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WO2000053609A1 - Procede de preparation de cefuroxime - Google Patents

Procede de preparation de cefuroxime Download PDF

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Publication number
WO2000053609A1
WO2000053609A1 PCT/IB2000/000240 IB0000240W WO0053609A1 WO 2000053609 A1 WO2000053609 A1 WO 2000053609A1 IB 0000240 W IB0000240 W IB 0000240W WO 0053609 A1 WO0053609 A1 WO 0053609A1
Authority
WO
WIPO (PCT)
Prior art keywords
cefuroxime
solvent
alkoxide
mixture
cefuroxime axetil
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/IB2000/000240
Other languages
English (en)
Inventor
Vijay Kumar Handa
Ramesh Dandala
Jagmohan Khanna
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.)
Ranbaxy Laboratories Ltd
Original Assignee
Ranbaxy Laboratories 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
Priority claimed from US09/264,977 external-priority patent/US6235896B1/en
Application filed by Ranbaxy Laboratories Ltd filed Critical Ranbaxy Laboratories Ltd
Priority to AU28207/00A priority Critical patent/AU2820700A/en
Publication of WO2000053609A1 publication Critical patent/WO2000053609A1/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

Definitions

  • the present invention is directed generally to a process for the preparation of cefuroxime axetil and more specifically to such a process, the starting ingredient being one of predominantly S-cefuroxime axetil, R,S mixture of cefuroxime axetil or R-cefuroxime axetil not meeting the purity criteria.
  • Cefuroxime is a cephalosporin antibiotic with a broad spectrum of activity against both gram-positive and gram-negative microorganisms. Due to poor absorption from the gastrointestinal tract following oral administration, its salt, cefuroxime sodium, is ideally suited to formulation as injectables.
  • cefuroxime axetil 1 -acetoxyethyl ester of cefuroxime, which is referred to as cefuroxime axetil.
  • Cefuroxime axetil is a prodrug of cefuroxime and is suitable for oral administration. As a result, it permits a more convenient and broader therapeutic use of cefuroxime.
  • Cefuroxime axetil possesses an asymmetric carbon atom at the 1 -position of the 1 -acetoxyethyl group and, therefore, can exist as R- and S-isomers and mixtures thereof. Cefuroxime axetil is marketed as a mixture of R- and S- isomers in an approximately 1 :1 ratio.
  • cefuroxime axetil While cefuroxime axetil is well suited to formulation for oral administration, it suffers from several deficiencies. Cefuroxime axetil is rapidly hydroiyzed in the intestine, thereby resulting in the formation of cefuroxime, which is poorly absorbed from the gastrointestinal tract. It has also been observed that oral administration of the R,S-mixture results in only about 50% bioavailability of the cefuroxime antibiotic, which is due to low overall solubility and the rapid hydrolysis of the ester portion of cefuroxime axetil by the esterase enzyme located in the gut. The non-absorbable cefuroxime remaining in the gut accounts for a partial loss of therapeutic activity and possibly the cause of side effects generally observed.
  • An object of the present invention is to provide a process for the preparation of cefuroxime from predominantly S-cefuroxime axetil, R, S mixture of cefuroxime axetil or R-cefuroxime axetil not meeting the purity criteria.
  • the present invention provides a process for the conversion of cefuroxime axetil as seen in Formula I as follows:
  • Formula II which comprises treating cefuroxime axetil with alkoxides in the presence of a suitable solvent(s) as described herein and isolating cefuroxime from the reaction mixture.
  • the reaction is carried out at a temperature ranging from approximately -80 to +40° C, most preferably at approximately -65 to +20° C.
  • aqueous hydrochloric acid is added to the reaction mixture, the solvent is removed under reduced pressure and water is added to the reaction mixture.
  • Cefuroxime is extracted with a water- immiscible solvent.
  • a basifying agent is added and cefuroxime is precipitated from the aqueous layer by acidification.
  • suitable solvent(s) denotes any lower alkanol or non-alcoholic polar solvent(s) and mixture thereof, which is capable of homogenizing the reaction mixture.
  • the lower alkanol includes those primary, secondary and tertiary alcohols having from one to six carbon atoms.
  • the lower alkanol solvents used are methyl, ethyl and isopropyl alcohol.
  • the nonalcoholic polar solvents include tetrahydrofuran, 1 ,4-dioxane, N,N- dimethylformamide and dimethylsulfoxide.
  • tetrahydrofuran and 1 ,4-dioxane are used. Mixtures of two or more lower alkanols and/or other non-alcoholic polar solvents can also be used.
  • any alkali alkoxides may be used, however, sodium alkoxides, such as sodium methoxide and sodium ethoxide, which are commercially available, are preferred.
  • Any water-immiscible solvent may be used for extraction purposes, however, keeping in mind commercial availability and cost benefits, it is preferred that the solvent be selected from the group consisting of ethyl acetate, ether or dichloromethane.
  • cefuroxime prepared according to the present invention may be converted into cefuroxime axetil or cefuroxime sodium by methods known per se.
  • Cefuroxime axetil (20.4 gm, predominantly S-isomer) was dissolved in a mixture of tetrahydrofuran (204 ml) and ethyl alcohol (58 ml). The solution was cooled to -60° C, sodium ethoxide (6.59 gm) was added in portions and the reaction mixture was stirred for 1 hour. Aqueous hydrochloric acid was added and the procedure described in Example 1 was followed to obtain cefuroxime (15.67 gm). EXAMPLE 4
  • Cefuroxime axetil (20.4 gm, S-isomer >90%, R-isomer ⁇ 10%) was dissolved in a mixture of tetrahydrofuran (204 ml) and methanol (39 ml). This clear solution was cooled to -60° C and sodium methoxide (5 gm) was added. The reaction mixture was stirred at -55 to -60° C for 1 hour. Hydrochloric acid was added and the procedure described in Example 2 was followed to obtain cefuroxime (15.19 gm).

Landscapes

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

Abstract

La présente invention concerne un procédé de préparation de céfuroxime à partir principalement d'axétil de S-céfuroxime, d'un mélange d'axétil R,S de céfuroxime ou d'axétil de R-céfuroxime ne satisfaisant aux critères de pureté. Ce procédé consiste à traiter l'axétil de céfuroxime avec des alkoxydes en présence d'un solvant ou d'un mélange de solvants convenables et à isoler le céfuroxime du milieu réactionnel.
PCT/IB2000/000240 1999-03-09 2000-03-08 Procede de preparation de cefuroxime Ceased WO2000053609A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU28207/00A AU2820700A (en) 1999-03-09 2000-03-08 Process for the preparation of cefuroxime

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US09/264,977 US6235896B1 (en) 1998-03-30 1999-03-09 Process for the preparation of cefuroxime
US09/264,977 1999-03-09

Publications (1)

Publication Number Publication Date
WO2000053609A1 true WO2000053609A1 (fr) 2000-09-14

Family

ID=23008447

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2000/000240 Ceased WO2000053609A1 (fr) 1999-03-09 2000-03-08 Procede de preparation de cefuroxime

Country Status (2)

Country Link
AU (1) AU2820700A (fr)
WO (1) WO2000053609A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100399195B1 (ko) * 2001-03-17 2003-09-26 신풍제약주식회사 무정형 세푸록심 악세틸의 제조방법
US6894162B2 (en) 2000-09-11 2005-05-17 Sandoz Gmbh Intermediates in cephalosporin production
WO2008132574A1 (fr) * 2007-04-27 2008-11-06 Parabolic Drugs Limited Purification de l'acide céfuroxime

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE783449A (fr) * 1971-05-14 1972-11-13 Glaxo Lab Ltd Perfectionnements relatifs aux antibiotiques
GB1342241A (en) * 1970-01-23 1974-01-03 Glaxo Lab Ltd Cephalosporin compounds
DE2439880A1 (de) * 1973-08-21 1975-04-03 Glaxo Lab Ltd Antibiotika und verfahren zu ihrer herstellung
GB1571683A (en) * 1976-02-16 1980-07-16 Glaxo Operations Ltd Ester derivatives of cefuroxime
US4258183A (en) * 1979-04-06 1981-03-24 Glaxo Group Limited Process for the preparation of cephalosporin compounds
US5063224A (en) * 1990-07-09 1991-11-05 Eli Lilly And Company R-cefuroxime axetil

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1342241A (en) * 1970-01-23 1974-01-03 Glaxo Lab Ltd Cephalosporin compounds
BE783449A (fr) * 1971-05-14 1972-11-13 Glaxo Lab Ltd Perfectionnements relatifs aux antibiotiques
DE2439880A1 (de) * 1973-08-21 1975-04-03 Glaxo Lab Ltd Antibiotika und verfahren zu ihrer herstellung
GB1571683A (en) * 1976-02-16 1980-07-16 Glaxo Operations Ltd Ester derivatives of cefuroxime
US4258183A (en) * 1979-04-06 1981-03-24 Glaxo Group Limited Process for the preparation of cephalosporin compounds
US5063224A (en) * 1990-07-09 1991-11-05 Eli Lilly And Company R-cefuroxime axetil

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6894162B2 (en) 2000-09-11 2005-05-17 Sandoz Gmbh Intermediates in cephalosporin production
KR100399195B1 (ko) * 2001-03-17 2003-09-26 신풍제약주식회사 무정형 세푸록심 악세틸의 제조방법
WO2008132574A1 (fr) * 2007-04-27 2008-11-06 Parabolic Drugs Limited Purification de l'acide céfuroxime

Also Published As

Publication number Publication date
AU2820700A (en) 2000-09-28

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