WO2006008161A1

WO2006008161A1 - Alkanoyl amide solvates of 2-(2-aminothiazole-4-yl)-2-(acyloxyimino)acetic acid

Info

Publication number: WO2006008161A1
Application number: PCT/EP2005/007963
Authority: WO
Inventors: Peter Kremminger; Herbert Silberberger
Original assignee: Sandoz AG
Current assignee: Sandoz AG
Priority date: 2004-07-22
Filing date: 2005-07-21
Publication date: 2006-01-26
Anticipated expiration: 2007-01-22
Also published as: GB0416380D0

Abstract

Subject of the present invention are N,N-dimethyl alkanoyl amide solvates of 2-(2-aminothiazole -4-yl)-2(acyloxyimino)acetic acid compounds of formula (I) which may be prepared in an 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

Alkanoyl Amide Solvates of 2-(2-aminothiazole-4-yl)-2-(acyloxyimino)acetic acid

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.

It is known e.g. from ES 2 013 828 that 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, 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-(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.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-(acyloxyimino)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 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

in crystalline form, wherein R₁ represents hydrogen, or unsubstituted or substituted alkyl, and R₄ denotes acyl. Preferably, a compound of formula I is in an anhydrous form.

In the meaning of 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 R₁ may be unsubstituted or one to three times substituted, e.g. one times substituted by halogen.

R₄ denotes acyl such as (C_1-6)acyl, e.g. formyl, acetyl, propanoyl or butanoyl. In a preferred embodiment R₄ denotes C₂-acyl, i.e. acetyl. In a preferred embodiment of the invention R₁ denotes methyl.

If not otherwise stated herein, 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

wherein Ri is defined as in formula I, and then effecting crystallization. For instance a hydrate of a 2-(2-aminothiazol-4-yl)-2-(acyloxyimino)-acetic acid compound, e.g. a monohydrate, a dihydrate or a mixture thereof, is dissolved in 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 N₁N- dimethyl alkanoyl amide of formula II. In order to accelerate crystallization 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. Typically 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 30⁰C to 70⁰C, e.g. 40°C to 6O⁰C. 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 -2O⁰C to 2O⁰C 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 (C₃.₆)ketones, nitriles such as

(C₂-₆)nitriles e.g. acetonitril, ethers such as (C_1-6)alkyl(Ci.₆)alkylether or THF, carboxylic acid esters such as acetic acid-(C-ι_-4)-alkyl esters, or chlorinated hydrocarbons such as methylenechloride. Suitable counter-solvents include further aliphatic, alicyclic or aromatic hydrocarbons such as (C₅.i₆)alkanes, (C₅.-ι₀)cycloalkanes or benzene that may be unsubstituted or substituted by (C₁^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 -

In another aspect 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-

(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 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. Examples of 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. 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 +1 O⁰C. 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-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.

Therefore, 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.

An 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.

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 mp: melting point

Example 1

(6/?,7ffl-7-rf(2Z)-(2-Amino-4-thiazolyl)(hvdroxyimino)acetvnamino1-3-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-cephenrM-carboxylic acid in the form of a salt with orf/jo-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. (6R₁7R)-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

Sy/?-2-(2-Aminothiazol-4-yl)-2-(methylcarbonyloxyimino)-acetic acid N,N- dimethylacetamide solvate

At a temperature of 50⁰C 15,Og sy/i-2-(2-aminothiazol-4-yl)-2-(methylcarbonyloxyimino)- acetic acid dihydrate (water content 13,5%) are dispensed into 54,0ml N₁N- dimethylacetamide and stirred for 90 min. The crystalline suspension is cooled to O⁰C and

150ml methylene chloride are added. The white crystals are filtered, washed three times, each with 30ml methylene chloride, and dried over night in vacuum at 30⁰C.

Weighed product: 15,9g

H₂O: 0.4% ¹H-nmr(DMSO-d) δ 1.94(s,3H), 2.14(s,3H), 2.77(s,3H), 2.92(s,3H), 7.19(s,3H), 7.37(br s,2H)

IR(golden gate): 3423, 3107, 1764, 1610, 1542, 1360, 1205, 1174 cm^'1 mp: 113 ⁰C (decomposition)

Example 3 Sy/7-2-(2-Aminothiazol-4-yl)-2-(methylcarbonyloxyimino)-acetic acid N,N- dimethylacetamide solvate

At a temperature of 5O⁰C 15,Og syn-2-(2-aminothiazol-4-yl)-2-(methylcarbonyloxyimino)- acetic acid monohydrate (water content 6,4%) are dispensed into 58,0ml N₁N- dimethylacetamide and stirred for 90 min. The crystalline suspension is cooled to 0⁰C and 150ml methylene chloride are added. The white crystals are filtered, washed three times, each with 30ml methylene chloride, and dried over night in vacuum at 3O⁰C. Weighed product: 17,Og H₂O: 0.2% Other physical and spectroscopic data identical as described in example 2.

Example 4

Svn-2-(2-Aminothiazol-4-yl)-2-(methylcarbonyloxyimino)-acetic acid- mercaptobenzothiazolylester 9,5 g crystalline dehydrated syπ-2-(2-aminothiazol-4-yl)-2-(methylcarbonyloxyimino)-acetic acid.N.N-dimethylacetamide solvate are suspended at room temperature in 70 ml of methylene chloride and then cooled to O⁰C. 8,0ml 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 ^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 under vacuum at 3O⁰C. Weighed product: 10,9g ¹H-nmr(DMSO-c/₆) δ2.22(s, 3H), 7.36(s, 1 H), 7.48(br s, 2H), 7.59(m, 2H), 8.09(m, 1H), 8.22(m, 1 H)

Example 5

7-r2-(2-aminothiazol-4-yl)-2-(methylcarbonyloxyimino)acetamido1-3-vinyl-cephem-4- carboxylic acid.joara-toluenesulfonate 15.Og 3-vinyl-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 30°C and mixed with 30ml DMAc. 27.6g syn-2-(2-aminothiazol-4-yl)-2- (methylcarbonyloxyimino) acetic acid -mercaptobenzthiazolylester is added in one 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 0°C. The crystalline product is filtered off and washed three times , each time with 75ml cold methylene chloride, and dried under vacuum at 30°C. Yield: 39.32g

¹H-nmr(DMSO-d₆) δ 2.21 (s,3H), 2.28(s,3H), 3.61&3.89(ABq, 2H₁J=IZJHz), 5.25(d,1H,J=4.8Hz), 5.32(d,1H,J=11.4Hz), 5.61 (d,1 H,J=17.5Hz), 5.84(dd,1 H,J=4.8&7.9Hz), 6.92(dd,1 H,J=11.1&17.4Hz), 7.12&7.48(AA'BB'm,4H), 7.22(s,1 H), 10.04(d,1 H,J=7.9Hz) Toluenesulfonic acid: 26.0% Mp: 145⁰C (decomposition).

Example 6 7-r2-(2-aminothiazol-4-yl)-2-(methylcarbonyloxyimino)acetamido1-3-vinyl-cephem-4- carboxylic acid. phosphate

21.43g 7-amino-3-vinyl-3-cephem-4-carboxylic acid is suspended in 214ml dichloromethane, mixed with 15.68ml HMDS and 29μl TMSI at ambient room temperature and heated for 2h under reflux conditions and passing a nitrogen stream through the solution. The mixture is cooled to 30⁰C and 42.9m! DMAc and 39.4g syn-2-(2-aminothiazol-4-yl)-2-

(methylcarbonyloxyimino)-acetic acid-mercaptobenzthiazolylester are added. The mixture is stirred for 2 h at 30⁰C, cooled to O⁰C 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 1 h at O⁰C 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,1 H,J=4.8Hz),

5.31(d,1H,J=11.4Hz), 5.60(d,1H,J=17.5Hz), 5.82(dd,1H,J=4.8&8.0Hz),

6.90(dd,1 H,J=11.2&17.6Hz), 7.08(s,1H), 9.91 (d,1 H,J=8.0Hz)

H₃PO₄: 16.9%

Mp: 170⁰C (decomposition)

Claims

1. An N,N-dimethyl alkanoyl amide solvate of 2-(2-aminothiazole-4-yl)-2- (acyloxyimino)acetic acid in crystalline form of formula

wherein R₁ represents hydrogen, or unsubstituted or substituted alkyl, and R₄ denotes acyl.

2. The compound according to claim 1 wherein Ri is methyl.

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. A compound according to any one of claims 1 to 4 wherein R₄ is acetyl.

6. A process for the preparation of an N,N-dimethyl alkanoyl amide solvate of formula I as defined in claim 1 comprising the step of dissolving a 2-(2-aminothiazol-4-yl)-2- (acyloxyimino)acetic acid compound in an N,N-dimethyl alkanoyl amide of formula

wherein R₁ is defined as in formula I of claim 1 , and effecting crystallization to obtain an N,N-dimethyl alkanoyl amide solvate 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 in an N, N- dimethyl alkanoyl amide of formula II.

8. 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 as defined in any one of claims 1 to 4, b. reacting the crystalline N.N-dimethyl alkanoyl amide solvate obtained from step a. with an activating agent to obtain 2-(2-aminothiazole-4-yl)-2- acyloxyimino 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 an N,N-dimethyl alkanoyl amide solvate 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 an N,N-dimethyl alkanoyl amide solvate 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 an N,N-dimethyl alkanoyl amide solvate of formula I in crystalline form as defined in any one of claims 1 to 5 in the production of cefdinir.