WO2004083217A1 - Procede ameliore de preparation de cefoxitine - Google Patents

Procede ameliore de preparation de cefoxitine Download PDF

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Publication number
WO2004083217A1
WO2004083217A1 PCT/IB2003/006239 IB0306239W WO2004083217A1 WO 2004083217 A1 WO2004083217 A1 WO 2004083217A1 IB 0306239 W IB0306239 W IB 0306239W WO 2004083217 A1 WO2004083217 A1 WO 2004083217A1
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WO
WIPO (PCT)
Prior art keywords
formula
sodium
cefoxitin
solvent
iii
Prior art date
Application number
PCT/IB2003/006239
Other languages
English (en)
Inventor
Pandurang Balwant Deshpande
Bhausaheb Pandharin Khadangale
Original Assignee
Orchid Chemicals & Pharmaceuticals Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Orchid Chemicals & Pharmaceuticals Ltd filed Critical Orchid Chemicals & Pharmaceuticals Ltd
Priority to US10/548,888 priority Critical patent/US7662955B2/en
Priority to AU2003294161A priority patent/AU2003294161A1/en
Publication of WO2004083217A1 publication Critical patent/WO2004083217A1/fr

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Classifications

    • 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 an improved process for the preparation of cefoxitin of formula (I).
  • US patent 4,210,750 and 4,292,750 disclose a process for the preparation cefoxitin, which involve the usage of an isocyanate wherein the labile substituent is hydrocarbyl or substituted hydrocarbyl group.
  • the main objective of the present invention is to provide a process for preparation of cefoxitin of the formula (I).
  • Another objective of the present invention is to provide novel intermediates of formulae (III) and (IN) their use in the preparation of cefoxitin of the formula (I).
  • Yet another objective of the present invention is to provide the process for the preparation of cefoxitin, which is easy to implement on commercial scales.
  • Another objective of the present invention is to provide novel intermediates of formula (III) & (IV) for the preparation of cefoxitin.
  • Still another objective of the present invention is to provide a high-yielding method of producing cefoxitin of the formula (I).
  • the present invention provides an improved process for the preparation of cefoxitin of the formula (I),
  • the said process comprising the steps of: (i) treating the compound of formula (II) with a halogenating agent in an organic solvent, followed by treatment with alkali/alkaline earth metal methoxides at a temperature in the range of -100°C to 0°C, isolating the product formed as an organic amine salt of the formula (III), where M represents an organic counter ion (ii) treating the salt of formula (III) with a base in the presence of solvent at a temperature in the range of -75 to 10°C, isolating the product formed as an organic amine salt of the formula (IN), where M + represents an organic counter ion, (iii) carbamoylating the compound of formula (IV) with isocyanate of formula (V) wherein R is a labile group in the presence of a solvent at a temperature in the range of -60°C to 10°C, and isolating to get cefoxitin of the formula (I), and
  • cefoxitin if required converting cefoxitin into cefoxitin sodium using source of sodium ion in the presence of solvent at a temperature in the range of -60°C to 0°C.
  • the synthesis of cefoxitin of the formula (I) is as shown in Scheme-I:
  • the halogenating agent used in step (i) is selected form t-butoxy chloride, N-chlorosuccinimide, N- bromosuccinimide, bromine or chlorine.
  • the organic solvent used in step (i) is selected from dichloromethane, methanol, chloroform, THF or ethylene chloride and the like or mixtures thereof.
  • the organic amine used in step (i) is selected from diethylamine, methylethylamine, triethylamine, cyclohexylamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, 1,8- diazabicyclo(5.4.0)undec-7-ene (DBU), l,5-diazabicyclo(4.3.0)non-5-ene, N,N'- diphenylethylenediamine, l,4-diazabicyclo(2.2.2)octane, N,N- diisopropylethylamine, N,N-diisopropylamine, octylamine, and the like, more particularly cyclohexyl
  • the alkali/alkaline earth metal methoxides employed in step (i) is selected from lithium methoxide, sodium methoxide, magnesium methoxide, and the like.
  • the solvent employed in step (ii) is selected from methanol, acetone, water, THF, ethyl acetate and the like or mixtures thereof; and the base employed in step (ii) is selected from sodium hydroxide, potassium hydroxide and the like, more particularly sodium hydroxide.
  • the organic amine used in step (ii) is selected from cyclohexylamine, dicyclohexylamine, N,N'- dibenzylethylenediamine, l,8-diazabicyclo(5.4.0)undec-7-ene (DBU), 1,5- diazabicyclo(4.3.0)non-5-ene, N,N' -diphenylethylenediamine, 1 ,4- diazabicyclo(2.2.2)octane, N,N-diisopropylethylamine, N,N-diisopropylamine, octylamine, more particularly benzathine salt (N,N'-dibenzylethylenediamine).
  • the solvent employed in step (iii) is selected from THF, methanol, dichloromethane, acetone, ethyl acetate, methyl acetate or mixtures thereof.
  • the labile group represented by R in step (iii) is selected from chlorosulphonyl, mono, di or trichloroacetyl, bromosulphonyl, trichloroethoxycarbonyl, trimethylsilyl or chlorobenzene sulphonyl group.
  • the starting material of formula (II) is prepared according to the procedures available in the prior art.
  • the sodium ion source used in step (iv) is such as sodium 2-ethyl hexonate, sodium acetate, sodium lactate and the like.
  • the solvent used in used in step (iv) is selected from methanol, acetone, THF, ethyl acetate, acetonitrle, isobutyl methyl ketone, ethyl methyl ketone, water and the like or mixtures thereof more particularly, acetone/methanol.
  • cefoxitin sodium may be washed with solvents like methanol, acetone, IPE, ethyl acetate, hexane, toluene and the like or mixtures thereof.
  • Step i Preparation of 7-oc-methoxy-7-(2-thienyl)acetamidocephalosporanic acid cyclohexy ⁇ amine salt
  • Step ii Preparation of 3-hydroxymethyl-7-oc-methoxy-7-[(2-thienyl) acetamido]-3-cephem-4-carboxylic acid N,N'-bis(phenylmethyl)-l,2- ethanediamine salt
  • step (ii) 7-oc-methoxy cephalothin (100 gm) obtained from step (ii) was added at 1 °C and cooled to -45 °C.
  • sodium hydroxide solution 28 gm in 167 ml water
  • pH was adjusted to 7.0 using aqueous acetic acid at -45°C.
  • the temperature of the reaction mass was raised to 28°C and distilled of approximately 400 ml reaction mass.
  • Step iii Preparation of 7-oc-methoxy-7-[(2-thienyl)acetamido]-3- caramoyloxymethyl-3-cephem-4-carboxylic acid
  • decarbomoyl cefoxitin benzathine salt 50 gm obtained from step (iii) was added, and cooled to -55°C, followed by slow addition of precooled solution of chloro sulphonyl isocynate (35.0 gm) in THF (50 ml) at -55 °C. Reaction mass was stirred till completion of the reaction. After completion of the reaction, the reaction mass was added into cold DM water and stirred for 2 hours.
  • reaction mass was adjusted to 6.0 with sodium carbonate solution (83 ml) and degassed for 30 minutes. Acetic acid was added to adjust the pH to 5.4-5.6, and activated carbon (3.5 gm) was added and stirred for 10 minutes. Carbon was filtered and washed the bed with water. To the filtrate ethyl acetate (9 ml) was added and pH of filtrate adjusted to 2.0 with 1:1 HC1 (14 ml). The reaction mass cooled to 10 °C, the solid obtained was filtered, washed with water, and dried to yield title compound in pure form.

Abstract

L'invention concerne un procédé amélioré de préparation de céfoxitine ayant la formule (I).
PCT/IB2003/006239 2003-03-20 2003-12-31 Procede ameliore de preparation de cefoxitine WO2004083217A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US10/548,888 US7662955B2 (en) 2003-03-20 2003-12-31 Process for the preparation of cefoxitin
AU2003294161A AU2003294161A1 (en) 2003-03-20 2003-12-31 An improved process for the preparation of cefoxitin

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN236/MAS/2003 2003-03-20
IN236CH2003 2003-03-20

Publications (1)

Publication Number Publication Date
WO2004083217A1 true WO2004083217A1 (fr) 2004-09-30

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2003/006239 WO2004083217A1 (fr) 2003-03-20 2003-12-31 Procede ameliore de preparation de cefoxitine

Country Status (1)

Country Link
WO (1) WO2004083217A1 (fr)

Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1748049A2 (fr) * 2005-07-27 2007-01-31 ACS DOBFAR S.p.A. Procédé de préparation de Céfoxitine
EP2048240A2 (fr) 2007-10-09 2009-04-15 ACS DOBFAR S.p.A. Procédé de production de 7-méthoxy-3-désacétylcéfalotin
CN101941983A (zh) * 2010-09-25 2011-01-12 海南天煌制药有限公司 一种高纯度头孢西丁钠的制备方法
CN101607967B (zh) * 2009-07-23 2011-06-15 河北九派制药有限公司 头孢西丁酸的制备方法
CN102358744A (zh) * 2011-09-02 2012-02-22 山东罗欣药业股份有限公司 一种头孢西丁钠结晶化合物及其组合物粉针
CN102399234A (zh) * 2011-12-06 2012-04-04 苏州中联化学制药有限公司 头孢西丁钠的制备方法
CN102633819A (zh) * 2012-04-24 2012-08-15 齐鲁安替（临邑）制药有限公司 一种头孢西丁的制备方法
CN102942577A (zh) * 2012-12-04 2013-02-27 罗诚 一种含有头孢西丁钠化合物的药物组合物
CN103012437A (zh) * 2012-12-04 2013-04-03 山东鑫泉医药有限公司 抗菌药物头孢西丁酸的制备方法
CN103304582A (zh) * 2013-06-28 2013-09-18 四川省惠达药业有限公司 一种头孢西丁钠的化合物、其制备方法及其药物组合物
CN103450225A (zh) * 2013-08-22 2013-12-18 海南葫芦娃制药有限公司 头孢西丁钠的制备方法
CN103910748A (zh) * 2014-04-26 2014-07-09 济南康和医药科技有限公司 替莫西林钠的制备方法
CN104072521A (zh) * 2014-06-27 2014-10-01 广东省石油化工研究院 一种头孢西丁酸的制备方法
CN104230956A (zh) * 2012-04-24 2014-12-24 齐鲁安替（临邑）制药有限公司 一种头孢西丁的制备方法
CN104402908A (zh) * 2014-10-23 2015-03-11 胡梨芳 头孢西丁钠化合物实体及其组合物和用途
CN104622695A (zh) * 2015-03-10 2015-05-20 华北制药河北华民药业有限责任公司 一种注射用头孢西丁钠粉针制剂
CN109096310A (zh) * 2017-06-20 2018-12-28 梁怡 一种1/4水头孢西丁钠化合物
CN109651403A (zh) * 2018-12-29 2019-04-19 上海上药新亚药业有限公司 一种头孢西丁钠的合成方法
CN110204556A (zh) * 2019-07-16 2019-09-06 重庆医药高等专科学校 （rs）-甲氧基头孢西丁的制备方法
CN110396105A (zh) * 2018-09-10 2019-11-01 广东金城金素制药有限公司 美弗先头孢西丁钠药物制剂在胃肠道手术预防感染应用
CN110396102A (zh) * 2019-01-15 2019-11-01 广东金城金素制药有限公司 头孢西丁钠药物制剂在经阴道子宫切除、腹腔子宫切除、剖腹（宫）产术前预防感染应用
CN111217836A (zh) * 2020-03-20 2020-06-02 侯二美 一种头孢西丁的制备方法
CN113583024A (zh) * 2021-08-30 2021-11-02 浙江国邦药业有限公司 一种头孢西丁钠关键中间体的合成方法

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GB1350772A (en) * 1971-01-27 1974-04-24 Merck & Co Inc Antibiotics and processes for their production
US3843641A (en) * 1971-11-29 1974-10-22 Merck & Co Inc Process for preparing penicillin and cephalosporin compounds
US3962224A (en) * 1972-10-10 1976-06-08 Merck & Co., Inc. Cephalosporin compounds
US4210750A (en) * 1972-07-27 1980-07-01 Merck & Co., Inc. Process for the preparation of 3-carbamoyl cephalosporins using isocyanates
US4297488A (en) * 1970-06-16 1981-10-27 Merck & Co., Inc. 7-α-Methoxy cephalosporins
EP0204517A2 (fr) * 1985-05-30 1986-12-10 Shionogi & Co., Ltd. Composés hydroxyméthylcéphem et leur préparation

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US4297488A (en) * 1970-06-16 1981-10-27 Merck & Co., Inc. 7-α-Methoxy cephalosporins
GB1350772A (en) * 1971-01-27 1974-04-24 Merck & Co Inc Antibiotics and processes for their production
US3843641A (en) * 1971-11-29 1974-10-22 Merck & Co Inc Process for preparing penicillin and cephalosporin compounds
US4210750A (en) * 1972-07-27 1980-07-01 Merck & Co., Inc. Process for the preparation of 3-carbamoyl cephalosporins using isocyanates
US3962224A (en) * 1972-10-10 1976-06-08 Merck & Co., Inc. Cephalosporin compounds
EP0204517A2 (fr) * 1985-05-30 1986-12-10 Shionogi & Co., Ltd. Composés hydroxyméthylcéphem et leur préparation

Cited By (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101266018B1 (ko) 2005-07-27 2013-05-21 에이씨에스 도브파 에스. 피. 에이. 나트륨 세폭시틴의 제조방법
EP1748049A3 (fr) * 2005-07-27 2007-06-06 ACS DOBFAR S.p.A. Procédé de préparation de Céfoxitine
US7605256B2 (en) 2005-07-27 2009-10-20 Acs Dobfar S.P.A. Process for preparing sodium cefoxitin
EP1748049A2 (fr) * 2005-07-27 2007-01-31 ACS DOBFAR S.p.A. Procédé de préparation de Céfoxitine
EP2048240A2 (fr) 2007-10-09 2009-04-15 ACS DOBFAR S.p.A. Procédé de production de 7-méthoxy-3-désacétylcéfalotin
CN101607967B (zh) * 2009-07-23 2011-06-15 河北九派制药有限公司 头孢西丁酸的制备方法
CN101941983A (zh) * 2010-09-25 2011-01-12 海南天煌制药有限公司 一种高纯度头孢西丁钠的制备方法
CN101941983B (zh) * 2010-09-25 2012-07-25 海南天煌制药有限公司 一种高纯度头孢西丁钠的制备方法
CN102358744A (zh) * 2011-09-02 2012-02-22 山东罗欣药业股份有限公司 一种头孢西丁钠结晶化合物及其组合物粉针
CN102399234A (zh) * 2011-12-06 2012-04-04 苏州中联化学制药有限公司 头孢西丁钠的制备方法
CN102633819A (zh) * 2012-04-24 2012-08-15 齐鲁安替（临邑）制药有限公司 一种头孢西丁的制备方法
CN104230956A (zh) * 2012-04-24 2014-12-24 齐鲁安替（临邑）制药有限公司 一种头孢西丁的制备方法
CN102942577A (zh) * 2012-12-04 2013-02-27 罗诚 一种含有头孢西丁钠化合物的药物组合物
CN103012437A (zh) * 2012-12-04 2013-04-03 山东鑫泉医药有限公司 抗菌药物头孢西丁酸的制备方法
CN103012437B (zh) * 2012-12-04 2015-08-05 山东鑫泉医药有限公司 抗菌药物头孢西丁酸的制备方法
CN103304582A (zh) * 2013-06-28 2013-09-18 四川省惠达药业有限公司 一种头孢西丁钠的化合物、其制备方法及其药物组合物
CN103304582B (zh) * 2013-06-28 2015-02-11 四川省惠达药业有限公司 一种头孢西丁钠的化合物、其制备方法及其药物组合物
CN103450225A (zh) * 2013-08-22 2013-12-18 海南葫芦娃制药有限公司 头孢西丁钠的制备方法
CN103910748A (zh) * 2014-04-26 2014-07-09 济南康和医药科技有限公司 替莫西林钠的制备方法
CN104072521A (zh) * 2014-06-27 2014-10-01 广东省石油化工研究院 一种头孢西丁酸的制备方法
CN104402908A (zh) * 2014-10-23 2015-03-11 胡梨芳 头孢西丁钠化合物实体及其组合物和用途
CN104622695A (zh) * 2015-03-10 2015-05-20 华北制药河北华民药业有限责任公司 一种注射用头孢西丁钠粉针制剂
CN104622695B (zh) * 2015-03-10 2016-05-18 华北制药河北华民药业有限责任公司 一种注射用头孢西丁钠粉针制剂
CN109096310A (zh) * 2017-06-20 2018-12-28 梁怡 一种1/4水头孢西丁钠化合物
CN110396105A (zh) * 2018-09-10 2019-11-01 广东金城金素制药有限公司 美弗先头孢西丁钠药物制剂在胃肠道手术预防感染应用
CN109651403A (zh) * 2018-12-29 2019-04-19 上海上药新亚药业有限公司 一种头孢西丁钠的合成方法
CN109651403B (zh) * 2018-12-29 2022-01-07 上海上药新亚药业有限公司 一种头孢西丁钠的合成方法
CN110396102A (zh) * 2019-01-15 2019-11-01 广东金城金素制药有限公司 头孢西丁钠药物制剂在经阴道子宫切除、腹腔子宫切除、剖腹（宫）产术前预防感染应用
CN110204556A (zh) * 2019-07-16 2019-09-06 重庆医药高等专科学校 （rs）-甲氧基头孢西丁的制备方法
CN110204556B (zh) * 2019-07-16 2020-09-18 重庆医药高等专科学校 (rs)-甲氧基头孢西丁的制备方法
CN111217836A (zh) * 2020-03-20 2020-06-02 侯二美 一种头孢西丁的制备方法
CN113583024A (zh) * 2021-08-30 2021-11-02 浙江国邦药业有限公司 一种头孢西丁钠关键中间体的合成方法

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