WO2007105253B1 - PREPARATION OF (1-OXA- OR l-THIA-)3- CEPHEM DERIVATIVES - Google Patents

PREPARATION OF (1-OXA- OR l-THIA-)3- CEPHEM DERIVATIVES

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Publication number
WO2007105253B1
WO2007105253B1 PCT/IT2007/000185 IT2007000185W WO2007105253B1 WO 2007105253 B1 WO2007105253 B1 WO 2007105253B1 IT 2007000185 W IT2007000185 W IT 2007000185W WO 2007105253 B1 WO2007105253 B1 WO 2007105253B1
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WO
WIPO (PCT)
Prior art keywords
process according
alkyl
formula
oxa
cephem
Prior art date
Application number
PCT/IT2007/000185
Other languages
French (fr)
Other versions
WO2007105253A2 (en
WO2007105253A8 (en
WO2007105253A3 (en
Inventor
Asta Leone Dall
Original Assignee
Carthesia S A A Di Emanuela Mi
Asta Leone Dall
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 ITMI20060466 external-priority patent/ITMI20060466A1/en
Priority claimed from ITMI20061096 external-priority patent/ITMI20061096A1/en
Application filed by Carthesia S A A Di Emanuela Mi, Asta Leone Dall filed Critical Carthesia S A A Di Emanuela Mi
Priority to EP07736690A priority Critical patent/EP1996595A2/en
Priority to JP2009500008A priority patent/JP2009530268A/en
Publication of WO2007105253A2 publication Critical patent/WO2007105253A2/en
Publication of WO2007105253A3 publication Critical patent/WO2007105253A3/en
Publication of WO2007105253B1 publication Critical patent/WO2007105253B1/en
Publication of WO2007105253A8 publication Critical patent/WO2007105253A8/en

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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
    • 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
    • C07D501/02—Preparation
    • 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
    • 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
    • C07D501/18—7-Aminocephalosporanic or substituted 7-aminocephalosporanic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D503/00—Heterocyclic compounds containing 4-oxa-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxapenicillins, clavulanic acid derivatives; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D503/02—Preparation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D503/00—Heterocyclic compounds containing 4-oxa-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxapenicillins, clavulanic acid derivatives; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D503/10—Heterocyclic compounds containing 4-oxa-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxapenicillins, clavulanic acid derivatives; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D505/00—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D505/02—Preparation
    • C07D505/06—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
    • C07D505/00—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D505/10—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
    • C07D505/12—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 substituted in position 7
    • C07D505/14—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 substituted in position 7 with hetero atoms directly attached in position 7
    • C07D505/16—Nitrogen atoms

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Molecular Biology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Communicable Diseases (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Oncology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Cephalosporin Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

There is described a process for the preparation of carboxy-protected 7β-amino-7α-methoxy-(l-oxa- or l-thia-)3-(l-substituted-lH-tetrazol-5-yl)thiomethyl-3- cephem-4-carboxylic acid. Said process comprises (a) reacting a carboxy- protected 7-amino-3-chloromethyl-(l-oxa- or 1-thia-) 3-cephem-4-carboxylate with an alkyl- or aryl-sulfenyl chloride; (b) reacting the corresponding 7-alkyl- or aryl-thioimino derivative with a l-(alkyl- o ω-hydroxyalkyl-)lH-tetrazol-5- ylthiol; and (c) reacting the corresponding 7-(alkyl- or aryl-)thioimino-3-(l- substituted-lH-tetrazol-5-yl)Momethyl- (1-oxa- or l-thia-)3-cephem with methanol in the presence of triphenylphosphine and aluminum chloride neutralized with a base. The reaction of the obtained carboxy-protected 7β-amino- 7α-methoxy-(1-oxa- or 1 -thia-)3 -(1-substituted- 1H-tetrazol-5 -yl)thiomethyl-3 - cephem-4-carboxylic acid with activated 2-(cyanomethylthio)acetic or 2- (difiuoromethyl thio)acetic acid affords, after final removal of the protecting ester group, cefmetazole and fiomoxef, respectively. The 7-(alkyl- or aryl)thioimino-3- (1-substituted-1H-tetrazol-5-yl)thiomethyl-1-dethia-1-oxa-3-cephem intermediates are new compounds.

Claims

AMENDED CLAIMS received by the International Bureau on 09 October 2007 (09.10.07)
1. A process for the preparation of a (1-oxa- or l-thia-)3-cephem derivative of formula I
Figure imgf000002_0001
wherein X represents oxygen or sulfur, Y represents an alkyl having from 1 to 3 carbon atoms or an ω-hydroxyalkyl having from 2 to 3 carbon atoms and R° represents a carboxy protecting group, or of a salt thereof, which comprises
(a) treating a carboxy-protected 7-amino-3-chloromethyl-(l-oxa- or 1-thia- )3-cephem-4-carboxylic acid of formula II
Figure imgf000002_0002
wherein X and R° are defined as above, or a salt thereof, with an (alkyl- or aryl-) sulfenyl chloride of formula III
W-S-Cl (III) wherein W is an alkyl having from 1 to 3 carbon atoms, a benzyl, non substituted or substituted with an alkyl having from 1 to 3 carbon atoms, or a phenyl, non substituted or substituted with an alkyl having from 1 to 3 carbon atoms; (b) treating the corresponding 7-(alkyl- or aryl-)thioimino-3-chloromethyl-
( 1-oxa- or l-thia-)3-cephem thus obtained of formula IV
Figure imgf000002_0003
wherein W, X and R° are as defined above, with a [1 -alkyl- or l-(ω- hydroxyalkyl)-] - 1 H-tetrazol-5-ylthiol of formula V
22
Figure imgf000003_0001
wherein Y is an alkyl of from 1 to 3 carbon atoms or a ω-hydroxyalkyl of from 2 to 3 carbon atoms, or with an alkaline metal salt thereof; (c) treating the corresponding 7-(alkyl- or aryl-)thioimino-3-(l-substituted-
IH- tetrazol-5-yl)thiomethyl-(l-oxa- or l-thia-)-3-cephem of formula VI
Figure imgf000003_0002
wherein W, X, R° e Y are as defined above, with methanol in the presence of aluminum trichloride neutralized with a base and a triarylphosphine or M(C1- C6)alkylphosphine , to obtain the compound of formula I as such or in form of an acid addition salt thereof.
2. The process according to claim 1, wherein, in step (a), said alkyl- or aryl- sulfenyl chloride has the formula III, wherein W is methyl, phenyl or p-tolyl.
3. The process according to anyone of claims 1 and 2, wherein, in step (a), a carboxy-protected 7-amino-3-chloromethyl-(l-oxa- or l-thia-)3-cephem-4- carboxylic acid of formula π, wherein X is oxygen or sulfur and R° is benzhydryl or p-methoxybenzyl, or a salt thereof, is used.
4. The process according to claim 1, wherein, in step (b), a [1 -alkyl- or 1-
(ω-hydroxyalkyl-)]lH-tetrazol-5-ylthiol of formula V, wherein Y is methyl or 2- hydroxyethyl, is used.
5. The process according to claim 4, wherein said [1 -alkyl- or l-(ω- hydroxyalkyl)-] lH-tetrazol-5-ylthiol of formula V, wherein Y is methyl or 2- hydroxyethyl, is in form of its sodium salt.
6. The process according to claim 1, wherein, in step (b), a [1 -alkyl- or 1- (ω-hydroxyalkyl-)] lH-tetrazol-5-ylthiol of formula V, wherein Y is methyl or 2- hydroxyethyl, in form of its sodium salt and a 7-(alkyl- or aryl-)thioimino-3- chloromethyl-(l-oxa- or l-thia-)3-cephem of formula IV, wherein X is oxygen or sulfur, R° is benzhydryl or 4-methoxybenzyl and W is methyl, phenyl or p-tolyl, are used.
7. The process according to claim 1 , wherein, in step (c), a 7-(alkyl- or aryl-) thioimino-3-(l-substituted-lH-tetrazol-5-yl)thiomethyl-(l-oxa- or l-thia-)3- cephem of formula VI, wherein X is oxygen or sulfur, R° is benzhydryl or 4- methoxybenzyl, Y is methyl o 2-hydroxyethyl and W is methyl, phenyl or p-tolyl, is used.
8. The process according to claim 1, wherein, in step (c), a compound of formula I, wherein X is oxygen or sulfur, Y is methyl or 2-hydroxyethyl and R° is a carboxy protecting group, is isolated.
9. The process according to claim 1, wherein, in step (c), said triarylphosphine or Ui(C1 -C6)alkylphosphine is selected from the group consisting of triphenylphosphine, tri(o-tolyl)phosphine, tri(2-furyl)phosphine and tri(n- butyl)phosphine.
10. The process according to claim 8, wherein said group R° is benzhydryl.
11. The process according to claim 8, wherein said group R° is 4- methoxybenzyl.
12. The process according to claim 1, wherein said base is sodium bicarbonate.
13. The process according to claim 1, wherein, in step (c), the compound of formula I is isolated in form of a salt thereof which is optionally neutralized to free base.
14. The process according to claim 13, wherein said salt is selected from the group consisting of hydrochloride, hydrobromide, methanesulfonate, p- toluenesulfonate and naphthalene-2-sulfonate salts.
15. The process according to claim 1, wherein, in step (c), a compound of formula F
Figure imgf000004_0001
wherein X' is oxygen, Y' is 2-hydroxyethyl and R° is a carboxy protecting group, is isolated.
16. The process according to claim 1, wherein, in step (c), a compound of formula I"
24
Figure imgf000005_0001
wherein X" is sulfur, Y" is methyl and R° is a carboxy protecting group, is isolated.
17. The process according claim 15, wherein said carboxy protecting group
R° is benzhydryl.
18. The process according to claim 15, wherein said carboxy protecting group R° is 4-methoxybenzyl.
19. The process according to claim 16, wherein said carboxy protecting group R° is benzhydryl.
20. The process according to claim 16, wherein said carboxy protecting group R° is 4-methoxybenzyl.
21. The process according to claim 15, wherein said compound of formula F is further reacted and treated with activated 2-(difluoromethylthio)acetic acid in the presence of a silylating agent to afford the compound of formula VIF
Figure imgf000005_0002
wherein X' is oxygen, Y' is 2-hydroxyethyl and R° is a carboxy protecting group which is removed by known methods to isolate flomoxef.
22. The process according to claim 21, wherein said silylating agent consists of hexamethyldisilazane and trimethylchlorosilane.
23. The process according to claim 21, wherein said carboxy protecting group R° is benzhydryl or 4-methoxybenzyl and the removal is carried out by treatment with trifluoroacetic acid and anisole in dichloromethane.
24. The process according to claim 16, wherein said compound of formula
I" is further reacted and treated with activated 2-(cyanomethylthio)acetic acid to obtain the compound of formula VII"
25
Figure imgf000006_0001
wherein X" is sulfur, Y" is methyl and R° is a carboxy protecting group which is removed by known methods to isolate cefmetazole.
25. The process according to claim 24, wherein said carboxy protecting group R° is benzhydryl or 4-methoxybenzyl and the removal is carried out by treatment with trifluoroacetic acid and anisole in dichloromethane.
26. The process according to claim 24, wherein said carboxy protecting group R° is benzhydryl or 4-methoxybenzyl and the removal is carried out by treatment with aluminum trichloride and anisole in dichloromethane.
27. A 7-(alkyl- or aryl-)thioimino-l-dethia-l-oxa-3-(l-substituted-lH- tetrazol-5-yl)thiomethyl-3-cephem of formula VF
Figure imgf000006_0002
wherein X' is oxygen, Y' is a ω-hydroxyalkyl having 2 or 3 carbon atoms, W is an alkyl having from 1 to 3 carbon atoms, a benzyl, non substituted or substituted with an alkyl having from 1 to 3 carbon atoms, or a phenyl, non substituted or substituted with an alkyl having from 1 to 3 carbon atoms and R° is a carboxy protecting group.
28. The 7-(alkyl- or aryl-)thioimino-l-dethia-l-oxa-3 -(I -substituted- IH- tetrazol-5-yl)thiomethyl-3-cephem according to claim 27, of formula VF, wherein X' is oxygen, Y' is 2-hydroxyethyl, W is methyl, phenyl or p-tolyl, and R° is benzhydryl or 4-methoxybenzyl.
29. The benzhydryl 7-methylthioimino-3-[l-(2-hydroxyethyl)-lH-tetrazol- 5-yl]thiomethyl- 1 -dethia- 1 -oxa-3 -cephem-4-carboxylate.
26
PCT/IT2007/000185 2006-03-15 2007-03-14 PREPARATION OF (1-OXA- OR l-THIA-)3- CEPHEM DERIVATIVES WO2007105253A2 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP07736690A EP1996595A2 (en) 2006-03-15 2007-03-14 PROCESS FOR THE PREPARATION OF (1-OXA- OR l-THIA-)3- CEPHEM DERIVATIVES AND RELATED INTERMEDIATES
JP2009500008A JP2009530268A (en) 2006-03-15 2007-03-14 Process for the preparation of (1-oxa- or 1-thia-) 3-cephem derivatives and related intermediates

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
ITMI20060466 ITMI20060466A1 (en) 2006-03-15 2006-03-15 PROCEDURE FOR THE PREPARATION OF 1-OXA-O 1-TIA-3-CEFEN DERIVATIVES AND RELATED INTERMEDIATES
ITMI2006A000466 2006-03-15
ITMI2006A001096 2006-06-06
ITMI20061096 ITMI20061096A1 (en) 2006-06-06 2006-06-06 PROCEDURE FOR THE PREPARATION OF (1-TIA-) 3-CEFEM DERIVATIVES

Publications (4)

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WO2007105253A2 WO2007105253A2 (en) 2007-09-20
WO2007105253A3 WO2007105253A3 (en) 2007-11-01
WO2007105253B1 true WO2007105253B1 (en) 2007-12-06
WO2007105253A8 WO2007105253A8 (en) 2008-10-30

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CN102952149B (en) * 2012-11-09 2015-06-24 浙江新和成股份有限公司 One-pot synthesis method of flomoxef intermediate

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CN101787040B (en) * 2010-03-02 2011-09-07 哈药集团制药总厂 Method for preparing cefmetazole sodium
CN101792454B (en) * 2010-03-17 2011-12-07 河北九派制药有限公司 Preparation method of 7-alpha amino 7-methoxyl-3-methly tetrazole sulfur methyl cafe-benzyl alkanoic acid
CN101792455B (en) * 2010-03-17 2012-07-04 河北九派制药有限公司 Preparation method of high-purity 7-alpha-amino-7-methoxy-3-methyltetrazole thiomethyl cephalosporin benzyl ester
CN102675342A (en) * 2011-03-15 2012-09-19 四平市精细化学品有限公司 Preparation method of 7 beta-amino-7 alpha-methoxy-3-((1-methyl-1H-tetrazole-5-group) sulfomethyl)-3-cephem-4-diphenylmethyl carboxylate
CN102391291B (en) * 2011-09-21 2014-06-04 河北九派制药有限公司 Cefmetazole acid preparation method
JP2015524426A (en) * 2012-07-25 2015-08-24 ジェ イル ファルマシューティカル シーオー．， エルティーディー．Ｊｅ Ｉｌ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｃｏ．， Ｌｔｄ． Novel production method of 1-oxacephalosporin derivative
CN102850379B (en) * 2012-08-30 2015-08-12 三峡大学 The synthetic method of methoxy cephalosporin intermediate 7-MAC
CN104151324B (en) * 2014-09-03 2016-08-24 齐鲁天和惠世制药有限公司 A kind of solvent crystallization prepares the method for ampicillin
CN104327100B (en) * 2014-09-30 2016-09-28 华北制药河北华民药业有限责任公司 High-purity 6315-S preparation technology
CN104557978B (en) * 2014-12-31 2017-07-18 重庆福安药业(集团)股份有限公司 A kind of preparation method of cefmetazole sodium
CN105037393B (en) * 2015-06-24 2017-11-10 浙江永宁药业股份有限公司 A kind of preparation method of Flomoxef Sodium
CN105399755B (en) * 2015-11-03 2018-05-11 浙江永宁药业股份有限公司 A kind of synthetic method of Flomoxef acid
KR102115644B1 (en) * 2017-09-13 2020-05-27 주식회사 동도물산 Method of manufacturing 7α-alkoxy oxacephem intermediate compound
CN107722041B (en) * 2017-11-12 2020-05-05 广州维奥康药业科技有限公司 Preparation method of cefmetazole acid
CN109608478A (en) * 2018-11-15 2019-04-12 山东晶辉生物技术有限公司 A kind of synthetic method of Flomoxef acid
CN109970766A (en) * 2019-04-22 2019-07-05 山西千岫制药有限公司 A kind of preparation method of Flomoxef acid
CN110003241A (en) * 2019-04-23 2019-07-12 山西千岫制药有限公司 A kind of preparation method of latamoxef parent nucleus
CN110804635B (en) * 2019-11-11 2021-08-17 济南康和医药科技有限公司 Synthesis method of latamoxef sodium
CN114292283A (en) * 2022-01-24 2022-04-08 广州维奥康药业科技有限公司 Preparation method of cefmetazole sodium impurity for injection

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WO2007105253A2 (en) 2007-09-20
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JP2009530268A (en) 2009-08-27
WO2007105253A8 (en) 2008-10-30
WO2007105253A3 (en) 2007-11-01

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