AFIELD OF INVENTION

The present invention relates to a novel ecofriendly, cost effective and commercially viable process for the preparation of Imipenem monohydrate of formula I.

BACKGROUND OF THE INVENTION

Imipenem monohydrate is the N-formimidoyl derivative of thienamycin. Imipenem of Formula I is chemically named as (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. It 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, which is partly due to its high stability in the presence of P-lactamases.

Imipenem was first disclosed in US patent 4,194,047, which describes a number of methods for the preparation of N-methylene derivatives of thienamycin including Imipenem. In this patent Imipenem is prepared starting from thienamycin. The starting compound thienamycin is not much stable and due to inherent instability of the starting compound the process for the preparation of Imipenem has been found to give the product in low yield and of poor quality.

The US patent 4,292,436 provides an alternate method for the preparation of imipenem from bicyclo ketone precursor of Formula II, wherein R is a protecting group, comprising activating the keto ester and reacting the activated keto ester with N-formimidoyl-2-aminoethanethiol to obtain carboxyl protected imipenem which on further hydrogenation gives Imipenem. However, the process gives low yields of the final product (59% in solution and 35% of isolated Imipenem monohydrate).

US patent 4,374,772 describes an improved process for preparing Imipenem from dilute aqueous solutions of thienamycin using benzylic formimidate reagents.

However, the process has the disadvantage of producing at least 5% of dimmer bis-thienamycin formamidene along with the desired proudct Imipenem.

US patent 4,894,450 uses new reagents bis(chloro-substituted phenyl) phosphorochloridate to activate the bicycloketone precursor of formula II, wherein R is a protecting group. Subsequent reaction with cysteamine hydrochloride, amidine formation and hydrogenolysis of the ester group gives good yield of Imipenem.

However, the reagent employed for activation is not available commercially and its preparation involves a cumbersome multistage purification process.

US patent 7,462,712 describes a process in which a keto ester compound of formula II is activated with a phosphorhalidate in the presence of a base and a catalytic amount of a dialkylaminopyridine, to obtain enolphosphate compound, which is further reacted in-situ with 2-aminoethanethiol to get thienamycin ester of formula III.

The thienamycin ester of formula III is reacted in-situ with benzyl formimidate to form a carboxyl protected Imipenem and further hydrogenated in aqueous medium to obtain Imipenem. In this process N-methylpyrrolidone (NMP) is used as solvent for the activating the keto ester to enol phosphate compound and for further in-situ reaction with 2-aminoethanethiol to get NMP solvate of thienamycin ester of formula III. However, when NMP is used as solvent for the above reaction the yield of the product is low.

An Indian Patent application no. 1178/CHE/2005 describes the similar above process with a difference in hydrogenation solvent. In this process a mixture of two organic solvents and water in which one organic solvent is selected from water immiscible solvents. This application also describes preparation of sterile Imipenem monohydrate by dissolving Imipenem monohydrate non-sterile in water, filtering in 0.2n filter and isolation by acetone or tetrahydrofuran.

US7332600 describes a process for preparation of crystalline imipenem monohydrate comprising dissolving crude imipenem in warm water containing sodium bicarbonate, subjecting to carbon treatment and precipitating crystalline imipenem monohydrate by adding acetone.

The inherent unstable nature of imipenem in solution as well as its sensitivity to heat and light renders formation of colored degradation impurities during production or storage. These colored impurities adversely affect the appearance of imipenem, which may appear from pale yellow to brownish powder instead of the desired white crystalline powder.

The purification of imipenem is difficult due to its unstable nature. The crystalline imipenem has low solubility in water at room temperature. Thus the purification process requires dissolving imipenem in large volume of water. The chromatographic purification also needs eluting with large volume of water. Recovery of the purified product is also uneconomical as it requires concentrating water at low temperature thus necessitating the use of lyophilization, reverse osmosis, or freeze crystalisation.

In light of the above drawbacks in the prior art processes, there is a need for the development of a process for the preparation of pure Imipenem, which is convenient to operate on an industrial scale and doesn't involve time consuming column chromatography.

SUMMARY OF THE INVENTION

The primary objective of the present invention is to solve the problems associated with the prior art and provide an efficient process, which provides obvious benefits with respect to cost and ease to operate on a large scale.

In particular, the present invention relates to a process for the preparation of pure crystalline imipenem monohydrate of Formula I comprising:

a) dissolving crude imipenem in carbonated water and morpholinopropane sulphonic acid (MOPS);

b) treating with activated carbon;

c) filtering by micron filter; and

d) adding an organic solvent to precipitate imipenem monohydrate as a crystalline product.

DETAIL DESCRIPTION OF THE INVENTION

In an embodiment of the present invention, the carbonated water and morpholinopropane sulphonic acid (MOPS) are dissolved completely. The pH is adjusted to 6.0 to 6.5 by using N-methylmorpholine. The crude imipenem is added into it to make slurry, which is heated to 35°C-45°C to dissolve completely.

In still another embodiment of the present invention, the dissolved reaction mass is cooled to 5°C. The reaction mass is treated with carbon. The carbon treatment is carried out at the ambient temperature. After carbon treatment the reaction mass is filtered by micron filter preferably by 0.2u filter.

In still another embodiment of the present invention, after carbon treatment an organic solvent selected from the group consisting lower alcohol such as methanol, ethanol, propanol, and isopropanol; ketones such as acetone and methyl ethyl ketone or mixtures thereof. The most preferred solvent is acetone.

In still another embodiment of the invention, the crude imipenem can be prepared as the process available in prior art by the process given in the examples.

Advantage of the process of the present invention:

a) In the present process the dissolution of imipenem takes place at low temperature, resulting in minimizing the impurity formation.

b) The crystallization time is significantly reduced as compared to the prior art process.

c) Avoids the use of capital intensive techniques of lyophilization or freeze crystallization and time consuming chromatography.

d) The present process gives a very stable imipenem whose colour doesn't change even after storing at room temperature.

e) We have repeated the prior art process where crude imipenem is dissolved in presence of morpholinopropane sulphonicacid alone, the yield obtained is approximately 80% whereas according to the present invention wherein crude imipenem is dissolved in carbonated water and morpholinopropane sulphonic acid the yield is 90% or more and purity increases significantly and theinamycin content reduces drastically.

The present invention is illustrated with the following non-limiting examples.

Example 1: Preparation of Non-Sterile (NS) Imipenem

(a) Process for the preparation of Thiena-NMP HCI Solvate
l-Azabicyclo[3.2.0]heptane-2-carboxylicacid 6-[(1R)-l-hydroxyethyl]-3,7-dioxo-, (4-nitrophenyl)methyl ester, (5R,6S) (50gm) was charged in to the flask containing Methylene Dichloride & N-methylpyrolidinone. The reaction mass was cooled to -20°C. Then N-Ethyldiisopropylamine was added & followed by Diphenylchlorophospate (49 gm) . After completion of reaction the reaction mass was further cooled to -60°C. N-Ethyldiisopropylamine & Cysteamine HCI (29gm) were added to the above obtained mass. After completion of reaction Acetone was added slowly and temperature was raised to -20°C. The solid was filtered and washed by acetone, dried under N2 atm for 4-5 hrs at room temperature to obtain Thiena-NMP HCI solvate.

Yield: 65gm (dry)

(b) Process for the preparation of crude Imipenem (Non-Sterile)

Thiena-NMP HCI solvate (50gm) was charged in to the flask containing Acetonitrile. The reaction mass was cooled to -20°C. N-Ethyldiisopropylamine and Benzyl Formimidate were added to it followed by HCI (22gm). After completion of the reaction, the reaction mass was quenched with buffer solution at 0°C to 5°C. The reaction mass was washed by methylene dichloride. N-Propanol was added to the aqueous layer in to the autoclave and followed by Palladium on Carbon. The reaction mixture was stirred at 10°C to 15°C under H2 atm. After completion of reaction, the reaction mass was filtered and charged in to the flask containing methylene dichloride at 5°C to 10°C .The aqueous layer was separated, treated with carbon and degassed under vacuum. The aqueous mass was filtered and chilled Acetone was added and stirred slowly. The solid was filtered and washed by acetone, dried under vacuum for 6-8 hrs.

Yield: 18-20 gm (dry)

Example 2: Preparation of Pure Crystaline Imipenem (Sterile)

Carbonated (C02) water (2000 ml) was taken in to the RBF. Morpholinopropane sulphonicacid (12gm) was charged in to the flask containing water for injection and dissolved completely, the pH was adjusted 6.0 to 6.5 by using N-methyl morpholine. Then crude imipenem (50gm) was added into it to get a slurry. The slurry mass was heated to 35°C-45°C to dissolve completely. Then the reaction mass cooled 5°C. Eno carbon (l0gm) was charged into the mass & stirred well for 30 minutes.The aqueous mass was filtered and followed by 0.2fi filtration. Acetone was charged to the filtered mass. The solid was filtered and washed by aqueous acetone. The solid was dried under vacuum for 6-8hrs. (m/c 6-8%).

Yield: 40 to 42.5 gm (dry); Purity -99.80%

Isomeric impurity less than - 0.05%; Theinamycin content less than 0.1%

Example 3; Preparation of Pure Crystaline Imipenem (Sterile)

Carbonated (C02) water (2000 ml) was taken in to the RBF. Morpholinopropane sulphonicacid (12gm) was charged in to the flask containing water For injection and dissolved completely, the pH was adjusted 6.0 to 6.5 by using N-methyl morpholine. Then crude imipenem (50gm) was added into it to get a slurry. The slurry mass was heated to 35°C-45°C to dissolve completely. Then the reaction mass cooled 5°C. Eno carbon (l0gm) was charged into the mass & stirred well for 30 minutes. The aqueous mass was filtered and followed by 0.2u filtration. Acetone was charged to the filtered mass. The solid was filtered and washed by 2% Morpholinopropane sulphonicacid (pH adjusted to 6.5-7.0 with the help of N-methyl morpholine) in water at 25 to 35°C. Finally filtered solid was washed with aqueous acetone. The solid was dried under vacuum for 6-8 hrs. (M/c 6-8%).

Yield: 38 to 40gm (dry); Purity -99.9%

Isomeric impurity less than - 0.04%; Theinamycin content less than 0.05%

We claim:

1. A process for the preparation of pure crystalline Imipenem of Formula I comprising:

a) dissolving crude imipenem in carbonated water and morpholinopropane sulphonic acid (MOPS);

b) treating with activated carbon;

c) filtering by micron filter; and

d) adding an organic solvent to precipitate imipenem monohydrate as a crystalline product.

2. A process according to claim 1, wherein the pH of the solution of carbonated water and morpholinopropane sulphonic acid in step (a) is adjusted to 6.0 to 6.5 using a base before the addition of crude imipenem.

3. A process according to claim 2, wherein the base is N-methylmorpholine.

4. A process according to claim 1, wherein the slurry of crude imipenem in carbonated water and morpholinopropane sulphonic acid is heated to 35°C-45 °C for dissolution in step (a)

5. A process according to claim 1, wherein the sterile imipenem is slurry washed by morpholinopropanesulphonic acid at temperature 25 °C-35 °C.

6. A process according to claim 5, wherein the slurry wash of sterile imipenem by morpholinopropanesulphonic acid is carried out at pH 6.5 to 7.

7. A process according to claim 1, wherein the carbon treatment is carried out at ambient temperature and filtrationis carried out using 0.2u micron filter.

8. A process according to claim 1, wherein the organic solvent is selected from the group comprising lower alcohol, a ketone and mixtures thereof.

9. A process according to claim 8, wherein the lower alcohol is selected from the group comprising methanol, ethanol, isopropanol, n-propanol ,n- butanol and a mixture thereof.

10. A process according to claim 8, wherein the ketone is selected from the group comprising acetone, methyl ethyl ketone and a mixture thereof.