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WO2006008161A1 - Solvates alcanoyle amide d'acide 2-(2-aminothiazole-4-yl)-2-(acyloxyimino)acetique - Google Patents

Solvates alcanoyle amide d'acide 2-(2-aminothiazole-4-yl)-2-(acyloxyimino)acetique Download PDF

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Publication number
WO2006008161A1
WO2006008161A1 PCT/EP2005/007963 EP2005007963W WO2006008161A1 WO 2006008161 A1 WO2006008161 A1 WO 2006008161A1 EP 2005007963 W EP2005007963 W EP 2005007963W WO 2006008161 A1 WO2006008161 A1 WO 2006008161A1
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WIPO (PCT)
Prior art keywords
acetic acid
formula
dimethyl
aminothiazole
acyloxyimino
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Ceased
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PCT/EP2005/007963
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English (en)
Inventor
Peter Kremminger
Herbert Silberberger
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Sandoz AG
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Sandoz AG
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    • 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
    • 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 N,N-dimethyl alkanoyl amide solvates of 2-(2-aminothiazole- 4-yl)-2-(acyloxyimino)acetic acid in crystalline form and a process for their preparation as well as a process for the preparation of cefdinir wherein such N,N-dimethyl alkanoyl amide solvates are used.
  • a 2-(2-aminothiazole-4-yI)-2-(acyloxyimino)acetic acid compounds e.g. syn-2-(2-aminothiazol-4-yl)-2-(acetoxyimino)-acetic acid and its derivatives
  • cefdinir which is ⁇ 6R, 7R)-7-[[(2Z)-(2-Amino-4-thiazolyl)(hydroxyimino)acetyl]amino]-3-ethenyl-8-oxo-5-thia-1 - azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
  • a process for the production of cefdinir includes a reaction step wherein a 2-(2-aminothiazole-4-yl)-2-(acyloxyimino)acetic acid compound is converted into an activated form thereof such as a mercaptobenzothiazolylester, a mixed acid anhydride, an acid halide or another conventional activated form by a reaction with an activating agent.
  • a 2-(2-aminothiazole-4-yl)-2-(acyloxyimino)acetic acid compound is converted into an activated form thereof such as a mercaptobenzothiazolylester, a mixed acid anhydride, an acid halide or another conventional activated form by a reaction with an activating agent.
  • Any crystal water of 2-(2- aminothiazole-4-yl)-2-(acyloxyimino)acetic acid also reacts with the activating agent and typically causes decreased yields in the activation step or/and the necessity of significantly increased amounts of activating agent, e.
  • halogenation agent such as phosphorous pentachloride (see ES 2 013 828). Therefore, it is highly desirable to use anhydrous derivatives of a 2-(2-aminothiazole-4-yl)-2-(acyloxyimino)acetic acid compound for an activation reaction.
  • 2-(2-aminothiazole-4-yl)-2-(acyloxyimino)acetic acid compounds for instance syn- 2-(2-aminothiazol-4-yl)-2-(acetoxyimino)-acetic acid are typically prepared from e.g. syn-2- (2-aminothiazol-4-yl)-2-(hydroxyimino)-acetic acid by reaction with alkanoic carboxylic acid anhydrides such as acetic acid anhydride under aqueous conditions and are crystallised in a hydrated form, e.g. as mono- or dihydrates.
  • alkanoic carboxylic acid anhydrides such as acetic acid anhydride under aqueous conditions
  • the present invention is intended to provide novel crystalline N,N-dimethyl alkanoyl amide solvates of 2-(2 ⁇ aminothiazole-4-yl)-2-(acyloxyimino)acetic acid compounds which are useful in a reaction step with an activating agent in order to produce cefdinir. It has surprisingly been found that the crystalline N,N-dimethyl alkanoyl amide solvates of 2-(2-aminothiazole- 4-yl)-2-(acyloxyimino)acetic acid compounds may be obtained in anhydrous form. In one aspect the present invention relates therefore to N,N-dimethyl alkanoyl amide solvates of 2-(2-aminothiazole-4-yl)-2-(acyloxyimino)acetic acid compounds of formula
  • a compound of formula I is in an anhydrous form.
  • Ri alkyl includes (d. 8 )alkyl, in particular (C 1-4 )alkyl, e.g. methyl, ethyl, n- propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl or tert-butyl.
  • An alkyl group of R 1 may be unsubstituted or one to three times substituted, e.g. one times substituted by halogen.
  • R 4 denotes acyl such as (C 1-6 )acyl, e.g. formyl, acetyl, propanoyl or butanoyl. In a preferred embodiment R 4 denotes C 2 -acyl, i.e. acetyl. In a preferred embodiment of the invention R 1 denotes methyl.
  • acyl includes (C ⁇ acyl, e.g. formyl, acetyl, propanoyl or butanoyl, preferably acetyl.
  • An anhydrous form of an N,N-dimethyl alkanoyl amide solvates of formula I may contain less than 1.0% (w/w) of water, i.e. from below detectable level, for instance from about 0% to below 1.0% (w/w), e.g. from about 0.01% to about 0.5% (w/w) such as from about 0.05% to about 0.2% (w/w) or even less than about 0.1% (w/w).
  • N,N-dimethyl alkanoyl amide solvates of formula I may be produced by dissolving a 2-(2- aminothiazol-4-yl)-2-(acyloxyimino)-acetic acid compound in a N,N-dimethyl alkanoyl amide of formula
  • Ri is defined as in formula I, and then effecting crystallization.
  • a hydrate of a 2-(2-aminothiazol-4-yl)-2-(acyloxyimino)-acetic acid compound e.g. a monohydrate, a dihydrate or a mixture thereof
  • a compound of formula II e.g. a compound of formula II.
  • Crystallisation of an N.N-dimethyl alkanoyl amide solvates of formula I may be effected analoguously, e.g. accordingly to conventional methods, for instance by cooling, chilling a solution made at elevated temperatures, or evaporating a part or all of the liquid solvent N 1 N- dimethyl alkanoyl amide of formula II.
  • the methods known in the art may be applied, e.g. adding a counter-solvent or friction of a glass stick on the surface of a glass vessel.
  • At least an equimolar amount of a compound of formula Il compared with the amount of 2- (2-aminothiazol-4-yl)-2-(acyloxyimino)-acetic acid compound is used.
  • an excess of a compound of formula II for example a 2 to 15 fold molar excess based on the amount of 2-(2-aminothiazol-4-yl)-2-(acyloxyimino)-acetic acid compound may be used in the crystallization reaction.
  • the reaction temperature is not critical for the crystallization of a N,N-dimethyl alkanoyl amide solvate of formula I. Suitable reaction temperatures are from 30 0 C to 70 0 C, e.g. 40°C to 6O 0 C. A reaction mixture may be kept for 30 to 180 minutes at the reaction temperature. In order to complete crystallisation of the solvate the temperature may be decreased then to -2O 0 C to 2O 0 C such as to -10°C to 0°C.
  • Counter-solvents which may optionally be added to facilitate crystallisation are liquids which, if added, decrease the solubility of an N,N-dimethyl alkanoyl amide solvate of formula I.
  • Suitable counter-solvents include ketones, such as (C 3 . 6 )ketones, nitriles such as
  • (C 2 - 6 )nitriles e.g. acetonitril, ethers such as (C 1-6 )alkyl(Ci. 6 )alkylether or THF, carboxylic acid esters such as acetic acid-(C- ⁇ -4 )-alkyl esters, or chlorinated hydrocarbons such as methylenechloride.
  • Suitable counter-solvents include further aliphatic, alicyclic or aromatic hydrocarbons such as (C 5 .i 6 )alkanes, (C 5 .- ⁇ 0 )cycloalkanes or benzene that may be unsubstituted or substituted by (C 1 ⁇ aIkVl.
  • Counter-solvents includes also mixtures of two or more of the mentioned counter-solvents.
  • a preferred counter-solvent is methylene-chloride.
  • the starting 2-(2-aminothiazol-4-yl)-2-(acyloxyimino)-acetic acid compounds e.g. in the form of hydrates may be produced by known methods.
  • - A 2-(2-aminothiazol-4-yl)-2-(acyloxyimino)-acetic acid compounds
  • the present invention relates to a process for the production of cefdinir comprising the steps a. preparing and isolating an N,N-dimethyl alkanoyl amide solvate of formula I in crystalline form, e.g. in an anhydrous form, as described above, b. reacting the crystalline N.N-dimethyl alkanoyl amide solvate obtained from step a. with an activating agent to obtain a 2-(2-aminothiazole-4-yl)-2- acyloxyimino acetic acid compound in an activated form, c. reacting the activated 2-(2-aminothiazole-4-yl)-2-acyloxyimino acetic acid compound obtained from step b. with a 7-amino-3-vinyl-3-cephem-4- carboxylic acid compound to obtain a 7-[2-(2-aminothiazole-4-yl)-2-
  • step a. The preparation of a crystalline N,N-dimethyl alkanoyl amide solvate of formula I, e.g. in an anhydrous form, in step a. may be carried out as described above. Isolation may be carried out in analogy to, e.g. according to conventional methods, e.g. by filtration. Step b. may be carried out in analogy to, e.g. according to methods known in the art, e.g. in analogy to a process as described in WO 2004/016623.
  • An activated form includes a mercaptobenzothiazolylester, a mixed acid anhydride, an acid halide such as an acid chloride or other conventional activated forms.
  • activating agents are bis- (benzothiazol-2-yl)-disulphide/triethylphosphite, bis-(benzothiazol-2-yl)-disulphide/ triphenylphosphine, phosphorous pentachloride, pivaloyl chloride/triethylamine etc.
  • Step c. may be carried out according to known methods.
  • Step d. may be effected according to methods known in the art, for instance by hydrolysis or alcoholysis with a strong acid. If step d. is performed by alcoholysis, it is desirous to use water-free strong acids. Suitable strong acids include strong organic acids such as trifluoroacetic acid, sulfonic acids such as methanesulfonic acid, benzenesulfonic acid or a toluene sulfonic acid, a sulfamic acid and water-free anorganic acids, e.g. sulphuric acid. Cleavage of the acetyl-group is usually carried out in a solvent which does not adversely affect the reaction.
  • strong organic acids such as trifluoroacetic acid, sulfonic acids such as methanesulfonic acid, benzenesulfonic acid or a toluene sulfonic acid, a sulfamic acid and water-free anorganic acids, e
  • Suitable solvents include alcohols such as methanol, ethanol, propanols, butanols.
  • the reaction is carried out at temperatures from -20 to 3O 0 C, preferably between -5 and +1 O 0 C.
  • anhydrous acid e.g. from 1.1 to 5.0 molar equivalents are used.
  • the present invention relates to a process for the production of an activated form of 2-(2-aminothiazole-4-yI)-2-acyloxyimino acetic acid compounds comprising the steps of preparing a crystalline N,N-dimethyi alkanoyl amide solvate of formula I as defined above, e.g. in an anhydrous form, and reacting the obtained crystalline N,N-dimethyl alkanoyl amide solvate of formula I of formula I with an activating agent in order to obtain a 2-(2-aminothiazole-4-yl)-2-acyloxyimino acetic acid compound in an activated form.
  • An N,N-dimethyl alkanoyl amide solvate of formula I in crystalline form, e.g. in anhydrous form, e.g. prepared by a process as set out above, is useful for the production of an activated form of 2-(2-aminothiazole-4-yl)-2-acylimino acetic acid compounds.
  • An activated form of 2-(2-aminothiazole-4-yl)-2-acylimino acetic acid compounds includes for example an acid halide such as an acid chloride, a mixed acid anhydride and a mercaptobenzothiazolyl ester or other conventional activated forms resulting from reactions with activating agents such as those listed above.
  • the present invention relates in another aspect to the use of an N,N-dimethyl alkanoyl amide solvate of formula I in crystalline form, preferably in an anhydrous form, in the preparation of an activated form of 2-(2-aminothiazole-4-yl)-2-acyloxyimino acetic acid compounds.
  • N,N-dimethyl alkanoyl amide solvate of formula I in crystalline form preferably in an anhydrous form, e.g. prepared by a process as set out above, is useful as an intermediate in the production of cefdinir. Therefore, the present invention relates in a further aspect to the use of a N,N-dimethyl alkanoyl amide solvate of formula I in crystalline form, preferably in an anhydrous form, in the production of cefdinir.
  • HMDS Hexamethyldisilazane
  • TMSI Trimethyliodsilane
  • Tributylamine 80ml Tributylamine are added and the solution is mixed with 13.2g of bis-(benzothiazol-2-yl)-disulphide and stirred thoroughly for 5 minutes, in a period of 20 minutes, 7.3ml of triethylphosphite are dispensed in and the solution is stirred vigorously for ⁇ A hours at 0 0 C, subsequently cooled to -15°C and stirred for a further VA hours. The yellowish crystalline product is filtered, washed three times, each time with 20 ml cold methylene chloride, and dried over night under vacuum at 3O 0 C.

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

Abstract

La présente invention concerne des solvates N-N-diméthyle alcanoyle amide d'acide 2-(2-aminothiazole-4-yl)-2-(acyloxyimino)acétique représentés par la formule générale (I), pouvant être préparés sous forme anhydre. Les composés cristallins représentés par la formule générale (I) peuvent être utilisés dans une étape de réaction avec un agent d'activation pour produire du cefdinir. L'invention concerne également un procédé destiné à la préparation de composés représentés par la formule générale (I).
PCT/EP2005/007963 2004-07-22 2005-07-21 Solvates alcanoyle amide d'acide 2-(2-aminothiazole-4-yl)-2-(acyloxyimino)acetique Ceased WO2006008161A1 (fr)

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GB0416380.4 2004-07-22
GB0416380A GB0416380D0 (en) 2004-07-22 2004-07-22 Organic compounds

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WO2006008161A1 true WO2006008161A1 (fr) 2006-01-26

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100448854C (zh) * 2006-06-26 2009-01-07 山东金城医药化工股份有限公司 一种制备氨噻肟酸的方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2013828A6 (es) * 1988-01-07 1990-06-01 Fujisawa Pharmaceutical Co Procedimiento para la preparacion de compuestos de 7-(2-(2-aminotiazol-4-il)-2-hidrociiminoacetamino)-3-cefem.
EP0555769A2 (fr) * 1992-02-14 1993-08-18 Hoechst Aktiengesellschaft Procédé pour la préparation d'esters de céphem, utilisés comme Prodrug
WO2004016623A1 (fr) * 2002-08-13 2004-02-26 Sandoz Ag Intermediaire de cefdinir

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2013828A6 (es) * 1988-01-07 1990-06-01 Fujisawa Pharmaceutical Co Procedimiento para la preparacion de compuestos de 7-(2-(2-aminotiazol-4-il)-2-hidrociiminoacetamino)-3-cefem.
EP0555769A2 (fr) * 1992-02-14 1993-08-18 Hoechst Aktiengesellschaft Procédé pour la préparation d'esters de céphem, utilisés comme Prodrug
WO2004016623A1 (fr) * 2002-08-13 2004-02-26 Sandoz Ag Intermediaire de cefdinir

Non-Patent Citations (1)

* 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, 1996, pages 1743 - 1749, XP008047991, ISSN: 0947-3440 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100448854C (zh) * 2006-06-26 2009-01-07 山东金城医药化工股份有限公司 一种制备氨噻肟酸的方法

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