WO2003040116A1 - Procede de preparation de chaines laterales de cephalosporines - Google Patents

Procede de preparation de chaines laterales de cephalosporines Download PDF

Info

Publication number
WO2003040116A1
WO2003040116A1 PCT/EP2002/012328 EP0212328W WO03040116A1 WO 2003040116 A1 WO2003040116 A1 WO 2003040116A1 EP 0212328 W EP0212328 W EP 0212328W WO 03040116 A1 WO03040116 A1 WO 03040116A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
residue
nitrogen
salts
methyl
Prior art date
Application number
PCT/EP2002/012328
Other languages
English (en)
Other versions
WO2003040116A8 (fr
Inventor
Walter Cabri
Marco Alpegiani
Giovanni Pozzi
Gomez Patricio Martin
Francesco Oliva
Valentina Pizzamiglio
Elena Pianta
Original Assignee
Antibioticos S.P.A.
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 Antibioticos S.P.A. filed Critical Antibioticos S.P.A.
Priority to KR10-2004-7006840A priority Critical patent/KR20040064270A/ko
Priority to JP2003542162A priority patent/JP2005508385A/ja
Priority to EP02802646A priority patent/EP1442029A1/fr
Publication of WO2003040116A1 publication Critical patent/WO2003040116A1/fr
Publication of WO2003040116A8 publication Critical patent/WO2003040116A8/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/40—Unsubstituted amino or imino radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/587—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with aliphatic hydrocarbon radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms, said aliphatic radicals being substituted in the alpha-position to the ring by a hetero atom, e.g. with m >= 0, Z being a singly or a doubly bound hetero atom
    • 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 process for the preparation of salts of organic nitrogen bases with carboxylic acids of formula (I)
  • - Q is nitrogen, a hydrocarbyl (CH) or chlorocarbyl (CC1) residue;
  • the salts of acids of formula (I) with organic nitrogen bases can be easily transformed into the corresponding free acids (I) or into solvates thereof, or into compounds of general formula (III), which can either be isolated or used in situ, for the preparation of third and fourth generation cephalosporanic antibiotics, such as Cefdinir and Cefdaloxime
  • Q and R are as defined above, and Z is a carboxy-activating group conventionally used in the synthesis of cephalosporanic antibiotics, such as an anhydride, an ester or an acyl halide.
  • Carboxylic acids of formula (I) are important syntons for the preparation of third and fourth generation cephalosporins having wide spectrum activity and high potency against Gram-positive and Gram-negative microorganisms .
  • Said salts can be advantageously used for the preparation of intermediates, which can be isolated or used in situ, for the preparation of third and fourth generation cephalosporins.
  • these salts allow faster reaction rates with advantages in terms of both yield and purity of the obtained products.
  • the present invention relates to a process for the preparation of salts of organic nitrogen bases with carboxylic acids of general formula (I)
  • - Q is nitrogen, a hydrocarbyl (CH) or chlorocarbyl (CC1) residue, preferably nitrogen;
  • - R is trityl, benzhydryl or para-methoxy benzyl, preferably trityl; which process comprises reacting a carboxylic acid of general formula
  • halide of formula (V) (V) RX wherein R has the meaning defined above and X is a halogen selected from chlorine, bromine and iodine, in the presence of a nitrogen organic base and of an organic inert solvent.
  • the nitrogen organic base can be selected from tertiary amines, preferably triethylamine, tributylamine, N-ethyl diisopropylamine, N-methyl morpholine, N-methyl pyrrolidine, N-methyl piperidine, trioctylamine; amidines, preferably diazabicyclononene (DBN) and diazabicycloundecene
  • the organic inert solvent can be selected from: halogenated hydrocarbons, preferably methylene chloride and dichloroethane; carboxylic acid esters, preferably ethyl acetate and butyl acetate; ketones, preferably acetone, diethyl ketone and methyl ethyl ketone; amides, for example N,N-dimethylformamide, N,N- dimethylacetamide, N-methylpyrrolidone; aromatic hydrocarbons, preferably benzene, toluene and xylene; ethers, preferably tetrahydrofuran, dioxane or ethylene glycol dimethyl ether; sulfoxides or sulfones, preferably dimethylsulfoxide, dimethyl sulfone and sulfolane; or mixtures thereof.
  • halogenated hydrocarbons preferably methylene chloride and dichloroethane
  • carboxylic acid esters preferably ethy
  • the reaction can be carried out at temperatures ranging from -50° to 200°C, preferably from 0° to 100°C.
  • the halide (N) is used typically in stoichiometric amounts to compound of formula (II) or in a slight molar excess, whereas the organic base can be present in a ratio ranging from 1 : 1 to 1 :10, preferably from 1 :2 to 1 :5.
  • the halide which is usually added to a mixture consisting of compound of formula (II), base and organic inert solvent, can be added directly in a single or more portions, or it can be dissolved in a suitable organic solvent, for example methylene chloride, dichloroethane, toluene or xylene, and then added to the reaction mixture in a time ranging from a few minutes to some hours.
  • a suitable organic solvent for example methylene chloride, dichloroethane, toluene or xylene
  • the reaction is usually considered complete when the residual compound (II) is lower than 3% (HPLC analysis).
  • the salts which will hereinafter be referred to as compounds (IA), usually crystallize during the reaction or upon cooling the mixture and can therefore be filtered off easily.
  • salts (IA) can be further purified from traces of the starting compound (II) and any water-soluble amines hydrochlorides present by treatment with water or an aqueous solvent.
  • Drying of salts (IA) does not require particular procedures and can be carried out, for example, under vacuum or by ventilation at temperatures from 30° to 100°C.
  • Salts (IA) can be used for the preparation of the corresponding free acids of formula (I) and the solvates thereof, for example with formamide, dimethylformamide, dimethylacetamide or N-methylpyrrolidone, according to conventional methods reported in literature (Liebigs Ann. 1996, 1743 - 1749).
  • salts (IA) can be used for the preparation of reactive derivatives of general formula (III), which can be isolated or used in situ in the acylation reactions to obtain cephalosporanic antibiotics, such as Cefdinir, Cefdaloxime and other third and fourth generation cephalosporins, according to the procedures described in literature (US 6,093,814, Organic Process Research & Development 1997, 1 121-123).
  • thioester of formula -C(0)-S-R 3 wherein R 3 is a heterocyclic residue selected from 2-pyridyl, benzothiazol-2-yl, benzoxazol-2-yl, benzimidazol-2-yl; preferred is the thioester with 2- mercaptobenzothiazole (EP 0037380, EP 0849269);
  • NR 3 R 1 is the residue of a nitrogen heterocycle selected from imidazolyl, 1,2,4- triazolyl, tetrazolyl, benzotriazolyl; preferred is the amide with benzotriazol-3-oxide-l-yl (The Journal of Antibiotics , 1993, 46(2), 359 - 361);
  • salts (IA) are usually more soluble in the organic solvents traditionally used for the activation reactions, such as methylene chloride, ethyl acetate and tetrahydrofuran, and the reactions are usually faster, give higher yields and yield compounds of formula (III) having higher purity.
  • Salts (IA) allow therefore to carry out a process for the preparation of cephalosporins of general formula (IX),
  • Q is as defined above and A is a typical residue of cephalosporins chemistry, preferably vinyl, (-CH ⁇ CH ⁇ or methoxymethylene (-CH 2 -0-CH 3 ).
  • Example 1 Preparation of (Z)-2-(2-aminothiazoI-4-yI)-2- trityloxyimino acetic acid triethylammonium salt.
  • the suspension was heated to 50°C and a further 1100 ml of ethanol was added in 30 minutes.
  • the mixture was gradually cooled to 10°C in an hour, acidified to pH 4.0 by addition of 20% hydrochloric acid, then kept for an hour at 10°C and filtered.
  • the solid was washed with water and dried to obtain 366 g of (Z)-2-(2-aminothiazol-4-yl)-2-trityloxyimino acetic acid.

Landscapes

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

Abstract

L'invention concerne un procédé de préparation de sels de bases d'azote organique avec des acides carboxyliques repésentés par la formule générale (I), dans laquelle Q et R sont tels que définis dans les spécifications, et utilisés dans la préparation de chaînes latérales de céphalosporines.
PCT/EP2002/012328 2001-11-09 2002-11-05 Procede de preparation de chaines laterales de cephalosporines WO2003040116A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
KR10-2004-7006840A KR20040064270A (ko) 2001-11-09 2002-11-05 세팔로스포린 측쇄의 제조방법
JP2003542162A JP2005508385A (ja) 2001-11-09 2002-11-05 セファロスポリン側鎖の製造方法
EP02802646A EP1442029A1 (fr) 2001-11-09 2002-11-05 Procede de preparation de chaines laterales de cephalosporines

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ITMI2001A002363 2001-11-09
IT2001MI002363A ITMI20012363A1 (it) 2001-11-09 2001-11-09 Metodo per la sintesi di catene laterali di cefalosporine

Publications (2)

Publication Number Publication Date
WO2003040116A1 true WO2003040116A1 (fr) 2003-05-15
WO2003040116A8 WO2003040116A8 (fr) 2004-06-17

Family

ID=11448586

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2002/012328 WO2003040116A1 (fr) 2001-11-09 2002-11-05 Procede de preparation de chaines laterales de cephalosporines

Country Status (6)

Country Link
EP (1) EP1442029A1 (fr)
JP (1) JP2005508385A (fr)
KR (1) KR20040064270A (fr)
CN (1) CN1309713C (fr)
IT (1) ITMI20012363A1 (fr)
WO (1) WO2003040116A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011029596A1 (fr) * 2009-09-11 2011-03-17 Lonza Ltd Procédé par préparer des dérivés d’acide 2-aminothiazol-4-yl acétique
US9139542B2 (en) 2013-03-13 2015-09-22 Theravance Biopharma Antibiotics Ip, Llc Crystalline form of a substituted thiazolylacetic acid triethylamine salt

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102659713B (zh) * 2012-05-07 2014-03-05 山东金城柯瑞化学有限公司 头孢地尼侧链酸活性酯的制备方法

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4935508A (en) * 1988-08-23 1990-06-19 Bristol-Myers Company Process for cephem prodrug esters
WO1992007840A1 (fr) * 1990-11-02 1992-05-14 Taisho Pharmaceutical Co., Ltd. Derive de thioester de thiazole
JPH0797368A (ja) * 1993-09-29 1995-04-11 Tokuyama Corp 保護水酸基含有複素環化合物の製造方法
JPH0841041A (ja) * 1994-08-01 1996-02-13 Tokuyama Corp ２−（２−アミノチアゾール−４−イル）−２−アセトキシイミノ酢酸またはその誘導体の製造方法
US5589594A (en) * 1992-02-14 1996-12-31 Hoechst Aktiengesellschaft Process for the preparation of cephem prodrug esters
EP0849269A1 (fr) * 1996-12-19 1998-06-24 F. Hoffmann-La Roche Ag Vinylpyrrolidin-cephalosporines substitues par des groupes basiques

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4935508A (en) * 1988-08-23 1990-06-19 Bristol-Myers Company Process for cephem prodrug esters
WO1992007840A1 (fr) * 1990-11-02 1992-05-14 Taisho Pharmaceutical Co., Ltd. Derive de thioester de thiazole
US5589594A (en) * 1992-02-14 1996-12-31 Hoechst Aktiengesellschaft Process for the preparation of cephem prodrug esters
US5637721A (en) * 1992-02-14 1997-06-10 Hoechst Aktiengesellschaft Process for the preparation of cephem prodrug esters
JPH0797368A (ja) * 1993-09-29 1995-04-11 Tokuyama Corp 保護水酸基含有複素環化合物の製造方法
JPH0841041A (ja) * 1994-08-01 1996-02-13 Tokuyama Corp ２−（２−アミノチアゾール−４−イル）−２−アセトキシイミノ酢酸またはその誘導体の製造方法
EP0849269A1 (fr) * 1996-12-19 1998-06-24 F. Hoffmann-La Roche Ag Vinylpyrrolidin-cephalosporines substitues par des groupes basiques

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 123, no. 13, 25 September 1995, Columbus, Ohio, US; abstract no. 169430, KOYANAGI S. ET AL: "Preparation of heterocycles for side chains of cephems" XP002234210 *
CHEMICAL ABSTRACTS, vol. 124, no. 25, 17 June 1996, Columbus, Ohio, US; abstract no. 343292, IWASAKI F. ET AL: "Method for producing 2-(2-aminothiazol-4-yl)-2-acetoxyiminoacetic acid and its derivative" XP002234212 *
CHEMICAL ABSTRACTS, vol. 127, no. 24, 15 December 1997, Columbus, Ohio, US; abstract no. 331464, ZHU Y ET AL: "Improved synthesis of (Z)-2--(2-aminothiazol-4-yl)-2-trityloxyiminoacetic acid" XP002234211 *
ZHONGGUO YIYAO GONGYE ZAZHI, vol. 28, no. 6, 1997, CHINA, pages 270 - 271 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011029596A1 (fr) * 2009-09-11 2011-03-17 Lonza Ltd Procédé par préparer des dérivés d’acide 2-aminothiazol-4-yl acétique
US9139542B2 (en) 2013-03-13 2015-09-22 Theravance Biopharma Antibiotics Ip, Llc Crystalline form of a substituted thiazolylacetic acid triethylamine salt

Also Published As

Publication number Publication date
KR20040064270A (ko) 2004-07-16
ITMI20012363A1 (it) 2003-05-09
CN1585758A (zh) 2005-02-23
CN1309713C (zh) 2007-04-11
WO2003040116A8 (fr) 2004-06-17
JP2005508385A (ja) 2005-03-31
EP1442029A1 (fr) 2004-08-04

Similar Documents

Publication Publication Date Title
JP3948628B2 (ja) セフディニルの製造方法
US6388070B1 (en) Thioester derivatives of thiazolyl acetic acid and their use in the preparation of cephalosporin compounds
CA2326441C (fr) Procede de purification d'un derive de cephalosporine
EP0175814B1 (fr) Procédé pour la préparation de dérivés céphem
EP0640608B1 (fr) Composés intermédiaires pour la synthèse de céphalosporins
KR100342600B1 (ko) 신규한 티아졸 화합물 및 그의 제조 방법
EP1442029A1 (fr) Procede de preparation de chaines laterales de cephalosporines
AU690482B2 (en) Process for producing cephalosporin antibiotics
FI109127B (fi) Menetelmä kefepiimidihydrokloridihydraattiantibiootin valmistamiseksi
HU213267B (en) Process for producing stereospecific cefepime-dihydrochloride-hydrate at ph 5-7,5
KR890002107B1 (ko) 세팔로스포린 유도체의 제조방법
US5594130A (en) Preparation of a cephalosporin antibiotic using the syn-isomer of a thiazolyl intermediate
JPH064641B2 (ja) セフアロスポリン誘導体の製造方法
KR930007260B1 (ko) 세팔로스포린 유도체의 제조방법
EP0613480A1 (fr) Procede de preparation de derives de cephem
KR100355115B1 (ko) 세프티오퍼 합성에 유용한 중간체 및 이를 이용한 세프티오퍼의 제조 방법
EP0528343A2 (fr) Procédé pour la production de céphalosporines et intermédiaires dans ce procédé
KR0174432B1 (ko) 신규한 결정성 세프디니르 중간체 및 그의 제조방법
JPS6242989A (ja) 溶接電極の自動整形および交換装置
KR890002215B1 (ko) 세펨유도체의 새로운 제조방법
KR100531669B1 (ko) 세펨 유도체의 제조방법
HU197579B (en) Process for production of derivatives of cefem carbonic acid
JPH02270882A (ja) ７α―メトキシセファロスポリン化合物の製造法
JPH0331287A (ja) セファロスポリン化合物の合成法
JPH0623189B2 (ja) アゼチジノン誘導体の製造法

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SD SE SG SI SK SL TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR IE IT LU MC NL PT SE SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
WWE Wipo information: entry into national phase

Ref document number: 2003542162

Country of ref document: JP

Ref document number: 1020047006840

Country of ref document: KR

WWE Wipo information: entry into national phase

Ref document number: 20028222148

Country of ref document: CN

WWE Wipo information: entry into national phase

Ref document number: 2002802646

Country of ref document: EP

CFP Corrected version of a pamphlet front page
CR1 Correction of entry in section i

Free format text: IN PCT GAZETTE 20/2003 UNDER (72, 75) REPLACE "POZZI, GIOVANNI, VIA BELVEDERE, 19/A, I-20045 BESANA BRIANZA" BY "POZZI, GIOVANNI, VIA BELVEDERE, 19/F, I-20045 BESANA BRIANZA"

WWP Wipo information: published in national office

Ref document number: 2002802646

Country of ref document: EP