The present invention relates to a process for the preparation of carbapenem compounds of Formula I.
(Formula Removed)wherein a)
b)
FORMULA I
is hydrogen or C-i-3 alkyl group, and A is selected from a group consisting of
(Formula Removed)
wherein P2 is hydrogen or an amino protecting group, R2 and Ra are same or different and are hydrogen, C1-5 alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or its stereoisomers, or salts thereof. The present invention specifically relates to a process for the preparation of Imipenem of Formula II.
(Formula Removed)FORMULA II
Carbapenem compounds of Formula I are known for their broad and potent antibacterial activity. A large number of derivatives have been prepared and investigated for clinical efficacy. Imipenem, meropenem, ertapenem, panipenem, doripenem and biapenem are some of the carbapenem antibiotics available in the market for treating various bacterial infections.
The processes for preparing carbapenem antibiotics and their intermediates are provided in several publications including US 4,350,631, US 4,994,568, US 4,194,047, US 4,329,481, US 4,374,772, US 4,894,450, US 5,493,018, WO 02/094828, US 4,292,436, US 4,943,569, US 5,122,604, US 5,317,016, US 5,478,820, US 4,990,613, WO 02/20476, WO 03/016312, WO 05/021560, WO 05/118586, WO 02/057266, WO 02/36594, WO 02/094773, WO 07/031858, WO 07/020960, Org. Process Res. Dev. 2003, 7, 846-850, Sunagawa M., et al., J. Antibiot. (Tokyo), 1990, 43(5), 519-532, Haruki M., etal., Heterocycles, 1995, 36, 145-159, and Heterocycles, 1984, 21, 29.
The processes provided in the prior art for preparing carbapenem compounds essentially follow the route depicted below:
(Formula Removed)wherein PI is a carboxyl protecting group, B is -P(0)(OR)2 or -SO2R, wherein R is substituted or unsubstituted Ci-e alkyl, aralkyl or aryl, and X is halogen, and P3, RI and A are as defined above.
The prior art processes invariably involve the isolation and purification of at least one of the intermediates of Formula IV, Formula V and Formula VI to obtain the final carbapenem compound of Formula I with desired purity and yield.
The present invention provides an advantageous process for the preparation of carbapenem compounds of Formula I, wherein the process completely eliminates the necessity of isolation and purification of any of the intermediates of Formula IV, Formula V and Formula VI. The present process is also efficient obtain the final compound of Formula I with a purity of about 99% or more, without compromising the
yield. Thus, the present process reduces the cost and time involved in preparing carbapenem compounds with higher purity.

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 Ci-C8 alkyl, optionally substituted C3-C8 alkenyl, optionally substituted C7-C19 aralkyl, optionally substituted C6-C12 aryl, optionally substituted C1C12 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.
A first aspect of the present invention provides a process for the preparation of carbapenem compounds of Formula I, (Formula Removed)
FORMULA I
is hydrogen or 61.3 alkyl group, and A is selected from a group consisting of(Formula Removed)
wherein P2 is hydrogen or an amino protecting group, R2 and R3 are same or different and are hydrogen, Ci-5 alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or its stereoisomers, or salts thereof, wherein the process comprises,
a) treating the compound of Formula III with a metal catalyst, (Formula Removed)
FORMULA III
wherein PI is a carboxyl protecting group, P3 is hydrogen or a hydroxyl protecting group, and RI are as defined above, to obtain a compound of Formula IV, (Formula Removed)
FORMULA IV
wherein P1f P3 and RI are as defined above,
b) reacting the compound of Formula IV with a compound X-B, wherein B is -P(0)(OR)2 or -SO2R, wherein R is substituted or unsubstituted d.6 alkyl, aralkyi or aryl, and X is
halogen, to obtain a compound of Formula V, (Formula Removed)
FORMULA V
wherein PI, Pa, R-i and B are as defined above,
c) reacting the compound of Formula V with a compound of Formula VII, (Formula Removed)
FORMULA VII wherein A is as defined above, to obtain a compound of Formula VI, (Formula Removed)FORMULA VI
wherein P1, P3, RI and A are as defined above,
d) deprotecting the compound of Formula VI to obtain the compound of Formula I, and
e) isolating the compound of Formula I from the reaction mixture thereof,
wherein the process is characterized by the fact that the compounds of Formula IV, Formula V and Formula VI are not isolated from the reaction mixture in any solid form before step e).
The compound of Formula III can be prepared according to the methods provided in WO 05/021560, US 4,350,631 or US 4,994,568. The compound of Formula II is cyclized by treating with a metal catalyst to obtain the compound of Formula IV. The metal catalyst is preferably a rhodium carboxylate. The metal catalyst is more preferably rhodium(ll)octanoate. The cyclization is carried out in the presence of an organic solvent. The organic solvent is preferably a water immiscible solvent selected
from a group consisting of toluene, methylene chloride, methyl t-butyl ether, xylene, 1,2-dichloroethane and cyclohexane. The cyclization is facilitated by heating the reaction mixture from about 40°C to about reflux temperature.
Subsequent to the cyclization, the organic solvent can be partially removed and a
second organic solvent can be added to the reaction mixture. The second organic
solvent is preferably selected from a group consisting of N-methylpyrrolidone, N-
ethylpyrrolidone, N-methylpiperidinone, 1,3-dimethyl-3,4,5,6-tetrahydro-2(H)-
pyrimidinone, dimethylformamide and dimethylacetamide. The compound X-B is added directly to the reaction mixture comprising the compound of Formula IV. The reaction of the compound of Formula IV with the compound X-B is effected by adding a secondary amine or a tertiary amine to the reaction mixture. The secondary amine is preferably diisopropylamine, dicyclohexylamine, 2,2,6,6-tetramethylethylpiperidine or 1,1,3,3-tetramethylguanidine. The tertiary amine is preferably diisopropylethylamine, triethylamine or tributylamine. The reaction is preferably carried out at a temperature of about 0°C or below. The formation of the compound of Formula V can be accompanied by stirring.
The compound of Formula V so obtained is not required to be isolated from the reaction mixture and the compound of Formula VII is added to the reaction mixture comprising the compound of Formula V. The reaction is facilitated by further addition of a secondary amine or a tertiary amine. The resultant compound of Formula VI is not required to be isolated from the reaction mixture and subjected to deprotection directly. The deprotection is carried out by contacting the reaction mixture comprising the compound of Formula VI with an aqueous buffer and the resultant mixture is hydrogenated using a noble metal catalyst. The noble metal catalyst is preferably palladium - carbon. Hydrogen gas or a compound capable of generating hydrogen gas can be used as a source of hydrogen for deprotection. The deprotected compound of Formula I is isolated from the reaction mixture by conventional methods such as filtration, concentration, distillation, layer separation, solvent precipitation, reverse osmosis or a combination thereof.
A second aspect of the present invention provides a process for the preparation of Imipenem of Formula II, (Formula Removed)
HO FORMULA II
or its salts and hydrates thereof, wherein the process comprises, a) treating the compound of Formula Ilia with a metal catalyst, (Formula Removed)
FORMULA Ilia
wherein PI is a carboxyl protecting group, and P3 is hydrogen or a hydroxyl protecting
group and RI is hydrogen, to obtain a compound of Formula IVa, (Formula Removed)
FORMULA IVa
wherein PI, P3 and RI are as defined above,
b) reacting the compound of Formula IVa with a compound X-B, wherein B is -P(0)(OR)2 or -SO2R, wherein R is substituted or unsubstituted d-e alkyl, aralkyi or aryl, and X is halogen, to obtain a compound of Formula Va, (Formula Removed)
FORMULA Va
wherein P1( P3, R1 and B are as defined above,
c) reacting the compound of Formula V with 2-aminoethanethiol of Formula Vila or its salts thereof,
(Formula Removed)FORMULA Vila
to obtain a compound of Formula Via, (Formula Removed)FORMULA Via
wherein PI, P3 and RI are as defined above,
d) reacting the compound of Formula Via with benzylformimidate or its salts thereof to
obtain a compound of Formula VIII, (Formula Removed)FORMULA VIM
d) deprotecting the compound of Formula VIII to obtain imipenem of Formula II, and

d) isolating imipenem of Formula II or its salts and hydrates thereof from the reaction
mixture thereof,

wherein the process is characterized by the fact that the compounds of Formula IVa, Formula Va, Formula Via and Formula VIII are not isolated from the reaction mixture in any solid form before step e).

A third aspect of the present invention provides a process for the preparation of Imipenem of Formula II,
(Formula Removed)FORMULA II
or its salts and hydrates thereof, wherein the process comprises, a) treating the compound of Formula Ilia with a metal catalyst, (Formula Removed)
FORMULA Ilia
wherein P-i is a carboxyl protecting group, and P3 is hydrogen or a hydroxyl protecting group and RI is hydrogen, to obtain a compound of Formula IVa, (Formula Removed)
FORMULA IVa
wherein PI, PS and RI are as defined above,
b) reacting the compound of Formula IVa with a compound X-B, wherein B is -P(0)(OR)2 or -SOaR, wherein R is substituted or unsubstituted Ci-e alkyl, aralkyi or aryl, and X is halogen, to obtain a compound of Formula Va, (Formula Removed)wherein P-i, PS,
FORMULA Va
and B are as defined above,
c) reacting the compound of Formula V with 2-aminoethanethiol of Formula Vila or its salts thereof, (Formula Removed)
FORMULA Vila
to obtain a compound of Formula Via,
(Formula Removed)
FORMULA Via
wherein PI, P3 and RI are as defined above,
d) reacting the compound of Formula Via with benzylformimidate or its salts thereof to
obtain a compound of Formula VIII, (Formula Removed)
FORMULA VIII
d) deprotecting the compound of Formula VIII to obtain imipenem of Formula II, and
e) isolating imipenem of Formula II or its salts and hydrates thereof from the reaction
mixture thereof,
wherein the process is characterized by the fact that the compound of Formula IVa is not isolated from the reaction mixture in any solid form before step b).
The compound of Formula Ilia can be prepared according to the methods provided in WO 05/021560. The compound of Formula lla is cyclized by treating with a metal catalyst to obtain the compound of Formula IVa. The metal catalyst is preferably a rhodium carboxylate. The metal catalyst is more preferably rhodium(ll)octanoate. The cyclization is carried out in the presence of an organic solvent. The organic solvent is preferably a water immiscible solvent selected from a group consisting of toluene,
methylene chloride, methyl t-butyl ether, xylene, 1,2-dichloroethane and cyclohexane. The cyclization is facilitated by heating the reaction mixture from about 40°C to about reflux temperature.
Subsequent to the cyclization, the organic solvent can be partially removed and a
second organic solvent can be added to the reaction mixture. The second organic
solvent is preferably selected from a group consisting of N-methylpyrrolidone, N-
ethylpyrrolidone, N-methylpiperidinone, 1,3-dimethyl-3,4,5,6-tetrahydro-2(H)-
pyrimidinone, dimethylformamide and dimethylacetamide. The compound X-B is added directly to the reaction mixture comprising the compound of Formula IVa. The reaction of the compound of Formula IVa with the compound X-B is effected by adding a secondary amine or a tertiary amine to the reaction mixture. The secondary amine is preferably diisopropylamine, dicyclohexylamine, 2,2,6,6-tetramethylethylpiperidine or 1,1,3,3-tetramethylguanidine. The tertiary amine is preferably diisopropylethylamine, triethylamine or tributylamine. A catalytic quantity of a dialkylaminopyridine can also be added to the reaction mixture to prevent impurity formation. The reaction is preferably carried out at a temperature of about 0°C or below. The formation of the compound of Formula Va can be accompanied by stirring.
The compound of Formula Va so obtained is not required to be isolated from the reaction mixture and 2-aminoethanethiol of Formula Vila is added to the reaction mixture comprising the compound of Formula Va. The 2-aminoethanethiol is preferably added as its hydrochloride salt. The reaction is facilitated by further addition of a secondary amine or a tertiary amine. The resultant compound of Formula Via is not required to be isolated from the reaction mixture and it is reacted directly with benzylformimidate, preferably with benzylformimidate hydrochloride. The formation of the compound of Formula VIII is facilitated by stirring the reaction mixture at a temperature of about -10°C or below. The compound of Formula VIII so obtained is not required to be isolated and it is subjected to deprotection directly. The deprotection is carried out by contacting the reaction mixture comprising the compound of Formula VIII with an aqueous buffer and the resultant mixture is hydrogenated using a noble metal catalyst. The noble metal catalyst is preferably palladium - carbon. Hydrogen gas or a compound capable of generating hydrogen gas can be used as a source of hydrogen for deprotection. The deprotected compound of Formula I is isolated from the reaction
mixture by conventional methods such as filtration, concentration, distillation, layer separation, solvent precipitation, reverse osmosis or a combination thereof.
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 IMIPENEM MONOHYDRATE:
(Formula Removed) (3S,4R)-3-[(1R)-Hydroxyethyl]-4-[3-(4-nitrobenzyloxy)carbonyl-2-oxo-3-diazopropyl]azetidin-2-one (32.5 g; 86.4 mmole) was suspended in dichloromethane (300 ml). Rhodium(ll)octanoate dimer (120 mg) was added to the suspension and the reaction mixture was refluxed for 3 h. The reaction mixture was concentrated by removing about 150 ml of dichloromethane. The concentrated solution was cooled to 0° to 5°C and N-methylpyrrolidone (300 ml) was added. The solution was cooled further to
-50°C, followed by the addition of diisopropylethylamine (26.7 g; 206 mmole) and dimethylaminopyridine (200 mg). Diphenylchlorophosphate (26.5 g; 99 mmole) was slowly added to the reaction mixture at -50° to -45°C. The reaction mixture was stirred for 30 minutes and cooled to -60°C. 2-Aminoethanethiol hydrochloride (12 g; 106 mmole; dissolved in 60 ml of N-methylpyrrolidone) was added to the reaction mixture at -60° to -55°C and stirred for 45 minutes at -55° to -50°C. Diisopropylethylamine (16.5 g; 127 mmole) and benzylformimidate hydrochloride (20 g; 116 mmole) were added to the reaction mixture at -50°C. The temperature was slowly raised to -25°C in 45 minutes and stirred for 30 minutes at -30° to -25°C. The reaction mixture was poured into the buffer of water - isopropanol (300 ml- 150 ml) having pH of 7.5 (N-methylmorpholine: Hydrochloric acid). The reaction mixture was hydrogenated over 5% palladium-carbon (15 g) at 6 to 8 Kg hydrogen pressure for 2 h. Palladium-carbon was subsequently removed by filtration and the filtrate was stirred with dichloromethane (600 ml). Aqueous layer was separated and treated with activated carbon (3 g) for 30 minutes at 5° to 10°C, followed by filtration through Celite bed and addition of acetone (1200 ml) at 0° to 5°C. The solid was filtered after 4 to 5 h, washed with acetone and dried under reduced pressure at 35°C to obtain the title compound. Yield: 12 g Purity: 99% (HPLC)
EXAMPLE 2
PREPARATION OF IMIPENEM MONOHYDRATE:
(3S,4R)-3-[(1R)-Hydroxyethyl]-4-[3-(4-nitrobenzyloxy)carbonyl-2-oxo-3-diazopropyl]azetidin-2-one (32.5 g; 86.4 mmole) was suspended in dichloromethane (300 ml). Rhodium(ll)octanoate dimer (120 mg) was added to the suspension and the reaction mixture was refluxed for 3 h. The reaction mixture was concentrated by removing about 150 ml of dichloromethane. The concentrated solution was cooled to 0° to 5°C and N-methylpyrrolidone (300 ml) was added. The solution was cooled further to -50°C, followed by the addition of diisopropylethylamine (26.7 g; 206 mmole) and dimethylaminopyridine (200 mg). Diphenylchlorophosphate (26.5 g; 99 mmole) was slowly added to the reaction mixture at -50° to -45°C. The reaction mixture was stirred for 30 minutes and cooled to -60°C. 2-Aminoethanethiol hydrochloride (12 g; 106 mmole; dissolved in 60 ml of N-methylpyrrolidone) was added to the reaction mixture at -60° to -55°C and stirred for 45 minutes at -55° to -50°C. Diisopropylethylamine (16.5 g;

127 mmole) and benzylformimidate hydrochloride (20 g; 116 mmole) were added to the reaction mixture at -50°C. The temperature was slowly raised to -25°C in 45 minutes and stirred for 30 minutes at -30° to -25°C. The reaction mixture was poured into the buffer of water - isopropanol (300ml - 150 ml) having pH of 7.5 (N-methylmorpholine: Hydrochloric acid). The reaction mixture was hydrogenated over 5% palladium-carbon (15 g) at 6 to 8 Kg hydrogen pressure for 2 h. Palladium-carbon was subsequently removed by filtration and the filtrate was stirred with dichloromethane (600 ml). Aqueous layer was separated and treated with activated carbon (3 g) for 30 minutes at 5° to 10°C, followed by filtration through Celite bed and addition of isopropanol (1200 ml) at 0° to 5°C. The solid was filtered after 4 to 5 h, washed with isopropanol and dried under reduced pressure at 35°C to obtain the title compound.
Yield: 12 g

WE CLAIM:
1. A process for the preparation of carbapenem compounds of Formula I,
(Formula Remo ved)
wherein a)
b)
FORMULA I
is hydrogen or C-|.3 alkyl group, and A is selected from a group consisting of
(Formula Remo ved)
wherein P2 is hydrogen or an amino protecting group, R2 and R3 are same or different and are hydrogen, C1-5 alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or its stereoisomers, or salts thereof, wherein the process comprises,
a) treating the compound of Formula III with a metal catalyst, (Formula Remo ved)
FORMULA III
wherein Pi is a carboxyl protecting group, P3 is hydrogen or a hydroxyl protecting group, and R! are as defined above, to obtain a compound of Formula IV, (Formula Remo ved)
FORMULA IV
wherein PL P3 and RI are as defined above,
b) reacting the compound of Formula IV with a compound X-B, wherein B is -P(O)(OR)2 or -S02R, wherein R is substituted or unsubstituted C-i-e alkyl, aralkyl or aryl, and X is halogen, to obtain a compound of Formula V, (Formula Remo ved)
wherein PL P3,c) reacting the compound of Formula V with a compound of Formula VII, (Formula Remo ved)
FORMULA VII
•
wherein A is as defined above, to obtain a compound of Formula VI,
(Formula Remo ved)FORMULA VI
wherein P1( P3, RI and A are as defined above,
d) deprotecting the compound of Formula VI to obtain the compound of Formula I, and
e) isolating the compound of Formula I from the reaction mixture thereof,
wherein the process is characterized by the fact that the compounds of Formula IV, Formula V and Formula VI are not isolated from the reaction mixture in any solid form before step e).
2. A process according to claim 1, wherein the metal catalyst is rhodium(ll)octanoate.
3. A process according to claim 1, wherein step a) is carried out in the presence of an
organic solvent.
4. A process according to claim 3, wherein the organic solvent is selected from a group
consisting of toluene, methylene chloride, methyl t-butyl ether, xylene, 1,2-
dichloroethane and cyclohexane.
5. A process according to claim 1, wherein steps b) and c) are carried out in the
presence a secondary amine or a tertiary amine.
6. A process according to claim 5, wherein step d) is carried out in the presence a noble
metal catalyst.
7. A process for the preparation of Imipenem of Formula II,

(Formula Removed)
FORMULA II
or its salts and hydrates thereof, wherein the process comprises, a) treating the compound of Formula Ilia with a metal catalyst,
(Formula Remo ved)FORMULA Ilia
wherein P1 is a carboxyl protecting group, and P3 is hydrogen or a hydroxyl protecting group and RI is hydrogen, to obtain a compound of Formula IVa, (Formula Remo ved)
wherein PI, P3 and RI are as defined above,
b) reacting the compound of Formula IVa with a compound X-B, wherein B is -P(O)(OR)2 or -SO2R, wherein R is substituted or unsubstituted C-|.6 alkyl, aralkyl or aryl, and X is halogen, to obtain a compound of Formula Va, (Formula Remo ved)
FORMULA Va
wherein PI, P3, R1 and B are as defined above,
c) reacting the compound of Formula V with 2-aminoethanethiol of Formula Vila or its salts thereof, (Formula Remo ved)
FORMULA Vila
to obtain a compound of Formula Via, (Formula Remo ved)
FORMULA Via
wherein PL P3 and Ri are as defined above,
d) reacting the compound of Formula Via with benzylformimidate or its salts thereof to
obtain a compound of Formula VIII, (Formula Remo ved)
FORMULA VIII
d) deprotecting the compound of Formula VIII to obtain imipenem of Formula II, and
e) isolating imipenem of Formula II or its salts and hydrates thereof from the reaction
mixture thereof,
wherein the process is characterized by the fact that the compounds of Formula IVa, Formula Va, Formula Vla and Formula VIII are not isolated from the reaction mixture in any solid form before step e).
7. A process for the preparation of Imipenem of Formula II, (Formula Remo ved)
8. FORMULA II
or its salts and hydrates thereof, wherein the process comprises, a) treating the compound of Formula Ilia with a metal catalyst,
(Formula Remo ved)FORMULA Ilia
wherein P^ is a carboxyl protecting group, and P3 is hydrogen or a hydroxyl protecting group and RI is hydrogen, to obtain a compound of Formula IVa, (Formula Remo ved)
FORMULA IVa
wherein P-i, P3 and RI are as defined above,
b) reacting the compound of Formula IVa with a compound X-B, wherein B is -P(0)(OR)2 or -SO2R, wherein R is substituted or unsubstituted Ci.6 alkyl, aralkyi or aryl, and X is halogen, to obtain a compound of Formula Va, (Formula Remo ved)
FORMULA Va
wherein PL P3, R^ and B are as defined above,
c) reacting the compound of Formula V with 2-aminoethanethiol of Formula Vila or its salts thereof,
FORMULA Vila
to obtain a compound of Formula Via, (Formula Remo ved)FORMULA Via
wherein PI, P3 and RI are as defined above,
d) reacting the compound of Formula Via with benzylformimidate or its salts thereof to
obtain a compound of Formula VIII, (Formula Remo ved)
d) deprotecting the compound of Formula VIII to obtain imipenem of Formula II, and
e) isolating imipenem of Formula II or its salts and hydrates thereof from the reaction
mixture thereof,
wherein the process is characterized by the fact that the compound of Formula IVa is not isolated from the reaction mixture in any solid form before step b).
9. A process according to claims 7 and 8, wherein step b) is carried out in the presence of a catalytic quantity of a dialkylaminopyridine.
10. A process according to claims 7 and 8, wherein 2-aminoethanethiol is employed as a hydrochloride salt.