WO2013121279A2 - Process to prepare ertapenem - Google Patents

Process to prepare ertapenem Download PDF

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WO2013121279A2
WO2013121279A2 PCT/IB2013/000211 IB2013000211W WO2013121279A2 WO 2013121279 A2 WO2013121279 A2 WO 2013121279A2 IB 2013000211 W IB2013000211 W IB 2013000211W WO 2013121279 A2 WO2013121279 A2 WO 2013121279A2
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Prior art keywords
ertapenem
sodium
process according
salt
ertapenem sodium
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PCT/IB2013/000211
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French (fr)
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WO2013121279A3 (en
Inventor
Shankar Reddy Budidet
Mallikarjuna Reddy Karuru
Sivakumar KURIMISETTY
Rajasekhara Raju KONDURU
Sivakumaran Meenakshisunderam
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Aurobindo Pharma Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
    • C07D477/10—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
    • C07D477/12—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6
    • C07D477/16—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6 with hetero atoms or carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 3
    • C07D477/20—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
    • C07D477/02—Preparation
    • C07D477/06—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
    • C07D477/08—Modification of a carboxyl group directly attached in position 2, e.g. esterification

Definitions

  • the present invention relates to a novel process for the preparation of Ertapenem of formula I
  • Ertapenem Sodium a ⁇ -methylcarbapenem antibiotic, chemically known as [4R- [3(3S*,5S*),4a,5p,6 (R*)]]-3-[[-5-[[(3-carboxyphenyl)amino]carbonyl]-3- pyrrolidinyl]thio]-6-( 1 -hydroxyethyl)-4-methyl-7-oxo- 1 -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 intraabdominal 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 caused by pathogens.
  • 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.
  • PNB represents p-nitrobenzyl and PNZ represents p- nitrobenzyloxycarbonyl .
  • US RE40,794 E discloses Ertapenem sodium as crystalline Form A and Form B and processes for preparing these forms.
  • US 7,022,841 B2 discloses Ertapenem sodium as crystalline Form C and its process.
  • This patent also discloses a process for reducing the levels of organic solvents in crystalline carbapenem to pharmaceutically acceptable levels, comprising washing the crystalline carbapenem containing organic solvent with an organic solvent containing water to produce a washed carbapenem solid containing residual organic solvent; wherein throughout the washing the water content of the crystalline carbapenem solids, correcting for residual organic solvents, is maintained at about 13% to about 25% and evaporating the residual organic solvent in the washed carbapenem solid using vacuum and/or inert gas at low temperature.
  • This process requires continuous monitoring and is not suitable for large scale production.
  • WO 2009/150630 A2 discloses crystalline Form D of Ertapenem monosodium, which is prepared by a process comprising treating Ertapenem sodium with methanol and water to form a solution, adding n-propanol and stirring the solution at low temperature to obtain a solid and thereafter treating 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.
  • WO 2012/089058 Al discloses crystalline Form E of Ertapenem sodium and its process.
  • Ertapenem sodium prepared according to above processes contains more residual solvent content, which cannot be removed/controlled in the later stages and is not suitable for preparing pharmaceutical dosage forms.
  • crystalline forms obtained according to prior art processes are not stable.
  • Present inventors have now developed an improved process for the preparation of stable crystalline Form of Ertapenem sodium having purity not less than 98% (by HPLC), which is reproducible, substantially free of residual solvents and suitable for preparing pharmaceutical dosage forms.
  • 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 for the preparation of Ertapenem sodium, which is free of residual solvents.
  • the present invention relates to a rocess to prepare Ertapenem of formula I,
  • R ⁇ is carboxy protecting group and R 2 is hydrogen or amino protecting group
  • the present invention relates to a process for the preparation of crystalline form of Ertapenem sodium, which comprises:
  • the present invention relates to a process for the preparation of crystalline Ertapenem sodium, which is substantially free of residual solvents, which comprises:
  • 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
  • is carboxy protecting and R 2 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.
  • 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 selected from isopropyl alcohol, methylene chloride, tetrahydrofuran, ethyl acetate, water and mixtures thereof at a temperature range from -5 to 20°C. After the completion of hydrogenation reaction, catalyst is filtered off and the aqueous layer containing Ertapenem of formula I is separated.
  • hydrogenation catalyst such as palladium on carbon in a solvent selected from isopropyl alcohol, methylene chloride, tetrahydrofuran, ethyl acetate, water and mixtures thereof at a temperature range from -5 to 20°C.
  • 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 Ertapenem sodium salt is obtained in crystalline or amorphous form.
  • the anti-solvent is added to the reaction mass to precipitate the product followed by filtration and isolation of Ertapenem salt.
  • the anti-solvent is selected from the group comprising of methanol, ethanol, isopropyl alcohol, n-propanol, n-butanol, acetone and tetrahydrofuran and mixtures thereof.
  • the compound of formula IV according to present invention is prepared by condensing compound of formula II,
  • R 2 is same as defined above
  • the salt of compound of formula III is hydrochloride salt.
  • the polar aprotic solvent is selected from ⁇ , ⁇ -dimethylformamide (DMF), N-methyl-2- pyrrolidinone (NMP) and N-ethyl-2-pyrrolidinone (NEP), preferably N,N- dimethylformamide; organic base is selected from triethylamine (TEA), N- methylmorpholine ( MM), ⁇ , ⁇ -diisopropylamine (DIPA), N- diisopropylethylamine (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,
  • Carboxy protecting group is selected from allyl, benzhydryl, p-methoxybenzyl and p-nitrobenzyl.
  • Amino protecting group is selected from allyloxycarbonyl, benzhydryloxycarbonyl, p-methoxybenzyloxycarbonyl and p- nitrobenzyloxycarbonyl.
  • the obtained compound of formula IV is optionailyisolated before hydrogenation to obtain Ertapenem of formula I.
  • Ertapenem of formula I is prepared by hydrogenating compound of formula IV(a),
  • 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),
  • the solvent is selected from ⁇ , ⁇ -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 ( MM), N,N-diisopropylamine (DIPA), N-ethyldiisopropylamine (DIPEA), dicyclohexylamine
  • DCHA 2,2,6,6-tetramethylpiperidine
  • TMP 2,2,6,6-tetramethylpiperidine
  • TMG 1,1 ,3,3-tetramethylguanidine
  • DBU 1,3-tetramethylguanidine
  • DBU 1,3-tetramethylguanidine
  • DBU l ,8-diazabicyclo-[5.4.0]undec-7-ene
  • DBN l ,5-diazabicyclo[4.3.0]non- 5-ene
  • lutidines lutidines.
  • the compound of formula IV(a) is optionally isolated before hydrogenating to obtain Ertapenem of formula I.
  • Another aspect of the present invention relates to a process for the preparation of crystalline form of Ertapenem sodium having powder X-ray diffraction (PXRD) °2 ⁇ peaks ( ⁇ 0.2) at 4.38, 4.47, 5.20, 5.25, 7.35, 7.44, 8.01 , 8.19, 9.53, 9.83, 10.88, 10.98, 12.64, 12.94, 19.06, and 19.21 , which comprises dissolving Ertapenem sodium in DM water at -5 to 25°C to obtain an aqueous solution; optionally seeding with crystalline Ertapenem sodium; adding water miscible solvent, selected from methanol, ethanol, isopropyl alcohol, n-propanol, tetrahydrofuran, acetone, acetonitrile or mixtures thereof, to the solution at 5 to -25°C to crystallize the product; and isolating the obtained crystalline Ertapenem sodium.
  • PXRD powder X-ray diffraction
  • the process further comprises, optionally addition of water miscible organic solvent selected from methanol, ethanol, isopropyl alcohol, n-propanol, tetrahydrofuran, acetone, acetonitrile, to form the aqueous solution before seeding.
  • water miscible organic solvent selected from methanol, ethanol, isopropyl alcohol, n-propanol, tetrahydrofuran, acetone, acetonitrile
  • the process further comprises, optionally adjusting the pH of the solution after addition of water miscible organic solvent to about 5.0 to 6.0 by adding dilute acetic acid and optionally treating with the activated carbon.
  • a process for the preparation of crystalline form of Ertapenem sodium having powder X-ray diffraction (PXRD) °2 ⁇ peaks ( ⁇ 0.2) at 4.38, 4.47, 5.20, 5.25, 7.35, 7.44, 8.01 , 8.19, 9.53, 9.83, 10.88, 10.98, 12.64, 12.94, 19.06, and 19.21 which comprises dissolving amorphous Ertapenem sodium in DM water at -5 to 25°C to obtain an aqueous solution; addition of water miscible organic solvent selected from methanol, ethanol, isopropyl alcohol, n- propanol, tetrahydrofuran, acetone, acetonitrile; seeding with crystalline Ertapenem sodium; adjusting the pH of the solution after addition of water misc
  • the seed of the crystalline Ertapenem sodium can be prepared by the process of the present invention.
  • a process for the preparation of crystalline Ertapenem sodium substantially free of residual solvents which comprises washing crystalline Ertapenem sodium containing residual solvents with an anhydrous solvent, selected from acetone, methyl tert- butyl ether, methyl acetate, ethanol or mixtures thereof; and drying the product under dry nitrogen, wherein drying is carried out at temperature less than 25°C; preferably at -5 to 10°C.
  • the residual content of the crystalline Ertapenem sodium before washing with anhydrous solvent is about 5%(w/w), which is reduced to about 1.5%(w/w) after washing with anhydrous solvent.
  • one of the residual solvent is methyl acetate, which is classified under ICH as class-3 solvent and is regarded as less toxic and lower risk to human health.
  • residual methyl acetate in Ertapenem sodium prepared according to the present invention is within the pharmaceutically acceptable levels.
  • An amorphous Ertapenem sodium used herein is prepared according to the processes known in the prior art.
  • the starting compounds of formulae II and III are prepared according the 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.
  • the reaction mixture was hydrogenated with 10% palladium on carbon (75 g) at 7-10 kg / Cm 2 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.
  • the reaction mixture was hydrogenated with 10% palladium on carbon ( 100 g) at 7-10 kg / Cm 2 at 0-10°C. After completion of the reduction, catalyst was filtered, separated aqueous layer and added dbout 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.
  • the reaction mixture was hydrogenated with 10% palladium on carbon ( 100 g) at 7-10 kg / Cm 2 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.
  • the reaction mixture was hydrogenated with 10% palladium on carbon (100 g) at 7-10 kg / Cm 2 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.
  • the reaction mixture was hydrogenated with 10% palladium on carbon (100 g) at 7- 10 kg / Cm 2 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.
  • the reaction mixture was hydrogenated with 10% palladium on carbon (100 g) at 7-10 kg / Cm 2 at 0-10°C. After completion of the reduction, catalyst was filtered, separated aqueous layer. 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.
  • Amorphous Ertapenem sodium (20 g) was dissolved in aqueous sodium acetate solution (2% w/w; 200 ml) at 0-5°C. Methanol (40 ml) was added to the solution and adjusted the pH to 5.0-6.0 with acetic acid. The solution was treated with activated carbon (2 g), filtered, seeded with crystalline Ertapenem Sodium (0.4 g) and added mixture of methanol and acetone (1 :3 ratio; 600 ml) to obtain crystalline Ertapenem sodium.
  • Amorphous Ertapenem sodium (20 g) was dissolved in aqueous sodium bicarbonate solution (2.0% w/w; 200 ml) at 0-5°C. Methanol (40 ml) was added to the solution and adjusted the pH to 5.0-6.0 with acetic acid. The solution was treated with activated carbon (2 g), filtered, seeded with crystalline Ertapenem Sodium (0.4 g) and added mixture of methanol and acetone (1 :3 ratio; 600 ml) to obtain crystalline Ertapenem Sodium.
  • Amorphous Ertapenem sodium (10 g) was dissolved in aqueous sodium bicarbonate solution (2.0% w/w 100 ml) and adjusted the pH to 5.0-6.0 with diluted acetic acid at 0-5°C.
  • the solution was treated with activated carbon ( 1 g) at 0 - 5°C, filtered and added mixture of methanol and tetrahydrofuran (1 :3 ratio; 50 ml).
  • the resulting solution was seeded with crystalline Ertapenem Sodium (0.2 g) and added mixture of methanol and tetrahydrofuran ( 1 :3 ratio; 250 ml) at 0 to - 20°C to obtain crystalline Ertapenem Sodium.
  • Amorphous Ertapenem sodium (10 g) was dissolved in DM water (100 ml). The solution was treated with activated carbon (1 g) at 0 - 5°C, filtered and added mixture of methanol and tetrahydrofuran ( 1 :3 ratio; 280 ml). The resulting solution was seeded with crystalline Ertapenem Sodium (0.2 g) and added mixture of methanol and tetrahydrofuran (1 :3 ratio; 120 ml) at 0 to -20°C to obtain crystalline Ertapenem Sodium.
  • Amorphous Ertapenem sodium (20 g) was dissolved in DM water (200 ml) at 0 to 10°C.
  • the solution was treated with activated carbon (2 g), filtered and added mixture of methanol and tetrahydrofuran (1 :3 ratio; 560 ml).
  • the resulting solution was seeded with Ertapenem Sodium (0.4 g) and added mixture of methanol and tetrahydrofuran (1 :3 ratio; 240 ml) at 0 to -20°C.
  • the solid product was filtered, washed with anhydrous acetone and dried with dry nitrogen at less than 25°C to obtain residual acetone less than 1.5% w/w.
  • Residual solvents by GC: Methanol: 2856 ppm; Tetrahydrofuran: 57 ppm; Acetone: 13000 ppm
  • Amorphous Ertapenem sodium (25 g) was dissolved in DM water (250 ml) at 0 to 10°C. The solution was treated with activated carbon (2.5 g), filtered and added mixture of methanol and tetrahydrofuran (1 :3 ratio; 700 ml). The resulting solution was seeded with Ertapenem Sodium (0.5 g) and added mixture of methanol and tetrahydrofuran (1 :3 ratio; 300 ml) at 0 to -20°C. The solid product was filtered, washed with anhydrous methyl tert butyl ether and dried with dry nitrogen at less than 25°C to obtain title compound.
  • Residual solvents by GC: Methanol: Not Detected, Tetrahydrofuran: 6559 ppm and MTBE: 31 14 ppm
  • Amorphous Ertapenem sodium (50 g) was dissolved in DM water (500 ml) at 0 to 10°C. The solution was treated with activated carbon (5 g) at 0 - 5°C, filtered and added mixture of methanol and tetrahydrofuran ( 1 :3 ratio; 1400 ml). The resulting solution was seeded with Ertapenem Sodium (1.0 g) and added mixture of methanol and tetrahydrofuran ( 1 :3 ratio; 600 ml) at 0 to -20°C. The solid product was filtered, washed with anhydrous methyl acetate and dried with dry nitrogen at less than 25°C to obtain title compound.
  • Residual solvents by GC: Methanol: Not Detected, Tetrahydrofuran: Not Detected and Methyl acetate: 15630 ppm

Abstract

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

Description

PROCESS TO PREPARE ERTAPENEM
FIELD OF THE INVENTION
The present invention relates to a novel process for the preparation of Ertapenem of formula I
Figure imgf000002_0001
or salt thereof.
BACKGROUND OF THE INVENTION
Ertapenem Sodium, a β-methylcarbapenem antibiotic, chemically known as [4R- [3(3S*,5S*),4a,5p,6 (R*)]]-3-[[-5-[[(3-carboxyphenyl)amino]carbonyl]-3- pyrrolidinyl]thio]-6-( 1 -hydroxyethyl)-4-methyl-7-oxo- 1 -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 intraabdominal 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 caused by pathogens.
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 :
Figure imgf000003_0001
wherein PNB represents p-nitrobenzyl and PNZ represents p- nitrobenzyloxycarbonyl .
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:
Figure imgf000003_0002
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 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 B l ; US 2009/0312539 Al ; Journal of Organic Chemistry 2002, 67, pp 4771 -4776 and Journal of Organic Chemistry 2005, 70, pp 7479-7487.
Further, US RE40,794 E discloses Ertapenem sodium as crystalline Form A and Form B and processes for preparing these forms. US 7,022,841 B2 discloses Ertapenem sodium as crystalline Form C and its process. This patent also discloses a process for reducing the levels of organic solvents in crystalline carbapenem to pharmaceutically acceptable levels, comprising washing the crystalline carbapenem containing organic solvent with an organic solvent containing water to produce a washed carbapenem solid containing residual organic solvent; wherein throughout the washing the water content of the crystalline carbapenem solids, correcting for residual organic solvents, is maintained at about 13% to about 25% and evaporating the residual organic solvent in the washed carbapenem solid using vacuum and/or inert gas at low temperature. This process requires continuous monitoring and is not suitable for large scale production.
WO 2009/150630 A2 discloses crystalline Form D of Ertapenem monosodium, which is prepared by a process comprising treating Ertapenem sodium with methanol and water to form a solution, adding n-propanol and stirring the solution at low temperature to obtain a solid and thereafter treating 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. WO 2012/089058 Al discloses crystalline Form E of Ertapenem sodium and its process.
The processes disclosed in prior 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. Hence, there is a need in the prior art to develop a process for preparing Ertapenem sodium, which is simple, easy to handle, commercially viable and involving simple isolation techniques.
Further, Ertapenem sodium prepared according to above processes contains more residual solvent content, which cannot be removed/controlled in the later stages and is not suitable for preparing pharmaceutical dosage forms. Further, crystalline forms obtained according to prior art processes are not stable. Present inventors have now developed an improved process for the preparation of stable crystalline Form of Ertapenem sodium having purity not less than 98% (by HPLC), which is reproducible, substantially free of residual solvents and suitable for preparing pharmaceutical dosage forms.
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 for the preparation of Ertapenem sodium, which is free of residual solvents.
Yet another objective of the present invention is to provide a process for the preparation of stable crystalline form of Ertapenem sodium with purity not less than 98% (by HPLC). Yet another objective of the present invention is, to provide a process to prepare Ertapenem or salt thereof, which involves simple isolation techniques.
SUMMARY OF THE INVENTION
The present invention relates to a rocess to prepare Ertapenem of formula I,
Figure imgf000006_0001
or salt thereof, which comprises:
a) h drogenating compound of formula IV,
Figure imgf000006_0002
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.
In another embodiment, the present invention relates to a process for the preparation of crystalline form of Ertapenem sodium, which comprises:
a) dissolving Ertapenem sodium in DM water at -5 to 25°C to obtain aqueous solution;
b) optionally, seeding with a crystalline form of Ertapenem sodium;
c) adding water miscible solvent to the solution at -5 to 25°C to crystallize the product; and
d) isolating crystalline Ertapenem sodium. In yet another embodiment, the present invention relates to a process for the preparation of crystalline Ertapenem sodium, which is substantially free of residual solvents, which comprises:
a) washing crystalline Ertapenem sodium containing residual solvents with anhydrous solvent; and
b) drying the product under dry nitrogen.
DETAILED DESCRIPTION OF THE INVENTION
In one aspect, 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
Figure imgf000007_0001
wherein R| is carboxy protecting 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.
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 selected from isopropyl alcohol, methylene chloride, tetrahydrofuran, ethyl acetate, water and mixtures thereof at a temperature range from -5 to 20°C. After the completion of hydrogenation reaction, catalyst is filtered off and the 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 Ertapenem sodium salt is obtained in crystalline or amorphous form.
The anti-solvent is added to the reaction mass to precipitate the product followed by filtration and isolation of Ertapenem salt. The anti-solvent is selected from the group comprising of methanol, ethanol, isopropyl alcohol, n-propanol, n-butanol, acetone and tetrahydrofuran and mixtures thereof.
The compound of formula IV according to present invention is prepared by condensing compound of formula II,
Figure imgf000008_0001
wherein Ph is phenyl group and Ri is same as defined above
with compound of formula III,
Figure imgf000008_0002
wherein R2 is same as defined above
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 Ν,Ν-dimethylformamide (DMF), N-methyl-2- pyrrolidinone (NMP) and N-ethyl-2-pyrrolidinone (NEP), preferably N,N- dimethylformamide; organic base is selected from triethylamine (TEA), N- methylmorpholine ( MM), Ν,Ν-diisopropylamine (DIPA), N- diisopropylethylamine (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 Ν,Ν-diisopropylamine. The reaction is carried out at a temperature about 20 to -50°C, preferably at -15 to -30 °C. The salt of compound of formulae III is selected from hydrochloride.
Carboxy protecting group is selected from allyl, benzhydryl, p-methoxybenzyl and p-nitrobenzyl. Amino protecting group is selected from allyloxycarbonyl, benzhydryloxycarbonyl, p-methoxybenzyloxycarbonyl and p- nitrobenzyloxycarbonyl.
The obtained compound of formula IV is optionailyisolated before hydrogenation to obtain Ertapenem of formula I.
In another embodiment of the present invention, Ertapenem of formula I is prepared by hydrogenating compound of formula IV(a),
Figure imgf000009_0001
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 or salt thereof.
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),
Figure imgf000009_0002
or acid salt thereof in a solvent in the presence of organic base. The solvent is selected from Ν,Ν-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 ( MM), 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), l ,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.
Another aspect of the present invention relates to a process for the preparation of crystalline form of Ertapenem sodium having powder X-ray diffraction (PXRD) °2Θ peaks (±0.2) at 4.38, 4.47, 5.20, 5.25, 7.35, 7.44, 8.01 , 8.19, 9.53, 9.83, 10.88, 10.98, 12.64, 12.94, 19.06, and 19.21 , which comprises dissolving Ertapenem sodium in DM water at -5 to 25°C to obtain an aqueous solution; optionally seeding with crystalline Ertapenem sodium; adding water miscible solvent, selected from methanol, ethanol, isopropyl alcohol, n-propanol, tetrahydrofuran, acetone, acetonitrile or mixtures thereof, to the solution at 5 to -25°C to crystallize the product; and isolating the obtained crystalline Ertapenem sodium.
The process further comprises, optionally addition of water miscible organic solvent selected from methanol, ethanol, isopropyl alcohol, n-propanol, tetrahydrofuran, acetone, acetonitrile, to form the aqueous solution before seeding.
The process further comprises, optionally adjusting the pH of the solution after addition of water miscible organic solvent to about 5.0 to 6.0 by adding dilute acetic acid and optionally treating with the activated carbon. In another embodiment, a process for the preparation of crystalline form of Ertapenem sodium having powder X-ray diffraction (PXRD) °2Θ peaks (±0.2) at 4.38, 4.47, 5.20, 5.25, 7.35, 7.44, 8.01 , 8.19, 9.53, 9.83, 10.88, 10.98, 12.64, 12.94, 19.06, and 19.21 , which comprises dissolving amorphous Ertapenem sodium in DM water at -5 to 25°C to obtain an aqueous solution; addition of water miscible organic solvent selected from methanol, ethanol, isopropyl alcohol, n- propanol, tetrahydrofuran, acetone, acetonitrile; seeding with crystalline Ertapenem sodium; adjusting the pH of the solution after addition of water miscible organic solvent to about 5.0 to 6.0 by adding dilute acetic acid; treating with activated carbon; adding water miscible solvent selected from methanol, ethanol, isopropyl alcohol, n-propanol, tetrahydrofuran, acetone, acetonitrile or mixtures thereof to the solution at 5 to -25°C to crystallize the product; and isolating the obtained crystalline Ertapenem sodium.
The seed of the crystalline Ertapenem sodium can be prepared by the process of the present invention.
In yet another aspect of the present invention relates to a process for the preparation of crystalline Ertapenem sodium substantially free of residual solvents, which comprises washing crystalline Ertapenem sodium containing residual solvents with an anhydrous solvent, selected from acetone, methyl tert- butyl ether, methyl acetate, ethanol or mixtures thereof; and drying the product under dry nitrogen, wherein drying is carried out at temperature less than 25°C; preferably at -5 to 10°C.
The residual content of the crystalline Ertapenem sodium before washing with anhydrous solvent is about 5%(w/w), which is reduced to about 1.5%(w/w) after washing with anhydrous solvent.
In the present invention, one of the residual solvent is methyl acetate, which is classified under ICH as class-3 solvent and is regarded as less toxic and lower risk to human health. Hence, residual methyl acetate in Ertapenem sodium prepared according to the present invention is within the pharmaceutically acceptable levels.
An amorphous Ertapenem sodium used herein is prepared according to the processes known in the prior art.
The starting compounds of formulae II and III are prepared according the 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.
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-PYRROLlDINYLJ THIO]-6-[(lR)-l-HYDROXYETHYL] -4-METHYL-7-OXO-1- AZABICYCLO[3.2.0IHEPT-2-ENE-2-CARBOXYLATE
(4-Nitrophenyl)methyl (4R,5R,6S)-3-[(diphenoxyphosphinyl)oxy-6-[( 1 R)-1- 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-[( 1 R)- 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-[(l R)-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 dbout 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-[( 1 R)- 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 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) EXAMPLE S
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- HYDROXYETHYLJ-4-METHYL-7-OXO-1-AZABICYCLO [3.2.0JHEPT-2- ENE-2-CARBOXYLATE
(4-Nitrophenyl)methyl(4R,5R,6S)-3-[(diphenoxyphosphinyl)oxy-6-[(l R)- 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-[( 1 R)- 1 -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]carbonyI]- l -[[(4- nitrophenyl)methoxy]carbonyl]-3-pyrrolidinyl]thio]-6-[( 1 R)- 1 -hydroxyethyl]-4- methyl-7-oxo- l -azabicyclo[3.2.0]hept-2-ene-2-carboxylate was added to a solution of sodium di hydrogen phosphate solution (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. 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: 24 g.
Chromatographic Purity: 86.67% (by HPLC) EXAMPLE S
PROCESS TO PREPARE CRYSTALLINE ERTAPENEM SODIUM
Amorphous Ertapenem sodium (20 g) was dissolved in aqueous sodium acetate solution (2% w/w; 200 ml) at 0-5°C. Methanol (40 ml) was added to the solution and adjusted the pH to 5.0-6.0 with acetic acid. The solution was treated with activated carbon (2 g), filtered, seeded with crystalline Ertapenem Sodium (0.4 g) and added mixture of methanol and acetone (1 :3 ratio; 600 ml) to obtain crystalline Ertapenem sodium.
Yield: 10.5 g.
Chromatographic Purity: 98.33% (by HPLC). EXAMPLE-9
PROCESS TO PREPARE CRYSTALLINE ERTAPENEM SODIUM
Amorphous Ertapenem sodium (20 g) was dissolved in aqueous sodium bicarbonate solution (2.0% w/w; 200 ml) at 0-5°C. Methanol (40 ml) was added to the solution and adjusted the pH to 5.0-6.0 with acetic acid. The solution was treated with activated carbon (2 g), filtered, seeded with crystalline Ertapenem Sodium (0.4 g) and added mixture of methanol and acetone (1 :3 ratio; 600 ml) to obtain crystalline Ertapenem Sodium.
Yield: 1 1 g.
Chromatographic Purity: 98.07% (by HPLC). EXAMPLE-10
PROCESS TO PREPARE CRYSTALLINE ERTAPENEM SODIUM
Amorphous Ertapenem sodium (10 g) was dissolved in aqueous sodium bicarbonate solution (2.0% w/w 100 ml) and adjusted the pH to 5.0-6.0 with diluted acetic acid at 0-5°C. The solution was treated with activated carbon ( 1 g) at 0 - 5°C, filtered and added mixture of methanol and tetrahydrofuran (1 :3 ratio; 50 ml). The resulting solution was seeded with crystalline Ertapenem Sodium (0.2 g) and added mixture of methanol and tetrahydrofuran ( 1 :3 ratio; 250 ml) at 0 to - 20°C to obtain crystalline Ertapenem Sodium.
Yield: 6 g.
Chromatographic Purity: 98.75% (by HPLC). EXAMPLE- 11
PROCESS TO PREPARE CRYSTALLINE ERTAPENEM SODIUM
Amorphous Ertapenem sodium (10 g) was dissolved in DM water (100 ml). The solution was treated with activated carbon (1 g) at 0 - 5°C, filtered and added mixture of methanol and tetrahydrofuran ( 1 :3 ratio; 280 ml). The resulting solution was seeded with crystalline Ertapenem Sodium (0.2 g) and added mixture of methanol and tetrahydrofuran (1 :3 ratio; 120 ml) at 0 to -20°C to obtain crystalline Ertapenem Sodium.
Yield: 7 g.
Chromatographic Purity: 99.16% (by HPLC). EXAMPLE-12
PROCESS TO PREPARE CRYSTALLINE ERTAPENEM SODIUM
Amorphous Ertapenem sodium (20 g) was dissolved in DM water (200 ml) at 0 to 10°C. The solution was treated with activated carbon (2 g), filtered and added mixture of methanol and tetrahydrofuran (1 :3 ratio; 560 ml). The resulting solution was seeded with Ertapenem Sodium (0.4 g) and added mixture of methanol and tetrahydrofuran (1 :3 ratio; 240 ml) at 0 to -20°C. The solid product was filtered, washed with anhydrous acetone and dried with dry nitrogen at less than 25°C to obtain residual acetone less than 1.5% w/w.
Yield: 13.80 g
Residual solvents (by GC): Methanol: 2856 ppm; Tetrahydrofuran: 57 ppm; Acetone: 13000 ppm
Chromatographic purity (by HPLC): 98.13% EXAMPLE-13
PROCESS TO PREPARE CRYSTALLINE ERTAPENEM SODIUM
Amorphous Ertapenem sodium (25 g) was dissolved in DM water (250 ml) at 0 to 10°C. The solution was treated with activated carbon (2.5 g), filtered and added mixture of methanol and tetrahydrofuran (1 :3 ratio; 700 ml). The resulting solution was seeded with Ertapenem Sodium (0.5 g) and added mixture of methanol and tetrahydrofuran (1 :3 ratio; 300 ml) at 0 to -20°C. The solid product was filtered, washed with anhydrous methyl tert butyl ether and dried with dry nitrogen at less than 25°C to obtain title compound.
Yield: 15.75 g
Residual solvents (by GC): Methanol: Not Detected, Tetrahydrofuran: 6559 ppm and MTBE: 31 14 ppm
Chromatographic purity (by HPLC): 98.96%
EXAMPLE-14
PROCESS TO PREPARE CRYSTALLINE ERTAPENEM SODIUM
Amorphous Ertapenem sodium (50 g) was dissolved in DM water (500 ml) at 0 to 10°C. The solution was treated with activated carbon (5 g) at 0 - 5°C, filtered and added mixture of methanol and tetrahydrofuran ( 1 :3 ratio; 1400 ml). The resulting solution was seeded with Ertapenem Sodium (1.0 g) and added mixture of methanol and tetrahydrofuran ( 1 :3 ratio; 600 ml) at 0 to -20°C. The solid product was filtered, washed with anhydrous methyl acetate and dried with dry nitrogen at less than 25°C to obtain title compound.
Yield: 28.3 g
Residual solvents (by GC): Methanol: Not Detected, Tetrahydrofuran: Not Detected and Methyl acetate: 15630 ppm
Chromatographic purity (by HPLC): 98.24%.

Claims

We Claim:
1 . An improved process for the preparation of Ertapenem of formula I,
Figure imgf000020_0001
or salt thereof, which comprises:
a hydrogenating compound of formula IV,
Figure imgf000020_0002
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.
The process according to claim 1 , wherein hydrogenation catalyst is palladi 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 carboxy protecting group is selected from the group comprising of allyl, benzhydryl, p-methoxybenzyl and p-nitrobenzyl.
7. The process according to claim 1 , wherein amino protecting group is selected from the group comprising of allyloxycarbonyl, benzhydryloxycarbonyl, p- methoxybenzyloxycarbonyl and p-nitrobenzyloxycarbonyl.
8. The process according to claim 1 , wherein salt is sodium salt of Ertapenem.
9. The process according to claim 8, wherein Ertapenem sodium salt is in crystalline form or amorphous form.
10. A process for the preparation of crystalline form of Ertapenem sodium, which comprises:
a) dissolving amorphous Ertapenem sodium in DM water at -5 to 25°C to obtain aqueous solution;
b) optionally, seeding with a crystalline form of Ertapenem sodium;
c) adding water miscible solvent to the solution at -5 to 25°C to crystallize the product; and
d) isolating crystalline Ertapenem sodium.
1 1. The process according to claim 10, wherein water miscible solvent is selected from the group comprising of methanol, ethanol, isopropyl alcohol, n- propanol, tetrahydrofuran, acetone, acetonitrile and mixtures thereof.
12. The process according to claim 10, wherein Ertapenem sodium crystalline form is characterised by powder X-ray diffraction (PXRD) containing 2Θ peaks (±0.2°) at 4.38, 4.47, 5.20, 5.25, 7.35, 7.44, 8.01 , 8.19, 9.53, 9.83, 10.88, 10.98, 12.64, 12.94, 19.06 and 19.21.
13. A process for preparing Ertapenem sodium substantially free of residual solvents, which comprises:
a) washing Ertapenem sodium containing residual solvents with anhydrous solvent; and
b) drying the product under dry nitrogen.
14. The process according to claim 13, wherein Ertapenem sodium is obtained in crystalline form.
15. The process according to claim 13, wherein anhydrous solvent is selected from group comprising of acetone, methyl tert-butyl ether, methyl acetate, ethanol and mixtures thereof.
16. The process according to claim 13, wherein residual solvent content in Ertapenem sodium after drying is about 1.5%(w/w).
17. Crystalline Ertapenem sodium having HPLC chromatographic purity more than 98% and residual solvent content 1.5%(w/w) or less.
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104788453A (en) * 2014-01-16 2015-07-22 浙江九洲药业股份有限公司 One-pot preparation process of monosodium ertapenem
US10434089B2 (en) 2017-01-25 2019-10-08 The Johns Hopkins University Avibactam and carbapenems antibacterial agents
CN110698479A (en) * 2018-07-09 2020-01-17 武汉启瑞药业有限公司 Synthetic method of ertapenem monosodium salt
CN113880839A (en) * 2021-11-01 2022-01-04 石药集团中诺药业（石家庄）有限公司 Novel synthesis method of ertapenem sodium crude product
CN114105988A (en) * 2022-01-24 2022-03-01 深圳市海滨制药有限公司 Synthetic method of ertapenem sodium

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5478820A (en) * 1992-02-04 1995-12-26 Zeneca Ltd. Antibiotic compounds
US7071330B2 (en) * 2001-01-16 2006-07-04 Williams John M Process for carbapenem synthesis
US20090312539A1 (en) * 2006-11-20 2009-12-17 Orchid Chemicals & Pharmaceuticals Limited An improved process for the preparation of carbapenem antibiotic
EP2141167A1 (en) * 2008-07-04 2010-01-06 ACS DOBFAR S.p.A. Process for synthesizing carbapenem using raney nickel
EP2388261A2 (en) * 2010-05-19 2011-11-23 Savior Lifetec Corporation Improved process for the preparation of carbapenem using carbapenem intermediates and recovery of carbapenem

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5478820A (en) * 1992-02-04 1995-12-26 Zeneca Ltd. Antibiotic compounds
US7071330B2 (en) * 2001-01-16 2006-07-04 Williams John M Process for carbapenem synthesis
US20090312539A1 (en) * 2006-11-20 2009-12-17 Orchid Chemicals & Pharmaceuticals Limited An improved process for the preparation of carbapenem antibiotic
EP2141167A1 (en) * 2008-07-04 2010-01-06 ACS DOBFAR S.p.A. Process for synthesizing carbapenem using raney nickel
EP2388261A2 (en) * 2010-05-19 2011-11-23 Savior Lifetec Corporation Improved process for the preparation of carbapenem using carbapenem intermediates and recovery of carbapenem

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104788453A (en) * 2014-01-16 2015-07-22 浙江九洲药业股份有限公司 One-pot preparation process of monosodium ertapenem
CN104788453B (en) * 2014-01-16 2017-02-15 浙江九洲药业股份有限公司 One-pot preparation process of monosodium ertapenem
US10434089B2 (en) 2017-01-25 2019-10-08 The Johns Hopkins University Avibactam and carbapenems antibacterial agents
US10842783B2 (en) 2017-01-25 2020-11-24 The Johns Hopkins University Avibactam and carbapenems antibacterial agents
CN110698479A (en) * 2018-07-09 2020-01-17 武汉启瑞药业有限公司 Synthetic method of ertapenem monosodium salt
CN113880839A (en) * 2021-11-01 2022-01-04 石药集团中诺药业（石家庄）有限公司 Novel synthesis method of ertapenem sodium crude product
CN114105988A (en) * 2022-01-24 2022-03-01 深圳市海滨制药有限公司 Synthetic method of ertapenem sodium
CN114105988B (en) * 2022-01-24 2022-04-29 深圳市海滨制药有限公司 Synthetic method of ertapenem sodium
WO2023138341A1 (en) * 2022-01-24 2023-07-27 深圳市海滨制药有限公司 Synthesis method for ertapenem sodium

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