Indian Patents. 269058:IMPROVED PROCESS FOR THE PREPARATION OF CARBAPENEM ANTIBIOTIC

Title of Invention	IMPROVED PROCESS FOR THE PREPARATION OF CARBAPENEM ANTIBIOTIC
Abstract	The present invention provides an improved process for the preparation of the carbapenem antibiotic of formula (I). The compound of the formula (I) is generically known as Imipenem and exhibits an extremely broad-spectrum antibiotic activity against gram-positive and gram-negative aerobic and anaerobic species.

Full Text	Field of the Invention The present invention provides an improved process for the preparation of the carbapenem antibiotic of formula (I). The compound of the formula (I) is generically known as Imipenem and exhibits an extremely broad-spectrum antibiotic activity against gram-positive and gram-negative aerobic and anaerobic species. Background of the Invention Imipenem is a broad spectrum /Mactam antibiotic, belonging to the group carbapenems. It is derived from a compound called theinamycin of formula (II). Imipenem has an excellent activity against aerobic and anaerobic Gram-positive as well as Gram-negative bacteria. It is useful for the treatment of Abdominal infections, Infection of the blood or tissues (septicaemia), Infection of the lungs and airways (lower respiratory tract infection), Infections of the sex organs and organs associated with urination (genito-urinary infections), Preventing infection following surgery. Originally Imipenem was disclosed in US patent 4,194,047; the said patent provides various processes for preparing Imipenem. US patent 4,260,543 discloses crystalline Imipenem monohydrate. According to this patent crystalline Imipenem monohydrate was prepared as by dissolving lyophilized sample of N-formimidoylthienamycin in water followed by diluting the said solution with alcohol at low temperature yield crystalline N-formimidoylthienamycin (Imipenem) monohydrate crystals. This patent suggests the technique of crystallisation of Imipenem in aqueous medium by the addition of organic solvent. US patent 4,374,772 discloses a process for preparing Imipenem by reacting thienamycin with benzyl formimidates as shown in given scheme: US patent application 2002/0095034 (abandoned) claims a process for the preparation of Imipenem by activating (3R,5R,6S)-2-oxo-6- [(1R)-1 - hydroxyethyl]carbapenem-3-carboxylic acid p-nitrobenzylester with diphenylphosphorohydrochloride followed by reacting the activated compound with cysteamine hydrochloride in the presence of a base to produce thienamycin p-nitrobenzyl ester hydrochloride in the form of N-methylpyrrolidinone solvate, which is reacted with alkyl formimidate to produce Imipenem p-nitrobenzyl ester, followed by deprotection. US patent 2004/0242865 claims isolation of pure crystalline Imipenem monohydrate by crystallizing Imipenem monohydrate from a solution thereof which contains an organic solvent, aqueous solvent, or a mixture thereof, without using lyophilization, freeze drying or chromatographic techniques. Activated Carbon is typically used in three different areas: 1. Taking impurities out of water as it is brought into a facility; 2. Removing halogens (any of the five elements fluorine, chlorine, bromine, iodine, and astatine that form part of group VII A of the periodic table and exist in the free state normally as diatomic molecules); and.. 3. Removing color and metabolic by-products in re-circulating systems. Even though the knowledge of carbon treatment for the removal of colored impurities and degradation impurities are widely reported in the literature and followed for many processes. US patent 2005/004859 provides a process for the preparation of crystalline Imipenem monohydrate which comprises: (a) dissolving crude Imipenem in water to obtain a solution; (b) subjecting the resultant solution to activated carbon treatment; and (c) adding an organic solvent to precipitate Imipenem monohydrate as a crystalline product. With our continued research for developing a process for the preparation of compound of formula (I), we have identified a process, which is not only commercially viable, but involves simple purification techniques affording good yield and quality of Imipenem. Objectives of the Invention The main objective of the present invention is to provide a simple and commercially viable, industrially scalable process for the preparation of compound of the formula (I). Another objective of the present invention is to provide a simple and commercially viable, industrially scalable process for the purification of compound of formula (I), which avoids chromatographic techniques. Yet another objective of the present invention is to provide a simple and commercially viable, industrially scalable process for the preparation of Sterile Imipenem monohydrate (I). , Summary of the Invention Accordingly, the present invention provides an improved process for preparation of compound of the formula (I) the said process comprising the steps of: i) converting the compound of formula (III) into compound of formula (IV) by activating the compound of formula (III) using an activating reagent in the presence of solvent and base, followed by reacting the ensuing activated compound with cysteiamine hydrochloride, ii) converting the compound of formula (IV) into compound of formula (V) by reacting the compound of formula (V) with alkyl formimidate hydrochlorides or arylalkyl formimidate hydrochlorides in the presence of solvent and base, and iii) deprotecting the compound of formula (V) by catalytic hydrogenation using mixture of solvents in the presence of morpholinoalkyl sulfonic acid or it salt as a buffer to yield Imipenem of formula (I), wherein the improvement consists of using mixture of two organic solvents and water in which one organic solvent is selected from water immiscible solvent, iv) optionally purifying the Imipenem, and v) adding an organic solvent to the aqueous layer to yield Imipenem monohydrate of formula (I). Description of the Invention In an embodiment of the present invention the carboxyl protecting group represented by Ri may be any of the well known, readily removable carboxyl protecting groups; which includes diphenylmethyl, benzyl, p-nitrobenzyl, methoxymethyl and the like preferably p-nitrobenzyl. In another embodiment of the present invention, the activating reagent used in (i) is selected from diphenylchloro phosphate, 2,4-dichlorodiphenylchloro phosphate, diethylthiocholoro phosphate, tosylate, mesylate and the like preferably diphenylphosphate. In another embodiment of the present invention, the base used in step (i) or (ii) is selected from diisopropylamine, ethyldiisopropylamine, triethylamine, pyridine or the like. In still another embodiment of the present invention, the solvent used in step (i) is selected from diethyl ether, tetrahydrofuran, tetrahydropyran, toluene, xylene, dichloromethane, ethylene dichloride, N,N-dimethyl formamide, N,N-dimethyl acetamide, N-methylpyrrolidinone, N-ethylpyrrolidinone, N-methylpiperidinone, acetonitrile, proprionitrile, and other such organic solvents known in the art or mixtures thereof. In another embodiment of the present invention the compound of formula (IV) can be taken into next step with or with out isolation. In the case of isolation, the compound of formula (IV) is isolated in the form of acid addition solvate of N- methylpyrrolidinone (NMP), N-ethylpyrrolidinone, N,N-dimethylacetamide, N,N-dimethylformamide and the like. In still another embodiment of the present invention, the solvent used in step (ii) is selected from dichloromethane, acetonitrile, dioxane, sulfolane, ethyl acetate, IPE and tetrahydrofiiran and the like or mixture thereof. In one more embodiment of the present invention the solvent used in the deprotection stage in step (iii) is selected from THF, dioxane, ethyl acetate, dichloromethane, DMF, ethanol, iso-propanol, butanol, and water. However it was identified that the deprotection is carried out in the mixture of THF (or dioxane): ethyl acetate: water, Imipenem obtained in aqueous solution has better quality. The presence of water immiscible solvent like in ethyl acetate in the reaction medium helps to remove the impurities obtained and is primarily responsible for the quality of final Imipenem in terms of related substances. Also the present invention provides a process wherein the reduction can be also performed in a single-phase solvent system consisting of THF, dioxane, DMF, ethanol, iso-propanol, butanol, and water or mixtures thereof. The catalyst used for reduction is selected from platinum oxide, Pd/C, Pt/C and the like, and buffer used is selected from morpholinoalkyl sulfonic acid (MOPS) or its salt such as morpholinopropane sulfonic acid, morpholinoethane sulfonic acid and their sodium salt. In an embodiment of the present invention he Imipenem isolated in step (v) may contain morpholinoalkyl sulfonic acid or its salt. In one more embodiment of the present invention the purification of Imipenem in step (v) is done by (i) treating the aqueous solution of Imipenem with silica gel followed by carbon treatment (ii) by converting Imipenem into salt of benzathine or N,N'-dicyclohexylethylene diamine followed by converting salt into Imipenem by utilizing the technique known in cephalosporin or penicillin chemistry (iii) by converting the Imipenem in to solvate using DMF, NMPO (N-Methyl pyrrolindin-2-one) followed by de-solvating the.ensuing product. In another embodiment of the present invention provides a process for preparation of pure Imipenem monohydrate by isolating the Imipenem containing MOPS or its salt followed by purification with water to get pure Imipenem monohydrate at a pH in the range of 4.0 to 7.0, preferably 4.0 to 5.0. In yet another embodiment of the present invention provides a sterile process for the preparation of pure Imipenem Monohydrate by dissolving the pure Imipenem monohydrate in water and subjecting the solution to sterile micron filtration (0.2 to 0.8 micron filtration) followed by addition of organic solvent to yield pure Imipenem Monohydrate. The foregoing technique has been found to be attractive from commercial, technological and ecological perspective. The present invention is illustrated with the following examples, which should not be construed to limit the scope of the invention. Example -1 Preparation of Thienamycin p-nitrobenzylester hydrochloride N-methylpyrrolidinone solvate To the solution of p-nitrobenzyl (3R, 5R, 6S)-2 oxo-5 [(lR)-l-hydroxyethyl)] carbapenem-3-carboxylate (lOOgm) in N-methylpyrrolidinone (500 ml) was added diisopopylethylamine (45gm) at -10°C followed by diphenylchlorophosphate (78gm) and stirred for 1 hr at -10°C. To the resulted mass was added the solution of cysteamine hydrochloride (36gm) in N-Methylpyrrolidinone (300ml) at 25°C, stirred for 30min. and diisopropylethylamine (25gm) was added at -10°C. the reaction mass was stirred further 2hrs to precipitate the solvate form. Acetone (21t) was added and stirred for lhr at -10°C. The precipitated mass was filtered washed with acetone (500ml) and dried und^r vacuum yielded lOOgm as white solid. Example-2 Preparation of Imipenem p-nitrobenzyl ester hydrochloride To the suspension of Thienamycin-p-nitrobenzyl ester hydrochloride N-Methylpyrrolidinone solvate (lOOgm) in acetonitrile (2.51t) at -10°C was added diisopropylethylamine (71 gm) and stirred for 15min., benzylformidate hydrochloride (63gm) was added in one lot at -10°C and stirred for 2hrs at -10°C. Isopropyl ether (2.51t) was added and stirred for 2hrs at -10°C.The resulted mass was filtered under nitrogen atmosphere and washed with acetonitrile (lit) followed by isopropyl ether (lit). The filtered solid was dried under vacuum yielded 85gm as off white solid. Example - 3 Preparation of pure Imipenem monohydrate To the solution of Imipenem p-nitro benzyl ester hydrochloride (85gm) in the mixture of THF (lilt) and MOPS solution (178gm in 1.71t water, the pH was adjusted to 7.0 with sodium hydroxide solution) stirred for 10 min. and added ethyl acetate (1.71t) followed by Pd-C 10% (85gm). The resulted suspension was hydrogenated under hydrogen pressure of 10kg at 10°C for 2hrs. The catalyst was filtered and the ethyl acetate layer was separated and the aqueous layer was re-extracted with ethyl acetate (lit), after complete removal of ethyl acetate under high vacuum the aqueous layer was added acetone (51t) and stirred for 10 hrs at 10°C to precipitate Imipenem hydrate having the assay of 90%. The crude Imipenem hydrate was stirred with water (300ml) at 10°C for 30min at a pH in the range of 4.0 to 5.0. The resulted mass was filtered, washed with water (30ml) followed by acetone (100ml) and dried under vacuum yielded pure Imipenem Monohydrate (30gm) with assay of 99%. Example - 4 Preparation of Sterile Imipenem monohydrate To water Imipenem Monohydrate was added and stirred to get clear solution; the clear solution was subjected to sterile filtration using 0.2-micron filtration. To filtrate acetone or THF was added to yield sterile Imipenem monohydrate. We claim: 1. An improved process for preparation of compound of the formula (I) by activating the compound of formula (III) using an activating reagent in the presence of solvent and base, followed by reacting the ensuing activated compound with cysteiamine hydrochloride, ii) converting the compound of formula (IV) into compound of formula (V) by reacting the compound of formula (IV) with alkyl formimidate Jiydrochlorides or arylalkyl formimidate hydrochlorides in the presence of solvent and base, and iii) deprotecting the compound of formula (V) by catalytic hydrogenation using mixture of solvent in the presence of morpholinoalkyl sulfonic acid or it salt as a buffer to yield Imipenem of formula (I) in aqueous medium, wherein the improvement consists of using mixture of two organic solvents and water in which one organic solvent is selected from water immiscible solvent, iv) optionally purifying the Imipenem, v) adding an organic solvent to the aqueous layer to yield Imipenem monohydrate (I). 2. A process for the preparation of pure Imipenem monohydrate, which comprises treating Imipenem monohydrate with water at a pH in the range of 4.0 to 7.0, preferably 4.0 to 5.0. 3. A process as claimed in claim 1, wherein the solvent used in step (i) is selected from diethyl ether, tetrahydrofuran, toluene, xylene, dichloromethane, ethylene dichloride, N,N-dirnethyl formamide, N,N-dimethyl acetamide, N-methylpyrrolidinone, N-ethylpyrrolidinone, N-methylpiperidinone, acetonitrile, or proprionitrile and activating reagent is selected from diphenylchloro phosphate, 2,4-dichlorodiphenylchloro phosphate, diethylthiocholoro phosphate, tosylate, or mesylate. 4. A process as claimed in claim 1, wherein the solvent used in step (ii) is selected from dichloromethane, acetonitrile, dioxane, sulfolane, ethyl acetate, IPE and tetrahydrofiiran and the like or mixture thereof and the base used is diisopropylamine, ethyldiisopropylamine, triethylamine, pyridine or the like. 5. A process as claimed in claim 1, wherein the solvent used in step (iii) is selected from THF, dioxane, acetone, ethyl acetate, dichloromethane, DMF, ethanol, iso-propanol, butanol, water or mixtures thereof. 6. A sterile process for the preparation of pure Imipenem monohydrate, which comprises the steps of: a) dissolving pure Imipenem monohydrate in water, b) subjecting to micron filtration, and c) isolating the Imipenem monohydrate from the filtrate of step (b) by adding an organic solvent. 7. A process as claimed in claim 1, wherein the solvent used in step (c) is selected from ethanol, propanol, isopropanol, butanol, THF, acetone, methyl ethyl ketone or mixtures thereof

Full Text

Field of the Invention
The present invention provides an improved process for the preparation of the carbapenem antibiotic of formula (I).

The compound of the formula (I) is generically known as Imipenem and exhibits an extremely broad-spectrum antibiotic activity against gram-positive and gram-negative aerobic and anaerobic species.
Background of the Invention
Imipenem is a broad spectrum /Mactam antibiotic, belonging to the group carbapenems. It is derived from a compound called theinamycin of formula (II).

Imipenem has an excellent activity against aerobic and anaerobic Gram-positive as well as Gram-negative bacteria. It is useful for the treatment of Abdominal infections, Infection of the blood or tissues (septicaemia), Infection of the lungs and airways (lower respiratory tract infection), Infections of the sex

organs and organs associated with urination (genito-urinary infections), Preventing infection following surgery.
Originally Imipenem was disclosed in US patent 4,194,047; the said patent provides various processes for preparing Imipenem.
US patent 4,260,543 discloses crystalline Imipenem monohydrate. According to this patent crystalline Imipenem monohydrate was prepared as by dissolving lyophilized sample of N-formimidoylthienamycin in water followed by diluting the said solution with alcohol at low temperature yield crystalline N-formimidoylthienamycin (Imipenem) monohydrate crystals. This patent suggests the technique of crystallisation of Imipenem in aqueous medium by the addition of organic solvent.
US patent 4,374,772 discloses a process for preparing Imipenem by reacting thienamycin with benzyl formimidates as shown in given scheme:

US patent application 2002/0095034 (abandoned) claims a process for the
preparation of Imipenem by activating (3R,5R,6S)-2-oxo-6- [(1R)-1 -
hydroxyethyl]carbapenem-3-carboxylic acid p-nitrobenzylester with
diphenylphosphorohydrochloride followed by reacting the activated compound with cysteamine hydrochloride in the presence of a base to produce thienamycin p-nitrobenzyl ester hydrochloride in the form of N-methylpyrrolidinone solvate,

which is reacted with alkyl formimidate to produce Imipenem p-nitrobenzyl ester, followed by deprotection.
US patent 2004/0242865 claims isolation of pure crystalline Imipenem monohydrate by crystallizing Imipenem monohydrate from a solution thereof which contains an organic solvent, aqueous solvent, or a mixture thereof, without using lyophilization, freeze drying or chromatographic techniques.
Activated Carbon is typically used in three different areas:
1. Taking impurities out of water as it is brought into a facility;
2. Removing halogens (any of the five elements fluorine, chlorine, bromine, iodine, and astatine that form part of group VII A of the periodic table and exist in the free state normally as diatomic molecules); and..
3. Removing color and metabolic by-products in re-circulating systems.
Even though the knowledge of carbon treatment for the removal of colored impurities and degradation impurities are widely reported in the literature and followed for many processes. US patent 2005/004859 provides a process for the preparation of crystalline Imipenem monohydrate which comprises: (a) dissolving crude Imipenem in water to obtain a solution; (b) subjecting the resultant solution to activated carbon treatment; and (c) adding an organic solvent to precipitate Imipenem monohydrate as a crystalline product.
With our continued research for developing a process for the preparation of compound of formula (I), we have identified a process, which is not only

commercially viable, but involves simple purification techniques affording good yield and quality of Imipenem.
Objectives of the Invention
The main objective of the present invention is to provide a simple and commercially viable, industrially scalable process for the preparation of compound of the formula (I).
Another objective of the present invention is to provide a simple and commercially viable, industrially scalable process for the purification of compound of formula (I), which avoids chromatographic techniques.
Yet another objective of the present invention is to provide a simple and commercially viable, industrially scalable process for the preparation of Sterile Imipenem monohydrate (I).
, Summary of the Invention
Accordingly, the present invention provides an improved process for preparation of compound of the formula (I)

the said process comprising the steps of:

i) converting the compound of formula (III) into compound of formula (IV) by activating the compound of formula (III) using an activating reagent in the presence of solvent and base, followed by reacting the ensuing activated compound with cysteiamine hydrochloride,
ii) converting the compound of formula (IV) into compound of formula (V) by reacting the compound of formula (V) with alkyl formimidate hydrochlorides or arylalkyl formimidate hydrochlorides in the presence of solvent and base, and
iii) deprotecting the compound of formula (V) by catalytic hydrogenation using mixture of solvents in the presence of morpholinoalkyl sulfonic acid or it salt as a buffer to yield Imipenem of formula (I), wherein the improvement consists of using mixture of two organic solvents and water in which one organic solvent is selected from water immiscible solvent,
iv) optionally purifying the Imipenem, and
v) adding an organic solvent to the aqueous layer to yield Imipenem monohydrate of formula (I).

Description of the Invention
In an embodiment of the present invention the carboxyl protecting group represented by Ri may be any of the well known, readily removable carboxyl protecting groups; which includes diphenylmethyl, benzyl, p-nitrobenzyl, methoxymethyl and the like preferably p-nitrobenzyl.
In another embodiment of the present invention, the activating reagent used in (i) is selected from diphenylchloro phosphate, 2,4-dichlorodiphenylchloro phosphate, diethylthiocholoro phosphate, tosylate, mesylate and the like preferably diphenylphosphate.
In another embodiment of the present invention, the base used in step (i) or (ii) is selected from diisopropylamine, ethyldiisopropylamine, triethylamine, pyridine or the like.
In still another embodiment of the present invention, the solvent used in step (i) is selected from diethyl ether, tetrahydrofuran, tetrahydropyran, toluene, xylene, dichloromethane, ethylene dichloride, N,N-dimethyl formamide, N,N-dimethyl acetamide, N-methylpyrrolidinone, N-ethylpyrrolidinone, N-methylpiperidinone, acetonitrile, proprionitrile, and other such organic solvents known in the art or mixtures thereof.
In another embodiment of the present invention the compound of formula (IV) can be taken into next step with or with out isolation. In the case of isolation, the compound of formula (IV) is isolated in the form of acid addition solvate of N-

methylpyrrolidinone (NMP), N-ethylpyrrolidinone, N,N-dimethylacetamide, N,N-dimethylformamide and the like.
In still another embodiment of the present invention, the solvent used in step (ii) is selected from dichloromethane, acetonitrile, dioxane, sulfolane, ethyl acetate, IPE and tetrahydrofiiran and the like or mixture thereof.
In one more embodiment of the present invention the solvent used in the deprotection stage in step (iii) is selected from THF, dioxane, ethyl acetate, dichloromethane, DMF, ethanol, iso-propanol, butanol, and water. However it was identified that the deprotection is carried out in the mixture of THF (or dioxane): ethyl acetate: water, Imipenem obtained in aqueous solution has better quality. The presence of water immiscible solvent like in ethyl acetate in the reaction medium helps to remove the impurities obtained and is primarily responsible for the quality of final Imipenem in terms of related substances. Also the present invention provides a process wherein the reduction can be also performed in a single-phase solvent system consisting of THF, dioxane, DMF, ethanol, iso-propanol, butanol, and water or mixtures thereof.
The catalyst used for reduction is selected from platinum oxide, Pd/C, Pt/C and the like, and buffer used is selected from morpholinoalkyl sulfonic acid (MOPS) or its salt such as morpholinopropane sulfonic acid, morpholinoethane sulfonic acid and their sodium salt.
In an embodiment of the present invention he Imipenem isolated in step (v) may contain morpholinoalkyl sulfonic acid or its salt. In one more embodiment of the present invention the purification of Imipenem in step (v) is done by (i) treating

the aqueous solution of Imipenem with silica gel followed by carbon treatment (ii) by converting Imipenem into salt of benzathine or N,N'-dicyclohexylethylene diamine followed by converting salt into Imipenem by utilizing the technique known in cephalosporin or penicillin chemistry (iii) by converting the Imipenem in to solvate using DMF, NMPO (N-Methyl pyrrolindin-2-one) followed by de-solvating the.ensuing product.
In another embodiment of the present invention provides a process for preparation of pure Imipenem monohydrate by isolating the Imipenem containing MOPS or its salt followed by purification with water to get pure Imipenem monohydrate at a pH in the range of 4.0 to 7.0, preferably 4.0 to 5.0.
In yet another embodiment of the present invention provides a sterile process for the preparation of pure Imipenem Monohydrate by dissolving the pure Imipenem monohydrate in water and subjecting the solution to sterile micron filtration (0.2 to 0.8 micron filtration) followed by addition of organic solvent to yield pure Imipenem Monohydrate.
The foregoing technique has been found to be attractive from commercial, technological and ecological perspective.
The present invention is illustrated with the following examples, which should not be construed to limit the scope of the invention.

Example -1
Preparation of Thienamycin p-nitrobenzylester hydrochloride N-methylpyrrolidinone solvate
To the solution of p-nitrobenzyl (3R, 5R, 6S)-2 oxo-5 [(lR)-l-hydroxyethyl)] carbapenem-3-carboxylate (lOOgm) in N-methylpyrrolidinone (500 ml) was added diisopopylethylamine (45gm) at -10°C followed by diphenylchlorophosphate (78gm) and stirred for 1 hr at -10°C. To the resulted mass was added the solution of cysteamine hydrochloride (36gm) in N-Methylpyrrolidinone (300ml) at 25°C, stirred for 30min. and diisopropylethylamine (25gm) was added at -10°C. the reaction mass was stirred further 2hrs to precipitate the solvate form. Acetone (21t) was added and stirred for lhr at -10°C. The precipitated mass was filtered washed with acetone (500ml) and dried und^r vacuum yielded lOOgm as white solid.
Example-2
Preparation of Imipenem p-nitrobenzyl ester hydrochloride
To the suspension of Thienamycin-p-nitrobenzyl ester hydrochloride N-Methylpyrrolidinone solvate (lOOgm) in acetonitrile (2.51t) at -10°C was added diisopropylethylamine (71 gm) and stirred for 15min., benzylformidate hydrochloride (63gm) was added in one lot at -10°C and stirred for 2hrs at -10°C. Isopropyl ether (2.51t) was added and stirred for 2hrs at -10°C.The resulted mass was filtered under nitrogen atmosphere and washed with acetonitrile (lit) followed by isopropyl ether (lit). The filtered solid was dried under vacuum yielded 85gm as off white solid.

Example - 3
Preparation of pure Imipenem monohydrate
To the solution of Imipenem p-nitro benzyl ester hydrochloride (85gm) in the mixture of THF (lilt) and MOPS solution (178gm in 1.71t water, the pH was adjusted to 7.0 with sodium hydroxide solution) stirred for 10 min. and added ethyl acetate (1.71t) followed by Pd-C 10% (85gm). The resulted suspension was hydrogenated under hydrogen pressure of 10kg at 10°C for 2hrs. The catalyst was filtered and the ethyl acetate layer was separated and the aqueous layer was re-extracted with ethyl acetate (lit), after complete removal of ethyl acetate under high vacuum the aqueous layer was added acetone (51t) and stirred for 10 hrs at 10°C to precipitate Imipenem hydrate having the assay of 90%. The crude Imipenem hydrate was stirred with water (300ml) at 10°C for 30min at a pH in the range of 4.0 to 5.0. The resulted mass was filtered, washed with water (30ml) followed by acetone (100ml) and dried under vacuum yielded pure Imipenem Monohydrate (30gm) with assay of 99%. Example - 4
Preparation of Sterile Imipenem monohydrate
To water Imipenem Monohydrate was added and stirred to get clear solution; the clear solution was subjected to sterile filtration using 0.2-micron filtration. To filtrate acetone or THF was added to yield sterile Imipenem monohydrate.

We claim:
1. An improved process for preparation of compound of the formula (I)

by activating the compound of formula (III) using an activating reagent in the presence of solvent and base, followed by reacting the ensuing activated compound with cysteiamine hydrochloride,
ii) converting the compound of formula (IV) into compound of formula (V) by reacting the compound of formula (IV)

with alkyl formimidate Jiydrochlorides or arylalkyl formimidate hydrochlorides in
the presence of solvent and base, and
iii) deprotecting the compound of formula (V) by catalytic hydrogenation using
mixture of solvent in the presence of morpholinoalkyl sulfonic acid or it salt as a
buffer to yield Imipenem of formula (I) in aqueous medium, wherein the
improvement consists of using mixture of two organic solvents and water in which
one organic solvent is selected from water immiscible solvent,
iv) optionally purifying the Imipenem,
v) adding an organic solvent to the aqueous layer to yield Imipenem
monohydrate (I).
2. A process for the preparation of pure Imipenem monohydrate, which comprises treating Imipenem monohydrate with water at a pH in the range of 4.0 to 7.0, preferably 4.0 to 5.0.
3. A process as claimed in claim 1, wherein the solvent used in step (i) is selected from diethyl ether, tetrahydrofuran, toluene, xylene, dichloromethane, ethylene dichloride, N,N-dirnethyl formamide, N,N-dimethyl acetamide, N-methylpyrrolidinone, N-ethylpyrrolidinone, N-methylpiperidinone, acetonitrile, or proprionitrile and activating reagent is selected from diphenylchloro phosphate, 2,4-dichlorodiphenylchloro phosphate, diethylthiocholoro phosphate, tosylate, or mesylate.

4. A process as claimed in claim 1, wherein the solvent used in step (ii) is selected from dichloromethane, acetonitrile, dioxane, sulfolane, ethyl acetate, IPE and tetrahydrofiiran and the like or mixture thereof and the base used is diisopropylamine, ethyldiisopropylamine, triethylamine, pyridine or the like.
5. A process as claimed in claim 1, wherein the solvent used in step (iii) is selected from THF, dioxane, acetone, ethyl acetate, dichloromethane, DMF, ethanol, iso-propanol, butanol, water or mixtures thereof.
6. A sterile process for the preparation of pure Imipenem monohydrate, which comprises the steps of:

a) dissolving pure Imipenem monohydrate in water,
b) subjecting to micron filtration, and
c) isolating the Imipenem monohydrate from the filtrate of step (b) by adding an organic solvent.
7. A process as claimed in claim 1, wherein the solvent used in step (c) is
selected from ethanol, propanol, isopropanol, butanol, THF, acetone, methyl ethyl
ketone or mixtures thereof

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Patent Number

269058

Indian Patent Application Number

1178/CHE/2005

PG Journal Number

40/2015

Publication Date

02-Oct-2015

Grant Date

29-Sep-2015

Date of Filing

25-Aug-2005

Name of Patentee

HOSPIRA,INC

Applicant Address

275 NORTH FIELD DRIVE,DEPT.Nleg,Bldg H-1 Lake Forest,Illinois 60045

Inventors:

#	Inventor's Name	Inventor's Address
1	NAGAPPAN ARUMUGAM	ORCHID CHEMICALS&PHARMACEUTICALS LTD, 476/14,OLD MAHABALIPURAM ROAD, SHOLINGANALLUR, CHENNAI-600 119 TAMILNADU
2	HENRY SYRIL SUDHAN	ORCHID CHEMICALS&PHARMACEUTICALS LTD, 476/14,OLD MAHABALIPURAM ROAD, SHOLINGANALLUR, CHENNAI-600 119 TAMILNADU
3	GANPATHY PANCHAPAKESAN	ORCHID CHEMICALS&PHARMACEUTICALS LTD, 476/14,OLD MAHABALIPURAM ROAD, SHOLINGANALLUR, CHENNAI-600 119 TAMILNADU

PCT International Classification Number

C07D477/20

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA