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EP1786793A1 - Tertiary amine salts of 2-(2-aminothiazole-4-yl)-2-(acyloxyimino)acetic acid - Google Patents

Tertiary amine salts of 2-(2-aminothiazole-4-yl)-2-(acyloxyimino)acetic acid

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Publication number
EP1786793A1
EP1786793A1 EP05778079A EP05778079A EP1786793A1 EP 1786793 A1 EP1786793 A1 EP 1786793A1 EP 05778079 A EP05778079 A EP 05778079A EP 05778079 A EP05778079 A EP 05778079A EP 1786793 A1 EP1786793 A1 EP 1786793A1
Authority
EP
European Patent Office
Prior art keywords
acetic acid
aminothiazole
formula
acyloxyimino
tertiary amine
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.)
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Application number
EP05778079A
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German (de)
French (fr)
Inventor
Peter Kremminger
Herbert Silberberger
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.)
Sandoz AG
Original Assignee
Sandoz AG
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Filing date
Publication date
Application filed by Sandoz AG filed Critical Sandoz AG
Publication of EP1786793A1 publication Critical patent/EP1786793A1/en
Withdrawn legal-status Critical Current

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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
    • C07D277/587—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

Definitions

  • the present invention relates to tertiary amine salts 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 tertiary amine salts are used.
  • a 2-(2-aminothiazole-4-yl)-2-(acyloxyimino)acetic acid compounds e.g. syn-2-(2-aminothiazol-4-yl)-2-(acetoxyimino)-acetic acid and its derivatives
  • cefdinir (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-(acyioxyimino)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-(acyioxyimino)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-(acyIoxyimino)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-(acyIoxyimino)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
  • 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 tertiary amine salts 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 now that crystalline tertiary amine salts of 2-(2-aminothiazole-4-yl)-2-(acyloxyimino)acetic acid compounds may be obtained in an anhydrous form.
  • the present invention relates therefore to tertiary amine salts of 2-(2- aminothiazole-4-yl)-2-(acyloxyimino)acetic acid compounds of formula
  • R-i, R 2 and R 3 independently represents unsubstituted or substituted alkyl, cyclo-alkyl or aryl, and R 4 denotes acyl.
  • R 1 , R 2 and R 3 alkyl includes (C 1-12 )alkyl such as (C 1-8 )alkyl, in particular (C 1- 4 )alkyl, e.g. ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl or tert-butyl.
  • Aryl includes (C 6- i 2 )aryl, e.g. phenyl or naphtyl, in particular phenyl.
  • Cycloalkyl includes (C 3-8 )cycloalkyl, preferably C 3 , C 5 or C 6 -cycloalkyl such as cyclohexyl.
  • any alkyl, cycloalkyl or aryl group of R 1 , R 2 and R 3 may be unsubstituted or one to three times substituted, e.g. one times substituted by halogen or alkyl.
  • Aryl and cycloalkyl may be also one to five times substituted by alkyl, e.g. (C 1-4 )alkyl or halogen.
  • R 1 , R 2 and R 3 each denote n-butyl, ethyl, phenyl or n-octyl.
  • Ri and R 2 denote iso-propyl and R 3 denotes ethyl.
  • Particularly preferred are compounds wherein R 1 , R 2 and R 3 each denote n-butyl.
  • 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.
  • acyl includes (C 1-6 )acyl, e.g. formyl, acetyl, propanoyl or butanoyl, preferably acetyl.
  • An anhydrous form of a crystalline tertiary amine salt of formula I may contain less than 1.0% (w/w) of water, i.e. 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).
  • Crystalline tertiary amine salts of formula I may be produced by contacting 2-(2-aminothiazol-4-yl)-2-(methylcarbonyloxyimino)-acetic acid dissolved or suspended in a solvent with an amine of formula R 1
  • the amount of added amine of formula Ii is not critical.
  • An equimolar amount of a 2-(2- aminothiazol-4-yl)-2-(acyloxyimino)-acetic acid compound dissolved or suspended in a solvent and of the amine of formula Il may be used, whereby a slight molar excess of the amine of formula II, e.g. around 1.01 to around 1.50 molar equivalents of an amine of formula Il per equivalent of 2-(2-aminothiazol-4-yl)-2-(acyloxyimino)-acetic acid compound may be of advantage.
  • a higher excess for example about 1.5 to about 5 molar equivalents of an amine of formula Il per equivalent of the 2-(2-aminothiazol-4-yl)-2- (acylcarbonyloxyimino)-acetic acid compound may also be used.
  • reaction temperature is not critical for the crystallization of a tertiary amine salt of formula I. Suitable reaction temperatures are from -3O 0 C to 7O 0 C, e.g. -2O 0 C to 35°C, particularly from -10°C to 25°C such as at ambient room temperature.
  • a salt of formula I is crystallized under mild temperature conditions such as at or below ambient room temperature because that would result in a very mild and gentle dehydration process leading to high yields and very high purities of the cefdinir to be prepared from a tertiary amine salt of formula I.
  • Suitable solvents for the crystallisation of a tertiary amine salt of formula I are solvents which may typically be used for crystallisation of amine salts of beta-lactam compounds.
  • Suitable solvents may include ketones, e.g. (C 3 . 6 )-ketones, nitriles, such as (C 1-6 )-nitriles, ethers, for example (C 2- 8)alkyl(C 2- 8)alkylethers or tetrahydrofuran (THF), amides such as dimethylacetamide or dimethylformamide and chlorinated hydrocarbons such as methylenechloride , and mixtures of two or more of said solvents.
  • ketones e.g. (C 3 . 6 )-ketones
  • nitriles such as (C 1-6 )-nitriles
  • ethers for example (C 2- 8)alkyl(C 2- 8)alkylethers or tetrahydrofuran (
  • Preferred solvents are acetone, THF and N,N-dimethylformamide.
  • a - Counter-solvents which may optionally be added to facilitate crystallisation are liquids which, if added, decrease the solubility of a tertiary amine salts of formula I.
  • Suitable counter- solvents are aliphatic, alicyclic or aromatic hydrocarbons such as (C 5-16 )alkanes, (C 5-10 )cycloalkanes or benzene that may be unsubstituted or substituted by (C 1-6 )alkyl, e.g. toluene, xylene, mesitylene or carboxylic acid esters such as acetic acid-(Ci- 4 )-alkyl esters, e.g. n-butylacetate or ethylacetate.
  • 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.
  • the present invention relates to a process for the production of cefdinir comprising the steps a. preparing a tertiary amine salt of formula I in crystalline form, preferably in an anhydrous form, as described above, b. reacting the crystalline amine salt 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. e.g. in anhydrous form
  • Step b. may be carried out in analogy, 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/triethy!phosphite, bis-(benzothiazol-2-yl)-di- sulphide/triphenylphosphine, phosphorous pentachloride, pivaloyl chloride/triethylamine etc.
  • Step c. may be carried out in analogy, e.g. according to known methods.
  • Step d. may be effected in analogy to, e.g. 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.
  • 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 +10 0 C.
  • an excess of 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-yl)-2-acyloxyimino acetic acid compounds comprising the steps of preparing a tertiary crystalline amine salt of formula I, e.g. in an anhydrous form, as defined above and reacting the obtained crystalline tertiary amine salt 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 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 a tertiary amine salt of formula I in crystalline form, e.g. in an anhydrous form, in the preparation of an activated form of 2-(2-aminothiazole-4-yi)-2-acyloxyimino acetic acid compounds.
  • a tertiary amine salt 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.
  • the present invention relates in a further aspect to the use of a tertiary amine salt of formula I in crystalline form, e.g. in an anhydrous form, in the production of cefdinir.
  • the mixture is cooled to 0 0 C and stirred at this temperature for 30 minutes.
  • the crystalline material is filtered, washed with a small portion of cold acetone and dried in vacuum.
  • syn-2-(2-aminothiazol-4-yl)-2-(methylcarbonyloxyimino)-acetic acid dihydrate are suspended in 100 ml of acetone at ambient temperature and 9.7ml of tri-(n-octyl)amine is added. The material dissolves and the mixture is cooled to -20 0 C for crystallisation and stirred at this temperature. The crystalline material is filtered, washed with a small portion of cold acetone and dried in vacuum.
  • the mixture is stirred for 2.0 h at 30 0 C, cooled to 0 0 C and the reaction mixture added dropwise at O 0 C to a solution of 7.0ml 85% phosphoric acid in 53.6ml MeOH and 11.2ml water, on which a thick crystalline suspension is formed.
  • the suspension is diluted with 257ml methylenechloride, stirred for 1h at 0 0 C and filtered.
  • the filter cake is washed once with a mixture of 90ml methylenechloride and 17ml MeOH, and then twice more, each time with 107ml methylenechloride, followed by vacuum drying at ambient room temperature.

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Abstract

Subject of the present invention are crystalline tertiary amine salts of 2-(2-aminothiazole-4­yl)-2-(acyloxyimino)acetic acid compounds of formula (I) wherein R1, R2 and R3 independently represents unsubstituted or substituted alkyl, cyclo­alkyl or aryl, and R4 denotes acyl, which may be obtained in anhydrous form. Crystalline compounds of formula I are useful in a reaction step with an activating agent in order to produce cefdinir. Additionally, a process to prepare compounds of formula I is a part of the present invention.

Description

TERTIARY AMINE SALTS OF 2~ (2-AMINOTHIAZOLE-4-YL) -2- (ACYLOXYXMINO)ACETIC ACID
The present invention relates to tertiary amine salts 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 tertiary amine salts are used.
It is known e.g. from ES 2 013 828 that a 2-(2-aminothiazole-4-yl)-2-(acyloxyimino)acetic acid compounds, e.g. syn-2-(2-aminothiazol-4-yl)-2-(acetoxyimino)-acetic acid and its derivatives, may be used as an intermediate compound in the production of 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. Usually, a process for the production of cefdinir includes a reaction step wherein a 2-(2-aminothiazole-4-yl)-2-(acyioxyimino)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-(acyIoxyimino)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.g. 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-(acyIoxyimino)acetic acid compound for an activation reaction.
However, 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. Thus, there is a need for anhydrous derivatives of 2-(2-aminothiazole-4-yl)-2-(acyloxyimino)acetic acid compounds.
The present invention is intended to provide novel crystalline tertiary amine salts 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 now that crystalline tertiary amine salts of 2-(2-aminothiazole-4-yl)-2-(acyloxyimino)acetic acid compounds may be obtained in an anhydrous form.
In one aspect the present invention relates therefore to tertiary amine salts of 2-(2- aminothiazole-4-yl)-2-(acyloxyimino)acetic acid compounds of formula
in crystalline form, preferably in anhydrous form, wherein R-i, R2 and R3 independently represents unsubstituted or substituted alkyl, cyclo-alkyl or aryl, and R4 denotes acyl.
In the meaning of R1, R2 and R3 alkyl includes (C1-12)alkyl such as (C1-8)alkyl, in particular (C1- 4)alkyl, e.g. ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl or tert-butyl. Aryl includes (C6-i2)aryl, e.g. phenyl or naphtyl, in particular phenyl. Cycloalkyl includes (C3-8)cycloalkyl, preferably C3, C5 or C6-cycloalkyl such as cyclohexyl.
Any alkyl, cycloalkyl or aryl group of R1, R2 and R3 may be unsubstituted or one to three times substituted, e.g. one times substituted by halogen or alkyl. Aryl and cycloalkyl may be also one to five times substituted by alkyl, e.g. (C1-4)alkyl or halogen. In preferred embodiments of the invention R1, R2 and R3 each denote n-butyl, ethyl, phenyl or n-octyl. In another preferred embodiment Ri and R2 denote iso-propyl and R3 denotes ethyl. Particularly preferred are compounds wherein R1, R2 and R3 each denote n-butyl.
R4 denotes acyl such as (C1-6)acyl, e.g. formyl, acetyl, propanoyl or butanoyl. In a preferred embodiment R4 denotes C2-acyl, i.e. acetyl.
If not otherwise stated herein, acyl includes (C1-6)acyl, e.g. formyl, acetyl, propanoyl or butanoyl, preferably acetyl.
An anhydrous form of a crystalline tertiary amine salt of formula I may contain less than 1.0% (w/w) of water, i.e. 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).
Crystalline tertiary amine salts of formula I, e.g. in an anhydrous form, may be produced by contacting 2-(2-aminothiazol-4-yl)-2-(methylcarbonyloxyimino)-acetic acid dissolved or suspended in a solvent with an amine of formula R 1
N
R /' R
wherein R1, R2 and R3 are defined as in formula I. For instance a hydrate of 2-(2- aminothiazol-4-yl)-2-(acyloxyimino)-acetic acid, e.g. a monohydrate, a dihydrate or a mixture thereof, is dissolved or suspended in a solvent with an amine of formula II. Crystallisation of a tertiary amine salt of formula I may occur upon stirring the solution or suspension. If desired, measures to initiate crystallization as known in the art such as cooling, adding a counter-solvent, partly evaporation of solvent or friction of a glass stick on the surface of a glass vessel may be applied in order to accelerate and complete crystallization.
The amount of added amine of formula Ii is not critical. An equimolar amount of a 2-(2- aminothiazol-4-yl)-2-(acyloxyimino)-acetic acid compound dissolved or suspended in a solvent and of the amine of formula Il may be used, whereby a slight molar excess of the amine of formula II, e.g. around 1.01 to around 1.50 molar equivalents of an amine of formula Il per equivalent of 2-(2-aminothiazol-4-yl)-2-(acyloxyimino)-acetic acid compound may be of advantage. A higher excess, for example about 1.5 to about 5 molar equivalents of an amine of formula Il per equivalent of the 2-(2-aminothiazol-4-yl)-2- (acylcarbonyloxyimino)-acetic acid compound may also be used.
The reaction temperature is not critical for the crystallization of a tertiary amine salt of formula I. Suitable reaction temperatures are from -3O0C to 7O0C, e.g. -2O0C to 35°C, particularly from -10°C to 25°C such as at ambient room temperature. Preferably, a salt of formula I is crystallized under mild temperature conditions such as at or below ambient room temperature because that would result in a very mild and gentle dehydration process leading to high yields and very high purities of the cefdinir to be prepared from a tertiary amine salt of formula I.
Suitable solvents for the crystallisation of a tertiary amine salt of formula I, e.g. in an anhydrous form, are solvents which may typically be used for crystallisation of amine salts of beta-lactam compounds. Suitable solvents may include ketones, e.g. (C3.6)-ketones, nitriles, such as (C1-6)-nitriles, ethers, for example (C2-8)alkyl(C2-8)alkylethers or tetrahydrofuran (THF), amides such as dimethylacetamide or dimethylformamide and chlorinated hydrocarbons such as methylenechloride, and mixtures of two or more of said solvents. Preferred solvents are acetone, THF and N,N-dimethylformamide. - A - Counter-solvents which may optionally be added to facilitate crystallisation are liquids which, if added, decrease the solubility of a tertiary amine salts of formula I. Suitable counter- solvents are aliphatic, alicyclic or aromatic hydrocarbons such as (C5-16)alkanes, (C5-10)cycloalkanes or benzene that may be unsubstituted or substituted by (C1-6)alkyl, e.g. toluene, xylene, mesitylene or carboxylic acid esters such as acetic acid-(Ci-4)-alkyl esters, e.g. n-butylacetate or ethylacetate.
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.
In another aspect the present invention relates to a process for the production of cefdinir comprising the steps a. preparing a tertiary amine salt of formula I in crystalline form, preferably in an anhydrous form, as described above, b. reacting the crystalline amine salt 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-
(acyloxyimino)-acetylamino]-3-vinyl-3-cephem-4-carboxylic acid compound, and d. splitting off the acyl-group at the imino group from a compound as obtained in step c. to obtain cefdinir.
The preparation of a tertiary amine salt of formula I in step a., e.g. in anhydrous form, may be carried out as described above. Step b. may be carried out in analogy, 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. Examples of activating agents are bis-(benzothiazol-2-yl)-disulphide/triethy!phosphite, bis-(benzothiazol-2-yl)-di- sulphide/triphenylphosphine, phosphorous pentachloride, pivaloyl chloride/triethylamine etc. Step c. may be carried out in analogy, e.g. according to known methods. Step d. may be effected in analogy to, e.g. 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. Suitable solvents include alcohols such as methanol, ethanol, propanols, butanols. The reaction is carried out at temperatures from -20 to 3O0C, preferably between -5 and +100C. Typically an excess of anhydrous acid, e.g. from 1.1 to 5.0 molar equivalents are used.
In another aspect the present invention relates to a process for the production of an activated form of 2-(2-aminothiazole-4-yl)-2-acyloxyimino acetic acid compounds comprising the steps of preparing a tertiary crystalline amine salt of formula I, e.g. in an anhydrous form, as defined above and reacting the obtained crystalline tertiary amine salt 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. A tertiary amine salt of formula I in crystalline form, preferably in an 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.
Therefore, the present invention relates in another aspect to the use of a tertiary amine salt of formula I in crystalline form, e.g. in an anhydrous form, in the preparation of an activated form of 2-(2-aminothiazole-4-yi)-2-acyloxyimino acetic acid compounds.
A tertiary amine salt 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 tertiary amine salt of formula I in crystalline form, e.g. in an anhydrous form, in the production of cefdinir.
The following Examples will indicate the different aspects of the present invention and are in no way intended to limit the scope of the present invention. All temperatures are given in 0C.
Abbreviations:
MeOH: Methanol HMDS: Hexamethyldisilazane
TMSI: Trimethyliodsilane
EtOH: Ethanol
TsOH: Toluene sulfonic acid DMAc: Dimethylacetamide
Example 1
(βR7ffl-7-rr(2Z)-(2-Amino-4-thiazolyl)(hvdroχyimino)acetvπamino1-3-ethenyl-8-oxo-5- thia-1-azabicyclor4.2.01oct-2-ene-2-carboxylic acid (Cefdinir)
A solution of 21.1 g of 7-[2-(2-aminothiazol-4-yl)-2-(methylcarbonyloxyimino)acetamido]-3- vinyl-cephem-4-carboxyIic acid in the form of a salt with orfΛo-phosphoric acid in 80 ml of MeOH is mixed at 0° with 3.9 ml of concentrated H2SO4, the mixture obtained is stirred at <10° and added dropwise to a solution of 17.5g NaHCO3 in 600ml of water. The pH value of the mixture obtained is adjusted to pH 5.3, 1.8 g of activated carbon are added, the mixture is stirred, and the activated carbon is filtered off and washed with H2O. The filtrate obtained is heated to 25° to 30° and the pH value is adjusted to pH 3 with 2n H2SO4. (6R17tf)-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 crystallises, is filtered off, washed and dried. Weighed product: 12.08 g.
Example 2
7r/-/>7-ibafy/)a/77/7?omty/77 fey/7-2-(2-arninothiazol-4-yl)~2-(methylcarbonyloxyirnino)- acetate)
25.Og syn-2-(2-aminothiazol-4-yl)-2-(methylcarbonyloxyimino)-acetic acid dihydrate (water content: 14.5%) are suspended in 100 ml of acetone at ambient temperature and 24.4ml of tri-(n-butyl)amine are added. The material dissolves and immediately begins to crystallize again. The mixture is cooled to -10°C and stirred at this temperature for 30 minutes. The cristalline material is filtered, washed with a small portion of cold acetone and dried in vacuum.
Weighed product: 32.7g H20: 0.1%
1H-nmr(CDCI3) δ 0.87(t,9H,J=7.4Hz), 1.29(m,6H), 1.58(m,6H), 2.08(s,3H), 2.89(m,6H),
6.78(s,1 H), 7.55(br s,2H)
IR(golden gate): 3431 , 3109, 2959, 2873, 1750, 1608, 1375, 1227 cnϊ1 mp: 105 0C (decomposition) X-ray diffraction pattern see figure 1 Figure 1 : X-ray diffraction pattern of tri-(n-butyl)ammonium (syn-2-(2-aminothiazol-4-yl)-2- (methylcarbonyloxyimino)-acetate) prepared according to Example 2; Analytical XRD equipment: Powder X-ray diffractometer AXS-BRUKER D-8; Cu-target ( wavelength CuKα1,2 : =.15406 nm), scintillation counter, parallel beam optics, theta/theta coupled, 9 position sampler changer; operating conditions: 4OkV, 40mA,continuous scan 2-40° theta/2Theta; step size 0.01 steps per second, counting time 2 seconds, room conditions; sample preparation: standard sample holders
S S 8 S
S S § S
(sdo) puQoss jsd s;unoo Example 3
Tri(n-butyl)ammonium feyn-2-(2-aminothiazol-4-yl)-2-(methylcarbonyloxyimino)- acetate)
5.Og syn-2-(2-aminothiazol-4-yl)-2-(methylcarbonyloxyimino)-acetic acid monohydrate (water content: 8.0%) is suspended in 20 ml of acetone at ambient temperature and 5.2 ml of tri-(n- buty!)amine are added. The material partly dissolves and immediately begins to crystallize again. The mixture is cooled to -100C and stirred at this temperature for 60 minutes. The crystalline material is filtered, washed with a small portion of cold acetone and dried in vacuum. Weighed product: 7.2g H2O: 0.5% Other physical and spectroscopic data identical as described in example 2.
Example 4 Tri-(n-butyl)ammonium feyw-2-(2-aminothiazol-4-yl)-2-(methylcarbonyloxyimino)- acetate)
5.Og sy/?-2-(2-aminothiazol-4-yl)-2-(methylcarbonyloxyimino)-acetic acid dihydrate are dissolved in 20 ml of N,N-dimethylformamide at ambient temperature and 5.8ml tri-(n- butyl)amine is added. The clear solution is cooled to 00C and white crystals are formed. 200ml acetone are added and the resulting crystal suspension is cooled to -100C and stirred at this temperature for 60 minutes. The crystalline material is filtered, washed with a small portion of cold acetone and dried in vacuum.
Weighed product: 5.7g
H2O: 0.1% Other physical and spectroscopic data identical as described in example 2.
Example 5
5.Og sy/?-2-(2-aminothiazol-4-yl)-2-(methylcarbonyloxyimino)-acetic acid dihydrate are dissolved in 20 ml of N,N-dimethylformamide at ambient temperature and 3.4ml of triethylamine are added. The material begins to crystallize and 200ml acetone are added.
The mixture is cooled to 00C and stirred at this temperature for 30 minutes. The crystalline material is filtered, washed with a small portion of cold acetone and dried in vacuum.
Weighed product: 5.7g H20: 0.3% 1H-IW(CD3OD) δ 1.30(t,9H,J=7.4Hz), 2.19(s,3H), 3.21(q,6H,J=7.4Hz), 7.08(s,1H) |R(golden gate): 3302, 3096, 2987, 1756, 1613, 1536, 1384, 1356, 1206 cm"1 mp: 104 °C (decomposition)
Example 6
Diisopropylethylammonium fev77-2-(2-aminothiazol-4-yl)-2-(methylcarbonyloxyirnino)- acetate)
5.Og syπ-2-(2-aminothiazol-4-yl)-2-(methylcarbonyloxyimino)-acetic acid dihydrate are dissolved in 20 ml of N,N-dimethylformamide at ambient temperature and 4.2m! of diisopropylethylamine are added. The material begins to crystallize and 200ml acetone are added. The mixture is stirred at this temperature for 60 minutes. The crystalline material is filtered, washed with a small portion of acetone and dried in vacuum.
Weighed product: 6.3g
H2O: 0.2% 1H-nmr(CD3OD) δ 1.35(m,15H), 2.19(s,3H), 3.20(q,2H,J=7.3Hz), 3.70(m,2H), 7.06(s,1H)
IR(goldengate): 3244, 3111,2986, 1752, 1613, 1541, 1387, 1363, 1218cm"1 mp: 1100C (decomposition)
Example7 rf/Tn-ocfW)ammon/om rsyn-2-(2-aminothiazol-4-yl)-2-(methylcarbonyloxyimino)- acetate)
5.Og syn-2-(2-aminothiazol-4-yl)-2-(methylcarbonyloxyimino)-acetic acid dihydrate are suspended in 100 ml of acetone at ambient temperature and 9.7ml of tri-(n-octyl)amine is added. The material dissolves and the mixture is cooled to -200C for crystallisation and stirred at this temperature. The crystalline material is filtered, washed with a small portion of cold acetone and dried in vacuum.
Weighed product 8.2g
H2O: 0.2%
1H-nmr(CDCI3) δ 0.82(t,9H,J=6.8Hz), 1.22(m,30H), 1.61(m,6H), 2.09(s,3H), 2.89(m,6H), 6.79(s,1H), 7.55(br s,2H)
IR(goidengate): 3427, 3100, 2924, 2855, 1757, 1612, 1365, 1216cm"1 mp: 900C (decomposition) Example 8
Svn-2-(2-Aminothiazol-4-yl)-2-(methylcarbonyloxyimino)-acetic acid- mercaptobenzothiazolylester
12.7 g crystalline anhydrous tri(n-butyl)ammonium (syn-2-(2-aminothiazol-4-yl)-2- (methylcarbonyloxyimino)-acetate) (water content 0.1% by weight) are dissolved at room temperature in 70 ml of methylene chloride and then cooled to 00C. 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 ΛA hours at 00C, 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 in a vacuum at 3O0C.
Weighed product: 11.2g
1H-nmr(DMSO-d6) δ2.22(s, 3H), 7.36(s, 1H), 7.48(br s, 2H), 7.59(m, 2H), 8.09(m, 1H),
8.22(m, 1 H)
Example 9
7-f2-(2-aminothiazol-4-yl)-2-(methylcarbonyloxyimino)acetamido1-3-vinyl-cephem-4- carboxylic acid.para-toluenesulfonate
15.Og 7-amino-3-vinyl-3-cephem-4-carboxylic acid are suspended in 150ml dichloromethane and the mixture heated to boiling. 13.6ml HMDS and 10μl TMSI are added and the mixture heated for 2h under reflux conditions and passing a nitrogen stream through the solution.
The clear solution is cooled to 300C and mixed with 30ml DMAc. 27.6g syn-2-(2- aminothiazo!-4-yi)-2-(methylcarbonyloxyirnino) acetic acid -mercaptobenzthiazolylester is added in 1 portion and stirred for 3h at 3O0C. The reaction mixture is added dropwise to a solution of 16.4Og TsOH. hydrate in a mixture of 31.5ml EtOH and 7.2ml water. The product crystallizes out. The suspension is diluted with 360ml methylene chloride and stirred for
60min at O0C. The crystalline product is filtered off and washed three times, each time with
75ml cold methylene chloride, and dried under vacuum at 300C.
Yield: 39.32g
1H-nmr(DMSO-d6) δ 2.21 (s,3H), 2.28(s,3H), 3.61&3.89(ABq, 2H,J=17.7Hz), 5.25(d,1H,J=4.8Hz), 5.32(d,1H,J=11.4Hz), 5.61(d,1H,J=17.5Hz), 5.84(dd,1 H,J=4.8&7.9Hz), 6.92(dd,1H,J=11.1 &17.4Hz), 7.12&7.48(AA'BB'm,4H), 7.22(s,1 H), 10.04(d,1H,J=7.9Hz) Toluenesulfonic acid: 26.0% Mp: 1450C (decomposition). Example 10
7-r2-(2-aminothiazol-4-yl)-2-(methylcarbonyloxyimino)acetamido1-3-vinyl-cephem-4- carboxylic acid. phosphate
21.43g 7-amino-3-viny-3l-cephem-4-carboxyIic acid are suspended in 214ml dichloromethane, mixed with 15.68ml HMDS and 29μl TMSI at RT and heated for 2h under reflux conditions and passing a nitrogen stream through the solution. The mixture is cooled to 300C and 42.9ml DMAc and 39.4g syA7-2-(2-aminothiazol-4-yl)-2- (methylcarbonyloxyimino)-acetic acid-mercaptobenzthiazolylester are added. The mixture is stirred for 2.0 h at 300C, cooled to 00C and the reaction mixture added dropwise at O0C to a solution of 7.0ml 85% phosphoric acid in 53.6ml MeOH and 11.2ml water, on which a thick crystalline suspension is formed. The suspension is diluted with 257ml methylenechloride, stirred for 1h at 00C and filtered. The filter cake is washed once with a mixture of 90ml methylenechloride and 17ml MeOH, and then twice more, each time with 107ml methylenechloride, followed by vacuum drying at ambient room temperature.
Yield: 42.6Og
1H-nmr(DMSO-d6) δ 2.17(s,3H), 3.59&3.88(ABq, 2H,J=17.6Hz), 5.23(d,1H,J=4.8Hz), 5.31 (d, 1 H, J=11.4Hz)1 5.60(d, 1 H1J=I 7.5Hz), 5.82(dd,1 H,J=4.8&8.0Hz), 6.90(dd,1 H,J=11.2&17.6Hz), 7.08(s,1H), 9.91(d,1H,J=8.0Hz) H3PO4: 16.9%
Mp: 170°C (decomposition)

Claims

Claims
1. A tertiary amine salt of 2-(2-aminothiazole-4-yl)-2-(acyloxyimino)acetic acid in crystalline form of formula
wherein R1, R2 and R3 independently represents unsubstituted or substituted alkyl, cyclo-alkyl or aryl, and R4 denotes acyl.
2. The compound according to claim 1 wherein R1, R2 and R3 each denote n-octyl, n- butyl, phenyl or ethyl, or wherein R1 and R2 each denote iso-propyl and R3 denotes ethyl.
3. The compound according to claim 1 or claim 2 in an anhydrous form.
4. The compound according to claim 3 with a water content of below 1 %(w/w).
5. The compound according to any one of claims 1 to 4 wherein R4 is acetyl.
6. A process for the preparation of a crystalline tertiary amine salt of formula I as defined in claim 1 comprising the step of bringing an amine of formula
N-R 1 Il
wherein Ri, R2 and R3 are as defined in claim 1 , into contact with a suspension or solution of a 2-(2-aminothiazole-4-yl)-2-
(acyloxyimino)acetic acid compound in a solvent to obtain an amine salt of formula I in crystalline form.
7. The process according to claim 6 wherein a 2-(2-aminothiazole-4-yl)-2-
(acylimino)acetic acid compound in the form of a hydrate is dissolved or suspended before it is contacted with the amine of formula II.
8. A process for the production of cefdinir comprising the steps a. preparing a tertiary amine salt of formula I in crystalline form as defined in any one of claims 1 to 5, b. reacting the crystalline amine salt obtained from step a. with an activating agent to obtain 2-(2-aminothiazole-4-yl)-2-acylxyimino acetic acid in an activated form, c. reacting the activated 2-(2-aminothiazole-4-yl)-2-acyloxyimino acetic acid obtained from step b. with 7-amino-3-vinyl-3-cephem-4-carboxylic acid to obtain a 7-[2-(2-aminothiazole-4-yl)-2-(acyloxyimino)-acetylamino]-3-vinyl-3- cephem-4-carboxylic acid, and d. splitting off the acyl-group at the imino group from a compound as obtained in step c. to obtain cefdinir.
9. The process according to claim 8 wherein the activated form of a 2-(2-aminothiazole-4- yl)-2-acyloxyimino acetic acid compound is a mercaptobenzothiazolylester, an acid halogenide or a mixed acid anhydride.
10. A process for the production of an activated form of a 2-(2-aminothiazole-4-yl)-2- acyloxyimino acetic acid compound wherein a tertiary amine salt of formula I as defined in any one of claims 1 to 5 is prepared and then reacted with an activating agent.
11. Use of a tertiary amine salt of formula I in crystalline form as defined in any one of claims 1 to 5 in the production of an activated form of a 2-(2-aminothiazole-4-yl)-2- acylimino acetic acid compound.
12. Use of a tertiary amine salt of formula I in crystalline form as defined in any one of claims 1 to 5 in the production of cefdinir.
EP05778079A 2004-07-22 2005-07-21 Tertiary amine salts of 2-(2-aminothiazole-4-yl)-2-(acyloxyimino)acetic acid Withdrawn EP1786793A1 (en)

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KR101058135B1 (en) 2008-04-04 2011-08-24 대웅바이오 주식회사 Useful Intermediates for Cefdinir Synthesis and Methods for Preparing Cefdinir Using the Same
US8614315B2 (en) * 2009-12-25 2013-12-24 Mahmut Bilgic Cefdinir and cefixime formulations and uses thereof
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