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WO2009004463A1 - Méthode perfectionnée de préparation d'intermédiaire de céfépime. - Google Patents

Méthode perfectionnée de préparation d'intermédiaire de céfépime. Download PDF

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Publication number
WO2009004463A1
WO2009004463A1 PCT/IB2008/001734 IB2008001734W WO2009004463A1 WO 2009004463 A1 WO2009004463 A1 WO 2009004463A1 IB 2008001734 W IB2008001734 W IB 2008001734W WO 2009004463 A1 WO2009004463 A1 WO 2009004463A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
hexamethyldisilane
preparation
cefepime
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/IB2008/001734
Other languages
English (en)
Inventor
Palanisamy Senthilkumar Udayampalayam
Sureshkumar Kanagaraj
Mohan Singaravel
Sekar Jeyaraj Michael
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Orchid Pharma Ltd
Original Assignee
Orchid Chemicals and 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 and Pharmaceuticals Ltd filed Critical Orchid Chemicals and Pharmaceuticals Ltd
Publication of WO2009004463A1 publication Critical patent/WO2009004463A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • C07D501/02—Preparation
    • C07D501/04—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
    • 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
    • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
    • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
    • C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
    • C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
    • C07D501/48—Methylene radicals, substituted by hetero rings
    • C07D501/56—Methylene radicals, substituted by hetero rings with the 7-amino radical acylated by carboxylic acids containing hetero rings

Definitions

  • the present invention provides an improved process for the preparation of the compound of formula (I).
  • HX represents HI, HCl, H 2 SO 4 and the like.
  • the compound of formula (I) is an important intermediate in the preparation of Cefepime or its salts.
  • Cefepime is chemically known as [6R-[6 ⁇ , 7 ⁇ (Z)]]-l-[7-[(2-amino-4- thiazolyl)(methoxyimino)acetylamino]-2-carboxy-8-oxo-5-thia-l-azabicyclo [4.2.0]oct-2-en-3-ylmethyl]-l-methylpyrrolidinium hydroxide inner salt or (6R,7R)-7- [2-(2-aminothiazol-4-yl)-2(Z)-(methoxyimino)acetamido]-3-(l- methylpyrrolidiniornethyl)-3-cephem-4-carboxylate.
  • Cefepime is the fourth- generation cephalosporin that is active against a wide range of gram-positive and gram-negative aerobic organisms and is disclosed in US Patent No. 4,406,899. According to this patent Cefepime is prepared by the following process:
  • WO 2006/075244 (Application No: IN 27/CHE/2005) discloses the preparation of compound of formula (I) using decalin, tetralin, hexane, cyclohexane and petroleum ether as solvent systems.
  • the main objective of the present invention is to provide a process for the preparation of compound of formula (I) in good purity, which is substantially free from ⁇ 2 isomer.
  • Another objective of the present invention is to provide a process for the preparation of intermediate of formula (I), which is easy to implement on commercial scale, and avoids solvents like cyclohexane, dichloromethane (MDC), and decalin.
  • MDC dichloromethane
  • silylating agent used in step (ii) is selected from hexamethyldisilazane (HMDS), trimethylchlorosilaneOTMCS), trimethylsilyl iodide (TMSI), N,O-bis-(trimethylsilyl)-acetamide (BSA), methyltrimethylsilyltrifluoroacetamide (MSTFA), N,O-bis-
  • the present invention makes use of hexamethyldisilane as a solvent system for carrying out the reaction, the use of which has been found to have advantages over the conventional solvent system. None of the prior art hitherto suggests or motivates the use of hexamethyldisilane as a solvent system. Accordingly, the use of hexamethyldisilane as a solvent system constitutes the novelty of the present invention. The conventional solvent system requires cumbersome solvent recovery process.
  • hexamethyldisilane obviates such problems and the recovery of hexamethydisilane is found to be good over the cycloalkane as the use of hexamethyldisilane yields good quality as well as quantity of final compound, and hence industrially advantageous.
  • cycloalkanes like cyclohexane methyl cyclopentane becomes a peroxide hazard if concentrated, through distillation or evaporation as mentioned in Jackson, J. Chem. Ed., 1970. Since, industrial process prefers recovery of solvent system, the present invention prefers such advantage. Accordingly, the present invention provides a novel solvent system that avoids the drawbacks associated with the processes reported in the prior art.
  • the present invention identifies the dual role of hexamethyldisilane as a solvent system and reagent.
  • iodotrimethylsilane is prepared by reacting hexamethyldisilane (HMD) with iodine at a temperature in the range of 10 0 C to 100 0 C. To this solution NMP was added to yield “solution B.”
  • isolation of compound of formula (I) is carried out by reacting the compound of formula (VI) obtained in step (iii) with water or lower alkanol or aqueous lower alkanol such as methanol, isopropyl alcohol, butanol and the like.
  • the compound of formula (I) can be prepared by reacting silylated 7-ACA of formula (II) with N-methylpyrrolidine of formula (IV) in hexamethyldisilane as a solvent system, to produce compound of formula (VI), followed by removing the silyl protecting group of formula (VI).
  • the compound of formula (I) can be prepared by utilizing the following scheme.
  • the compound of formula (VII) is prepared by reacting silylated 7-ACA of formula (III) with iodotrimethylsilane in hexamethyldisilane.
  • a suspension of iodine [88.5 g] in hexamethyldisilane was heated to 60-70 0 C under nitrogen atmosphere and maintained for 3-6 hours.
  • the above solution was cooled to O 0 C and added N-methylpyrrolidine (26 g) in hexamethyldisilane (25 mL).
  • the resultant slurry was stirred at 0-15 0 C for 30 minutes.
  • the suspension was heated to 30-50 0 C and maintained till completion of reaction.
  • reaction mixture was cooled to 3-5 0 C.
  • Cold aqueous methanol (50%) was added at 5-10 0 C followed by concentrated hydrochloric acid.
  • the aqueous phase was separated and combined with the aqueous methanol extract of the organic phase.
  • methanol and activated carbon were added, stirred and filtered.
  • the filtrate was diluted with aqueous methanol.
  • the product was crystallized by adjusting the pH using triethylamine at 15-2O 0 C.
  • the crystallized product was filtered and washed with cold aqueous methanol (10%) followed by cold methanol. Drying under vacuum at 35 -4O 0 C afforded pure title compound.
  • a suspension of iodine [88.5g] in hexamethyldisilane at 20-30 0 C was heated to 60-70 0 C under nitrogen atmosphere and maintained for 3-6 hours.
  • the above solution was cooled to O 0 C and added N-methylpyrrolidine in hexamethyldisilane.
  • the resultant slurry was stirred at 0-15 0 C for 30 minutes.
  • the suspension was heated to 30-50 0 C and maintained till completion of reaction.
  • reaction mixture was cooled to 3-5 0 C.
  • Cold aqueous methanol (50%) was added into the reaction mixture followed by concentrated hydrochloric acid.
  • the aqueous phase was separated and combined with aqueous methanol extract of the organic phase.
  • methanol and activated carbon were added, stirred and filtered.
  • the filtrate was diluted with aqueous methanol.
  • the product was crystallized by adjusting the pH to 3.0 - 3.5 using triethylamine.
  • the crystallized product was filtered and washed with cold aqueous methanol followed by cold methanol. Drying under vacuum at 35 -4O 0 C afforded pure title compound.

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

Abstract

La présente invention porte sur un procédé de préparation du composé représenté par la Formule (I) dans laquelle HX représente HI, HCl, H2SO4 et similaires. Le composé de la Formule (I) est un intermédiaire important dans la préparation de Céfépime.
PCT/IB2008/001734 2007-07-04 2008-07-02 Méthode perfectionnée de préparation d'intermédiaire de céfépime. Ceased WO2009004463A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1437CH2007 2007-07-04
IN1437/CHE/2007 2007-07-04

Publications (1)

Publication Number Publication Date
WO2009004463A1 true WO2009004463A1 (fr) 2009-01-08

Family

ID=40225732

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2008/001734 Ceased WO2009004463A1 (fr) 2007-07-04 2008-07-02 Méthode perfectionnée de préparation d'intermédiaire de céfépime.

Country Status (1)

Country Link
WO (1) WO2009004463A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102276631A (zh) * 2011-06-16 2011-12-14 哈药集团制药总厂 一种盐酸头孢吡肟的制备方法
CN102675345A (zh) * 2012-06-01 2012-09-19 苏州中联化学制药有限公司 一种盐酸头孢吡肟的制备方法
CN104926851A (zh) * 2015-07-17 2015-09-23 山东博苑医药化学有限公司 溶解加碘制备三甲基碘硅烷
CN117003768A (zh) * 2023-06-16 2023-11-07 国药集团威奇达药业有限公司 头孢哌酮杂质a的制备方法
CN117659046A (zh) * 2023-12-07 2024-03-08 艾美科健（中国）生物医药有限公司 头孢泊肟酯中间体7-amca的合成方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5594131A (en) * 1992-07-24 1997-01-14 Bristol-Myers Squibb Company Process for preparing cephalosporin intermediates
WO2006008749A1 (fr) * 2004-07-16 2006-01-26 Hetero Drugs Limited Procede de preparation d'intermediaires de cephalosporine pures
WO2006075244A2 (fr) * 2005-01-17 2006-07-20 Orchid Chemicals & Pharmaceuticals Ltd Procede ameliore de fabrication d'un intermediaire antibiotique de cephalosporine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5594131A (en) * 1992-07-24 1997-01-14 Bristol-Myers Squibb Company Process for preparing cephalosporin intermediates
WO2006008749A1 (fr) * 2004-07-16 2006-01-26 Hetero Drugs Limited Procede de preparation d'intermediaires de cephalosporine pures
WO2006075244A2 (fr) * 2005-01-17 2006-07-20 Orchid Chemicals & Pharmaceuticals Ltd Procede ameliore de fabrication d'un intermediaire antibiotique de cephalosporine

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102276631A (zh) * 2011-06-16 2011-12-14 哈药集团制药总厂 一种盐酸头孢吡肟的制备方法
CN102675345A (zh) * 2012-06-01 2012-09-19 苏州中联化学制药有限公司 一种盐酸头孢吡肟的制备方法
CN104926851A (zh) * 2015-07-17 2015-09-23 山东博苑医药化学有限公司 溶解加碘制备三甲基碘硅烷
CN104926851B (zh) * 2015-07-17 2016-02-24 山东博苑医药化学有限公司 溶解加碘制备三甲基碘硅烷
CN117003768A (zh) * 2023-06-16 2023-11-07 国药集团威奇达药业有限公司 头孢哌酮杂质a的制备方法
CN117659046A (zh) * 2023-12-07 2024-03-08 艾美科健（中国）生物医药有限公司 头孢泊肟酯中间体7-amca的合成方法

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