EP1442029A1 - Verfahren zur herstellung von cephalosporin-seitenketten - Google Patents

Verfahren zur herstellung von cephalosporin-seitenketten

Info

Publication number
EP1442029A1
EP1442029A1 EP02802646A EP02802646A EP1442029A1 EP 1442029 A1 EP1442029 A1 EP 1442029A1 EP 02802646 A EP02802646 A EP 02802646A EP 02802646 A EP02802646 A EP 02802646A EP 1442029 A1 EP1442029 A1 EP 1442029A1
Authority
EP
European Patent Office
Prior art keywords
formula
residue
nitrogen
salts
methyl
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.)
Withdrawn
Application number
EP02802646A
Other languages
English (en)
French (fr)
Inventor
Walter Cabri
Marco Alpegiani
Giovanni Pozzi
Gomez Patricio Martin
Francesco Oliva
Valentina Pizzamiglio
Elena Pianta
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.)
Olon SpA
Original Assignee
Antibioticos SpA
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 SpA filed Critical Antibioticos SpA
Publication of EP1442029A1 publication Critical patent/EP1442029A1/de
Withdrawn legal-status Critical Current

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)
EP02802646A 2001-11-09 2002-11-05 Verfahren zur herstellung von cephalosporin-seitenketten Withdrawn EP1442029A1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
IT2001MI002363A ITMI20012363A1 (it) 2001-11-09 2001-11-09 Metodo per la sintesi di catene laterali di cefalosporine
ITMI20012363 2001-11-09
PCT/EP2002/012328 WO2003040116A1 (en) 2001-11-09 2002-11-05 A process for the preparation of cephalosporins side chains

Publications (1)

Publication Number Publication Date
EP1442029A1 true EP1442029A1 (de) 2004-08-04

Family

ID=11448586

Family Applications (1)

Application Number Title Priority Date Filing Date
EP02802646A Withdrawn EP1442029A1 (de) 2001-11-09 2002-11-05 Verfahren zur herstellung von cephalosporin-seitenketten

Country Status (6)

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

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011029596A1 (en) * 2009-09-11 2011-03-17 Lonza Ltd Process for preparing 2-aminothiazol-4-yl-acetic acid derivates
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
EP2970164B1 (de) 2013-03-13 2017-05-03 Theravance Biopharma Antibiotics IP, LLC Kristalline form eines substituierten thiazolylessigsäure triethylamin salzes

Family Cites Families (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
TW212181B (de) * 1992-02-14 1993-09-01 Hoechst Ag
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
JP3518817B2 (ja) * 1994-08-01 2004-04-12 株式会社トクヤマ 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
TW415949B (en) * 1996-12-19 2000-12-21 Hoffmann La Roche Vinyl pyrrolidine cephalosporin derivatives with basic substituents

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO03040116A1 *

Also Published As

Publication number Publication date
WO2003040116A1 (en) 2003-05-15
CN1585758A (zh) 2005-02-23
ITMI20012363A1 (it) 2003-05-09
KR20040064270A (ko) 2004-07-16
JP2005508385A (ja) 2005-03-31
WO2003040116A8 (en) 2004-06-17
CN1309713C (zh) 2007-04-11

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