temperature and then added to a mixture of methylene chloride (500 ml) and water (500 ml). The organic layer was collected and washed with water (250 ml). The organic layer was concentrated and the residue was recrystallized with isopropylalcohol to obtain the title compound.
Yield: 70%
PMR (CDCI3) Data: 8.15 (d, 2H), 7.50 (d, 2H), 5.21 (s, 2H), 4.62 (m, 1H), 4.70 (m, 1H), 4.06 (t, 1H), 3.41 (t, 1H), 3.26 (t, 2H), 3.10 (s, 3H), 2.90 (s, 3H), 2.72 (t, 1H) and 1.88 (1H, br)
c) Preparation of meropenem:
4-nitrobenzyl (4/?,5f?,6S)-3-[(diphenoxyphosphoryl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (50 g) and 4-nitrobenzyl (2S,4S)-2-[(dimethylamino)carbonyl]-4-mercaptopyrrolidine-1 -carboxylate (30 g) obtained by step a) or by step b) were dissolved in a mixture of N,N-dimethylformamide (200 ml) at ambient temperature. The solution was then cooled to -45°C followed by drop-wise addition of diisopropylethylamine (11 g) under stirring while maintaining the temperature between -50 to -45°C. After stirring the reaction mixture for about 1 h, it was poured in to a mixture of ethyl acetate (500 ml) and water (300 ml). The organic layer was separated and added to a mixture of 5% palladium on carbon (50 gm) in aqueous buffer (500 ml) containing N-methylmorpholine and acetic acid (pH about 7.0). The above biphasic reaction mass was hydrogenated for 3 h under pressure at 20-25°C. After completion of the reaction, the mixture was filtered and aqueous layer was separated. The aqueous layer was concentrated by reverse osmosis and tetrahydrofuran was added to the condensate at a temperature of about 5-10°C. The resultant mixture was stirred for about 5 h to the title compound as a trihydrate.
Yield: 21.6 gm
EXAMPLE 2
PREPARATION OF DORIPENEM
a) Preparation of 4-nitrobenzyl (2S,4S)-2-{[(aminosulfonyl)amino]methyl}-4-
mercaptopyrrolidine-1-carboxylate
4-Nitrobenzyl (2S,4S)-4-(acetylthio)-2-{[(aminosulfonyl)(tert-butoxy
carbonyl)amino]methyl}pyrrolidine-1-carboxylate (56 g) was suspended in methanol (250 ml), followed by the addition of acetyl chloride (4.13 g). The reaction mixture was refluxed for 2 h and the completion of the reaction was monitored by thin layer chromatography. After the completion of the reaction, the reaction mixture was cooled to ambient temperature and poured into a mixture of dichloromethane (500 ml) and water (500 ml). The organic layer was collected, washed with water and concentrated to obtain the title compound.
Yield: 50 g
b) Preparation of doripenem:
N,N-Dimethylformamide (250 ml) was added to the concentrate obtained from step a) followed by the addition of enolphosphate (50 g) at ambient temperature. The resulting solution was cooled to -40°C and diisopropylethylamine (11 g) was added to this solution drop wise under stirring while maintaining the temperature -40° to -35°C. After stirring for 1 hour at the same temperature, the reaction mixture was poured into a mixture of ethylacetate (500 ml) and water (300 ml). The organic layer was separated and added to a mixture of 5% palladium on carbon (50 g) in aqueous buffer (500 ml) containing N-methylmorpholine and acetic acid (pH 6.5 to 7.0). The biphasic reaction mass was then hydrogenated for 3 hours under pressure at ambient temperature. After the completion of the reaction, the reaction mixture was filtered and the aqueous layer was separated. The analysis of the aqueous layer by HPLC showed the formation of the title compound in 85% yield.

WE CLAIM:
1. A process for the preparation of the compound of Formula VI,
(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, R1 and R2 are same or different and are hydrogen, C1-5 alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, wherein the said process comprises
a) treating the thiol compound of Formula IV with acetyl chloride, silica chloride,
thionyl chloride or oxalyl chloride,
(formula removed)
wherein P1, R1 and R2 are as defined above, R3 is a thiol protecting group selected from a group comprising of acetyl or benzoyl, to get the compound of
(formula removed)
wherein P1, R1 and R2 are as defined above,
b) reacting the compound of Formula I with a compound of Formula III,
(formula removed)
wherein P2 and P3are 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 VI, c) isolating the compound of Formula VI from the reaction mass thereof.
2. A process as claimed in claim 1, wherein the compound of Formula VI is
meropenem.
3. A process as claimed in claim 1, wherein the compound of Formula VI is
ertapenem.
4. A process for the preparation of the compound of Formula VII,
(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 thiol compound of Formula V with acetyl chloride, silica chloride, thionyl chloride or oxalyl chloride,

(formula removed)
wherein P1 is as defined above, R3 is a thiol protecting group selected from a group comprising of acetyl or benzoyl, to get the compound of formula II,
(formula removed)
wherein P1 is as defined above,
b) reacting the compound of Formula II with a compound of Formula III,
(formula removed)
wherein P2 and P3 are as defined above and X represents OP(0)(OR)2 or OSO2R, wherein R represents substituted or unsubstituted C1-6 alkyl, aralkyl or aryl, to get the compound of Formula VII,
c) isolating the compound of Formula VII from the reaction mass thereof.
5. A process as claimed in claim 4, wherein the compound of Formula VII is
doripenem.
6. A process as claimed in claims 1 and 4, wherein step a) is carried out in the
presence of an organic solvent selected from a group comprising of C1-5 alkanol, aromatic hydrocarbon, halogenated hydrocarbon, ketone, ester and ether.
7. A process as claimed in claim 6, wherein the organic solvent is C1-5 alkanol.
8. A process as claimed in claims 1 and 4, wherein step b) comprises deprotection of the compounds of Formula VI and Formula VII.
9. A process as claimed in claim 8, wherein deprotection is carried out in the presence of palladium carbon and an aqueous buffer.
10. A process as claimed in claim 8, wherein deprotection is carried out in the presence of non-nucleophilic buffer and in biphasic solvent system.