Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents

Definitions

• the present invention relates to an improved process for the preparation of crystalline ertapenem or pharmaceutically acceptable salts, or hydrates or solvates thereof. Further, the present invention relates to an improved process for the preparation of pure crystalline ertapenem sodium without isolating any intermediates such as di -protected ertapenem of formula (4) and ertapenem free base.
• the present invention provides an improved process for preparing a crystalline compound of formula (1) or pharmaceutically acceptable salts, or hydrates, or solvates thereof, comprising of following steps:
• the condensation reaction may be conducted at a temperature of about 20 °C to about -50 °C. In preferred embodiment, the condensation reaction of present invention is conducted at a temperature of about -35 °C to about -45 °C. The reaction may be stirred for a period of at least 1 hour at below 0 °C such as -35 °C to about -45 °C.
• reaction mass is diluted with suitable solvent at about -30 °C and subjected for pH adjustment to about 2 to about 3 with an acid at -20 to 0 °C.
• suitable solvent at about -30 °C
• the resultant di-protected ertapenem compound of formula (4) or its salts is extracted into organic solvent.
• the solvent layer is taken for hydrogenation in subsequent step (b).
• the acid used is selected from the group consisting of acetic acid, formic acid, propanoic acid, citric acid, phosphoric acid, sulphuric acid, hydrochloric acid or mixture thereof.
• the acid used is hydrochloric acid.
• the base used in step (b) is sodium ion source selected from the group consisting of sodium hydroxide, sodium bicarbonate, sodium carbonate, mixture of carbon dioxide and sodium hydroxide or mixture thereof.
• base used is sodium bicarbonate.
• the solvent is selected from, but is not limited to alcoholic solvents such as branched or straight chain Ci-C 4 alcohols such as methanol, ethanoi, n-propanol, isopropyl alcohol, and the like; esters like ethyl acetate, butyl acetate, etc; nitriles such as acetonitrile, propionitrile, butyronitrile, and the like; ethers such as diethyl ether, diisopropyl ether, methyl tertiary- butyl ether, methyl ethyl ether, tetrahydrofuran, dioxane, etc; dichloromethane, N,N- dimethylformamide, water or mixtures thereof.
• the solvent used is mixture of water, methanol and ethyl acetate.
• the crystalline ertapenem or its pharmaceutically acceptable salt is characterized by X-ray diffraction pattern by using Cu Ka radiation, having the wavelength 1.541 A using a Bruker X-ray difractometer D8.
• the crystalline ertapenem or its pharmaceutically acceptable salt comprises at least four characteristic peaks at diffraction angles 2-theta of 4.4, 5.2, 7.1, 7.4, 8.0, 8,6, 10,9, 11.5, 15.5, 17.1, and 19.1 ⁇ 0.2 degrees.
• the present invention provides a process for the preparation of pure crystalline ertapenem sodium, which comprises:
• the step ii) involves deprotection of compound formula (4) or its salt to provide ertapenem sodium.
• step (i) or step (a) The reaction mixture obtained in step (i) or step (a), containing (4- nitrophenyl)methyl(4R,5S,6S)-3-[[(3S,5S)-5[[(3-carboxyphenyl)-amino]carbonyl]-l-[[(4- nitrophenyl)methoxy]carbonyl]-3-pyrro
• the solvent is water or alcohols or mixtures thereof.
• the reaction mass is hydrogenated using metal catalyst, preferably palladium on carbon (wet or dry) at 0.5-10 kg/Cm 2 of hydrogen pressure at a temperature of -10 °C to 20 °C.
• the pH of the reaction mass is reduced with acid, for example, acetic acid and then filtered to remove catalyst.
• the filtrate is then washed with mixture of water and water immiscible solvent such as esters such as ethyl acetate, and then the layers are separated.
• the aqueous layer may be subjected for pH adjustment to about 6 to about 7 with a mixture of acid and alcohol, for example, acetic acid and methanol.
• the resultant reaction mass may be treated with activated carbon to remove impurities and then crystallized as per step iii).
• the step (iii) involves crystallization of ertapenem sodium from mixture of alcohol and acetic acid at -20 to 0 °C.
• the alcohol is selected from branched or straight chain C 1 -C 4 alcohols such as methanol, ethanol, isopropyl alcohol, n-propanol and the like.
• the alcohol is mixture of methanol and n-propanol.
• the temperature of crystallization is -20 to 0 °C.
• the temperature is -8 to -12 °C.
• the quantity of alcohol may range from 25 to 100 times with respect to the compound of formula (2).
• the ratio of water and alcohol used for crystallization is 10:90 to 30:70.
• the mole ratio of acetic acid for crystallization may range from 0.2 to 0.6 per mole ratio of compound of formula 2.
• the crystallization process involves dilution of the reaction solution with a mixture of one or more alcoholic solvents and acetic acid, optionally seeding with ertapenem or a pharmaceutically acceptable salt thereof, combining a mixture of methanol and n-propanol to the reaction mixture for a period of at least 30 minutes, and stirring the mixture for a period of at least 1 hour to provide crystalline ertapenem sodium.
• the process of the present invention provides ertapenem sodium from compound of formula (2) and (3) without involving isolation of diprotected ertapenem of formula (4) and ertapenem free base.
• the resultant crystalline ertapenem sodium of the present invention has purity greater than or equal to 98.8 % and residual solvent content well below the pharmaceutically acceptable level.
• the crystalline ertapenem sodium of the present invention contains less than 1% of impurity of ring opened hydrolysis product. Furthermore, the crystalline ertapenem sodium of the present invention contains less than 0.5 % or less than 0.3 % of each impurity of ProMABA, Dimer-I, Dimer-II, Dimer-III, Dimer.H 2 0-I and Dimer.H 2 0-II determined by HPLC.
• the present invention provides a process for the purification of crystalline ertapenem or its pharmaceutically acceptable salts, which comprises:
• the crude ertapenem or its pharmaceutically acceptable salt used for dissolution can be in any polymorphic form, either amorphous or crystalline forms, which is then converted to a pure crystalline polymorph form of ertapenem or its salts by using process of the present invention.
• the dissolution of the present invention is performed by the addition of ertapenem or its salts to the solution comprising solvent, sodium hydroxide and carbon dioxide, having pH of about 6 to about 8 at a temperature of below 15 °C.
• the dissolution temperature is about 0 to about 5 °C.
• the combination of 0.5 to 1 .5 mole ratio of sodium hydroxide per mole ratio of ertapenem sodium and carbon dioxide gas provides preferred basic conditions to dissolve the ertapenem sodium without initiating any degradation.
• the solvent used for the dissolution is selected from the group consisting of but is not limited to alcoholic solvents such as branched or straight chain C-.-C alcohols, such as methanol, ethanol, isopropyl alcohol, n-propanol etc.; esters like ethyl acetate, butyl acetate, etc.; ketones like acetone, methyl ethyl ketone, etc.; nitriles such as acetonitrile, propionitrile, butyronitrile, etc., ethers such as diethyl ether, diisopropyl ether, methyl tertiary-butyl ether, methyl ethyl ether, tetrahydrofuran, dioxane, etc.; water and/or mixtures thereof.
• the solvent is water or alcohols or mixture thereof.
• the resultant solution may be treated with activated carbon or Ceca carbon or norit carbon and then filtered using micron filters.
• the preferred micron filter is membrane filter, which is useful to filter heat-sensitive solution of ertapenem sodium.
• the membrane filter may be prepared by using homogenous polymers of mixed cellulosic esters (MCE), polyvinylidene fluoride (PVF; also known as PVDF), or poiytetrafluoroethyienc (PTFE) and have pore sizes ranging from 0.1 to 0.22 ⁇ .
• the present invention also involves use of the membrane filter, which comprise materials of stabilized cellulose based membrane, Gaskets with PVF or PTFE, spacer with fiber, for example, Polypropylene, and sealing compound of silicon polyolefm.
• the membrane filter is used to cut off endotoxic bacteria having molecular weight of greater than 3 kD to 10 kD to get the solution having BET less than 0.5 EU/mg.
• the resultant solution of ertapenem sodium obtained from 0.22 ⁇ filter and/or ultrafiltration contain BET (bacterial endotoxin) less than 0.5 EU/mg level or less than 0.2 EU/mg level.
• the BET of the solution is less than 0.1 EU/mg.
• the resultant reaction solution of step (b) is taken for pH adjustment to about 4 to about 6 with an acid while maintaining the temperature less than 15 °C.
• the temperature used for pH adjustment is preferably from about 5 to -15 °C.
• the acid is selected from the group, but is not limited to organic acid or mineral acid such as acetic acid, lactic acid, formic acid, citric acid, oxalic acid, uric acid, hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, methane sulphonic acid, boric acid, hydrofluoric acid, hydrobromic acid and perchloric acid, etc., or mixtures thereof.
• the acid used is hydrochloric acid or acetic acid.
• the purification process or step (b) involves use of an acid in the combination of an alcohol, for example, methanol for the adjustment of pH of about 4 or about 6, preferably 5.5 ⁇ 0.2 without degradation of the product.
• the resultant solution is further subjected for crystallization by the addition of pre-cooled alcohol followed by stirring at lower temperature ranging from -30 to 15 °C.
• the alcoholic solvent is selected from branched or straight chain C 1 -C4 alcohols such as methanol, ethanoi, n-propanoi, isopropyl alcohol, and the like.
• the present invention comprises addition of pre-cooled alcohol to the reaction solution contained at pH between 4 to about 6 at a temperature of 0 to 5 °C.
• the present invention comprises addition of pre-cooled n-propanol and methanol in portion-wise to the reaction solution contained at pH 5.5 ⁇ 0.2.
• the addition of alcohol may be carried out for a period of about 15 minutes to 1 hour or more to reduce/remove the formation of impurities by degradation of the product.
• the reaction mixture is cooled to 0 to -30 °C and then stirred for a period of at least 1 hour or more to enhance the precipitation of the solid.
• the obtained solid is isolated by using suitable techniques such as filtration by gravity, filtration under vacuum, centrifugation and the like. The filtration may be conducted in the presence of nitrogen gas or argon gas.
• the resultant wet cake may be washed with pre-cooled solvent such as absolute alcohol such as methanol or ester solvent such as methyl acetate or ketone solvent such as acetone or mixture thereof. Finally, the wet cake is dried at a temperature of about 20 to about 40 °C for a period of about 5 to 10 hours or more.
• solvent such as absolute alcohol such as methanol or ester solvent such as methyl acetate or ketone solvent such as acetone or mixture thereof.
• the wet cake is dried at a temperature of about 20 to about 40 °C for a period of about 5 to 10 hours or more.
• the ertapenem or a pharmaceutically acceptable salt thereof has purity greater than or equal to 98% by HPLC.
• the present invention provides a process for the purification of crystalline ertapenem sodium, which comprises:
• step b) adjusting the pH of the solution to about 4 to about 6 by using hydrochloric acid; c) filtering the suspension of step b) through filters to remove bacterial endotoxin to less than 0.5 EU/mg;
• step (c) adding methanol and n-propanol to the filtrate of step (c);
• step (d) stirring the reaction mixture of step (d) at least about 5 minutes
• the present invention provides a pharmaceutical composition
• a pharmaceutical composition comprising ertapenem or pharmaceutically acceptable salts thereof obtained from the present invention and one or more pharmaceutically acceptable excipients.
• the excipient(s) used for the composition is carbonate source such as carbon dioxide, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, calcium carbonate, cesium carbonate, magnesium carbonate, lithium carbonate, and a mixture thereof.
• the composition of the present invention may be prepared in presence of base which is selected from group consisting of sodium hydroxide, lithium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, magnesium hydroxide, lithium raethoxide, sodium ethoxide, potassium ethoxide, lithium tert-butoxide, sodium tert-butoxide, magnesium tert-butoxide and potassium tert-butoxide.
• the composition of the ertapenem or pharmaceutically acceptable salts thereof is useful for intravenous and intramuscular administration.
• Enol phosphate compound of formula 2 (100 g ), protected side chain of compound of formula 3 (74.95g ), tributyl phosphine (1 ml; 50% solution in ethyl acetate) and DMAP (1 .5 g) were charged into dimethyl formamide (500 ml) at 0-10 °C under nitrogen and cooled to -35 to -40 °C. DIPEA (65.14 g) was added to the reaction mixture at -35 to -40 °C in 25-45 minutes and stirred for 2-4 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (1200 ml) and hydrochloric acid (26.5mL Cone.
• Step-2 preparation of crude ertapenem sodium
• Acetic acid (20 mL) was charged into autoclave and stirred for 5-10 minutes.
• the reaction mixture was filtered through hyfio filter and washed the hyfio bed with mixture of water (300mL) and ethyl acetate (500mL) followed by ethyl acetate (500 mL) at 0-10 °C.
• the aqueous layer was separated from filtrate and diluted with methanol (380 mL) at -1 to -5 °C and adjusted the pH of the reaction mass to 6,5 ⁇ 0.2 using mixture of acetic acid: methanol ( 1 : 1).
• the reaction mixture was treated with Ceca carbon (25 g) at -1 to -5 °C and then filtered through hyflow bed. The bed was washed with mixture of methanol (400 mL) and water (40 mL), and then cooled to -2 to -5°C.
• the mixture of solvents (1650 mL «-Propanol + 120 mL methanol + 25 mL acetic acid) were added to the filtrate within 10-15 minutes and stirred for 10 - 15 minutes.
• the mixture of solvents (3300 mL w-Propanol + 1700 mL methanol) again was added to the reaction mixture within 2-3 hours and stirred with moderate RPM for 6 - 8 hours at -8 to -12 °C.
• the resultant suspension was filtered, washed with mixture of solvents ( 150 mL «-Propanol + 150 mL methanol) followed by with acetone (2X400 mL) under nitrogen atmosphere and dried at 20-30 °C for 3 - 6 hours under vacuum.
• reaction mass was filtered through hyfio bed and washed the bed with water (30 mL) and n-propanol (22.5 mL) at 0 to 5 °C.
• the reaction mass was filtered through micron filter.
• the pH of the resultant reaction mass was adjusted to 5.5 ⁇ 0.2 with mixture of HCl and methanol at 3 to -3 °C.
• the mixture of solvents (30 mL w-propanol and 75 mL methanol) was added to the reaction mass and cooled to -8 to -12°C.
• the mixture of solvents (1 12.5 mL n- Propanol + 112.5 mL methanol) again was added to the reaction mass within 90 to 120 minutes and stirred for 4 to 5 hours at -15 to -20°C.
• the reaction mass was filtered under nitrogen, washed with mixture of solvents (22.5 mL 3 ⁇ 4-Propanoi + 22.5 mL methanol) followed by with acetone at 10 - 20°C.
• the resultant solid was dried under vacuum for 5 - 10 hours at 20 - 30°C.

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Citations (15)

• 2014
  • 2014-12-10 WO PCT/IB2014/066744 patent/WO2015087245A1/en active Application Filing
  • 2014-12-10 IN IN3862MU2013 patent/IN2013MU03862A/en unknown

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