FORM 2
THE PATENTS ACT 1970
(39 of 1970)
&
The Patents [Amendment] Rules, 2006
COMPLETE SPECIFICATION
(See section 10 and rule 13)

1. TITLE OF THE INVENTION
Process For Preparing Imipenem And Its Monohydrate
2. APPLICANT
NAME : Frichem Private Limited
NATIONALITY : IN
ADDRESS ; 12, Concord, Bullock Road, Band Stand, Bandra West, Mumbai -400 050, India
3. PREAMBLE TO THE DESCRIPTION
COMPLETE
The following specification describes the invention and the manner in which it is to be performed.

Field of the Invention
The present invention relates to an improved process for preparing carbapenem antibiotic or its hydrate. More particularly, the present invention provides a process for preparing highly pure crystalline imipenem monohydrate with reduced thienamycin content and other impurities.
Background of the Invention
The first carbapenem antibiotic to be discovered was thienamycin, isolated from naturally occurring Streptomyces cattleya by Merck Co., U.S.A. in 1976.
Since thienamycin is highly chemically unstable despite superior pharmacological effects, it has not been developed into medicines. Many attempts have been made to overcome the chemical instability of thienamycin while maintaining the pharmacological effects of thienamycin. For example, imipenem, which is a novel thienamycin derivative synthesized by Merck Co., is prepared by modifying the amine group of thienamycin into an N-formimidoyl group. Imipenem is a new concept antibiotic with ensured stability. Imipenem is prepared by chemical total synthetic route, unlike conventional cephalosporin antibiotics.
N-formimidoyl derivative of thienamycin which is known as imipenem is the first clinically available member of a new class of P-lactam antibiotics that possess the carbapenem ring system. Imipenem exhibits an extremely broad spectrum of activity against gram-positive and gram-negative aerobic and anaerobic species. The chemical name of Imipenem is (5R, 6S)-6-[(lR)-l-Hydroxyethyl]-3-[[2-[(iminomethyl)amino]ethyl]thio]-7-oxo-l-azabicyclo [3.2.0]hept-2-ene-2-carboxylic acid. Imipenem is an intravenous p-lactam antibiotic and its combination with Cilastatin sodium and sodium bicarbonate is marketed in US as PRIMAXIN®
The first industrial synthesis of imipenem was reported in 1981. Since 1989, improved synthetic processes of imipenem have been suggested. Imipenem was first disclosed in U.S.

Patent No. 4,194,047 and obtained by using column of XAD-2 (150 cc) which is eluted with water and then lyophilized to get white solid. The compound obtained by lyophilization is found to be largely amorphous and stated to be thermodynamically unstable. This process of imipenem production was found to give a product in low yield and of poor quality.
U.S. Patent No. 4.260,543 discloses thermodynamically stable form of crystalline imipenem monohydrate obtained by crystallization of lyophilized sample of imipenem. However, this process is not satisfactory on a commercial scale as it requires lyophilization, followed by crystallization. Moreover, the prolonged process for isolation of the final product leads to degradation of imipenem, thus affecting the purity of the product.
U.S. Patent No. 4,292,436 discloses process for the purification of imipenem by washing an aqueous solution containing imipenem with an ethyl acetate to remove organic impurities. The aqueous layer is diluted to get pure imipenem solution. U.S. Patent No. 4,292.436 also discloses an alternate process for the preparation of imipenem wherein crude imipenem is purified by column chromatography using Dowex-50 to give crystalline imipenem. However, the process gives low yield of the final product (59% in solution and 35% of isolated imipenem monohydrate).
Another process for the preparation of highly crystalline imipenem by freeze crystallization is disclosed in J. Pharm. Sci, 85, 174(1996) by Connolly et. al. However, the above processes are tedious, cumbersome and unsuitable for industrial use.
An improved process for preparing imipenem was also disclosed in U.S. Patent No. 4,374,772 wherein dilute aqueous solutions of thienamycin was treated with benzyl formimidate hydrochloride. However, this process has the disadvantage of producing at least 5% of dimer bis-thienamycin formamidine along with the desired product imipenem.
U.S. Patent No. 7,241,885 disclosed the crystallization method by treating an aqueous solution containing crude imipenem with organic solvent and isolating the pure crystalline imipenem monohydrate. U.S. Patent No. 7,332,600 discloses the process comprising

dissolving crude imipenem in warm water in presence of base to obtain a solution, subjecting the resultant solution to activated carbon treatment, and adding an organic solvent to precipitate imipenem monohydrate as a crystalline product. The product so obtained by these processes also results in the formation of the side products during the reaction i.e. thienamycin impurity and colored impurities. These impurities are difficult to detect as they don't have any ultra-violet absorption and are not reflected in the qualitative determination of purity by HPLC, but the quantitative determination shows that the product contains 5-10% of these impurities.
Further, the purification of imipenem is difficult due to its unstable nature. The crystalline imipenem has relatively low solubility in water at room temperature, as a result the purification and chromatographic process requires large volumes of water for dissolving imipenem and further involving tedious process for removing the water. As imipenem being inherently unstable in solution and sensitive to heat and light thee colored impurities adversely affect the appearance of imipenem powder, which may appear from pale yellow to brownish powder instead of the desired white crystalline powder. However the product obtained by the process contains thienamycin content more than 1 %. As per U.S. Patent No. 7,332,600, crude imipenem is added to warm water at 45 to 47 °C containing the base. followed by rapidly cooling up to 5 to 10 °C within 10 to 15 min, which is extremely difficult to achieve during large scale production. This uncontrolled temperature may leads to generation of thienamycin impurities as well as colored impurity on industrial scale, thus affecting the purity of final product.
In light of the existing processes mere still exists a need to develop an alternate process for large scale production of white crystalline imipenem that is economical, less tedious and time consuming. Further, there is need to develop a simple process for producing imipenem that involves fewer steps and generates minimal impurities.
Objects and summary of the Invention

It is an object of the present invention to provide an improved process for preparing crystalline imipenem monohydrate which is free from polymeric impurities, colored impurities and thJenamycin.
It is another object of the present invention to provide a process for preparing crystalline imipenem monohydrate in high yield and purity during large scale industrial production.
It is yet another object of the present invention to provide a simple, cost effective and commercially viable process for preparing highly pure thermally stable crystalline imipenem monohydrate having uniform degree of crystallinity without involving use of sophisticated, time consuming and costly techniques like lyophilization at any stage.
The above and other objects of the present invention are attained according to following preferred embodiments of the present invention. However the scope of the invention is not restricted to the particular embodiments discussed herein after.
In accordance with one embodiment of the present invention, there is provided a process for preparing crystalline imipenem monohydrate having color value less than about 0.15 absorbance unit, comprising hydrogenating the carboxyl protected imipenem of formula V by using metal catalyst in an aqueous medium to obtain imipenem followed by filtering reaction mass and passing the resulting aqueous solution through a solid adsorbent resin column. combining the fractions containing imipenem monohydrate, subsequently adding a water miscible organic solvent to the resultant solution and isolating pure crystalline imipenem monohydrate.
In accordance with another embodiment of the present invention, the solid adsorbent resin column comprises a resin that is a copolymer of styrene and di vinyl benzene, selected from Diaion HP20: Diaion HP21, Diaion HP30, Diaion HP40, and Diaion HP50: Sepabeads SP800, Sepabeads SP825, Sepabeads SP850, Sepabeads SP875, Sepabeads SP70, and Sepabeads SP700, and Amberlite XAD-4, Amberlite XAD-]6HP, Amberlite XAD-1180, and Amberlite XAD-2000.

In accordance with still another embodiment of the present invention, the ratio of crude imipenem and the solid adsorbent resin is about 1:1 (w/v) to about 1:10 (w/v), preferably about 1:6 (w/v)..
In accordance with still another embodiment of the present invention, the metal catalyst is platinum oxide, platinum/carbon, palladium hydroxide and palladium/carbon.
Detailed Description of the Invention While this specification concludes with claims particularly pointing out and distinctly claiming that, which is regarded as the invention, it is anticipated that the invention can be more readily understood through reading the following detailed description of the invention and study of the included examples.
The disclosed embodiment of the present invention discloses a process for preparing and isolating crystalline imipenem monohydrate. The process of the present invention uses a solid adsorbent resin column thereby controlling the formation of colored impurities and making the process economical, commercially viable and feasible for large-scale manufacture of crystalline imipenem monohydrate.
According to the invention, the process for preparing crystalline imipenem monohydrate having color value less than about 0.15 absorbance unit comprises hydrogenating the carboxyl protected imipenem of formula V by using metal catalyst in an aqueous medium to obtain imipenem followed by filtering reaction mass and passing the resulting aqueous solution through a solid adsorbent resin column, combining the fractions containing imipenem monohydrate, subsequently adding a water miscible organic solvent to the resultant solution and isolating pure crystalline imipenem monohydrate.
According to an embodiment of the invention the crystalline imipenem monohydrate is prepared from the activated keto ester (II) on reaction with cysteamine hydrochloride (III) and isolating the product as PNBT- Solvate (IV), followed by hydrogenation and passing the

aqueous solution containing crude imipenem through solid adsorbent resin (HP-20) column, subsequently treating with organic water miscible solvent at low temperature, and isolating the crystalline imipenem monohydrate. The process according to the present invention is as mentioned in scheme 1 below:

Scheme 1
According to the invention, the process for isolating crystalline imipenem monohydrate, wherein the ratio of crude imipenem and solid adsorbent resin is about 1:1 (w/v) to about 1:10 (w/v), preferably the ratio is about 1:2 (w/v) to about 1:6 (w/v), more preferably 1:6 (w/v),
The resultant product obtained by the process of the present invention is having improved colour (color value less than 0.15 Absorbance Unit) and purity more than 98.0 %. The process disclosed herein is feasible for large-scale industrial manufacture of crystalline imipenem monohydrate.

Accordingly, the present invention, the hydrogenation step of protected imipenem is carried out using metal catalyst in the presence of N-methylmorpholine and lower alcohols. Examples of lower alcohols include methanol, ethanol, isopropanol and propanol. Examples of metal catalyst include platinum oxide, platinum/carbon, palladium hydroxide and palladium/carbon. After completion of hydrogenation, the catalyst is filtered, aqueous solution containing imipenem is passed through solid adsorbent resin column and the resultant solution is treated with a water miscible organic solvent at low temperature to get the crystalline imipenem monohydrate.
The water miscible solvent system from which the product may be crystallized will desirably be selected from water soluble organic solvents either alone or in admixture with water. Examples of such water-miscible organic solvents include lower alcohols such as methanol, ethanol, propanol and isopropanol; ketones such as acetone; glycol ethers such as monoethylene glycol; amides such as N,N-dimethylformamide, N,N-dimethylacetamide; lactams such as N-methylpyrrolidone and cyclic ethers such as tetrahydrofuran, dioxane, or mixture(s) thereof.
According to the present invention, the aqueous solution containing the crude imipenem prior to passing through the solid adsorbent resin column may be washed with water immiscible organic solvent. Examples of such water immiscible organic solvents include carboxylic acid ester such as ethyl acetate, an alkyl ketone having six or more carbons such as methylisobutyl ketone, chlorinated hydrocarbon such as dichloromethane, ether such as diethyl ether, aromatic hydrocarbon such as toluene, or a mixture thereof.
The solid adsorbent resin column according to the present invention are selected from, but not limited to resin that is a copolymer of styrene and divinylbenzene. Specific examples of such resin includes Diaion HP20, Diaion HP21, Diaion HP30, Diaion HP40, and Diaion HP50, Sepabeads SP800, Sepabeads SP825, Sepabeads SP850, Sepabeads SP875, Sepabeads SP70, and Sepabeads SP700, and Amberlite XAD-4, Amberlite XAD-16HP, Amberlite XAD-1180, and Amberlite XAD-2000. Solid adsorbent Resin column used is preferably

styrene type Diaion HP20, Diaion HP21, Diaion HP30, Diaion HP40, and Diaion HP50, most preferably HP20 is used.
Accordingly, in still another embodiment of the present invention, the aqueous solution of imipenem is treated with activated carbon and/or solid adsorbent resin. Such a treatment found to be advantage in terms of increasing stability of the imipenem and color wherein the imipenem having color value less than 0.15 Absorbance Unit.
Further details of the invention will be apparent form examples. However, these are not intended in any way to limit the scope of the present invention.
Example-1
Preparation of Crystalline Imipenem Monohydrate
Step I: (5R. 6S)-p-Nitrobenzyl-3-(diphenylphosphono)-6-[(lR)-l-hydroxyethyl]-l-azabi cyclo[3.2.0]hept-2-ene-7-one-2-carboxylate.
To a solution of p-Nitrobenzyl (3R, 5R, 6S)-2oxo-6-[(l R)-l-hydroxyethyl)]carbapenem-3-carboxylate (100.0 g, 0.29 mol) in TV-methyl pyrrolidone and dichloromethane, a solution of dimethylaminopyridine (0.68 g) in dichloromethane was added at -55°C. To this reaction mixture diisopropyl ethyl amine (85.2 g, 0.66 mol) followed by diphenyl chlorophosphate (81.13 g, 0.3 mol) in dichloromethane (30 ml) was added. The reaction temperature was raised to -45°C and stirred for a period of time to get the (5R.6S)-p-Nitrobenzyl-3-(diphenylphosphono)-6-[(lR)-l -hydroxy ethyl]-l-azabicyclo[3.2.0]hept-2-ene-7-one-2-carboxylate, which was used in the next step without isolation.
Step II - Preparation of (5R,6S)-p-nitrobenzyl-3-[(2-aminoethyl)thio]-6-[(lR)-l-hydroxyethyl]-l-azabicyclo[3.2.0]hept-2-ene-7-one-2-carboxylate as N-methyl pyrrolidone solvate.
A solution of cysteamine (2-aminoethanethiol) hydrochloride (38.25 g, 0.34 mol) in N-

methyl pyrrolidone (150 ml) was added to the reaction mixture from step I and cooled to -65°C. The reaction mixture was stirred for about 2 hours, followed by the raising the temperature of reaction mixture to 0 to 5°C. To this reaction mixture 2-propanol was added and reaction mixture was allowed to settle for 2 to 3 hours. The crystalline precipitate obtained was filtered, washed with 2-propanol and dried to yield 115 gm of (5R,6S)-p-nitroberizyl-3-[(2-aniinoethyl)thio]-6-[(lR)-l-hydroxye1hyl]-l-azabicyclo[3.2.0]hept-2-ene-7-one-2-carboxylate as N-methyl pyrrolidone solvate.
Step III: Preparation of (5R,6S) p-nitrobenzyl-3-[2-[(iminomethyl)amino]ethyl]thio]-6-[(l R)-l-hydroxy ethyI]-l-azabicyclo[3.2.0]hept-2-ene-7-one-2-carboxylate
(5R,6S)-p-Nitrobenzyl-3-[(2-aminoethyl)thio]-6-[(lR)-l-hydroxyethyl]-l-azabicyclo[3.2.0] hept-2-ene-7-one-2-carboxylate as N-methyl pyrrolidone solvate (100 gm; 0.18 moles) was added to a mixture of diisopropylethylamine (32 gm, 0.247 moles), dichloromethane and methanol at -25°C followed by cooling the reaction mixture to -55 C. To this reaction mixture benzylformimidate hydrochloride (50.32 gm, 0.293 moles) was added and stirred for about 20 minutes. After completion of reaction, water was added and the aqueous layer was separated from organic layer followed by washing of aqueous layer with dichloromethane. The aqueous layer containing (5R,6S) p-Nitroben l-3-[2-[(iminomethyl)amino]ethyl]thio]-6-[(l R)-l-hydroxyethyl]-l-azabicyclo[3.2.0]hept-2-ene-7-one-2-carboxylate thus obtained was used in the next step without isolation.
Step IV - Preparation of [5R-[5a,6a(R*)]]-6-(l-hydroxyethyI)-3-[[2-[(iminomethyl)amino] ethyl]thio]-7-oxo-l-azabicylo[3.2.0]hept-2-ene-2-carboxylic acid (imipenem monohydrate)
To the aqueous layer from Step III, a buffer solution (made up of water (340 ml), N-methylmorpholine (82.8 gm), 2-propanol (521 ml) and Acetic acid (30 gm)) was added at 0 to 5°C. The reaction mixture was then hydrogenated at 6-7 kg/cm2 pressure by using palladium on carbon (2.5%, 36 g). After completion of the reaction catalyst was filtered and filtrate was washed with dichloromethane followed by layer separation. The obtained aqueous layer was treated with activated carbon (3.0 g) followed by filtration and the residue

was washed with distilled water (25 ml). The filtrate was passed through HP-20 column and fractions containing the desired product were combined and acetone (3300 ml) was added. The reaction mixture was seeded with pure imipenem monohydrate (3.0 g) and was allowed to settle at 0 to 5 °C. The crystalline precipitate obtained was filtered, washed with acetone (3*100 ml) and dried to yield 35.0 g of white crystalline imipenem monohydrate.
While this invention has been described in detail with reference to certain preferred embodiments, it should be appreciated that the present invention is not limited to those precise embodiments. Rather, in view of the present disclosure, which describes the current best mode for practicing the invention, many modifications and variations would present themselves to those skilled in the art without departing from the scope and spirit of this invention.

We claim:
1. A process for preparing crystalline imipenem monohydrate having color value
less than about 0.15 absorbance unit, comprising:
a. hydrogenating the carboxyl protected imipenem of formula V by using
metal catalyst in an aqueous medium to obtain imipenem,

wherein R is carboxy protecting group;
b. filtering the reaction mass of step (a) and passing the resulting aqueous
solution through a solid adsorbent resin column;
c. combining the fractions containing imipenem monohydrate;
d. adding a water miscible organic solvent to the solution of step (d); and
e. isolating pure crystalline imipenem monohydrate.
2. The process of claim 1, wherein the solid adsorbent resin column comprising a resin that is a copolymer of styrene and divinylbenzene.
3. The process of claim 3, wherein the solid adsorbent is selected from the group consisting of Diaion HP20, Diaion HP21, Diaion HP30, Diaion HP40, and Diaion HP50, Sepabeads SP800, Sepabeads SP825, Sepabeads SP850, Sepabeads SP875, Sepabeads SP70, and Sepabeads SP700, and Amberlite XAD-4, Amberlite XAD-16HP, Amberlite XAD-1180, and Amberlite XAD-2000.
4. The process of claim 1. wherein ratio of crude imipenem and the solid adsorbent resin is about 1:1 (w/v) to about 1:10 (w/v).

5. The process of claim 4. wherein the ratio of crude imipenem and the solid adsorbent resin is about 1:2 (w/v) to about 1:6 (w/v), preferably about 1:6 (w/v)..
6. The process of claim 1, wherein the process further comprising washing the resulting aqueous solution of step (b) containing imipenem with a water immiscible organic solvent.
7. The process of claim 6, wherein the water immiscible organic solvent comprises one or more of a carboxylic acid ester, an alkyl ketone having six or more carbons, chlorinated hydrocarbon, ether and aromatic hydrocarbon.
8. The process of claim 7, wherein the water immiscible organic solvent is selected from the group consisting of ethyl acetate, methylisobutyl ketone, dichloromethane, diethyl ether, toluene and mixture(s) thereof.
9. The process according to claim 1, wherein the water miscible organic solvent comprises a lower alcohol, a ketone, and mixture(s) thereof
10. The process according to claim 9, wherein the lower alcohol is selected from the group consisting of methanol, ethanol, propanol, isopropanol, and mixture(s) thereof and ketone is acetone, methyl ethyl ketone and a mixture thereof
11. The process according to claim 1, wherein the metal catalyst is platinum oxide, platinum/carbon, palladium hydroxide and palladium/carbon.