FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of carbapenem compounds of Formula I.

wherein R represents hydrogen or a C1-3 alkyl group; Gr represents different moieties present in carbapenem antibiotics.

BACKGROUND OF THE INVENTION

A number of carbapenem compounds have been prepared and investigated for clinical efficacy viz., Meropenem, Ertapenem, Doripenem, Faropenem, Panipenem, Biapenem and the like. These carbapenem compounds are being used for the treatment of various bacterial infections.

US Pat. No. 4,888,344 discloses crystalline Meropenem trihydrate along with non-toxic carbonate composition. According to this patent, Meropenem was obtained by deprotecting the protecting groups of the penultimate compound by hydrogenation.

US Pat. No. 4,943,569 claims Meropenem and process for its preparation. This patent discloses process for the preparation of Meropenem by reacting compound of formula (1a) with [2S,4S]-1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl-4-mercaptopyrrolidine of formula (lb) using diisopropylmethyl amine and acetonitrile to yield protected Meropenem of formula (lc), followed by deprotection to yield Meropenem.

US Patent No. 5,478,820 discloses Ertapenem and its salts.

This patent discloses process for the preparation of Ertapenem and its derivatives by reacting compound of formula (2a) with compound of formula (2b) wherein R1 and R10 is 1-hydroxyethyl, 1-fluoroethyl or hydroxymethyl; R2 is hydrogen or C1-4 alkyl; R3 is hydrogen or C1-4 alkyl; R4 and R5 are the same or different and are selected from hydrogen, halo, cyano, C1-4 alkyl, nitro, hydroxy, carboxy, C1-4 alkoxy, and the like; R10 is a group R1, protected 1-hydroxyethyl or protected hydroxymethyl; and wherein at least one protecting group is present; COOR6 and COOR7 is carboxy or protected carboxy; L is a leaving group; in the presence of a base such as an organic amine for example di-isopropylethylamine or an inorganic base for example an alkali metal carbonate such as potassium carbonate.

US Pat No. 5,317,016 claims Doripenem and its analogous compounds. US '016 also discloses a process for the preparation of Doripenem.

U.S. Patent No. 5,872,250 discloses a process for synthesizing penem compounds comprising reacting the side chain compound of formula (4a) with penem moiety of formula (4b) wherein P independently represents H or a protecting group, and R1 and R2 independently represent H, C10 alkyl, aryl or heteroaryl; said C1-10 alkyl, aryl or heteroaryl, in the presence of an amine selected from the group consisting of diisopropylamine (DIPA), dicyclohexylamine (DCHA), 2,2,6,6-tetramethylpiperidine (TMP), 1,1,3,3-tetramethylguanidine (TMG), l,8-diazabicyclo[4.3.0.] undec-7-ene (DBU) and 1,5-diazabicyclo[4.3.0] non-5-ene (DBN).

The above prior art references discloses process for the condensation of side chain compound with penem moiety using various bases such as diisopropyl amine, DIPEA, inorganic bases such as alkali metal carbonates, TMG, TMP DBU and the like. None of the references disclose the use of metal oxides, which are easy to handle and recover. . In the prior art processes it is difficult to recover the base/reagents and the by-product (Diphenyl phosphonic acid) formed. Further the processes involve complex purification process.

The inventors of the present invention during their continuous efforts found that the use of an inorganic base such as alkaline earth metal oxide / transition metal oxide is more eco friendly and easy to handle. Further, it is easy to purify the reaction mass and recover the diphenylphosphate as salt of metal associated with metal oxide. These metal oxides control the reaction pH which minimizes the degradation of both products and reagents and helps to obtain high yield and purity.

SUMMARY OF THE INVENTION
The present invention relates to an improved process for the preparation of carbapenem compounds of Formula (I)

wherein R is hydrogen or a C1.3 alkyl group, and Gr is selected from a group consisting of:

and or its stereoisomers, hydrates or salts thereof, which comprises : (i) condensing a compound of formula (II)

with protected side chain compound of formula -HS-Gr1, wherein Gr1 is selected from the group consisting of

wherein P1 is hydrogen or a carboxy protecting group; P2 and P3 are hydrogen or nitrogen protecting groups, using an inorganic base such as alkaline earth metal oxide / transition metal oxide in an organic solvent to produce protected carbapenem compound of formula (III)

wherein Gr1 is as defined above and
(ii) hydrogenating the protected compound of formula (III) using hydrogen and a metal
catalyst in an organic solvent to produce Carbapenem compound of formula (I).

DETAILED DESCRIPTION OF THE INVENTION

The condensation of compound of formula (II) with protected side chain of compound -HS-Gr1 is carried out using an inorganic base such as alkaline earth metal oxide / transition metal oxide selected from MgO, ZnO, CaO and the like in the present of a solvent. The solvent used according to the present invention is selected from dioxane, tetrahydrofuran, dimethylformamide, dimethyl acetamide dimethyl sulfoxide, acetone, acetonitrile, hexamethylphosphoramide, N-methyl pyrrolidone and the like or mixtures thereof. The reaction may be carried out at a temperature in the range of 20 to 60° C.

The hydrogenation of protected compound of formula (III) is carried out using hydrogen in the form of gas or atomic hydrogen and a metal catalyst such as platinum or palladium-on-carbon, Raney nickel. Solvents used in the catalytic reduction suitably include organic solvents such as methanol, ethanol, isopropanol, tetrahydrofuran, 2-methyl THF, dioxane, acetic acid and the like or mixture thereof or mixture of organic solvents and water or buffer solutions, such as phosphoric acid, morpholinopropanesulfonic acid. The reaction may be carried out at a temperature in the range of 5 to 60° C.

The amino protecting group according to the present invention may be selected from lower alkoxycarbonyl group, e.g., t-butyloxycarbonyl, etc.; a halogenoalkoxycarbonyl group, e.g., 2-iodoethyloxycarbonyl, 2,2,2-trichloroethyloxycarbonyl, etc.; an aralkyloxycarbonyl group, e.g., benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, and the like.; and a trialkylsilyl group, e.g., trimethylsilyl, t-butyldimethylsilyl, etc.

The carboxy protecting group according to the present invention, include straight or branched chain (C1-C12)alkyl groups (eg isopropyl, t-butyl); lower alkoxy lower alkyl groups (eg methoxymethyl, ethoxymethyl, isobutoxymethyl); lower aliphatic acyloxy lower alkyl groups, (eg acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl); lower alkoxycarbonyloxy lower alkyl groups (eg 1-methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl); an aralkyloxycarbonyl group, e.g., benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, and the like; aryl lower alkyl groups (eg p-methoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, benzhydryl and phthalidyl); tri(lower alkyl)silyl groups (eg trimethylsilyl and t-butyldimethylsilyl); tri(lower alkyl)silyl lower alkyl groups (eg trimethylsilylethyl); and (C1-C6)alkenyl groups (eg allyl and vinylethyl).

Another aspect of the present invention relates to a process for the preparation of Meropenem trihydrate compound of Formula (1)
which comprises:

(i) condensing a compound of formula (II)
wherein R is a methyl group, P1 is a carboxy protecting group with protected side chain compound of formula (ia)

wherein P is a nitrogen protecting group using an inorganic base such as alkaline earth metal oxide / transition metal oxide, wherein in an organic solvent to produce protected Meropenem of formula (IIIa) and

(ii) hydrogenating the protected Meropenem of formula (IIIa) using hydrogen and a metal catalyst in an organic solvent to produce Meropenem compound of formula (1).

Yet another aspect of the present invention relates to a process for the preparation of Ertapenem of Formula (2)
which comprises:
(ii) condensing a compound of formula (II)

wherein R is a methyl group, P1 is a carboxy protecting group with protected side chain compound of formula (IIIa1)

wherein P2 is a nitrogen protecting group using an inorganic base such as alkaline earth metal oxide / transition metal oxide in an organic solvent to produce protected Ertapenem of formula (IIIb) and

(u) hydrogenating the protected brtapenem ot lormula (111b) using hydrogen and a metal catalyst in an organic solvent to produce Ertapenem of formula (2).

Yet another aspect of the present invention relates to a process for the preparation of Doripenem of Formula (3)
which comprises :

(i) condensing a compound of formula (II)

wherein R is a methyl group, P1 is a carboxy protecting group with protected side chain compound of formula (iiial)

wherein P and P are hydrogen or nitrogen protecting groups using an inorganic base such as alkaline earth metal oxide / transition metal oxide in an organic solvent to produce protected Doripenem of formula (IIIc)

(ii) hydrogenating the protected Doripenem of formula (IIIc) using hydrogen and a metal catalyst in an organic solvent to produce Doripenem of formula (3).

Yet another aspect of the present invention relates to a process for the preparation of Imipenem of Formula (4)

Where R represents hydrogen atom which comprises :

(i) condensing a compound of formula (II)

Wherein R represents hydrogen with protected side chain compound of formula (iva)

wherein P is a nitrogen protecting group using an inorganic base such as alkaline earth metal oxide / transition metal oxide in an organic solvent to produce protected Imipenem of formula (IIId)

(ii) hydrogenating the protected Imipenem of formula (IIId) using hydrogen and a metal catalyst in an organic solvent to produce Imipenem of formula (4). Yet another aspect of the present invention relates to a process for the preparation of Biapenem of Formula (5)

which comprises .

(i) condensing a compound of formula (II)

wherein R is a methyl group, P1 is a carboxy protecting group with compound of formula (ve)
using an inorganic base such as alkaline earth metal oxide / transition metal oxide in an organic solvent to produce protected Biapenem of formula (IIIe) and

(ii) hydrogenating the protected Biapenem of formula (IIIe) using hydrogen gas and a metal catalyst in an organic solvent to produce Biapenem of formula (5).

In another aspect of the present invention relates to a process for the preparation of Meropenem trihydrate compound of Formula (1)
which comprises :

(i). condensing a compound of formula (IIa1)

with protected side chain compound of formula (ia2)
using MgO in an organic solvent to produce protected Meropenem of formula (IIIal)
(ii). hydrogenating the protected Meropenem of formula (Illal) using hydrogen and a metal catalyst in an organic solvent to produce Meropenem trihydrate (1).

The compound of formula (II) is prepared by the processes known in the art for example as disclosed in US Pat. Nos. 4,888,344; 4,943,569; 5,478,820 and 5,317,016.

Advantages of the invention
1. Unreacted metal oxide can be easily recovered and reused which makes the process economical.

2. The recovered alkaline earth metal oxide / transition metal oxide is free of the final product and starting material due to which the catalyst does not need any purification before further use. At the same time the there is no yield loss of the final product.

3. Alkaline earth metal oxide / transition metal oxide being a solid, easy to handle unlike other conventional bases used in this type of reaction.

4. The metal oxide remains insoluble in the reaction medium which can be filtered after the completion of the reaction.

5. The metal oxide is easy to handle to on large scale as it is non-corrosive, environmental friendly and personnel friendly (no-smell and non-toxic).

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Examples:

Example 1: Preparation of Meropenem trihydrate

Step (a) : Preparation of ((4R,5S,6S)-4-nitrobenzyl 3-(((3S,5S)-5-(dimethylcarbamoyI)-
l-(((4-nitrobenzyl)oxy)carbonyl)pyrrolidin-3-yl)thio)-6-((R)-l-hydroxyethyl)-4-methyl-
7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate

To a degassed DMF were added ((4R,5R,6S)-4-nitrobenzyl 3-((diphenoxyphosphoryl)oxy)-6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate) (50.0 g, 0.0841 mol), (2S,4S)-4-nitrobenzyl 2-(dimethylcarbamoyl)-4-mercaptopyrrolidine-l-carboxylate (29.6 g, 0.0837 mol) and MgO (5.1 g, 0.127 mol) was added in one portion and the heterogeneous mixture was stirred at ambient temperature. After the completion of the reaction, the reaction mixture was filtered and washed with DMF. The filtrate was quenched with DI water and ice. The slurry was diluted with ethyl acetate and cylohexane . The resulting clear solution was stirred for 4 h. The precipitate obtained was filtered and dried at to obtain 42.0 g (72%) of title compound as a white solid.

Step (b)
Preparation of Meropenem trihydrate

To a four neck round bottomed flask equipped with an overhead stirrer, temperature probe, an addition runnel and cooling bath was added water and 2-Methyl THF . The solution was stirred at a temperature between 12 and 15 °C. It was labeled as stock solution. 30 mL of the stock solution was kept aside for washing. Meanwhile, ((4R,5S,6S)-4-nitrobenzyl 3-(((3S,5S)-5-(dimethylcarbamoyl)-l-(((4-nitrobenzyl)oxy)carbonyl)pyrrolidin-3-yl)thio)-6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate , 12.0 g, 0.0171 mol) was added to the RB. The resulting slurry (hazy) was stirred at the same temperature for 10 min. Pd/C was added to the autoclave vessel. Hydrogen was applied and the reaction mixture was stirred at 20-23 °C. The progress of the reaction was monitored by HPLC. After the completion of the reaction, the reaction mixture was filtered through sintered bed, and bed washed with DI water under nitrogen. The filtrate was concentrated and the concentrated aqueous layer was transferred to a round bottomed flask. Acetone , lot 1) was added over a period of 10 min. The reaction mixture was cooled to 10 °C, seeded with a pure Meropenem trihydrate (5.00 mg), cooled between 0 and 3 °C. Acetone (lot 2) was added over 30 min followed by stirring for 30 min. Acetone (lot 3) was added over 30 min . The reaction mixture was stirred at the same temperature , filtered, washed with chilled acetone), dried to get Meropenem trihydrate as a white solid (5.00 g, 66.4%).

Example 2 : Preparation of Meropenem trihydrate
Alternate procedure Example 1. step (a)
To a degassed DMF (by purging N2 for 20 min) maintained at a temperature between 25 and 28 °C, were added ((4R,5R,6S)-4-nitrobenzyl 3-((diphenoxyphosphoryl)oxy)-6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate) (3.00 g, 0.0005 mol) and ((2S,4S)-4-nitrobenzyl 2-(dimethylcarbamoyl)-4-mercaptopyrrolidine-l-carboxylate ) (1.78 g, 0.0005 mol,) in DMF. Zn oxide (10% w/w of 1) was added in one portion and the heterogeneous mixture was stirred at a temperature between 25 and 28 °C. The progress of the reaction was monitored by TLC {Sample preparation: 0.1 mL of the reaction mixture was dissolved in MeOH. The diluted solution was analyzed by TLC. Solvent system is CHCl3:MeOH::9:l. Rf of 1: 0.7 Rf of 2: 0.4 Rf of 3: 0.5}.

Example 3 : Preparation of Meropenem trihydrate
Alternate procedure Example 1. step (a)
To a degassed DMF (by purging N2 for 20 min) maintained at a temperature between 25 and 28 °C, were added ((4R,5R,6S)-4-nitrobenzyl 3-((diphenoxyphosphoryl)oxy)-6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate) (3.00 g, 0.0005 mol) and ((2S,4S)-4-nitrobenzyl 2-(dimethylcarbamoyl)-4-mercaptopyrrolidine-l-carboxylate) (1.78 g, 0.0005 mol,) in DMF. Calcium oxide (10% w/w of 1) was added in one portion and the heterogeneous mixture was stirred at a temperature between 25 and 28 °C.

Claims :

1. An improved process for the preparation of carbapenem compounds of Formula (I)

wherein R is hydrogen or a C1-3 alkyl group, and Gr is selected from a group consisting of:
and or its stereoisomers, hydrates or salts thereof, which comprises : (i) condensing a compound of formula (II)

with protected side chain compound of formula -HS-Gr1, wherein Gr1 is selected from the group consisting of
wherein P1 is hydrogen or a carboxy protecting group; P2 and P3 are nitrogen protecting groups, using an inorganic base such as alkaline earth meal oxide / transition metal oxide in an organic solvent to produce protected carbapenem compound of formula (III)

wherein Gr1 is as defined above and

(ii) hydrogenating the protected compound of formula (III) using hydrogen and a metal Catalyst in an organic solvent to produce Carbapenem compound of formula (I).

2. A process according to claim 1 wherein the metal oxide is selected from MgO, ZnO and CaO.

3. A process according to claim 1 wherein the solvent used is selected from dioxane, tetrahydrofuran, dimethylformamide, dimethyl acetamide dimethyl sulfoxide, acetone, acetonitrile, hexamethylphosphoramide, N-methyl pyrrolidone and mixtures thereof

4. A process according to claim 1 wherein the hydrogenation of the protected compound of formula (III) is carried out using hydrogen gas or atomic hydrogen and a metal catalyst such as platinum or palladium-on-carbon.

5. A process according to claim 1 wherein the organic solvent used for catalytic reduction is selected from methanol, ethanol, isopropanol, tetrahydrofuran, 2-Methyl THF dioxane, acetic acid, or mixture thereof or mixture of organic solvents and water or buffer solutions, such as phosphoric acid, morpholinopropanesulfonic acid.

6. A process according to claim 1 wherein the hydrogenation reaction is carried out at a temperature in the range of 5 to 60° C.

7. A process for the preparation of Meropenem trihydrate compound of Formula (Ia)
which comprises :

(i). condensing a compound of formula (IIal)

with protected side chain compound of formula (ia2) using MgO in an organic solvent to produce protected Meropenem of formula (IIIa1)

(ii). hydrogenating the protected Meropenem of formula (IIIa1) using hydrogen gas and a metal catalyst in an organic solvent to produce Meropenem trihydrate.

8. A process according to claim 7 wherein the solvent used is selected from dioxane, tetrahydrofuran, dimethylformamide, dimethyl acetamide dimethyl sulfoxide, acetone, acetonitrile, hexamethylphosphoramide, N-methyl pyrrolidone and mixtures thereof

9. A process according to claim 7 wherein the hydrogenation of the protected compound of formula (III) is carried out using hydrogen gas and a metal catalyst such as platinum or palladium-on-carbon.

10. A process according to claim 7 wherein the organic solvent used for catalytic reduction is selected from methanol, ethanol, isopropanol, tetrahydrofuran, 2-Methyl THF dioxane, acetic acid, or mixture thereof or mixture of organic solvents and water or buffer solutions, such as phosphoric acid, morpholinopropanesulfonic acid.