DESC:PROCESS FOR PREPARATION OF ERTAPENEM AND SALTS THEREOF

FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of ertapenem of formula (1)

and pharmaceutically acceptable salts, or hydrates, or solvates thereof. Further, the present invention also relates to a process for purification of crystalline ertapenem sodium.
BACKGROUND OF THE INVENTION

Ertapenem is a synthetic broad-spectrum carbapenem antibiotic and commercially available as the sodium salt. Ertapenem is chemically known as [4R,5S,6S]-3-[[(3S,5S)-5-[[(3-Carboxyphenyl)amino]carbonyl]-3-pyrrolidinyl]thio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, (Formula 1). Ertapenem sodium has good antibacterial activities against gram-positive and gram negative aerobic and anaerobic bacteria, which is marketed in the United States under the brand name Invanz®.

U.S. Patent No. 5,478,820 ("the '820 patent") discloses ertapenem and its sodium salt form. Example 12 of the '820 patent discloses a process for the preparation of ertapenem in which protected enol phosphate is condensed with protected side chain compound in acetonitrile to obtain diprotected ertapenem, which is subsequently hydrogenated in presence of Pd/carbon to obtain Ertapenem. The product is isolated by using column purification and then freeze-dried. Example 4 of the '820 patent discloses the disodium salt of ertapenem, which is prepared by dissolving crude product in water using NaHCO3, followed by purification using column chromatography and subsequently lyophilized.

U.S. Patent No. 5, 872, 250 discloses the ertapenem in which protected enol phosphate is condensed with protected side chain compound in the presence of secondary amines such as diisopropylamine (DIPA), dicyclohexylamine (DCHA), 2,2,6,6-tetramethylpiperidine (TMP), 1,1,3,3-tetramethylguanidine (TMG), 1,8-diazabicyclo undec-7-ene (DBU) and 1,5-diazabicyclo non-5-ene (DBN).

U.S. Patent No. 7,145,002 discloses a process for producing ertapenem or its sodium salt and/or its solvate in crystalline form. The US ‘002 discloses that contact of ertapenem sodium with water and alcoholic solvents results in the formation of crystalline solvates. The example 1 and 2 of US ‘002 provide a process for isolation of ertapenem monosodium from a mixture of methanol, 1-propanol and water followed by washing with aqueous isopropyl alcohol. However, this process results into formation of ertapenem sodium that contains higher amount of residual solvent and palladium content.

U.S. Patent No. 6,504,027 discloses a process for preparing ertapenem sodium through monoprotected ertapenem, by condensing protected enol phosphate with hydrochloride salt of unprotected side chain in presence of 1,1 ,3,3-tetramethylguanidine (TMG), which is subsequently deprotected and treated with a C4-10 alcohol, adjusted the pH to 5.5 and crystallized to produce a crystalline ertapenem sodium.

Various other prior arts, CN 101376641, CN 101376645, CN 101376642, CN 101376633, CN101376643, disclose a process for Ertapenem sodium which involves condensation of protected or unprotected enol phosphate with protected or unprotected side chain compound in presence of base such as diisopropylethylamine followed by reduction to provide Ertapenem sodium. However, the process of prior art requires use of longer hours or isolation of protected intermediate and/or ertapenem free base that makes the process expensive.

U.S. Patent No. 7,022,841 discloses ertapenem sodium type C crystal, prepared by a washing type A or type B crystals with one or more solvents selected from the group consisting of methyl acetate, acetonitrile, tetrahydrofuran, acetone, or aqueous organic solvent mixture. The US ‘841 patent also discloses a method for reducing the residual solvent from crystal form A, B and C of ertapenem sodium at low temperature by passing a nitrogen stream through the wet crystals.

U.S. Patent No. 8,293,894 discloses amorphous ertapenem sodium and its process. The process involves condensation of protected enol phosphate with protected side chain compound in the presence of base to obtain the diprotected ertapenem, which is then deprotected by hydrogenation and isolated ertapenem sodium as amorphous using alcohol.

U.S. Patent Application No. 2011/0172201 A1 discloses crystalline form D of ertapenem monosodium, which involves dissolution of ertapenem sodium in solution of aqueous sodium bicarbonate, adjustment of pH with acetic acid in methanol to provide pH 5.5 to 5.7, which is then subjected for crystallization in a mixture of methanol, water and n-propanol by seeding ertapenem sodium at a low temperature to obtain a solid and thereafter washing the solid with acetone.

CN 102363617 A discloses crystalline form of ertapenem sodium, which is prepared by process comprising, dissolving ertapenem sodium in aqueous solution at 0°C; cooling the solution to -2 to -10 °C; adding methanol and n- propanol to obtain crystalline ertapenem sodium. U.S. Patent Application No. 2013/281427 A1 discloses crystalline form E of ertapenem sodium and its process.

Still, there is a need to develop an improved process for the preparation of the ertapenem of the formula (1) its pharmaceutically acceptable salts, which is commercially viable and which has advantage over the processes as described in the prior art documents.

SUMMARY OF THE INVENTION

The present invention relates to an improved process for the preparation of ertapenem of formula (1) or pharmaceutically acceptable salts or hydrates, or solvates thereof.

In an aspect, the present invention provides an improved process for preparing a crystalline compound of formula (1) or pharmaceutically acceptable salts, or hydrates, or solvates thereof, comprising of following steps:

a) reacting enol phosphate compound of formula (2) or its salts, with protected side chain compound of formula (3) in the presence of a base and dimethylaminopyridine to obtain di-protected ertapenem compound of formula (4) or its salts;

b) deprotecting the compound of formula (4) or its salts with metal catalyst in the presence of base to provide Ertapenem of formula (1), or its pharmaceutically acceptable salts, or hydrates, or solvates.

In another aspect, the present invention provides a process for the preparation of pure crystalline ertapenem sodium, which comprises:
i) reacting enol phosphate compound of formula (2) or its salts, with protected side chain compound of formula (3) in the presence of a base and dimethylaminopyridine to obtain di-protected ertapenem compound of formula (4) or its salts;

ii) deprotecting the compound of formula (4) or its salts with metal catalyst in the presence of base to provide ertapenem sodium; and
iii) crystallizing the ertapenem sodium from a mixture of alcohol and acetic acid at -20 to 0 ?C.

In another aspect, the present invention provides a process for the purification of crystalline ertapenem or its pharmaceutically acceptable salts, which comprises:
a) dissolving ertapenem or its pharmaceutically acceptable salts in a solution of aqueous sodium hydroxide and carbon dioxide gas;
b) adjusting the pH of the solution to about 4 to about 6 by using acid; and
c) isolating the pure crystalline ertapenem or its pharmaceutically acceptable salts.

In another aspect, the present invention provides a process for the purification of crystalline ertapenem sodium, which comprises:
a) dissolving ertapenem sodium in a solution of aqueous sodium hydroxide and carbon dioxide gas;;
b) adjusting the pH of the solution to about 4 to about 6 by using hydrochloric acid;
c) filtering the suspension of step b) through filters to remove bacterial endotoxin to less than 0.5 EU/mg;
d) adding methanol and n-propanol to the filtrate of step (c);
e) stirring the reaction mixture of step (d) for at least about 15 minutes; and
f) isolating the pure crystalline ertapenem sodium.

Ertapenem or its pharmaceutically acceptable salts obtained from the present invention is useful for the treatment of patients with moderate to severe infections caused by gram-positive and gram negative aerobic and anaerobic bacteria.

BRIEF DESCRIPTION OF THE DRAWING

Fig. 1 is an illustration of a XRPD spectrum of crystalline ertapenem sodium prepared according to the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to an improved process for the preparation of crystalline ertapenem or pharmaceutically acceptable salts, or hydrates or solvates thereof. Further, the present invention relates to an improved process for the preparation of pure crystalline ertapenem sodium without isolating any intermediates such as di-protected ertapenem of formula (4) and ertapenem free base.

The term “pure” as used herein, unless otherwise defined, refers to ertapenem or pharmaceutically acceptable salt thereof that contains purity greater than or equal to 95% or greater than or equal to 98 % or greater than or equal to 98.5%.

The “salt” or “pharmaceutically acceptable salt” as used herein, unless otherwise defined, refers to inorganic or organic salt. Inorganic salt may include sodium, potassium, magnesium and the like.

In an aspect, the present invention provides an improved process for preparing a crystalline compound of formula (1) or pharmaceutically acceptable salts, or hydrates, or solvates thereof, comprising of following steps:

a) reacting enol phosphate compound of formula (2) or its salts, with protected side chain compound of formula (3) in the presence of a base and dimethylaminopyridine to obtain di-protected ertapenem compound of formula (4) or its salts;

b) deprotecting the compound of formula (4) or its salts with metal catalyst in the presence of base to provide Ertapenem of formula (1), or its pharmaceutically acceptable salts, or hydrates, or solvates.

The condensation step (a) comprises reaction of side chain of formula (3) or its salts with Enol phosphate compound of formula (2) in presence of a solvent, base and in the presence of catalyst such as dimethylaminopyridine (DMAP) optionally in presence of tributyl phospine.

The condensation reaction may be conducted at a temperature of about 20 ?C to about -50 ?C. In preferred embodiment, the condensation reaction of present invention is conducted at a temperature of about -35 ?C to about -45 ?C. The reaction may be stirred for a period of at least 1 hour at below 0 ?C such as -35 ?C to about -45 ?C.

The base used in step (a) is selected from the group consisting of 1,1,3,3-tetramethylguanidine (TMG), diisoproprylamine (DIPA), dicyclohexylamine (DCHA), 2,2,6,6-tetramethylpiperidine (TMP), N,N,N’,NN’’-tetraethylcyclohexylguanidine (TECHG), N,N’,N’’,N’’-dicyclohexyldiethylguanidine (DCDEG), 1,8-diazabicyclo[4.3.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), diisopropylethylamine (DIPEA) or mixture thereof. Preferably the base used is diisopropylethylamine (DIPEA).

The quantity of base used for condensation reaction may range from 1 to about 4 mole ratio per mole ratio of enol phosphate compound of formula (2). In a preferred embodiment, the condensation reaction is performed in presence of 3 mole ratio of base per mole ratio of compound of formula 2. The base may be added to the reaction mixture for a period of 10 minutes to 1 hour or more based on batch size.

The condensation reaction of present invention is performed in presence of catalyst i.e. dimethylaminopyridine (DMAP), optionally in presence of tributyl phosphine. The quantity of catalyst is kept minimum, which includes less than 1 or less than 0.5 or less than 0.05 mole ratio per mole ratio of compound of formula (2). The mole ratio of DMAP and tributyl phosphine is about 1 or less per mole ratio of compound of formula (2). In an embodiment, the mole ratio of DMAP and tributyl phosphine used for the condensation reaction is in the range of 0.5 to 0.1 per mole ratio of compound formula (2).

The inventors of the present invention found that the use of catalyst, particularly DMAP, enhances the reaction rate and reduces the reaction time to provide pure compound of formula (4).

The solvent used in step (a) is selected from the group consisting of acetonitrile, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), propionitrile, N-ethylpyrrolidinone, N-methylpyrrolidinone, dichloromethane, ethyl acetate, tetrahydrofuran or mixture thereof. Preferably the solvent used is N,N-dimethylformamide (DMF).

After completion of reaction, the reaction mass is diluted with suitable solvent at about -30 ºC and subjected for pH adjustment to about 2 to about 3 with an acid at -20 to 0 ºC. The resultant di-protected ertapenem compound of formula (4) or its salts is extracted into organic solvent. The solvent layer is taken for hydrogenation in subsequent step (b). The acid used is selected from the group consisting of acetic acid, formic acid, propanoic acid, citric acid, phosphoric acid, sulphuric acid, hydrochloric acid or mixture thereof. Preferably the acid used is hydrochloric acid.

The simple work-up process and the use of DMAP for the reaction of the present invention gave the purity of diprotected ertapenem greater than 95% by HPLC without requiring crystallization and purification techniques.

The step b) involves deprotection of compound formula (4) to provide ertapenem or pharmaceutically acceptable salt thereof.

The organic layer obtained in step (a), containing (4-nitrophenyl)methyl(4R,5S,6S)-3-[[(3S,5S)-5[[(3-carboxyphenyl)-amino]carbonyl]-1-[[(4-nitrophenyl)methoxy]carbonyl]-3-pyrrolidinyl]thio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (i.e Diprotected Ertapenem), is combined with the solution of base and solvent and then deprotected by hydrogenation in presence of metal catalyst.

The base used in step (b) is sodium ion source selected from the group consisting of sodium hydroxide, sodium bicarbonate, sodium carbonate, mixture of carbon dioxide and sodium hydroxide or mixture thereof. Preferably base used is sodium bicarbonate.

The catalyst used in step (b) is selected from the group consisting of a noble metal catalyst such as palladium, platinum, platinum oxide, rhodium, raney nickel or its complex formed with any of alumina, silica, calcium carbonate, barium carbonate, strontium carbonate, barium sulphate, polymer, carbon or mixture thereof. Preferably the catalyst used is Pd on carbon.

The solvent used for deprotection in step (b) may be a mixture of solvents. The solvent is selected from, but is not limited to alcoholic solvents such as branched or straight chain C1-C4 alcohols such as methanol, ethanol, n-propanol, isopropyl alcohol, and the like; esters like ethyl acetate, butyl acetate, etc; nitriles such as acetonitrile, propionitrile, butyronitrile, and the like; ethers such as diethyl ether, diisopropyl ether, methyl tertiary-butyl ether, methyl ethyl ether, tetrahydrofuran, dioxane, etc; dichloromethane, N,N-dimethylformamide, water or mixtures thereof. Preferably, the solvent used is mixture of water, methanol and ethyl acetate.

In an embodiment, the reaction mass is hydrogenated using metal catalyst, preferably palladium on carbon (wet or dry) at 0.5-10 kg/Cm2 of hydrogen pressure at a temperature of -10 ºC to 20 ºC.

After completion of the reaction, the pH of the reaction mass is reduced with acid, for example, acetic acid and then filtered to remove catalyst. The filtrate is then washed with mixture of water and water immiscible solvent such as esters such as ethyl acetate, and then separated layers. The aqueous layer may be subjected for pH adjustment to about 6 to about 7 with a mixture of acid and alcohol, for example, acetic acid and methanol. The resultant reaction mass may be treated with activated carbon to remove impurities.

The resultant reaction solution is subjected for crystallization of ertapenem or pharmaceutically acceptable salt thereof at a temperature less than 0 ºC. The crystallization process involves dilution of the reaction solution with a mixture of one or more alcohol solvents and acetic acid at a temperature of below 0 ºC, optionally seeding with ertapenem or a pharmaceutically acceptable salt thereof, combining a mixture of methanol and n-propanol to the reaction mixture for a period of at least 30 minutes, and stirring the mixture for a period of at least 1 hour to provide precipitate of ertapenem or a pharmaceutically acceptable salt.

The crystalline ertapenem or its pharmaceutically acceptable salt is characterized by X-ray diffraction pattern by using Cu Ka radiation, having the wavelength 1.541 Å using a Bruker X-ray difractometer D8. The crystalline ertapenem or its pharmaceutically acceptable salt comprises at least four characteristic peaks at diffraction angles 2-theta of 4.4, 5.2, 7.1, 7.4, 8.0, 8.6, 10.9, 11.5, 15.5, 17.1, and 19.1 ±0.2 degrees.

In another aspect, the present invention provides a process for the preparation of pure crystalline ertapenem sodium, which comprises:
i) reacting enol phosphate compound of formula (2) or its salts, with protected side chain compound of formula (3) in the presence of a base and dimethylaminopyridine to obtain di-protected ertapenem compound of formula (4) or its salts;

ii) deprotecting the compound of formula (4) or its salt with metal catalyst in the presence of base to provide ertapenem sodium; and
iii) crystallizing the ertapenem sodium from mixture of alcohol and acetic acid at -20 to 0 ?C.

The condensation step (i), is same as step (a), which comprises reaction of side chain of compound of formula (3) or its salts with Enol phosphate compound of formula (2) in presence of a solvent, base, for example, DIPEA, and in the presence of catalyst such as dimethylaminopyridine (DMAP) optionally in presence of tributyl phospine. The solvent is selected from DMF, DMAc and the like.

The condensation reaction may be conducted at a temperature of about 20 ?C to about -50 ?C. Preferably, the reaction is conducted at a temperature of about -35 ?C to about -45 ?C for a period of at least 1 hour.

The resultant di-protected ertapenem compound of formula (4) or its salts of the present invention is directly used for further step without involving any isolation procedure.

The step ii) involves deprotection of compound formula (4) or its salt to provide ertapenem sodium.

The reaction mixture obtained in step (i) or step (a), containing (4-nitrophenyl)methyl(4R,5S,6S)-3-[[(3S,5S)-5[[(3-carboxyphenyl)-amino]carbonyl]-1-[[(4-nitrophenyl)methoxy]carbonyl]-3-pyrrolidinyl]thio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (i.e. Diprotected Ertapenem) is combined with the mixture of base such as aqueous sodium bicarbonate, metal catalyst on with or without Ceca carbon and in presence of hydrogen gas pressure.

The catalyst used in step (ii) is selected from the group consisting of a noble metal catalyst such as palladium, platinum, platinum oxide, rhodium, raney nickel or its complex formed with any of alumina, silica, calcium carbonate, barium carbonate, strontium carbonate, barium sulphate, polymer, carbon or mixture thereof. Preferably the catalyst used is Pd on carbon.

The solvent used for deprotection in step (ii) may be a mixture of solvents. The solvent is selected from, but is not limited to alcoholic solvents such as branched or straight chain C1-C4 alcohols such as methanol, ethanol, n-propanol, isopropyl alcohol, and the like; esters like ethyl acetate, butyl acetate, etc; nitriles such as acetonitrile, propionitrile, butyronitrile, and the like; ethers such as diethyl ether, diisopropyl ether, methyl tertiary-butyl ether, methyl ethyl ether, tetrahydrofuran, dioxane, etc; dichloromethane, N,N-dimethylformamide, water or mixtures thereof. Preferably, the solvent is water or alcohols or mixtures thereof.

In an embodiment, the reaction mass is hydrogenated using metal catalyst, preferably palladium on carbon (wet or dry) at 0.5-10 kg/Cm2 of hydrogen pressure at a temperature of -10 ºC to 20 ºC.

After completion of reaction, the pH of the reaction mass is reduced with acid, for example, acetic acid and then filtered to remove catalyst. The filtrate is then washed with mixture of water and water immiscible solvent such as esters such as ethyl acetate, and then the layers are separated. The aqueous layer may be subjected for pH adjustment to about 6 to about 7 with a mixture of acid and alcohol, for example, acetic acid and methanol. The resultant reaction mass may be treated with activated carbon to remove impurities and then crystallized as per step iii).

The step (iii) involves crystallization of ertapenem sodium from mixture of alcohol and acetic acid at -20 to 0 ?C.

The alcohol is selected from branched or straight chain C1-C4 alcohols such as methanol, ethanol, isopropyl alcohol, n-propanol and the like. Preferably, the alcohol is mixture of methanol and n-propanol. The temperature of crystallization is -20 to 0 ?C. Preferably, the temperature is -8 to -12 ?C. The quantity of alcohol may range from 25 to 100 times with respect to the compound of formula (2). Preferably, the ratio of water and alcohol used for crystallization is 10:90 to 30:70. The mole ratio of acetic acid for crystallization may range from 0.2 to 0.6 per mole ratio of compound of formula 2.

The crystallization process involves dilution of the reaction solution with a mixture of one or more alcoholic solvents and acetic acid, optionally seeding with ertapenem or a pharmaceutically acceptable salt thereof, combining a mixture of methanol and n-propanol to the reaction mixture for a period of at least 30 minutes, and stirring the mixture for a period of at least 1 hour to provide crystalline ertapenem sodium.

The process of the present invention provides ertapenem sodium from compound of formula (2) and (3) without involving isolation of diprotected ertapenem of formula (4) and ertapenem free base.

The resultant crystalline ertapenem sodium of the present invention has purity greater than or equal to 98.8 % and residual solvent content well below the pharmaceutically acceptable level.

Further, the crystalline ertapenem sodium of the present invention contains less than 1% of impurity of ring opened hydrolysis product. Furthermore, the crystalline ertapenem sodium of the present invention contains less than 0.5 % or less than 0.3 % of each impurity of ProMABA, Dimer-I, Dimer-II, Dimer-III, Dimer.H2O-I and Dimer.H2O-II determined by HPLC.

In another aspect, the present invention provides a process for the purification of crystalline ertapenem or its pharmaceutically acceptable salts, which comprises:
a) dissolving ertapenem or its pharmaceutically acceptable salts in a solution of aqueous sodium hydroxide and carbon dioxide gas;
b) adjusting the pH of the solution to about 4 to about 6 by using acid; and
c) isolating the pure crystalline ertapenem or its pharmaceutically acceptable salts.

The ertapenem or its pharmaceutically acceptable salts used for dissolution has the purity of less than about 90% or less than about 98 % by HPLC is converted to pure crystalline ertapenem or its pharmaceutically acceptable salt.

The crude ertapenem or its pharmaceutically acceptable salt used for dissolution can be in any polymorphic form, either amorphous or crystalline forms, which is then converted to a pure crystalline polymorph form of ertapenem or its salts by using process of the present invention.

The dissolution of the present invention is performed by the addition of ertapenem or its salts to the solution comprising solvent, sodium hydroxide and carbon dioxide, having pH of about 6 to about 8 at a temperature of below 15 ?C. Preferably, the dissolution temperature is about 0 to about 5 ?C.

The combination of 0.5 to 1.5 mole ratio of sodium hydroxide per mole ratio of ertapenem sodium and carbon dioxide gas provides preferred basic conditions to dissolve the ertapenem sodium without initiating any degradation.

The solvent used for the dissolution is selected from the group consisting of, but is not limited to alcoholic solvents such as branched or straight chain C1-C4 alcohols, such as methanol, ethanol, isopropyl alcohol, n-propanol etc.; esters like ethyl acetate, butyl acetate, etc.; ketones like acetone, methyl ethyl ketone, etc.; nitriles such as acetonitrile, propionitrile, butyronitrile, etc.; ethers such as diethyl ether, diisopropyl ether, methyl tertiary-butyl ether, methyl ethyl ether, tetrahydrofuran, dioxane, etc.; water and/or mixtures thereof. Preferably, the solvent is water or alcohols or mixture thereof.

The resultant solution may be treated with activated carbon or Ceca carbon or norit carbon and then filtered using micron filters. The preferred micron filter is membrane filter, which is useful to filter heat-sensitive solution of ertapenem sodium. The membrane filter may be prepared by using homogenous polymers of mixed cellulosic esters (MCE), polyvinylidene fluoride (PVF; also known as PVDF), or polytetrafluoroethylenc (PTFE) and have pore sizes ranging from 0.1 to 0.22 µm.

The present invention also involves use of the membrane filter, which comprise materials of stabilized cellulose based membrane, Gaskets with PVF or PTFE, spacer with fiber, for example, Polypropylene, and sealing compound of silicon polyolefin. The membrane filter is used to cut off endotoxic bacteria having molecular weight of greater than 3 kD to 10 kD to get the solution having BET less than 0.5 EU/mg.

The resultant solution of ertapenem sodium obtained from 0.22 µm filter and/or ultrafiltration contain BET (bacterial endotoxin) less than 0.5 EU/mg level or less than 0.2 EU/mg level. Preferably, the BET of the solution is less than 0.1 EU/mg.

The resultant reaction solution of step (b) is taken for pH adjustment to about 4 to about 6 with an acid while maintaining the temperature less than 15 ?C. The temperature used for pH adjustment is preferably from about 5 to -15 ?C.

The acid is selected from the group, but is not limited to organic acid or mineral acid such as acetic acid, lactic acid, formic acid, citric acid, oxalic acid, uric acid, hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, methane sulphonic acid, boric acid, hydrofluoric acid, hydrobromic acid and perchloric acid, etc., or mixtures thereof. Preferably, the acid used is hydrochloric acid or acetic acid.

In an embodiment, the purification process or step (b) involves use of an acid in the combination of an alcohol, for example, methanol for the adjustment of pH of about 4 or about 6, preferably 5.5± 0.2 without degradation of the product.

The resultant solution is further subjected for crystallization by the addition of pre-cooled alcohol followed by stirring at lower temperature ranging from -30 to 15 ?C. The alcoholic solvent is selected from branched or straight chain C1-C4 alcohols such as methanol, ethanol, n-propanol, isopropyl alcohol, and the like.

In an embodiment, the present invention comprises addition of pre-cooled alcohol to the reaction solution contained at pH between 4 to about 6 at a temperature of 0 to 5 ?C. In a preferred embodiment, the present invention comprises addition of pre-cooled n-propanol and methanol in portion-wise to the reaction solution contained at pH 5.5± 0.2.

The addition of alcohol may be carried out for a period of about 15 minutes to 1 hour or more to reduce/remove the formation of impurities by degradation of the product. After completion of the addition, the reaction mixture is cooled to 0 to -30 ?C and then stirred for a period of at least 1 hour or more to enhance the precipitation of the solid.

The obtained solid is isolated by using suitable techniques such as filtration by gravity, filtration under vacuum, centrifugation and the like. The filtration may be conducted in the presence of nitrogen gas or argon gas. The resultant wet cake may be washed with pre-cooled solvent such as absolute alcohol such as methanol or ester solvent such as methyl acetate or ketone solvent such as acetone or mixture thereof. Finally, the wet cake is dried at a temperature of about 20 to about 40 ?C for a period of about 5 to 10 hours or more.

The ertapenem or a pharmaceutically acceptable salt thereof has purity greater than or equal to 98% by HPLC.

In another aspect, the present invention provides a process for the purification of crystalline ertapenem sodium, which comprises:
a) dissolving ertapenem sodium in a solution of aqueous sodium hydroxide and carbon dioxide gas;
b) adjusting the pH of the solution to about 4 to about 6 by using hydrochloric acid;
c) filtering the suspension of step b) through filters to remove bacterial endotoxin to less than 0.5 EU/mg;
d) adding methanol and n-propanol to the filtrate of step (c);
e) stirring the reaction mixture of step (d) at least about 15 minutes; and
f) isolating the pure crystalline ertapenem sodium.

In another aspect, the present invention provides a pharmaceutical composition comprising ertapenem or pharmaceutically acceptable salts thereof obtained from the present invention and one or more pharmaceutically acceptable excipients.

The excipient(s) used for the composition is carbonate source such as carbon dioxide, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, calcium carbonate, cesium carbonate, magnesium carbonate, lithium carbonate, and a mixture thereof. The composition of the present invention may be prepared in presence of base which is selected from group consisting of sodium hydroxide, lithium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, magnesium hydroxide, lithium methoxide, sodium ethoxide, potassium ethoxide, lithium tert-butoxide, sodium tert-butoxide, magnesium tert-butoxide and potassium tert-butoxide. The composition of the ertapenem or pharmaceutically acceptable salts thereof is useful for intravenous and intramuscular administration.

The present invention is further described by the following Examples. These examples are for illustrative purpose and need not to be construed to limit the scope of the invention.

Examples
Example-1: Preparation of crude Ertapenem Sodium
Step -1: Preparation of Di-protected Ertapenem of Formula (IV)

Enol phosphate compound of formula 2 (100 g ), protected side chain of compound of formula 3 (74.95g ), tributyl phosphine (1 ml; 50% solution in ethyl acetate) and DMAP (1.5 g) were charged into dimethyl formamide (500 ml) at 0-10 °C under nitrogen and cooled to -35 to -40 °C. DIPEA (65.14 g) was added to the reaction mixture at -35 to -40 °C in 25-45 minutes and stirred for 2-4 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (1200 ml) and hydrochloric acid (26.5mL Conc. HCl and 2000mL water) and then adjusted pH of the reaction mass to 2.5+0.5 at 0 – 10 ?C by using diluted aqueous hydrochloric acid solution. The two layers were separated and the resultant organic layer was washed with 5% sodium chloride (500 mL).

Purity: ? 95% by HPLC.

Step-2: preparation of crude ertapenem sodium

Pd/C (wet;150g, 2.5%)) and Ceca carbon (75 g) were charged into the solution of aqueous sodium bicarbonate (56g in 800 ml of water) at 0-5 ºC under nitrogen. Water (200 mL), ethyl acetate (1000 mL) layer containing diprotected Ertapenem of step-1 and ethyl acetate (200 mL) were charged simultaneously into to the hydrogenator at 0-5 ?C. Hydrogen gas pressure (1 - 6 Kg) was applied to the hydrogenator slowly and maintained for 2-3 hour at 0 – 10 ?C. After completion of reaction, the hydrogen pressure was released by applying nitrogen gas. Acetic acid (20 mL) was charged into autoclave and stirred for 5-10 minutes. The reaction mixture was filtered through hyflo filter and washed the hyflo bed with mixture of water (300mL) and ethyl acetate (500mL) followed by ethyl acetate (500 mL) at 0-10 ?C. The aqueous layer was separated from filtrate and diluted with methanol (380 mL) at -1 to -5 ?C and adjusted the pH of the reaction mass to 6.5 ±0.2 using mixture of acetic acid: methanol (1:1). The reaction mixture was treated with Ceca carbon (25 g) at -1 to -5 ?C and then filtered through hyflow bed. The bed was washed with mixture of methanol (400 mL) and water (40 mL), and then cooled to -2 to -5°C. The mixture of solvents (1650 mL n-Propanol + 120 mL methanol + 25 mL acetic acid) were added to the filtrate within 10-15 minutes and stirred for 10 - 15 minutes. The mixture of solvents (3300 mL n-Propanol + 1700 mL methanol) again was added to the reaction mixture within 2-3 hours and stirred with moderate RPM for 6 - 8 hours at -8 to -12 °C. The resultant suspension was filtered, washed with mixture of solvents (150 mL n-Propanol + 150 mL methanol) followed by with acetone (2X400 mL) under nitrogen atmosphere and dried at 20-30 °C for 3 - 6 hours under vacuum.

Yield: 38 g
Purity: 98.89% by HPLC.
Impurities: Ring opened hydrolysis product: 0.57%, proMABA: 0.14%, Dimer-I: 0.21%, Dimer-II: 0.04%, Dimer-III:0.06%, Dimer.H2O-I: 0.06%, Dimer H2O-II: not detected.
Water content: 6.38%.

Example-2:
Process for pure crystalline ertapenem sodium
Carbon dioxide gas was purged to the mixture of water (120 mL) and sodium hydroxide (1.2 g) under nitrogen atmosphere at 0- 5 °C to get pH of 6.5 to 7.0. Ertapenem sodium (15g; Purity: 95.6%) was charged lot wise to the solution and stirred at 0 – 5 °C. n-propanol (22.5 mL) was charged to the solution and stirred. Ceca carbon (1.5 g) was charged to the reaction mass and stirred for 5-10 minutes at 0 – 5 °C. The reaction mass was filtered through hyflo bed and washed the bed with water (30 mL) and n-propanol (22.5 mL) at 0 to 5 ?C. The reaction mass was filtered through micron filter. The pH of the resultant reaction mass was adjusted to 5.5± 0.2 with mixture of HCl and methanol at 3 to -3 °C. The mixture of solvents (30 mL n-propanol and 75 mL methanol) was added to the reaction mass and cooled to -8 to -12ºC. The mixture of solvents (112.5 mL n-Propanol + 112.5 mL methanol) again was added to the reaction mass within 90 to 120 minutes and stirred for 4 to 5 hours at -15 to -20°C. The reaction mass was filtered under nitrogen, washed with mixture of solvents (22.5 mL n-Propanol + 22.5 mL methanol) followed by with acetone at 10 - 20°C. The resultant solid was dried under vacuum for 5 -10 hours at 20 - 30°C.

Yield: 0.63 w/w
Purity: Ring opened hydrolysis product: 0.57%, proMABA: 0.16%, Dimer-I: 0.47%, Dimer-II: 0.13%, Dimer-III: 0.02%, Dimer.H2O-I: 0.06%, Dimer H2O-II: 0.02%.

Water content: 10.1%.

Bacterial Endotoxin: 0.2 EU/mg
,CLAIMS:We Claim:
1. A process for preparing a crystalline compound of formula (1) or pharmaceutically acceptable salts, or hydrates, or solvates thereof, the process comprising of following steps:

a) reacting enol phosphate compound of formula (2) or its salts, with protected side chain compound of formula (3) in the presence of a base and dimethylaminopyridine to obtain di-protected ertapenem compound of formula (4) or its salts;

b) deprotecting the compound of formula (4) or its salt with metal catalyst in the presence of base to provide Ertapenem of formula (1), or its pharmaceutically acceptable salts, or hydrates, or solvates.

2. The process of claim 1, where the condensation step (a) is carried out optionally in the presence of tributyl phosphine.

3. The process of claim 1, where the base of step (a) is selected from the group of 1,1,3,3-tetramethylguanidine, diisoproprylamine, dicyclohexylamine, 2,2,6,6-tetramethylpiperidine, N,N,N’,NN’’-tetraethylcyclohexylguanidine, N,N’,N’’,N’’-dicyclohexyldiethylguanidine, 1,8-diazabicyclo[4.3.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene, diisopropylethylamine or mixture thereof.

4. The process of claim 1, wherein the condensation reaction of step (a) is carried in presence of solvent selected from the group of acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, propionitrile, N-ethylpyrrolidinone, N-methylpyrrolidinone, dichloromethane, ethyl acetate, tetrahydrofuran or mixture thereof.

5. The process of claim 1, wherein the base of step (b) is selected from the group of sodium hydroxide, sodium bicarbonate, sodium carbonate, mixture of carbon dioxide and sodium hydroxide, or mixture thereof.

6. The process of claim 1, wherein the metal catalyst is selected from the group of palladium, platinum, platinum oxide, rhodium, raney nickel or its complex formed with any of alumina, silica, calcium carbonate, barium carbonate, strontium carbonate, barium sulphate, polymer, carbon or mixture thereof.

7. A process for the preparation of pure crystalline ertapenem sodium, which comprises:
i) reacting enol phosphate compound of formula (2) or its salts, with protected side chain compound of formula (3) in the presence of a base and dimethylaminopyridine to obtain di-protected ertapenem compound of formula (4) or its salts;

ii) deprotecting the compound of formula (4) or its salt with metal catalyst in the presence of base to provide ertapenem sodium; and
iii) crystallizing the ertapenem sodium from mixture of alcohol and acetic acid at -20 to 0 ?C.

8. The process of claim 7, wherein the crystalline ertapenem sodium has purity of greater than or equal to 98 % by HPLC.

9. A process for the purification of crystalline ertapenem or its pharmaceutically acceptable salts, which comprises:
a) dissolving ertapenem or its pharmaceutically acceptable salts in a solution of aqueous sodium hydroxide and carbon dioxide gas;
b) adjusting the pH of the solution to about 4 to about 6 by using acid; and
c) isolating the pure crystalline ertapenem or its pharmaceutically acceptable salts.

10. The process of claim 9, wherein the acid of step b) is acetic acid or hydrochloric acid.