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WO2006010978A1 - Formes polymorphes de cefdinir, et son sel d'imidazole - Google Patents

Formes polymorphes de cefdinir, et son sel d'imidazole Download PDF

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Publication number
WO2006010978A1
WO2006010978A1 PCT/IB2004/002171 IB2004002171W WO2006010978A1 WO 2006010978 A1 WO2006010978 A1 WO 2006010978A1 IB 2004002171 W IB2004002171 W IB 2004002171W WO 2006010978 A1 WO2006010978 A1 WO 2006010978A1
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Prior art keywords
cephem
vinyl
amino
thiazolyl
carboxylic acid
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Ceased
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PCT/IB2004/002171
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English (en)
Inventor
Siddiqui Mohammed Jaweed Mukarram
Rashid Abdul Rehman Khan
Avinash Seshrao Mane
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Wockhardt Ltd
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Wockhardt Ltd
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Priority to PCT/IB2004/002171 priority Critical patent/WO2006010978A1/fr
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Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic 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; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring

Definitions

  • the present invention relates to a novel crystalline form of ,yy «-7-[2-(2-aminothiazolyl)- 2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid (Cefdinir) - imidazole salt having Formula (I)
  • Cefdinir-imidazole salt provides an improved process for isolation of pure, crystalline and amorphous Cefdinir.
  • An efficient process for isolation of Cefdinir in more than 99 % HPLC purity is also discussed herein.
  • Polymorphic crystalline Forms C & D and an amorphous form, their respective preparation methods and characteristics based on specific Infra Red and X-ray powder diffraction values are also discussed in this invention.
  • Cefdinir is chemically known as _ «yn-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino- acetamido]-3-vinyl-3-cephem-4-carboxylic acid. This molecule was disclosed first time in U.S. Patent No. 4,559,334. It is a third generation Cephalosporin antibiotic and has broader antibacterial spectrum over the general gram positive and gram negative bacteria than other antibiotics for oral administration. It has been reported that Cefdinir has an excellent antibacterial activity against Staphylococci and Sreptococci. Cefdinir preferably is used in form of monohydrate as antibiotic discussed in J. Antibiotics, Vol. XLI, No. 6, 829 (1988) by Y. Inamoto, et al.
  • U.S. Patent No. 4,559,334 discloses a manufacturing process of Cefdinir.
  • the process comprises the reaction of 7-amino-3-vinyl-3-cephem-4-carboxylic acid ester with haloacetyloxyacetic acid followed by nitrosation to produce the amino protected ester derivative of Cefdinir. Amino function was made free by treating the intermediate product with thiourea followed by hydrolysis to yield Cefdinir.
  • the patent also discloses Cefdinir sodium salt and ester derivatives of Cefdinir.
  • Cefdinir was isolated by chromatographic purification on nonionic adsorption resin followed by pH adjustment to 2.0 with 10 % hydrochloric acid while its sodium salt was isolated by chromatographic purification followed by lyophilization.
  • Cefdinir may be obtained in impure form according to the known production processes such as disclosed in U.S. Patents 4,559,334; 4,870,168; 6,093,814, WO 92/7840, WO 01/79211, JP 2/000790, JP 4/173781 and JP 1/238587. Since, Cefdinir is synthesized through a complicated reaction consisting of 4 steps from the expensive 7-amino-3-vinyl-3- cephem-4-carboxylic acid derivative impurities increases due to formation of side products or degradation of the molecule and also increases the cost of its production.
  • PCT application No. WO 98/452299 and U.S. Patent No. 6,350,869 disclose processes for production of crystalline 7-(Z)-[2-(2-aminothiazolyl-4-yl)-2-hydroxyimino- acetamido]-3-vinyl-3-cephem-4-carboxylic acid / dicyclohexylammonium salt having formula
  • Cefdinir is unstable under basic conditions described in J. o Pharmaceutical Sciences Vol. 85, No. 9, 976 (1996) and degrades heavily in presence of amines, e.g., terf-octylamine under similar conditions.
  • the yield of Cefdinir dicyclohexylamine salt isolated from crude Cefdinir is not reported in the above reference.
  • the Cefdinir purified by making dicyclohexyl amine salt is isolated in lesser yield due to above discussed factor.
  • the '082 patent application describes a new crystalline form of Cefdinir obtained between a temperature between about O 0 C to about +6 0 C from a dilute aqueous solution of Cefdinir in the presence of at least one organic solvent, in a total percentage (v/v on the aqueous solution) not exceeding 10 % and at a pH between about 1.5 to about 3.0.
  • the X-ray diffraction spectrum of the crystalline Cefdinir obtained in the '082 patent application showed specific d-space values (in angstrom) at about 15.24, 11.30, 10.90, 7.51, 5.66, 5.48, 4.91, 4.76, 4.55, 4.23, 4.17, 3.99, 3.74, 3.64, 3.53, 3.46, 3.39, 3.26, 3.17, 3.08, 2.96, 2.89, 2.82, 2.81, 2.63, 2.57, 2.54, 2.39, 2.31, 1.99 and 1.97.
  • the present invention is directed to a new process for the preparation of highly pure crystalline _tyn-7-[2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4- carboxylic acid (Cefdinir), which has potential applications as anti-microbial agent.
  • the invention is directed to a crystalline Cefdinir-imidazole salt and its manufacturing process from crude Cefdinir having chemical Formula (II)
  • the Cefdinir- imidazole salt is prepared by reacting crude Cefdinir with imidazole in a mixture of acetone and water from about 25 0 C to about 3O 0 C.
  • the same salt is produced in a mixture of acetone and methanol by stirring at about 25 0 C to about 30° C.
  • the present invention is directed to a process for the preparation of crystalline Cefdinir Form C by dissolving Cedinir-imidazole salt in aqueous ethyl acetate and adjusting the pH about 2.5 by sulfuric acid and filtrating the crystals.
  • the present invention provides a process for the preparation of crystalline Cefdinir Form D by dissolving Cefdinir-imidazole salt in water at about 55 0 C followed by adjusting the pH at 2.5 by addition of sulfuric acid and filtering the crystals.
  • the invention is directed to a process for the preparation of amorphous Cefdinir by dissolving Cedinir-imidazole salt in formic acid and pouring the solution slowly into aqueous methanol.
  • Cefdinir-imidazole salt, crystalline Forms C & D and amorphous Cefdinir prepared in the present invention are characterized based on specific Infra Red and X-Ray Powder Diffraction peaks.
  • Figure 1 is an Infra Red Spectrum of crystalline ,yyn-7-[2-(2-amino-4-thiazolyl)-2- hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid - imidazole salt.
  • Figure 2 is an X-Ray Diffraction Pattern (XRD) of crystalline S3>/z-7-[2-(2-amino-4- thiazolyl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid - imidazole salt.
  • XRD X-Ray Diffraction Pattern
  • Figure 3 is an Infra Red Spectrum of crystalline 5yn-7-[2-(2-amino-4-thiazolyl)-2- hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid Form C.
  • Figure 4 is an X-Ray Diffraction Pattern (XRD) of crystalline 5yn-7-[2-(2-amino-4- thiazolyl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid Form C.
  • XRD X-Ray Diffraction Pattern
  • Figure 5 is an Infra Red Spectrum of crystalline j)w-7-[2-(2-ammo-4-thiazolyl)-2- hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid Form D.
  • Figure 6 is an X-Ray Diffraction Pattern (XRD) of crystalline 5y «-7-[2-(2-amino-4- thiazolyl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid Form D.
  • XRD X-Ray Diffraction Pattern
  • Figure 7 is an Infra Red Spectrum of amorphous yyn-7-[2-(2-amino-4-thiazolyl)-2- hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid.
  • Figure 8 is an X-Ray Diffraction Pattern (XRD) of amorphous yyn-7-[2-(2-amino-4- thiazolyl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid.
  • XRD X-Ray Diffraction Pattern
  • the present invention relates to a process for the manufacture and efficient isolation process of 5yn-7-[2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4- carboxylic acid (Cefdinir) by making its imidazole salt and its subsequent hydrolysis in acidic medium.
  • the preparatory processes of polymorphic Forms C & D and amorphous Cefdinir are also disclosed in aqueous and organic solvents or mixtures thereof.
  • the present invention is directed to a manufacturing process of -ryn-7-[2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4- carboxylic acid.
  • the schematic presentation of synthetic process of 5yn-7-[2-(2-amino-4- thiazolyl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid Formula (II) is shown in Scheme I:
  • impure Cefdinir may be purified by converting Cefdinir into a crystalline salt of Cefdinir with imidazole.
  • Cefdinir imidazole salt may be conveniently used to produce highly pure Cefdinir.
  • Cefdinir imidazole salt of Formula I is a very useful intermediate in obtaining different new forms of Cefdinir, e.g.
  • Benzhydril-7-amino-3-vinyl-3- cephem-4-carboxylate hydrochloride (IV) is reacted with mixed anhydride of 2-(2- tritylaminothiazol-4-yl)-2-(syn)trityloxyimino acetic acid (III) obtained by reaction with methanesulfonyl chloride in dichloromethane to give benzhydril-7-[2(2-tritylaminothiazol-4- yl)-2-(syn)trityloxyimino acetamido]-3-vinyl-3-cephem-4-carboxylate (V) in 80% yield using usual extraction procedure.
  • the reagents used to prepare mixed anhydride of Formula III compound other than methanesulfonyl chloride may be p-toluene sulfonyl chloride, pivaloyl chloride, ethylchloro-formate, isobutyl chloroformate or a complex obtained from dimethylformamide and phosphorous oxychloride, sulfonyl chloride, thionyl chloride or oxalyl chloride in presence of organic base, e.g. triethylamine and tributylamine etc.
  • Crystalline compound of Formula V is converted to crude Cefdinir in a single step using 85 to 95 % aqueous formic acid, preferably 90% aqueous formic acid from about 10 0 C to about 5O 0 C, preferably about 25° to about 35 0 C.
  • Impure Cefdinir is obtained by concentrating the mixture under vacuum followed by diluting with organic solvent, e.g., acetone, ethyl acetate or di-isopropyl ether etc.
  • Cefdinir in the free form or in the form of a solvate such as hydrate, e.g., monohydrate or in pure form may be obtained from compound of Formula I by dissolving it in water and acidifying the solution with dilute acid to pH from 2.0 to 3.0 preferably between about 2.4 to about 2.8.
  • Precipitated Cefdinir is isolated by conventional filtration or centrifugation techniques.
  • imidazole salt of 5)>rt-7-[2-(2-amino-4-thiazolyl)— 2- hydroxy-iminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid is obtained by suspending crude yyn-7-[2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4- carboxylic acid in suitable polar solvent.
  • suitable polar solvents include N, N- dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, tetrahydrofuran, alcohols or acetone etc. or combination with water or mixtures of solvents.
  • suitable solvents include aqueous alcohols, e.g., methanol, ethanol, isopropanol or butanol etc.
  • the preferable ratio of solvent may be methanol or acetone or in combination with water in various ratios, e.g., about 5 : 1, 10 : 1, 20 : 1, 50 : 1, or 100 : l.
  • This reaction is typically undertaken from about 1O 0 C to about 5O 0 C and more preferably between 15 0 C to 35 0 C.
  • Reaction time are typically, between about 1 and about 6 hours, preferably being between about 2 to about 4 hours.
  • the slurry thus obtained is cooled between about O 0 C to about 25 0 C.
  • polar organic solvent or mixtures of organic solvents or aqueous organic solvents.
  • Suitable polar solvents include, aliphatic esters, more preferably ethyl acetate at a temperature from about 25 0 C to about 37 0 C.
  • the organic solvent is preferably taken less than 20 % in water (v/v). pH of the reaction mixture is kept from about 1.0 to about 5.0, more preferably from about 2.0 to about 3.0.
  • Infra Red spectrum of 5yn-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-3-vinyl-3-cephem-4-carboxylic acid Form C include peaks at about 3315, 2984, 2361, 1760, 1666, 1613, 1541, 1426, 1353, 1301, 1190, 1136, 1045, 1013, 911, 814, 791, 761, 630 and 570 cm 1 ( Figure 3).
  • Crystalline Form D of Cefdinir is obtained by dissolving 5yn-7-[2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamido]- 3-vinyl-3-cephem-4- carboxylic acid-imidazole salt in deionized water between about 30°C to 100 0 C temperature followed by cooling about below 2O 0 C.
  • the preferable pH of the reaction mixture is adjusted between about 2 to about 5.0 more particularly between about 2 to 3.0 for precipitating the title compound.
  • the preferable volume ratio of water in Cefdinir- imidazole salt is between about 20 to 40 times, more particularly about 30 times (v/w).
  • the preferable acid used for pH adjustment is sulfuric acid.
  • Form D X-Ray Powder Diffraction (2 theta) pattern of .yyn-7-[2-(2-amino-4- thiazolyl)-2-hydroxyimino-acetamido]-3-vinyl-3-cephem-4-carboxylic acid Form D is characterized that include peaks at about 8.40, 10.58, 10.70, 10.94, 11.64, 11.74, 11.68, 14.00, 14.22, 14.90, 15.04, 15.24, 15.52, 18.18, 18.76, 19.16, 21.12, 21.26, 21.42, 21.60, 21.90, 22.30, 22.42, 22.66, 23.70, 23.04, 23.94, 24.22, 24.44, 24.52, 24.72, 25.10, 25.36, 25.68, 25.84, 25.98, 26.12, 26.40, 26.65, 27.06, 27.380, 27.520, 27.760, 28.14, 28.54, 28.66, 28.940, 32
  • amorphous ,yy «-7-[2-(2-amino-4-thiazolyl)-2- hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid is obtained by dissolving syn- 7-[2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamido]- 3-vinyl-3-cephem-4-carboxylic acid- imidazole salt in organic acid, preferably formic acid or acetic acid.
  • the ratio of Cefdinir -imidazole salt to formic acid is about 1 to 5 times (w/v) preferably 2 times.
  • the acid soluble Cefdinir-imidazole salt is added slowly to the aqueous alcohol between about - 2O 0 C to -5°C.
  • the volume ratio of alcohol is preferably below 20 % in water.
  • Infra Red spectrum of amorphous jy/z-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-3-vinyl- 3-cephem-4-carboxylic acid is characterized by the following peaks at about 3306, 2361, 1765, 1634, 1533, 1352, 1167, 1056, 1013, 917, 855, 729, 622, 568 and 490 cm 1 ( Figure 7).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Cephalosporin Compounds (AREA)

Abstract

La présente invention a trait à un nouveau sel cristallin d'imidazole et des formes polymorphes C, D de Syn-7-[2-(2-amino-4-thiazolyl)-hydroxyiminoacetamido]-3-vinyl-3-cephem-4 d'acide carboxylique et une forme amorphe de Syn-7-[2-(2-amino-4-thiazolyl)-hydroxyiminoacetamido]-3-vinyl-3-cephem-4 d'acide carboxylique.
PCT/IB2004/002171 2004-06-30 2004-06-30 Formes polymorphes de cefdinir, et son sel d'imidazole Ceased WO2006010978A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7244842B2 (en) * 2002-11-15 2007-07-17 Orchid Chemicals & Pharmaceuticals Ltd. Amorphous hydrate of a cephalosporin antibiotic
US7250508B2 (en) 2002-08-13 2007-07-31 Sandoz Ag Cefdinir intermediate
US7307072B2 (en) * 2004-11-30 2007-12-11 Astellas Pharma Inc. Oral pharmaceutical suspension of Cefdinir crystal
CN104447794A (zh) * 2014-11-18 2015-03-25 成都医路康医学技术服务有限公司 一种头孢地尼的制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6093814A (en) * 1995-12-27 2000-07-25 Hanmi Pharmaceutical Co., Ltd. Process for preparation of cefdinir
US6294668B1 (en) * 1996-11-06 2001-09-25 Hoffman-La Roche Inc. Vinylpyrrolidinone cephalosporin derivatives
US6350869B1 (en) * 1997-04-04 2002-02-26 Biochemie Gesellschaft M.B.H. Crystalline amine salt of cefdinir

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6093814A (en) * 1995-12-27 2000-07-25 Hanmi Pharmaceutical Co., Ltd. Process for preparation of cefdinir
US6294668B1 (en) * 1996-11-06 2001-09-25 Hoffman-La Roche Inc. Vinylpyrrolidinone cephalosporin derivatives
US6350869B1 (en) * 1997-04-04 2002-02-26 Biochemie Gesellschaft M.B.H. Crystalline amine salt of cefdinir

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7250508B2 (en) 2002-08-13 2007-07-31 Sandoz Ag Cefdinir intermediate
US7825241B2 (en) 2002-08-13 2010-11-02 Sandoz Ag Cefdinir intermediate
US7244842B2 (en) * 2002-11-15 2007-07-17 Orchid Chemicals & Pharmaceuticals Ltd. Amorphous hydrate of a cephalosporin antibiotic
US7307072B2 (en) * 2004-11-30 2007-12-11 Astellas Pharma Inc. Oral pharmaceutical suspension of Cefdinir crystal
US7351419B2 (en) 2004-11-30 2008-04-01 Astellas Pharma Inc. Oral pharmaceutical suspension of Cefdinir crystal
CN104447794A (zh) * 2014-11-18 2015-03-25 成都医路康医学技术服务有限公司 一种头孢地尼的制备方法

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