Title of Invention

A PROCESS FOR THE PREPARATION OF CARBAPENEM DERIVATIVES

Abstract An improved process for preparing Carbapenem derivatives of Formula I, by traeting the aqueous solution by n-butanol or spray drying.
Full Text

FIELD OF THE INVENTION
The present invention relates to an improved process for preparing carbapenam derivatives of Formula I

wherein R represents hydrogen or C1-3 alkyl group; R represents a group of the

The carbapenem derivatives of Formula I may be converted to their pharmaceutically acceptable salts and esters.
BACKGROUND OF THE INVENTION
Carbapenem-type antibacterial agents are excellent antibacterials having strong antibacterial activity against a wide spectrum of bacteria ranging from gram-positive bacteria to gram-negative bacteria including Pseudomonos aeruginosa. Some of the carbapenems, which are active against bacteria are Thienamycin, Imipenem, Meropenem and ertapenem.
In view of the importance of Carbapenem derivatives as an anti-bacterial agents, 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.
Meropenem was first disclosed in US 4,943,569. Example 2 discloses a process to prepare Meropenem, which comprises reacting (4R,5S,6S,8R,2'S,4'S)-p-nitrobenzyl-3 - [4-( 1 -p-nitrobenzy loxy carbony 1-2-dimethylaminecarbony l)pyrrolidiny Ithio] -4-methyl-6-( 1 -hydroxyethyl)-1 -azabicyclo [3,2,0]hept-2-ene-7-one-2-carboxylate was dissolved in a mixture of 1.9 ml of tetrahydrofuran and 0.3 ml of ethanol, and the mixture was hydrogenated in a morpholinopropanesulfonic acid buffer solution (pH=7.0, 1.9 ml) under atmospheric pressure of hydrogen for 3 hours at room temperature in the presence of 30 mg of 10% palladium-carbon, which had been activated in hydrogen atmosphere for 1 hour followed by washing with water. After filtering off the catalyst, tetrahydrofiiran and ethanol were distilled off under reduced pressure, and the residual solution was washed with ethyl acetate. The aqueous layer was again distilled under reduced pressure to remove organic solvents, and the residual solution was subjected to polymer chromatography (CHP-20P) to obtain (4R,5S,6S,8R,2'S,4'S)-3-[4.(2-dimethylaminecarbonyl)pyrrolidinylthio]-4-methyl-6-(l-hydroxyethyl)-l-azabicyclo[3,2,0]hept-2-ene-7-one-2-carboxylic acid from the fraction eluted with water. This process is not industrially feasible and not economical.
US 4,888,344 discloses a process to prepare crystalline Meropenem trihydrate. The process comprises, reacting Lyophilized product of non-crystalline meropenem was dissolved in water at 30°C and cooled in a water bath, whereupon precipitation of a

small amount of crystals was observed. Acetone was added thereto, and the resultant mixture was stirred for 1 hr. The precipitated crystals were collected by filtration, washed with acetone and dried at room temperature under reduced pressure for 2 hrs to give crystalline meropenem trihydrate.
US 4,374,772 patent discloses a process to prepare Imipenem, which comprises reacting benzylic formimidate with thienamycin in presence of water at pH 7-8.5 to produce //-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 to prepare Imipenem, which comprises 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.
Due to the above drawbacks in the prior art processes, there is a need for the development of a process for the preparation of Carbapenem derivatives, which is convenient to operate on an industrial scale and economically viable.
OBJECTIVE
The objective of the present invention is to provide an improved process for
preparing Carbapenem derivatives.
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In yet another objective of the present invention is to provide an improved process for the preparation of Carbapenem derivatives, which is simple, industrially applicable and economically viable.

Yet another objective of the present invention is that the solvent, which is used for reducing the volume of water, can be recycled and used for further process.
SUMMARY OF THE INVENTION
The present invention relates to an improved process for the preparation of Carbapenem derivatives of Formula I,

wherein R represents hydrogen or C1.3 alkyl group; R represents a group of the

which comprises,
(a) preparing Carbapenem by hydrogenolysis of Carbapenem derivative PNB
ester hydrochloride using palladium on carbon in 4-morpholinepropane
sulfonic acid solution and n-butanol;
(b) separating the aqueous layer;
(c) reducing the volume of water and
(d) adding polar solvent to precipitate crude Carbapenem derivatives.

DETAILED DESCRIPTION OF THE INVENTION
In an aspect of the present invention, the hydrogenation is carried out at a temperature ranging from 0-20°C, preferably 5-10°C and adjusted the pH to 6.5-7.5, preferably 7.0-7.1.
In an aspect of the present invention, the volume of water is reduced by addition of n-butanol and stirring the resulting solution.
In yet another aspect of the present invention, the volume of water is reduced by spray drying the aqueous solution containing Carbapenem derivatives.
In yet another aspect of the present invention, after reducing of water volume the resulting solution is subjected to carbon treatment.
In yet another aspect of the present invention, the polar solvent is selected from methanol, isopropanol, acetone and mixtures thereof; preferably isopropanol is used.
In another aspect of the present invention, the crude Carbapenem derivatives so obtained is purified using conventional purification methods.
EXAMPLE-1
PREPARATION OF CRYSTALLINE IMIPENEM MONOHYDRATE
STEP A
PREPARATION OF IMIPENEM PNB ESTER HYDROCHLORIDE
The thienamycin PNB ester hydrochloride N-ethylpyrrolidinone solvate (500 g) was suspended in dry tetrahydrofuran (7200 ml) at 25°C and cooled to -55°C. To this diisopropylamine (150 g) was added dropwise, followed by benzylformimidate

hydrochloride (220 g) at -55 to -50°C. The mixture was stirred for 2 h at about 45 to 40°C.
STEPS
PREPARATION OF IMIPENEM
The above suspension obtained from Step A was poured in to a mixture of 1% aqueous 4-morpholinepropane sulfonic acid solution (20 Lt) and n-butanol (36.0 Lt) maintained at 5-10°C and the pH of the solution adjusted to 7.7 to 7.9. The solution was hydrogenated at 6.0 to 7.0 Kg/Cm^ pressure for 3h at 5-10°C over palladium hydroxide (20%) on charcoal. The mixture was filtered and pH of filtrate adjusted to 7.0-7.1 and separated the aqueous layer (15.60 Lt).
STEPC
PREPARATION OF CRUDE CRYSTALLINE IMIPENEM MONOHYDRATE
The aqueous layer (15.60 Lt) containing Imipenem obtained at Step B was stirred with n-butanol (74.0 Lt) aqueous layer volume was reduced 2.75 Lt which contain Imipenem. The aqueous portion was washed with ethyl acetate and degassed to remove ethyl acetate. The aqueous portion was given carbon treatment and isopropanol (8.25 Lt) was added dropwise to filtered aqueous solution and seeded with Imipenem, then the resulting reaction mass was stirred at 8"10°C for 10 h. The crystalline product so obtained was filtered, washed with acetone and dried at 30-35°C for 3h to obtain crude crystalline Imipenem monohydrate (100 g). CHROMATOGRAPHIC PURITY: 95.4 %
STEPD
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

resin was washed with 1% w/w aqueous 4-morphoUne 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, then the resulting reaction mass 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 (by HPLC): 99.17 %
EXAMPLE-2
PREPARATION OF CRYSTALLINE IMIPENEM MONOHYDRATE
STEP A
PREPARATION OF IMIPENEM PNB ESTER HYDROCHLORIDE
The thienamycin PNB ester hydrochloride N-ethylpyrrolidinone solvate (30 g) was suspended in dry tetrahydrofuran (432 ml) at 25°C and cooled to -55°C. To this diisopropylamine (9 g) was added dropwise, followed by benzylformimidate hydrochloride (13.2 g) at -55 to -50°C. The mixture was stirred for 2 h at about -45 to -40X.
STEPB
PREPARATION OF IMIPENEM
The above suspension obtained from Step A was poured in to a mixture of 1% w/w aqueous 4-morpholinepropane sulfonic acid solution (1200 ml) and n-butanol (2160 ml) maintained at 5-10°C and the pH of the solution adjusted to 7.7 to 7.9. The solution was hydrogenated at 6.0 to 7.0 Kg/Cm^ pressure for 3h at 5-10°C

over palladium hydroxide (20%) on charcoal. The mixture was filtered and pH of filtrate adjusted to 7.0-7.1 and separated the aqueous layer (950 ml).
STEP C
PREPARATION OF CRUDE CRYSTALLINE IMIPENEM MONOHYDRATE
The aqueous layer (950 ml) containing Imipenem obtained at Step B was washed with ethyl acetate and subjected to spray drying in a mini spray drier (Model Buchi: B-191) at a temperature of 35-40°C using nitrogen gas to obtain aqueous layer volume of 70 ml which contains Imipenem. The aqueous portion was given carbon treatment and isopropanol (8.25 Lt) was added dropwise and seeded with Imipenem, then the resulting reaction mass was stirred at 8-10°C for 10 h. The crystalline product so obtainted was filtered washed with acetone and dried at 30-35°C for 3 h to obtain crude crystalline Imipenem monohydrate (6.4 g). CHROMATOGRAPHIC PURITY (by HPLC): 94.65 %
STEPD
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 resin was 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, then the resulting reaction mass 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 (by HPLC): 99.31 %

EXAMPLE-3
PREPARATION OF CRYSTALLINE MEROPENEM TRIHYDRATE
STEP A
PREPARATION OF PNB ESTER OF MEROPENEM
[4R,5R,6S]-3-[(Diphenyloxyphosphinyl)oxy]-6-(l -hydroxyethyl)-4-methyl-7-oxo-1 -azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, (4-nitrophenyl)methyl ester (10 g) was suspended in acetonitrile (50 ml) and diisopropylethylamine (2,6 g) was added at -30 to -20°C. A solution of (2S-cis)-2-[(dimethylamino)carbonyl]-4-mercapto-l-pyrrolidinecarboxylic acid, (4-nitrophenyl)methyl ester (7.2 g) in acetonitrile (50 ml) was added and stirred for 3 h at -20 to -30°C. After completion of reaction acetonitrile was distilled off by distillation under reduced pressure and residue was diluted with ethyl acetate (100 ml) and washed with water (3x60 ml). Finally, organic layer was washed with 10% w/w aqueous sodium chloride solution (40 ml) and solvent was distilled off to obtain a foamy solid (12.5 g).
STEPB
PREPARATION OF MEROPENEM TRIHYDRATE
[4R,5S,6S]-3-[[(3S,5S)-5-(Dimethylamino)carbonyl]-l-[[4-nitrophenyl)methoxy)-carbonyl]-3-pyrrolidinyl]thio]-6-[l-hydroxyethyl)-4-methyl-7-oxo-l-azabicyclo-[3.2.0] hept-2-ene-2-carboxylic acid, (4-nitrophenyl)methyl ester [(12.5 g) as prepared in step-A] was dissolved in tetrahydrofuran (200 ml), 1.5% w/w morpholinopropanesulfonic acid (200 ml; Ph 6.5-7.0) and 10% palladium on carbon (15 g, 50% wet) was added. The mixture was hydrogenated under a hydrogen pressure of 5 Kg/cm for 5 h at room temperature. After removal of catalyst by filtration, the tetrahydrofuran was distilled off by distillation under reduced pressure. The resulting aqueous solution was washed with methylene chloride (2x100 ml) and treated with DOWEX ion exchange resin (10 g). The resin was removed by filtration

and the filtrate (290 ml) was concentrated to reduce the aqueous volume to 30 ml by spray drying in mini spray dryer (Model Buchi B-191) at a temperature 35±2°C using nitrogen gas. The concentrated solution was cooled to 0-5°C and tetrahydrofuran (60 ml) was added slowly and stirred for 1 h. The resulting crystals were collected by filtration and washed with acetone (10 ml) and dried at 30-35°C under reduced pressure for 2 h to give Meropenem trihydrate. YIELD: 2.0 g CHROMATOGRAPHIC PURITY (by HPLC): 99.1 %
STEPC
PREPARATION OF PURE MEROPENEM TRIHYDRATE
Meropenem trihydrate (2.0 g) was dissolved in preheated water (40 ml, 55-60°C) to
get clear solution. This was cooled to 20°C and carbon (0.1 g) was added, followed
by stirring at 5-10°C for 10 min. The carbon was removed through hyflo, and to the
resulting solution acetone (80 ml) was added slowly, and then stirred at 5-10°C for
1 h. The pure Meropenem trihydrate was isolated and dried at 30-35°C.
YIELD: 1.7 g
CHROMATOGRAPHIC PURITY (by HPLC): 99.79 %




WE CLAIM
1. An improved process for preparing crystalline Carbapenem derivatives of
Formula I,

wherein R1 represents hydrogen or C1.3 alkyl group; R2 represents a group of the

and their pharmaceutically acceptable salts and esters.
2. The process according to claim 1, comprises
(a) preparing Carbapenem by hydrogenolysis of Carbapenem derivative PNB ester hydrochloride using palladium on carbon in 4-morpholinepropane sulfonic acid solution and n-butanol;
(b) separating the aqueous layer;
(c) reducing the volume of water; and

(d) adding protic solvent to precipitate crude Carbapenem derivatives.
3. The process according to claim 2, the hydrogenation is carried out at a
temperature ranging from 0-20°C, preferably 5-10°C and adjusted the pH to 6.5-
7,5, preferably 7.0-7.1.
4. The process according to claim 2, the volume of water is reduced by by addition
of n-butanol and stirring the resulting solution.
5. The process according to claim 2, the volume of water is reduced by spray drying
the aqueous solution containing Carbapenem derivative.
6. The process according to claim 2, the polar solvent is selected from methanol,
isopropanol, acetone and mixtures thereof; preferably isopropanol is used.
7. The process according to claim 2, the carbapenem derivative is Thienamycin.
8. The process according to claim 2, the carbapenem derivative is Imipenem.
9. The process according to claim 2, the carbapenem derivative is Meropenem.
10. The process according to claim 2, the carbapenem derivative is Ertapenem.


Documents:

209-CHE-2005 AMANDED CLAIMS 07-01-2010.pdf

209-CHE-2005 AMANDED PAGE OF SPECIFICATION 07-01-2010.pdf

209-CHE-2005 EXAMINATION REPORT REPLY RECIEVED 07-01-2010.pdf

209-che-2005-abstract.pdf

209-che-2005-claims.pdf

209-che-2005-correspondnece-others.pdf

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

209-che-2005-form 1.pdf

209-che-2005-form 3.pdf

209-che-2005-form 5.pdf

209.jpg


Patent Number 246139
Indian Patent Application Number 209/CHE/2005
PG Journal Number 07/2011
Publication Date 18-Feb-2011
Grant Date 15-Feb-2011
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 KARURU MALLIKARJUNA REDDY 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 RAMESH DANDALA AUROBINDO PHARMA LIMITED, PLOT NO.2,MAITRIVIHAR COMPLEX, AMEERPET, HYDERABAD-500 038
5 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