Classifications

• • 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

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• 2013
  • 2013-02-11 WO PCT/IB2013/000211 patent/WO2013121279A2/fr not_active Ceased

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