WO2009138847A2 - Procédé de préparation amélioré de céfozoprane - Google Patents

Procédé de préparation amélioré de céfozoprane Download PDF

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Publication number
WO2009138847A2
WO2009138847A2 PCT/IB2009/005564 IB2009005564W WO2009138847A2 WO 2009138847 A2 WO2009138847 A2 WO 2009138847A2 IB 2009005564 W IB2009005564 W IB 2009005564W WO 2009138847 A2 WO2009138847 A2 WO 2009138847A2
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Prior art keywords
cefozopran
hydrochloride
water
organic solvent
iii
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PCT/IB2009/005564
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WO2009138847A3 (fr
Inventor
Ramar Padmanabhan
Konda Athmaram Ramesh
Sivakumaran Sundaravadivelan
Raja Mohamed Anish Raja
Udayampalayam Palanisamy Senthilkumar
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Orchid Pharma Ltd
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Orchid Chemicals and Pharmaceuticals Ltd
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Priority to JP2011509028A priority Critical patent/JP2011520866A/ja
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Publication of WO2009138847A3 publication Critical patent/WO2009138847A3/fr
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/433—Thidiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
    • A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • 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 Cefozopran of formula (I), its hydrochloride, its hydrate and its solvate.
  • the present invention further provides novel crystalline forms of Cefozopran hydrochloride.
  • the present invention also provides an improved process for the preparation of pharmaceutical composition comprising Cefozopran.
  • Cefozopran a semisynthetic parenteral cephalosporin, against acute respiratory tract infections caused by Klebsiella pneumoniae DT-S. In the model of chronic respiratory tract infection caused by K. pneumoniae 27. The therapeutic effect of cefozopran against urinary tract infections caused by Pseudomonas aeruginosa P9. Against thigh muscle infections caused by methicillin-resistant S. aureus N133, cefozopran was the most effective agent. The potent therapeutic effect of cefozopran in those experimental infections in mice suggests that it would be effective against respiratory tract, urinary tract, and soft tissue infections caused by a variety of gram- positive and gram-negative bacteria in humans.
  • the chemical designation is 1-[[(6R 3 TR)- 7-[[(2Z)-(5-Amino-l,2,4-thiadiazol-3-yl)(methoxyimino)acetyl]amino]-2-carboxy-8-oxo- 5-thia-l-azabicyclo[4.2.0]oct-2-en-3-yl]methyl]imidazo[l,2-b]pyridazinium inner salt.
  • the marketed form of Cefozopran is FIRSTCIN ® which is a combination of Cefozopran hydrochloride with sodium carbonate and sodium chloride.
  • Cefozopran is first disclosed in US patent No. US 4,864,022, which also discloses a process for preparing Cefozopran and its hydrochloride. This patent further discloses the preparation of Cefozopran inter from 7-ACA and Cefozopran by reacting Cefozopran inter with activated aminothiadiazole.
  • Cefozopran nitrate or oxalate salt into its hydrochloride salt required resin to remove the nitrate or oxalate anion due to which the yield obtained is minimized.
  • JP patent No. 10,152,490 claims process for the preparation of Cefozopran by condensing Cefozopran inter with acid chloride of aminothiadiazole using bases like sodium hydroxide, ammonia solution, triethylamine, sodium acetate, potassium acetate, sodium carbonate, and potassium carbonate.
  • PCT publication No. 97/39002 claims a process for the preparations of Cefozopran inter involving the silylated 7-ACA and imidazo[l,2-b]pyridiazine and silylation of 7- ACA is carried out with hexamethyldisilazane in inert solvent in the presence of sulfur containing acid or an ammonium salt or Lewis acid.
  • JP patent No. 3,737,642 claims the manufacturing method of cephalosporin injections by dissolving Cefozopran hydrochloride and basic carbonate in water or ethyl alcohol solution, and freeze-drying subsequently, whose basic carbonate is sodium carbonate or sodium bicarbonate.
  • This patent involves the use of organic solvent for lyophilization which resulted in high residual solvents in the final product and it requires high purity organic solvents with known impurities at lower level leads to higher manufacturing cost.
  • secondary solvent like ethanol in the final lyophilization solution tend to operator safety concerns due to high degree of flammability or explosion potential and also have potential adverse environment effect, spoil the vacuum pump, and hence commercially not viable
  • composition of Cefozopran was prepared by dissolving Cefozopran hydrochloride with metal carbonate(s) and salt in a mixture of water and water miscible organic solvent(s) followed by removal of water miscible organic solvent by extraction with water immiscible organic solvent and isolating the product by freeze-drying or precipitation or spray-drying the obtained solution.
  • This process obviates the complexity associated with the high content of residual solvent in the final product and lyophilization using an organic solvent(s). None of the prior art suggests or even motivates the present invention.
  • the primary objective of the invention is to provide an improved process for the preparation of Cefozopran of formula (I) with good purity directly from the reaction mixture.
  • Another objective of the present invention is to provide a commercial process for direct isolation of Cefozopran
  • Yet another objective of the present invention is to provide novel Cefozopran hydrochloride hydrate or solvate and novel crystalline forms of Cefozopran hydrochloride or its hydrate.
  • the present invention provides an improved process for the preparation of Cefozopran of formula (I) and its hydrochloride salt
  • the said process comprising the steps of: i) condensing a compound of formula (II) wherein HX represents an acid; with active thioester of aminothiadiazole acetic acid of formula (III) in a two or more mixtures of water miscible organic solvent and water, in the presence of organic bases; wherein the improvement consists of use of at least two water miscible organic solvent along with water; ii) optionally adding water miscible solvents; iii) isolating Cefozopran of formula (I) by filtration; iv) optionally purifying Cefozopran; v) converting Cefozopran into its hydrochloride salt in a solvent; vi) mixing the step (v) solution with IPA; and vii) isolating Cefozopran hydrochloride IPA solvate.
  • the present invention provides novel Cefozopran hydrochloride IPA solvate, also provides a process for preparing the same.
  • the said process comprising the steps of: a) converting Cefozopran into its hydrochloride salt in a solvent; b) mixing the step (a) solution with IPA; and c) isolating Cefozopran hydrochloride IPA solvate.
  • in still another aspect of the present invention also provides an improved lyophilization process for the preparation of pharmaceutical composition comprising Cefozopran, the said process comprising the steps of: i) obtaining Cefozopran hydrochloride in a mixture of water and water miscible organic solvent(s); ii) adding sodium chloride and sodium carbonate either mixture or independently in the form of solid and/or solution; iii) washing the obtained solution in step (ii) with water immiscible organic solvent(s); iv) optionally degassing the aqueous solution; and v) lyophilizing aqueous solution of step (iii) or step (iv) to get pharmaceutical composition of Cefozopran.
  • Drawings of the Invention comprising the steps of: i) obtaining Cefozopran hydrochloride in a mixture of water and water miscible organic solvent(s); ii) adding sodium chloride and sodium carbonate either mixture or independently in the form of solid and/or solution; iii) washing the
  • Figure-1 Powder XRD pattern of crystalline form of Novel crystalline Cefozopran hydrochloride having moisture content in the range of 15-20 %.
  • Figure-2 Powder XRD pattern of crystalline form of Novel crystalline Cefozopran hydrochloride having moisture content in the range of 4-8 %, analyzed by X-Ray Powder Diffractometer of following features:
  • activated aminothiadiazole ester of formula (III) used in step (i) for condensation is selected from group comprising 2-(5- Amino-l,2,4-thiadiazol-3yl)-2(Z)-methoxyiminoacetamido-2-mercaptobenzothiazole ester, 2-mercapto-5-methyl-l,3,4-oxadiazolyl-(Z)-2-(5-Amino-l,2,4-thiadiazol-3yl)-2- methoxyimino acetate and the like; alternatively the 2-(5-Amino-l,2,4-thiadiazol-3yl)- 2(Z)-methoxyiminoacetic acid activated using its corresponding halo compound.
  • water miscible organic solvent used in step (i) for condensation is selected from acetone, tetrahydrofuara, methylethyl ketone, diglyme, butanone, sulfolane, dioxane, DMF, acetonitrile, methanol, ethanol, isopropyl alcohol and the like; preferably tetrahydrofuran, and acetone.
  • Applicant found the use of combination of two water miscible organic solvents and water for the reaction was found to yield good quality product and reaction proceeds smoothly, which constitutes one of the novelty of the present invention.
  • base used in step (i) for condensation is selected from triethylamine, diethylamine, diisopropylamine, N- ethyldiisopropylamine, TMG (1,1,3,3-Tetramethylguanidine), DBU (1,8- Diazabicyclo[5.4.0]undec-7-ene), DBN (l,5-Diazabicyclo[4.3.0]non-5-ene), sodium acetate, sodium 2-ethylhexanoic acid, sodium bicarbonate and the like, preferably N- ethyldiisopropylamine.
  • isolation of Cefozopran is done by optionally adding water miscible organic solvent or cooling the reaction mixture, preferably adding water miscible organic solvents.
  • the reaction mixture before isolating the product, was optionally subject to ultrasonic waves, which not only helps to reduce the precipitation time but also ensures the complete precipitation thereby increasing the yield of the product.
  • the said ultrasonication technology thus found to be useful in terms of reducing crystallization time and also ensures the complete precipitation and hence over all cost and batch cycle time is minimized.
  • Beta-Lactams antibiotics like cefaclor, cefadroxil, cefalonium, cefaloram, cefamandole, cefaparole, cefatriazine, cefazaflur, cefazedone, cefazolin, cefbuperazone, cefanel, cefcapene, cefclidin, cefdaloxime, cefdinir, cefditoren, cefedrolor, cefempidone, cefepime, cefetamet, cefetecol, cefetriaole, cefivtril, cefixime, cefmatilen, cefmenoxine, cefmepidium, cefmetazole, ceminox, cefodizime, cefonicid, cefoperazone, ceforanide, cefoselis, cefotaxime, cefotetan,
  • Cephaloridine cephalothin, cephapirin, cepharanthine, cephradine, aztreonam, biapenem, Doripenem, ertapenem, faropenem, Imipenem, Meropenem, Panipenem, sulopenem, sulbactam, tazobactam, piperazilin etc.
  • water miscible organic solvent used in step (ii) after condensation is selected from THF, acetone, ethyl methyl ketone, diglyme, butanone, dioxane, DMF (N, N-dimethyl formamide), acetonitrile, methanol, ethanol, isopropyl alcohol and the like, preferably acetone, or THF.
  • purification of Cefozopran is carried out by converting Cefozopran into its organic acid addition salt or its solvate, by treating Cefozopran with an organic acid and subsequent neutralization to get pure Cefozopran.
  • organic acid used for the conversion of Cefozopran into its organic acid addition salt is selected from trifluoroacetic acid, trichloroacetic acid acetic acid, formic acid, and the like, preferably trifluoroacetic acid.
  • base used for the neutralization of Cefozopran organic acid addition salt is selected from ammonia, sodium hydroxide, sodium carbonate, sodium acetate, sodium 2-ethylhexanoic acid, sodium bicarbonate triethylamine, diethylamine, diisopropylamine, N-ethyldiisopropylamine, TMG (1,1,3,3- Tetramethylguanidine), DBU (l,8-Diazabicyclo[5.4.0]undec-7-ene), DBN (1,5- Diazabicyclo[4.3.0]non-5-ene), and the like, preferably ammonia.
  • solvent used in step (v) or step (a) for the conversion of Cefozopran into its hydrochloride is selected from THF, acetone, ethyl methyl ketone, diglyme, butanone, dioxane, DMF, acetonitrile, methanol, ethanol, isopropyl alcohol water and the like or mixtures thereof, preferably mixture of acetone and water.
  • the novel crystalline Cefozopran hydrochloride as depicted in Figure -I and II are found to have better flow properties, and are thermodynamically more stable, and hence industrially more preferable.
  • the said crystal obtained by dissolving Cefozopran hydrochloride IPA solvate in water or directly from the reaction mixture.
  • the solution of Cefozopran hydrochloride in water is obtained by dissolving Cefozopran hydrochloride IPA solvate in water.
  • crystallizing Cefozopran hydrochloride is by stirring the reaction mixture or by seeding with crystalline Cefozopran hydrochloride and the like, preferably by stirring the reaction mixture.
  • isolation of crystalline Cefozopran hydrochloride or its hydrate is by filtration, decantation and the like, preferably by filtration.
  • the applicant found that the wet Cefozopran hydrochloride having PXRD as depicted in Figure-I and having moisture content in the range of 15-20 %, further drying the obtained wet Cefozopran hydrochloride having
  • the reaction mixture before isolating the product, was optionally exposure to ultrasonic waves, which allows crystallizing the product specifically thereby isolating the product with high purity and narrow particle size distribution, and reduces the time required for completion of crystallization.
  • the isolated novel crystalline Cefozopran hydrochloride has good purity and stability. Further Cefozopran buffered prepared using the novel crystalline Cefozopran hydrochloride also has good purity and stability.
  • water miscible organic solvent used in step (i) for the preparation of pharmaceutical composition of Cefozopran is selected from acetone, methanol, ethanol, THF, isopropyl alcohol and the like or mixtures thereof.
  • step (ii) for the preparation of pharmaceutical composition of Cefozopran is selected from methylene chloride, ethyl acetate, isopropyl acetate, n-butyl acetate and the like or mixtures thereof. The applicant found that the product isolated by freeze- drying the aqueous solution containing pharmaceutical products and an organic solvents have high residual solvent content in the final product and the purity of the isolated product also found to be less.
  • removing water miscible organic solvent from the aqueous solution by washing with water immiscible organic solvent before lyophlization can be extended for any pharmaceutical products, including but not limited to Betalactams antibiotics like cefaclor, cefadroxil, cefalonium, cefaloram, cefamandole, cefaparole, cefatriazine, cefazaflur, cefazedone, cefazolin, cefbuperazone, cefanel, cefcapene, cefclidin, cefdaloxime, cefdinir, cefditoren, cefedrolor, cefempidone, cefepime, cefetamet, cefetecol, cefetriaole, cefivtril, cefixime, cefmat
  • the starting material used in the present invention is prepared by utilizing the process available in the literature, or by utilizing the process given in Scheme - III.
  • the starting material of the present inversion is prepared by silylating 7-Aminocephalosporanic acid (7- ACA) using silylating agents like hexamethyldisilazane in an organic solvent preferably in dichloromethane, followed by reacting the silylated 7- ACA with solution of trimethylsilyl iodide (prepared by treating hexamethyldisilane and iodine in an organic solvent, preferably dichloromethane), the ensuing product was reacted with triethylamine and imidazo[l,2-b]pyridazine (which is prepared by utilizing the technique provided in literature or by using the process depicted in Scheme-IV or V).
  • the compound of formula II was isolated from reaction mixture by quenching into mixture of methanol and dil.HCl, followed by adjusting the pH (to ⁇ 3) of aqueous layer using triethylamine.
  • the compound of the formula II thus obtained was optionally purified by dissolving the crude compound in mixture of methanol and dil. HCl, followed by subjecting the clear solution to carbon treatment, and adjusting the pH of the aqueous layer to ⁇ 3 in the presence of EDTA and sodium dithionite, using TEA.
  • Cefozopran (20 g) was added into a mixture of purified water (80 mL) and acetone (40 mL) at 0-5°C. The pH of the reaction mixture was adjusted to ⁇ 0.5 using dil. HCl. To the clear solution was added carbon (2.0 g). The carbon was removed by filtration and washed the bed with purified water. The filtrate was slowly added into isopropyl alcohol (1000 mL). The precipitated IPA solvate of Cefozopran hydrochloride was filtered and washed with isopropyl alcohol. Drying with nitrogen afforded Cefozopran hydrochloride IPA solvate (Solvation: 0.4-0.7 moles with respect to Cefozopran hydrochloride).
  • Cefozopran (25.0 g) was stirred in a mixture of water (62.5 mL) and methanol (100 mL) at 25-35°C. To this mixture was added dil. HCl to adjust pH to 0.50-1.50 at 25- 35 0 C and treated with carbon (2.5 g). The carbon was removed by filtration and the clear filtrate was added into IPA at 25-35 0 C. The reaction mass was circulated through a set up providing ultrasonic waves with the frequency of 50 Hz. The product obtained was filtered, washed with IPA and dried under moist nitrogen followed by dry nitrogen to get Cefozopran hydrochloride (Yield: 23.0 g).
  • Method-B A solution of Cefozopran hydrochloride IPA solvate (10 g) in water (50 mL) was stirred at 25-30 0 C for a time sufficient to crystallize Cefozopran hydrochloride or its hydrate. The crystallized product was filtered, washed with water and dried to afford novel crystalline Cefozopran hydrochloride as depicted in Figure-II (moisture content in the range of 4-8 %).
  • Example 4 Preparation of pharmaceutical composition of Cefozopran with sodium carbonate and sodium chloride:
  • Method-A Cefozopran hydrochloride obtained according to example 2 (A) (5 g), sodium chloride (0.56 g) and sodium carbonate (0.96 g) were added into acetone (25 mL). To this purified water (50 mL) was added at 25-30 0 C and stirred to get clear solution. The clear solution was washed with dichloromethane (2 x 50 mL). The aqueous layer was treated with carbon and filtered through 0.2 micron filter paper. The clear solution was freeze-dried to get pharmaceutical composition of Cefozopran with pharmaceutically acceptable level of residual solvents. Residual solvent before washing: Acetone: 25.6 % Residual solvent after washing: Acetone: 0.17-0.70 %; Dichloromethane: Not detected.
  • Cefozopran hydrochloride (5 g) prepared according to example 3A, sodium chloride (0.56 g) and sodium carbonate (0.96 g) were added into ethanol (25 mL). To this purified water (50 mL) was added at 25-30 0 C and stirred to get clear solution. The clear solution was washed with dichloromethane (2 x 50 mL). The aqueous layer was treated with carbon and filtered through 0.2 micron filter paper. The clear solution was freeze-dried to get pharmaceutical composition of Cefozopran with pharmaceutically acceptable level of residual solvents.
  • Cefozopran hydrochloride 25 g was added in acetone (125 mL) and stirred to make slurry. To this slurry, water (125 mL) was added and stirred at 25-30 0 C to get clear solution. A solution of sodium carbonate (4.8 g) and sodium chloride (2.8 g) in water (62.5 mL) was slowly added to adjust pH to 7.0-9.0. The resulting solution was stirred for 15 min at 25-30 0 C. The resultant solution is washed with ethyl acetate. The aqueous layer was treated with activated carbon and the carbon was removed by filtration. This filtrate was filtered through 0.2 micron filter and freeze-dried to get Cefozopran buffered.
  • Cefozopran hydrochloride 25 g was added in acetone (125 mL) and stirred to make slurry. To this slurry, water (125 mL) was added and stirred at 25-30 0 C to get clear solution. A solution of sodium carbonate (4.8 g) and sodium chloride (2.8 g) in water (62.5 mL) was slowly added to adjust pH to 8.0-9.0. The resulting solution was stirred for 60 min at 25-30 0 C. The resultant solution is washed with dichloromethane. The aqueous layer was treated with activated carbon and the carbon was removed by filtration. This filtrate was filtered through 0.2 micron filter and freeze-dried to get Cefozopran buffered.
  • Cefozopran hydrochloride 25 g was added in acetone (125 mL) and stirred to make slurry. To this slurry, water (125 mL) was added and stirred at 25-30 0 C to get clear solution. A solution of sodium carbonate (4.8 g) and sodium chloride (2.8 g) in water (62.5 mL) was slowly added to adjust pH to 8.0-9.0. The resulting solution was stirred for 120 min at 25-30 0 C. The resultant solution is washed with ethyl acetate. The aqueous layer was treated with activated carbon and the carbon was removed by filtration. This filtrate was filtered through 0.2 micron filter and freeze-dried to get Cefozopran buffered.
  • MOPS solution was washed with ethyl acetate and added 10% Pd-C.
  • the resulted suspension was hydrogenated under hydrogen pressure.
  • the catalyst was removed by filtration.
  • the aqueous layer was washed with dichloromethane and treated with activated carbon.
  • the carbon was removed by filtration and the carbon bed was washed with water.
  • To the clear filtrate was added cold acetone and the reaction mass was circulated through a set up providing ultrasonic waves with the frequency of 50 Hz for 2-4 hrs to effect complete crystallization of Imipenem monohydrate.
  • the crystals were filtered and washed with aqueous acetone followed by acetone. Drying under vacuum afforded pure crystals of Imipenem monohydrate.

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Abstract

La présente invention concerne un procédé de préparation amélioré permettant la préparation de céfozoprane de formule (I), de son chlorhydrate, de son produit d'hydratation et de son produit de dissolution. La présente invention concerne plus particulièrement un procédé de préparation de produit de dissolution dans l'alcool isopropylique (IPA) de chlorhydrate de Céfozoprane, de nouvelles formes cristallines de chlorhydrate de Céfozoprane ou de son produit d'hydratation et un procédé amélioré permettant la préparation d'une composition pharmaceutique à base de Céfozoprane.
PCT/IB2009/005564 2008-05-14 2009-05-12 Procédé de préparation amélioré de céfozoprane Ceased WO2009138847A2 (fr)

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JP2011509028A JP2011520866A (ja) 2008-05-14 2009-05-12 セフォゾプランの改良した製造方法

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WO2011141847A1 (fr) * 2010-05-10 2011-11-17 Orchid Chemicals And Pharmaceuticals Limited Procédé amélioré pour la préparation de méropénem
CN102443017A (zh) * 2010-10-13 2012-05-09 石药集团中奇制药技术（石家庄）有限公司 一种盐酸头孢唑兰的制备方法
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CN102898445A (zh) * 2012-10-11 2013-01-30 南通康鑫药业有限公司 一种头孢唑兰的制备方法
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WO2023273210A1 (fr) * 2021-06-30 2023-01-05 海南海灵化学制药有限公司 Procédé de mesure d'impuretés de chlorhydrate de céfozopran

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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Family Cites Families (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ZA791653B (en) * 1978-04-07 1980-05-28 Glaxo Group Ltd Cephalosporin compounds
JPH0662639B2 (ja) * 1987-12-04 1994-08-17 武田薬品工業株式会社 セフェム塩酸塩の結晶
JP3012986B2 (ja) * 1989-06-12 2000-02-28 武田薬品工業株式会社 セフェム化合物及びその製造法
JP2919112B2 (ja) * 1991-05-13 1999-07-12 武田薬品工業株式会社 セファロスポリン注射剤およびその製造法
JPH06128268A (ja) * 1992-10-16 1994-05-10 Takeda Chem Ind Ltd セフェム化合物、その製造法および抗菌組成物
JPH10291993A (ja) * 1997-02-19 1998-11-04 Takeda Chem Ind Ltd セファロスポリン誘導体の結晶及びその製造法
JP3737642B2 (ja) * 1999-01-18 2006-01-18 武田薬品工業株式会社 セファロスポリン注射剤およびその製造法
CA2379650C (fr) * 1999-07-30 2008-09-02 Eisai Co., Ltd. Procede de preparation de sels d'addition acides inorganiques d'antibiotiques de base et oxalates intermediaires
JP3865698B2 (ja) * 2002-02-08 2007-01-10 武田薬品工業株式会社 医薬組成物
EP1618894B1 (fr) * 2003-04-28 2018-06-13 Takeda Pharmaceutical Company Limited Composition pour injection

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011141847A1 (fr) * 2010-05-10 2011-11-17 Orchid Chemicals And Pharmaceuticals Limited Procédé amélioré pour la préparation de méropénem
CN101921276A (zh) * 2010-09-07 2010-12-22 江苏天禾迪赛诺制药有限公司 美罗培南的结晶精制方法
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CN102443016A (zh) * 2010-10-13 2012-05-09 石药集团中奇制药技术（石家庄）有限公司 一种盐酸头孢唑兰中间体的制备方法
CN102443017B (zh) * 2010-10-13 2014-10-29 石药集团中奇制药技术（石家庄）有限公司 一种盐酸头孢唑兰的制备方法
CN102443016B (zh) * 2010-10-13 2015-01-07 石药集团中奇制药技术（石家庄）有限公司 一种盐酸头孢唑兰中间体的制备方法
CN102920666A (zh) * 2011-08-09 2013-02-13 石药集团中奇制药技术（石家庄）有限公司 一种盐酸头孢唑兰冻干粉
CN102898445A (zh) * 2012-10-11 2013-01-30 南通康鑫药业有限公司 一种头孢唑兰的制备方法
CN105153201A (zh) * 2015-08-29 2015-12-16 济南康和医药科技有限公司 一种盐酸头孢唑兰的制备方法
WO2023273210A1 (fr) * 2021-06-30 2023-01-05 海南海灵化学制药有限公司 Procédé de mesure d'impuretés de chlorhydrate de céfozopran

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