Title of Invention

A PROCESS FOR THE PREPARATION OF PURE CRYSTALLINE IMIPENEM MONOHYDRATE

Abstract An improved purification process for preparing Crystalline Imipenem monohydrate of Formula I,
Full Text

FIELD OF THE INVENTION
The present invention relates to an improved purification process for preparing Crystalline Imipenem monohydrate of Formula I.

BACKGROUND OF THE INVENTION
Imipenem monohydrate i.e. [5R-[5a,6a(R*)]]-6-(l-Hydroxyethyl)-3-[[2-[iminomethyl)amino]ethyl]thio]-7-oxo-l-azabicyclo-[3,2,0]hept-2-ene-2-carboxylic acid monohydrate of Formula I is active against a wide range of gram-negative and gram-positive bacteria. Imipenem works by interfering with the bacterial ability to form cell-walls, and therefore the break-up and die,
Imipenem is partially inactivated by an enzyme in the kidney which can reduce its effectiveness. Imipenem monohydrate is co-administered with cilastatin sodium, which blocks the effect of the enzyme. Cilastatin does not have any antibacterial effects and does not affect the antibacterial activity of Imipenem. It is currently being marketed as PRIMAXIN I.V.
In view of the importance of Imipenem monohydrate as an anti-bacterial compound, several synthetic methods have been reported in the literature, which are as summarized below:
Imipenem was first disclosed in US 4,194,047. Example 5 discloses a process to prepare Imipenem, which comprises reacting thienamycin with methyl formimidate hydrochloride in the presence of sodium hydroxide and at pH 8.5. Then the solution

is chromatographed on a column of XAD-2 resin (150 cc), which is eluted with water, and the resulting solution is lyophilized to produce Imipenem as a white solid. This process is not industrially feasible and not economical.
US 4,260,543 specifically discloses Imipenem monohydrate. The process comprises, dissolving lyophilized N-formimidoyl thienamycin in water and diluted with ethanol. The resulting solution is immersed in an ice-bath, stirred with a magnetic stirrer and seeded with iV-formimidoyl thienamycin monohydrate crystals for 1.5 h to produce crystals of Imipenem monohydrate.
US 4,374,772 patent discloses a process comprising, reacting benzylic formimidate with thienamycin in presence of water at pH 7-8.5 to produce N-formimidoyl thienamycin. The disadvantage according to above process is low purity, wherein upto 5% of dimer is present in the final compound.
US 4,894,450 patent discloses a process comprising, reacting protected bicyclic ketone with phosphorohalidate to give diprotected bicyclic ester, which was reacted with cysteamine hydrochloride in the presence of N-ethyl pyrrolidine to give protected thienamycin or solvate. Subsequently reaction with benzyl formimidate followed by hydrogenation of the ester provided Imipenem monohydrate. However, isolation of Imipenem from aqueous solution is not given clearly.
US 2005/0004349 Al publication discloses a process to prepare crystalline Imipenem monohydrate, which comprises dissolving Imipenem in water to obtain a solution and then subjecting to carbon treatment, followed by precipitation using an organic solvent. The disadvantage of above process is that Imipenem decompose quickly in water and produces low yields.

Due to the above drawbacks in the prior art processes, there is a need for the development of a process for the preparation of Imipenem, which is convenient to operate on an industrial scale and produce Imipenem monohydrate in higher yields and better quality.
OBJECTIVE
The objective of the present invention is to provide an improved process for preparing crystalline Imipenem monohydrate.
Another objective of the present invention is to provide an improved process for preparing crystalline Imipenem monohydrate with high yield and high purity
Yet another objective of the present invention is to provide an improved process for the preparation of crystalline Imipenem monohydrate, which is simple, industrially applicable and economically viable.
SUMMARY OF THE INVENTION
The present invention relates to an improved process for the preparation of Crystalline Imipenem monohydrate of Formula I,

which comprises,
(a) dissolving crude Imipenem monohydrate in hot 4-morpholinepropanesulfonic acid solution (MOPS) to obtain a clear solution;

(b) cooling the reaction mass to 0-20°C and then adjusted the pH of the solution to 7-8 with inorganic base;
(c) subjecting the reaction mass to resin treatment, followed by carbon treatment;
(d) adding an polar solvent to precipitate Imipenem monohydrate as a crystalline product.
DETAILED DESCRIPTION OF THE INVENTION
In yet another embodiment of the present invention, the hot MOPS solution is prepared by dissolving MOPS in DM water at 25-30°C, followed by adjusting the pH to 5.0-8.0, preferably 6.0-7.0 using aqueous sodium hydroxide solution. Then heated the solution to 50-70°C, preferably 55-60°C.
In an aspect of the present invention, the reaction is cooled to 0-20°C, preferably 0-5°C and pH of the solution is adjusted to 7.0-8.0, preferably 7.0-7.5.
In yet another embodiment of the present invention, the resin is prepared in DM water followed by pH adjustment to 5.0-7.0, preferably 6.0-6.5 using DM water.
In yet another embodiment of the present invention, Imipenem monohydrate solution is passed through resin at 0-20°C, preferably 5-10°C.
In yet another embodiment of the present invention, the Imipenem monohydrate solution obtained after resin treatment, adjusted the pH to 6.0-7.5, preferably 7.0-7.5 using aqueous sodium hydroxide solution.

In yet another embodiment of the present invention, polar solvent is added to precipitate Imipenem monohydrate. The protic solvent is selected from methanol, isopropanol, acetone and mixtures thereof; preferably isopropanol is used.
EXAMPLE-1
PREPARATION OF PURE CRYSTALLINE IMIPENEM MONOHYDRATE
Imipenem monohydrate (10 g) crude was dissolved in hot 3.5 % w/w morpholine propane sulfonic acid aqueous solution (190 ml, pH 6.7-7.0) and cooled to 10°C. The aqueous solution was eluted through DOWEX 1x2-200 ion exchange resin (50 g) and washed with 1% w/w aqueous 4-morpholine propane sulfonic acid (160 ml). PH of combined eluant was adjusted to 7.0-7.1 with 10% w/w sodium hydroxide aqueous solution and given carbon treatment. Isopropanol (1110 ml) was added to 22-25°C in 40 min and seeded with Imipenem, and then the resulting solution was stirred at 8-10°C for 2 h. The crystalline product so obtained was filtered, washed with acetone and dried at 30-35°c for 3 h to obtain crystalline Imipenem monohydrate. YIELD: 7.0 g CHROMATOGRAPHIC PURITY: 99.17 %



WE CLAIM
1. An improved process for preparing crystalline Imipenem monohydrate of
Formula I,

which comprises,
(a) dissolving crude Imipenem monohydrate in hot 4-morpholinepropanesulfonic acid solution (MOPS) to obtain a clear solution;
(b) cooling the reaction mass to 0-20°C and then adjusted the pH of the solution to 7-8 with inorganic base;
(c) subjecting the reaction mass to resin treatment, followed by carbon treatment;
(d) adding an protic solvent to precipitate Imipenem monohydrate as a crystalline product.

2. The process according to claim 1, the hot MOPS solution is prepared by dissolving MOPS in DM water at 25-30°C, followed by adjusting the pH to 5.0-8.0, preferably 6.0-7.0 using aqueous sodium hydroxide solution. Then heated the solution to 50-70°C, preferably 55-60°C.
3. The process according to claim 1, the reaction is cooled to 0-20°C, preferably 0-5°C and pH of the solution is adjusted to 7.0-8.0, preferably 7.0-7.5.

4. The process according to claim 1, the resin is prepared in DM water followed by
pH adjustment to 5.0-7,0, preferably 6.0-6.5 using DM water.
5. The process according to claim 1, Imipenem monohydrate solution is passed
through resin at 0-20°C, preferably 5-10°C.
6. The process according to claim 1, the Imipenem monohydrate solution obtained
after resin treatment, adjusted the pH to 6.0-7.5, preferably 7.0-7.5 using aqueous
sodium hydroxide solution.
7. The process according to claim 1, polar solvent is added to precipitate Imipenem
monohydrate. The protic solvent is selected from methanol, isopropanol, acetone
and mixtures thereof; preferably isopropanol is used.


Documents:

210-che-2005 amanded claims 08-03-2010.pdf

210-CHE-2005 AMANDED CLAIMS 05-03-2010.pdf

210-che-2005 claims.pdf

210-che-2005-abstract.pdf

210-che-2005-claims.pdf

210-che-2005-correspondnece-others.pdf

210-che-2005-description(complete).pdf

210-che-2005-form 1.pdf

210-che-2005-form 3.pdf

210-che-2005-form 5.pdf

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Patent Number 239407
Indian Patent Application Number 210/CHE/2005
PG Journal Number 13/2010
Publication Date 26-Mar-2010
Grant Date 18-Mar-2010
Date of Filing 04-Mar-2005
Name of Patentee AUROBINDO PHARMA LIMITED
Applicant Address PLOT NO.2, MAITRIVIHAR COMPLEX, AMEERPET, HYDERABAD-500 038
Inventors:
# Inventor's Name Inventor's Address
1 NAGARI MADUGU MAHESH AUROBINDO PHARMA LIMITED, PLOT NO.2, MAITRIVIHAR COMPLEX, AMEERPET, HYDERABAD-500 038
2 VIJAY KUMAR HANDA AUROBINDO PHARMA LIMITED, PLOT NO.2, MAITRIVIHAR COMPLEX, AMEERPET, HYDERABAD-500 038
3 ARUN KUMAR GUPTA AUROBINDO PHARMA LIMITED, PLOT NO.2, MAITRIVIHAR COMPLEX, AMEERPET, HYDERABAD-500 038
4 MEENAKSHISUNDERAM SIVAKUMARAN AUROBINDO PHARMA LIMITED, PLOT NO.2, MAITRIVIHAR COMPLEX, AMEERPET, HYDERABAD-500 038
PCT International Classification Number C07D
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA