WO2011029596A1 - Procédé par préparer des dérivés d’acide 2-aminothiazol-4-yl acétique - Google Patents

Procédé par préparer des dérivés d’acide 2-aminothiazol-4-yl acétique Download PDF

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Publication number
WO2011029596A1
WO2011029596A1 PCT/EP2010/005538 EP2010005538W WO2011029596A1 WO 2011029596 A1 WO2011029596 A1 WO 2011029596A1 EP 2010005538 W EP2010005538 W EP 2010005538W WO 2011029596 A1 WO2011029596 A1 WO 2011029596A1
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WO
WIPO (PCT)
Prior art keywords
formula
aminothiazol
acid
ester
triarylmethyloxyiminoacetic
Prior art date
Application number
PCT/EP2010/005538
Other languages
English (en)
Inventor
Danmei Dai
Wei Zhu
Siming Wang
Original Assignee
Lonza 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 Lonza Ltd filed Critical Lonza Ltd
Publication of WO2011029596A1 publication Critical patent/WO2011029596A1/fr

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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

Definitions

  • the present invention relates to a process for preparing a (2-aminothiazol-4-yl)-triaryl:
  • the object of the present invention was to provide a cost efficient process for preparing (2-aminothiazol-4-yl)-triarylmethyloxyiminoacetic acid and esters thereof, which results in good yields and can be carried out under mild conditions and compliant with Good Manufacturing Practice (GMP).
  • GMP Good Manufacturing Practice
  • R 4 is as defined above, with an alcohol of the formula R I R 2 R 3 COH, wherein R ⁇ R and R J are as defined above, in the presence of BF 3 to form a (2-aminothiazol- 4-yl)triarylmethyloxyiminoacetic acid ester of the formula II, and, optionally, subjecting the (2-aminothiazol-4-yl)triarylmethyloxyiminoacetic acid ester of the formula II to hydrolysis to obtain the (2-aminothiazol-4-yl)triarylmethyloxyiminoacetic acid of the formula I.
  • alkyl as used herein means a linear or branched alkyl group, such as methyl, ethyl, fl-propyl, isopropyl, «-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, «-hexyl and isohexyl.
  • alkoxy means a group consisting of an alkyl group as defined above and an ether oxygen, such as methoxy, ethoxy, propoxy and isopropoxy.
  • the phenyl groups of residues R 1 , R 2 and R 3 may be substituted with one or more, typically one or two substituents, wherein the substituents may be the same or different. Suitable substituents are halogens, such as fluorine, chlorine, bromine and iodine, nitro, hydroxy, Cj-6 alkyl, preferably Ci-3 alkyl, and C ⁇ alkoxy, preferably Ci_ 3 alkoxy.
  • R 1 , R 2 and R 3 each are unsubstituted phenyl groups.
  • the residue R 4 is a Ci_6-alkyl group, preferably a C alkyl group.
  • R 4 is methyl, ethyl or propyl, more preferably ethyl.
  • the starting material in the process of the invention can be the (E)-isomer or the (2T)-isomer of the (2-aminothiazol-4-yl)hydroxyiminoacetic acid ester of the formula III, so as to result in the corresponding (E)- or (Z)-(2-aminothiazol-4-yl)-triarylmethyloxyiminoacetic acid or acid ester of the formula I or II, respectively.
  • the starting material is a (Z)-(2-aminothiazol- 4-yl)hydroxyiminoacetic acid ester.
  • the boron trifluoride (BF 3 ) used in step (a) is usually provided in the form of a BF 3 adduct.
  • Suitable adducts are ether adducts, such as BF 3 -(CH 3 ) 2 0, BF 3 -(C 2 H 5 ) 2 0, BF 3 (C 4 H 9 ) 2 0 and BF 3 THF, carboxylic acid adducts, such as BF 3 CH 3 COOH, alcohol adducts, such as BF 3 CH 3 OH, adducts with ammonia or amines, such as BF 3 -NH 3 and BF 3 -N(C 2 H5) 3 , or adducts such as BF 3 -CH 3 CN or BF 3 -2 H 2 0.
  • Ether adducts (etherates) such as BF 3 (C 2 H 5 ) 2 0 are most preferred.
  • the (2-aminothiazol-4-yl)hydroxyiminoacetic acid ester of the formula III and the alcohol of the formula R'R 2 R 3 C0H are typically used in about equimolar amounts.
  • BF 3 or the adduct thereof is typically used in an amount of from 2 to 3 equivalent weights with respect to the compound of the formula III.
  • the reaction in step (a) of the process of the invention is typically carried out in an organic solvent.
  • the organic solvent is a polar organic solvent, such as a carboxylic acid, a carboxylic acid ester, an alkyl cyanide (nitrile), a ketone, an ether, or a mixture thereof.
  • Preferred solvents are acetic acid, acetonitrile, acetone, tetrahydrofuran, dioxane, ethyl acetate, and mixtures thereof.
  • Ethyl acetate and mixtures of ethyl acetate and acetic acid for example in a volumetric ratio of from 25: 1 to 1 :1, are most preferred.
  • the reaction is usually carried out at a temperature of from 0 °C to 60 °C, preferably of from 15 °C to 45 °C, for example at ambient temperature.
  • the reaction is usually completed within a period of 24 hours.
  • the (2-aminothiazol-4-yl)triarylmethyloxyiminoacetic acid ester of the formula II obtained in reaction step (a) is desirably isolated, for example by filtration, and washed to remove impurities.
  • washing with inorganic and/or organic bases in particular with an organic base, for example a tertiary amine such as N(C H 5 ) 3 , removes acid impurities and results in better yields of the desired (2-aminothiazol-4-yl)triarylmethyloxyiminoacetic acid of the formula I in the following reaction step (b).
  • organic base for example a tertiary amine such as N(C H 5 ) 3
  • the (2-aminothiazol-4-yl)triarylmethyloxyiminoacetic acid ester of the formula II is subjected to ester hydrolysis.
  • Hydrolysis of the (2-aminomiazol-4-yl)triarylmethyloxyirninoacetic acid ester of the formula II is carried out according to conventional methods, for example as disclosed in EP-A-0 555 769.
  • the ester of the formula II is subjected to alkaline hydrolysis under heating, using a strong base, for example an alkali metal hydroxide such as NaOH or KOH.
  • the resulting mixture is acidified to obtain the (2-aminothiazol-4-yl)triarylmethyloxyiminoacetic acid of the formula I.
  • the reaction mixture is usually cooled to a temperature below 30 °C, preferably below 20 °C, and the pH is adjusted to between 3.5 and 7.0, in particular to between 4.0 and 5.5, preferably using a weak acid having a pK a of at least 3, for example acetic acid, to avoid cleavage of the triarylmethyl group.
  • the (2-aminothiazol-4-yl)triarylmethyloxyiminoacetic acid of the formula I obtained in step (b) of the process of the invention can be used for the preparation of (2-aminothiazol-4-yl)-triaryl- methyloxyiminoacetic acid dialkoxythiophosphoryl esters of the formula (IV)
  • R 1 , R 2 and R 3 are as defined above and R 5 is alkyl, which is an important intermediate in the preparation of Cefdinir.
  • Conversion of the (2-aminothiazol-4-yl)triaryl- methyloxyiminoacetic acid of the formula I to give the thiophosphoryl ester of the formula IV can be carried out according to conventional methods, for example as disclosed in EP-A-0 812 846 and EP-A-0 620 228, by reacting a compound of the formula I with a chlorothiophosphate of the formula V
  • the (2-aminothiazol-4-yl)triarylmethyloxyiminoacetic acid of the formula I is reacted with the chlorothiophosphate of the formula V under an inert gas, for example N 2 , and in the presence of a catalyst and a base.
  • an inert gas for example N 2
  • Suitable catalysts useful in thiophosphorylation are those described in EP-A-0 620 228 and include tertiary amines, quaternary ammonium compounds and phosphonium compounds.
  • tertiary amine catalyst include l,4-diazabicyclo[2.2.2]octane (DABCO ® ), 2,4-dimethyl-2,4-diazapentane, 2,5-dimethyl-2,5-diazahexane, 1 ,4-dimethyl- 1 ,4-diazacyclo- hexane (1,4-dimethylpiperazine) and 2,6-dimethyl-2,6-diazaheptane.
  • DABCO ® 2,4-diazabicyclo[2.2.2]octane
  • DABCO ® 2,4-dimethyl-2,4-diazapentane
  • 2,5-dimethyl-2,5-diazahexane 1, 1 ,4
  • Examples of quaternary ammonium compounds include tetra-n-butylammonium bromide, tetra-H-butylammonium chloride and cetyltrimethylammonium bromide.
  • Examples of phosphonium compounds include tetra-n-butylphosphonium bromide.
  • Tertiary amine catalysts such as DABCO are preferred.
  • Suitable bases useful in the phosphorylation reaction include inorganic bases, for example alkali carbonates and hydrogencarbonates, such as sodium carbonate and hydrogencarbonate and potassium carbonate and hydrogencarbonate, and organic bases, for example tertiary amines such as triethylenediamine, tri( «-butyl)amine, diisopropylethylamine, pyridine and N,N-dimethylaniline. Tri( «-butyl)amine and diisopropylethylamine are preferred.
  • the reaction is usually carried out in a polar or non-polar organic solvent, such as dichloro- methane, dichloroethane, chloroform, carbon tetrachloride, toluene, xylene, acetonitrile, ethyl acetate, dioxane, tetrahydrofuran, acetone, N,N-dimethylforrnamide, N,N-dimethylacetamide, or mixtures thereof.
  • the reaction is conventionally carried out at a temperature of from -40 °C to 60 °C for a period of from 1 to 24 h.
  • the mixture was concentrated at 40 ⁇ 5 °C and 20 mbar. 75 mL of water was added and the mixture stirred for 1 h at 40 ⁇ 5 °C.
  • the crude product was filtered and washed twice with 75 mL of water and saturated aqueous NaHC0 3 , and then was re-slurried in a mixture of 28.2 g of N(C 2 H5)3 and 75 g of water.
  • the product was filtered and washed twice with 30 mL of methanol. The product was dried over P 2 0 5 for 15 h at 60 °C and 2 mbar to obtain 32.4 g of the title product as a white solid (98.2% HPLC purity, 92.0% yield).

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

Abstract

L’invention concerne un procédé pour préparer un acide (2-aminothiazol-4-yl)-triarylmethyloxy- iminoacétique représenté par la formule (I) ou un ester de celui-ci représenté par la formule (II), dans lesquelles R1, R2 et R3 indépendamment représentent éventuellement des groupes phényle substitués et R4 représente C1-6 alkyle, par réaction d’un ester d’acide (2-aminothiazol-4-yl)hydroxyiminoacétique représenté par la formule (III), dans laquelle R4 est tel que défini ci-dessus, avec un alcool représenté par la formule R1R2R3COH, dans laquelle R1, R2 et R3 sont tels que définis ci-dessus, en présence de BF3 afin de former un ester d’acide (2-aminothiazol-4-yl)triaryl-méthyloxyiminoacétique représenté par la formule (II), et éventuellement hydrolyser l’ester représenté par la formule (II) afin d’obtenir l’acide représenté par la formule (I).
PCT/EP2010/005538 2009-09-11 2010-09-09 Procédé par préparer des dérivés d’acide 2-aminothiazol-4-yl acétique WO2011029596A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP09170051.8 2009-09-11
EP09170051 2009-09-11

Publications (1)

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WO2011029596A1 true WO2011029596A1 (fr) 2011-03-17

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102977089A (zh) * 2012-12-06 2013-03-20 山东优胜美特医药有限公司 一种高纯度头孢地尼抗菌素7－位侧链合成关键原料的制备方法

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0355821A2 (fr) 1988-08-23 1990-02-28 Bristol-Myers Squibb Company Procédé de préparation de prodrug esters de céphem
EP0555769A2 (fr) 1992-02-14 1993-08-18 Hoechst Aktiengesellschaft Procédé pour la préparation d'esters de céphem, utilisés comme Prodrug
EP0620228A1 (fr) 1993-04-10 1994-10-19 Lucky Ltd. Nouveaux dérivés thiophosphate réactifs de l'acide thia(dia)zole acétique et procédé pour les préparer
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
JPH0967354A (ja) 1995-09-01 1997-03-11 Tokuyama Corp 保護水酸基を含有するチアゾール酢酸誘導体の製造方法
EP0812846A1 (fr) 1996-06-10 1997-12-17 F. Hoffmann-La Roche Ag Préparation de dérivés de céphem et isooxacéphem
WO2003040116A1 (fr) * 2001-11-09 2003-05-15 Antibioticos S.P.A. Procede de preparation de chaines laterales de cephalosporines

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0355821A2 (fr) 1988-08-23 1990-02-28 Bristol-Myers Squibb Company Procédé de préparation de prodrug esters de céphem
EP0555769A2 (fr) 1992-02-14 1993-08-18 Hoechst Aktiengesellschaft Procédé pour la préparation d'esters de céphem, utilisés comme Prodrug
EP0620228A1 (fr) 1993-04-10 1994-10-19 Lucky Ltd. Nouveaux dérivés thiophosphate réactifs de l'acide thia(dia)zole acétique et procédé pour les préparer
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
JPH0967354A (ja) 1995-09-01 1997-03-11 Tokuyama Corp 保護水酸基を含有するチアゾール酢酸誘導体の製造方法
EP0812846A1 (fr) 1996-06-10 1997-12-17 F. Hoffmann-La Roche Ag Préparation de dérivés de céphem et isooxacéphem
WO2003040116A1 (fr) * 2001-11-09 2003-05-15 Antibioticos S.P.A. Procede de preparation de chaines laterales de cephalosporines

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DEFOSSA E ET AL: "SYNTHESIS OF HR 916 K: AN EFFICIENT ROUTE TO THE PURE DIASTEREOMERS OF THE 1-(PIVALOYLOXY)ETHYL ESTERS OF CEPHALOSPORINS", LIEBIGS ANNALEN: ORGANIC AND BIOORGANIC CHEMISTRY, VCH PUBLISHERS, US, vol. 11, 1 January 1996 (1996-01-01), pages 1743 - 1749, XP008047991, ISSN: 0947-3440 *
DEFOSSA, E. ET AL., LIEBIGS ANN., 1996, pages 1743 - 1749

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102977089A (zh) * 2012-12-06 2013-03-20 山东优胜美特医药有限公司 一种高纯度头孢地尼抗菌素7－位侧链合成关键原料的制备方法

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