FIELD THE INVENTION

The present invention relates to a novel process for the preparation of Ertapenem of formula I,
or salt thereof.

BACKGROUND OF THE INVENTION
Ertapenem Sodium, a P-methylcarbapenem antibiotic, chemically known as [4R-[3(3S*,5S*),4a,5p,6P(R*)]]-3-[[-5-[[(3-carboxyphenyl)amino]carbonyl]-3-pyrrolidinyl]thio]-6-(l-hydroxyethyl)-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid monosodium is commercially available as Invanz®.

Ertapenem sodium is used for the treatment of patients with complicated intra¬abdominal infections; complicated skin and skin structure infections including diabetic foot infections without osteomyelitis; community acquired pneumonia; complicated urinary tract infections including pyelonephritis and acute pelvic infections including postpartum endomyometritis, septic abortion and post surgical gynecologic infections.

Ertapenem was disclosed for the first time in US 5,478,820 by Zeneca Limited, which also discloses a process to prepare Ertapenem and its sodium salt. Example 12 of the US 5,478,820 discloses a process to prepare 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 of formula I. The process is as summarized in scheme 1.

Scheme 1:
wherein PNB represents p-nitrobenzyl and PNZ represents p-nitrobenzy loxy carbony 1.
US 6,504,027 and US RE40,794 E disclose a process to prepare 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 to obtain Ertapenem sodium. The process is as summarized in scheme II.

Scheme II:
wherein X represents charge balancing counter ion and PNB is same as defined above.
US 7,071,330 B2 discloses a process to prepare Ertapenem from protected intermediates by hydrogenation in presence of pre-reduced metal catalyst.

Several other processes to prepare Ertapenem and its intermediates are disclosed in US 2004/0198973 Al; US 5,856,321 A; US 5,652,233 A; US 6,180,783 Bl; US 2009/0312539 Al; Journal of Organic Chemistry 2002, 67, pp 4771-4776 and Journal of Organic Chemistry 2005, 70, pp 7479-7487.
The processes disclosed in the above references involve tedious operations such as purging carbon dioxide, continuous adjustment of pH during hydrogenolysis, extracting the reaction mass with mixture of isoamyl alcohol-diphenyl phosphoric acid to remove organic bases, resin treatment and column chromatography subsequently lyophilization for isolation of Ertapenem.

However, there is a need in the prior art to develop a process for the preparing Ertapenem sodium, which is simple, easy to handle, commercially viable and involving simple isolation techniques.

OBJECTIVE OF THE INVENTION

The main objective of the present invention is to provide a process to prepare Ertapenem of formula I or salt thereof having high purity.

Another objective of the present invention is, to provide a process to prepare Ertapenem or salt thereof, which involves simple isolation technique.

SUMMARY OF THE INVENTION

The present invention relates to a process to prepare Ertapenem of formula I,
or salt thereof, which comprises:

a) hydrogenating compound of formula IV,
wherein Ri is carboxy protecting group and R2 is hydrogen or amino protecting group
using hydrogenation catalyst in presence of N-methylmorpholine, 2,6-Lutidine or mixture thereof to yield Ertapenem of formula I;

b) optionally treating Ertapenem with the counter ion source to produce Ertapenem salt; and
c) optionally precipitating and isolating Ertapenem salt.

DETAILED DESCRIPTION OF THE INVENTION

In an embodiment, present invention provides a process for the preparation of Ertapenem of formula I or salt thereof, which comprises hydrogenating compound of formula IV or salt thereof,

wherein Ri is carboxy protecting group and R2 is hydrogen or amino protecting group using hydrogenation catalyst in presence of N-methylmorpholine, 2,6-Lutidine or mixture thereof in a mixture of water and organic solvent to yield reaction mass containing Ertapenem of formula I.

The solution of N-methylmorpholine and 2,6-Lutidine is prepared by dissolving N-methylmorpholine and 2,6-Lutidine in water.

The compound of formula IV is hydrogenated with hydrogenation catalyst such as palladium on carbon in a solvent.

The solvent is selected from isopropyl alcohol, methylene chloride, tetrahydrofuran, ethyl acetate, water and mixtures thereof. After completion of hydrogenation, catalyst is filtered off and aqueous layer containing Ertapenem of formula I is separated.

The obtained Ertapenem is treated with the counter ion source to produce Ertapenem salt, preferably treated with sodium ion source, which is selected from sodium bicarbonate, sodium dihydrogen phosphate, disodium hydrogen phosphate, Sodium acetate.

The anti-solvent is added to the reaction mass to precipitate the product followed by filtration and isolation of Ertapenem salt. The anti-solvent used for precipitating Ertapenem salt is selected from the group comprising of methanol, ethanol, isopropyl alcohol, n-propanol, n-butanol, acetone and tetrahydrofuran and mixtures thereof. The obtained Ertapenem salt is optionally purified by processes known in the prior art.

The compound of formula IV according to present invention is prepared by condensing compound of formula II,

wherein Ph is phenyl group and R\ carboxy protecting group with compound of formula III,

wherein R2 is amino protecting group or salt thereof in polar aprotic solvent in the presence of an organic base to produce compound of formula IV.

The salt of compound of formula III is hydrochloride salt. The polar aprotic solvent is selected from N,N-dimethylformamide (DMF), N-methyl-2-pyrrolidinone (NMP) and N-ethyl-2-pyrrolidinone (NEP), preferably N,N-dimethylformamide. The organic base is selected from triethylamine (TEA), N-methylmorpholine (NMM), N,N-diisopropylamine (DIPA), N-ethyldiisopropylamine (DIPEA), dicyclohexylamine (DCHA), 2,2,6,6-tetramethylpiperidine (TMP), 1,1,3,3-tetramethylguanidine (TMG), 1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU), l,5-diazabicyclo[4.3.0]non-5-ene (DBN) and lutidines, preferably N,N-diisopropylamine. The reaction is carried out at a temperature about 20 to -50°C, preferably at -15 to -30 °C.

Carboxy protecting group is selected from allyl, benzhydryl, p-methoxybenzyl and p-nitrobenzyl. Amino protecting group is selected from allyloxycarbonyl, benzhydryloxycarbonyl, p- Methoxybenzyloxycarbonyland p- nitrobenzyloxycarbonyl.

The obtained compound of formula IV is optionally isolated before hydrogenating to obtain Ertapenem of formula I.

The starting compounds of formulae II and III are prepared according to processes known in the prior art reference including US 5,721,368; US 5,648,501; US 6,060,607 and US 6,063,931 which are expressly incorporated herein as reference.

In another embodiment of the present invention, Ertapenem of formula I is prepared by hydrogenating compound of formula IV(a),

wherein R\ is same as defined above in presence of N-methylmorpholine, 2,6-Lutidine or mixture thereof in a mixture of water and organic solvent to yield reaction mass containing Ertapenem of formula I.

The compound of formula IV(a) is prepared by condensing compound of formula II with 3-[[[(2S,4S)-4-mercapto-2-pyrrolidinyl]carbonyl]amino] benzoic acid of formula 111(a), or acid salt thereof in a solvent in the presence of organic base.

The solvent is selected from N,N-dimethylformamide (DMF), N-methyl-2- pyrrolidinone (NMP) and N-ethyl-2-pyrrolidinone (NEP) at a temperature of about 20 to -50°C to produce compound of formula IV(a).

The organic base is selected from triethylamine (TEA), N-methylmorpholine (NMM), N,N- diisopropylamine (DIPA), N-ethyldiisopropylamine (DIPEA), dicyclohexylamine (DCHA), 2,2,6,6-tetramethylpiperidine (TMP), 1,1,3,3-tetramethylguanidine (TMG), l,8-diazabicyclo-[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) and lutidines.

The compound of formula IV(a) is optionally isolated before hydrogenating to obtain Ertapenem of formula I.

The invention is illustrated with the following examples, which are provided by way of illustration only and should not be construed to limit the scope of the invention.

EXAMPLE 1
Preparation of (4-nitrophenyl)methyl(4R,5S,6S)-3-[[(3S,5S)-5-[[(3-
carboxyphenyl)amino]carbonyl]-3-pyrrolidinyl]thio)-6-[(lR)-l-
hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate
(4-Nitrophenyl)methyl (4R,5R,6S)-3-[(diphenoxyphosphinyl)oxy-6-[(lR)-l-
hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (50 g, 0.084 moles) was added to a mixture of 3-[[[(2S,4S)-4-mercapto-2-pyrrolidinyl]carbonyl]amino] benzoic acid hydrochloride (30.6 g, 0.101 moles), diisopropylamine (34 g, 0.336 moles) and N,N-dimethylformamide (300 ml) at -10 to -30°C and stirred for 3 h at -10 to -30°C. After the completion of reaction, water (750 ml) was added, adjusted the pH to 3 to 5 with diluted hydrochloric acid, extracted the title compound with ethyl acetate (500 ml) and taken for hydrogenation in next step.

EXAMPLE-2
Preparation of Ertapenem sodium
The organic layer obtained in example-1, containing (4-nitrophenyl)methyl(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-carboxylate was added to a solution of N-methylmorpholine (6.8 g, 0.067 moles), 2,6-Lutidine (22.51 g, 0.21 moles) and water (350 ml). The reaction mixture was hydrogenated with 10% palladium on carbon (75 g) at 7-10 kg / Cm2 at 0-10°C. After completion of the reduction, catalyst was filtered, separated the aqueous layer and added about 8% w/w sodium bicarbonate solution (80 g). To the aqueous solution, ethanol (2000 ml) followed by isopropyl alcohol (4000 ml)

were added at 0 to -15°C and stirred for 2 h. The solid product was filtered,
washed with ethanol and dried at 0-5°C to produce title compound.
Yield: 25.4 g
Chromatographic Purity: 94% (by HPLC)

EXAMPLE-3
Preparation of Ertapenem sodium
The organic layer obtained in example-1, containing (4-nitrophenyl)methyl(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-carboxylate was added to a solution of N-methylmorpholine (6.8 g, 0.067 moles), 2,6-Lutidine (22.51 g, 0.21 moles), and water (350 ml). The reaction mixture was hydrogenated with 10% palladium on carbon (100 g) at 7-10 kg / Cm2 at 0-10°C. After completion of the reduction, catalyst was filtered, separated aqueous layer and added about 9% w/w disodium hydrogen phosphate solution (80 g). To the aqueous solution, ethanol (2000 ml) followed by isopropyl alcohol (4000 ml) were added at 0 to -15°C and stirred for 2 h. The solid product was filtered, washed with ethanol and dried at 0-5°C to produce the title compound. Yield: 23 g Chromatographic Purity: 92.6% (by HPLC)

EXAMPLE-4
Preparation of Ertapenem sodium
The organic layer obtained in example-1, containing (4-nitrophenyl)methyl(4R, 5S,6S)-3-[[(3S,5S)-5-[[(3-carboxyphenyl)-amino]-carbonyl]-3-pyrrolidinyl]thio]-6-[(lR)-l-hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate was added to a solution of N-methylmorpholine (6.8 g, 0.067 moles), 2,6-Lutidine (22.51 g, 0.21 moles), and water (350 ml). The reaction mixture was hydrogenated with 10% palladium on carbon (100 g) at 7-10 kg / Cm2 at 0-10°C. After completion of the reduction, catalyst was filtered, separated aqueous layer and added about 10% w/w sodium acetate solution (62 g).

To the aqueous solution, ethanol (2000 ml) followed by isopropyl alcohol (4000 ml) were added
at 0 to -15°C and stirred for 2 h. The solid product was filtered, washed with ethanol and dried at 0-5°C to produce the title compound.

Yield: 20 g

Chromatographic Purity: 92.74% (by HPLC)

EXAMPLES

Preparation of (4-nitrophenyl)methyl(4R,5S,6S)-3-[[(3S,5S)-5-[[(3- carboxyphenyl)-amino]carbonyl]-l-[[(4-nitrophenyl)methoxy]carbonyl]-3-pyrrolidinyl]thio]-6-[(lR)-l-hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo [3.2.0] hept-2-ene-2-carboxy late (4-Nitrophenyl)methyl(4R,5R,6S)-3-[(diphenoxyphosphinyl)oxy-6-[(lR)-l-hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (50 g, 0.084 moles) was added to a mixture of 3-[[[(2S,4S)-4-Mercapto-l-(4-nitrobenzyloxy)carbonyl-2-pyrrolidinyl]carbonyl]amino]benzoic acid (39.33 g, 0.088 moles), N-ethyldiisopropylamine (32.6 g, 0.252 moles) and N,N-dimethylformamide (300 ml) at 0 to -30°C and stirred for 4 h at -20 to -30°C. After completion of the reaction, water (750 ml) was added, adjusted the pH to 3-5 with diluted hydrochloric acid, extracted the title compound with ethyl acetate (500 ml) and taken for hydrogenation in the next step.

EXAMPLE-6
Preparation of Ertapenem sodium
The organic layer obtained in example-5, containing (4-nitrophenyl)methyl (4R,5S,6S)-3-[[(3S,5S)-5-[[(3-carboxyphenyl)-amino]carbonyl]-l-[[(4-nitrophenyl)methoxy]carbonyl]-3-pyrrolidinyl]thio]-6-[(lR)-l-hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate was added to a solution of N-methylmorpholine (6.8 g, 0.067 moles), 2,6-Lutidine (22.51 g, 0.21 moles) and water (350 ml). The reaction mixture was hydrogenated with 10% palladium on carbon (100 g) at 7-10 kg / Cm2 at 0-10°C. After completion of the reduction, catalyst was filtered, separated aqueous layer and added about 8% w/w sodium bicarbonate solution (80 g). To the aqueous solution, ethanol (2000 ml) followed by isopropyl alcohol (4000 ml) were added at 0 to -15°C and stirred for 2 h. The solid product was filtered, washed with ethanol and dried at 0-5°C to produce the title compound. Yield: 20 g. Chromatographic Purity: 92.60% (by HPLC)

EXAMPLE-7
Preparation of Ertapenem sodium
The organic layer obtained in example-5, containing (4-nitrophenyl)methyl (4R,5S,6S)-3-[[(3S,5S)-5-[[(3-carboxyphenyl)-amino]carbonyl]-l-[[(4-nitrophenyl)methoxy]carbonyl]-3-pyrrolidinyl]thio]-6-[(lR)-l-hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate was added to a solution of N-methylmorpholine (6.8 g, 0.067 moles), 2,6-Lutidine (22.51 g, 0.21 moles) and water (350 ml). The reaction mixture was hydrogenated with 10% palladium on carbon (100 g) at 7-10 kg / Cm2 at 0-10°C. After completion of the reduction, catalyst was filtered, separated aqueous layer and added about 10% w/w sodium acetate solution (62 g). To the aqueous solution, ethanol (2000 ml) followed by isopropyl alcohol (4000 ml) were added at 0 to -15°C and stirred for 2 h. The solid product was filtered, washed with ethanol and dried at 0-5 °C to produce the title compound. Yield: 18 g. Chromatographic Purity: 91.09% (by HPLC)

COMPARATIVE EXAMPLE Preparation of Ertapenem sodium The organic layer obtained in example-5, containing (4-nitrophenyl)methyl(4R,5S,6S)-3-[[(3S,5S)-5-[[(3-carboxyphenyl)-amino] carbonyl]-! -[[(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 was added to a solution of sodium dihydrogenphosphate solution (350 ml). The reaction mixture was hydrogenated with 10% palladium on carbon (lOOg) at 7-10 kg/Cm2 at 0-10°C. After completion of the reduction, catalyst was filtered, separated aqueous layer. To the aqueous solution, ethanol (2000ml) followed by isopropyl alcohol (4000ml) was added at 0 to -15°C and stirred for 2 h. The solid product was filtered, washed with ethanol and dried at 0-5°C to produce the title compound. Yield: 24 g. Chromatographic Purity: 86.67% (by HPLC)

We Claim:

1. An improved process for the preparation of Ertapenem of formula I,
or salt thereof, which comprises:

a) hydrogenating compound of formula IV,
wherein R| is carboxy protecting group and R2 is hydrogen or amino protecting group
using hydrogenation catalyst in presence of N-methylmorpholine, 2,6-Lutidine or mixture thereof to yield Ertapenem of formula I;

b) optionally treating Ertapenem with counter ion source to produce Ertapenem salt; and

c) optionally precipitating and isolating Ertapenem salt.

2. The process according to claim 1, wherein hydrogenation is carried out in a mixture of water and organic solvent.

3. The process according to claim 2, wherein organic solvent is selected from the group comprising of tetrahydrofuran, ethyl acetate, water and mixtures thereof.

4. The process according to claim 1, wherein hydrogenation catalyst is palladium on carbon.

5. The process according to claim 1, wherein counter ion source is selected from sodium bicarbonate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium acetate.

6. The process according to claim 1, wherein salt is sodium salt of Ertapenem.

7. An improved process for the preparation of Ertapenem or salt thereof, which comprises hydrogenating compound of formula IV(a), wherein Rj is carboxy protecting group in presence of N-methylmorpholine, 2,6-Lutidine or mixture thereof in a mixture of water and organic solvent.

8. The process according to claim 1 and 7, wherein carboxy protecting group is selected from the group comprising of allyl, benzhydryl, p-methoxybenzyl and p-nitrobenzyl.

9. The process according to claim 1, wherein amino protecting group is selected from the group comprising of allyloxycarbonyl, benzhydryloxycarbonyl, p-methoxybenzyloxycarbonyl and p-nitrobenzyloxycarbonyl.

10. A process for the preparation of Ertapenem or salt thereof substantially as described herein.