WO2011029596A1

WO2011029596A1 - Process for preparing 2-aminothiazol-4-yl-acetic acid derivates

Info

Publication number: WO2011029596A1
Application number: PCT/EP2010/005538
Authority: WO
Inventors: Danmei Dai; Wei Zhu; Siming Wang
Original assignee: Lonza AG
Current assignee: Lonza AG
Priority date: 2009-09-11
Filing date: 2010-09-09
Publication date: 2011-03-17
Anticipated expiration: 2012-03-11

Abstract

The invention provides a process for preparing a (2-aminothiazol-4-yl)-triarylmethyloxy- iminoacetic acid of the formula (I) or an ester thereof of the formula (II) wherein R¹, R² and R³ independently are optionally substituted phenyl groups and R⁴ is C_1-6alkyl, by reacting a (2-aminothiazol-4-yl)hydroxyiminoacetic acid ester of the formula (III) wherein R⁴ is as defined above, with an alcohol of the formula R¹R²R³COH, wherein R¹, R² and R³ are as defined above, in the presence of BF₃ to form a (2-aminothiazol-4-yl)triaryl-methyloxyiminoacetic acid ester of the formula (II), and, optionally, hydrolyzing said ester of formula (II) to obtain the acid of formula (I).

Description

Process for preparing 2-aminothiazol-4-yl-acetic acid derivates

The present invention relates to a process for preparing a (2-aminothiazol-4-yl)-triaryl:

oxyiminoacetic acid of the formula I or an ester thereof of the formula II

(I) (Π) wherein R¹, R² and R³ independently are optionally substituted phenyl groups and R⁴ is Ci_6 alkyl.

(Z)-(2-Aminothiazol-4-yl)-trityloxyiminoacetic acid and acid esters as well as the thiophosphate derivatives obtainable therefrom, in particular (2)-(2-aminothiazol-4-yl)-trityloxyiminoacetic acid diethoxythiophosphoryl ester, are important intermediates in the preparation of Cephem and Isoxacephem derivatives (EP-A-0 812 846) such as Cefdinir, a semi synthetic broad- spectrum antibiotic.

Several methods for tritylating ethyl (Z)-(2-aminothiazol-4-yl)hydroxyiminoacetate using trityl chloride to produce ethyl (Z)-(2-aminothiazol-4-yl)-trityloxyiminoacetate and the corresponding acid thereof have been disclosed. These methods comprise the use of potassium tert- butoxide (EP-A-0 555 769; Defossa, E. et al., Liebigs Ann. (11), 1743-1749; 1996), sodium hydride (EP-A-0 355 821, JP-A-07-097368) and phenyllithium (JP-A-09-067354) and suffer from the drawback that they require reagents which are expensive or difficult to handle and that yield in the desired final product is not sufficient for large scale preparation. The object of the present invention, therefore, 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). This object has been achieved by the present invention which provides a process for preparing a (2-aminothiazol-4-yl)-triarylmethyloxyiminoacetic acid of the formula I or an ester thereof of the formula II

(I) (Π) wherein R¹, R² and R³ independently are optionally substituted phenyl groups and R⁴ is Ci_6 alkyl, said process comprising:

(a) reacting a (2-aminothiazol-4-yl)hydroxyiminoacetic acid ester of the formula III

wherein R⁴ is as defined above, with an alcohol of the formula R^IR²R³COH, wherein R\ R and R^J are as defined above, in the presence of BF₃ 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.

The term 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.

The term alkoxy as used herein 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 R¹ , R² and R³ 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. Preferably, R¹ , R² and R³ each are unsubstituted phenyl groups.

The residue R⁴ is a Ci_6-alkyl group, preferably a C alkyl group. Preferably, R⁴ 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. Preferably, the starting material is a (Z)-(2-aminothiazol- 4-yl)hydroxyiminoacetic acid ester.

The boron trifluoride (BF₃) used in step (a) is usually provided in the form of a BF₃ adduct. Suitable adducts are ether adducts, such as BF₃-(CH₃)₂0, BF₃-(C₂H₅)₂0, BF₃ (C₄H₉)₂0 and BF₃ THF, carboxylic acid adducts, such as BF₃ CH₃COOH, alcohol adducts, such as BF₃ CH₃OH, adducts with ammonia or amines, such as BF₃-NH₃ and BF₃-N(C₂H5)₃, or adducts such as BF₃-CH₃CN or BF₃-2 H₂0. Ether adducts (etherates) such as BF₃ (C₂H₅)₂0 are most preferred.

The (2-aminothiazol-4-yl)hydroxyiminoacetic acid ester of the formula III and the alcohol of the formula R'R²R³C0H are typically used in about equimolar amounts. BF₃ 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. Preferably, 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 H₅)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).

To obtain the (2-aminothiazol-4-yl)triarylmethyloxyiminoacetic acid of the formula I, 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. Preferably, 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. For acidification, 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)

wherein R¹, R² and R³ are as defined above and R⁵ 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

wherein R is as defined above.

Preferably, 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 N₂, and in the presence of a catalyst and a base.

Suitable catalysts useful in thiophosphorylation are those described in EP-A-0 620 228 and include tertiary amines, quaternary ammonium compounds and phosphonium compounds. Examples of the 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. 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 present invention is illustrated in more detail by the following non-limiting examples.

Examples

General methods of analysis

High performance liquid chromatography (HPLC) in Examples 1 to 3 below was performed under the following conditions:

1H NMR was carried out at 400 MHz with tetramethylsilane as an internal standard (0 ppm). ¹³C NMR was carried out at 100 MHz.

Example 1

Preparation of ethyl (Z)-(2-aminothiazol-4-yl)triphenylmethyloxyiminoacetate

20.0 g (0.093 mol) of ethyl (Z)-(2-aminothiazol-4-yl)hydroxyiminoacetate and 25.4 g (0.098 mol) of triphenylmethanol were charged into a reactor inerted with N₂ at 0 ± 5 °C, followed by 90 mL of ethyl acetate and lO mL of acetic acid. 27.7 g (0.195 mol) of boron trifluoride diethyl etherate were added dropwise over 30 min at 0 ± 5 °C and the mixture was stirred for 1.0 h. Then the reaction mixture was warmed to 25 ± 5 °C and stirred for another 23 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 NaHC0₃, and then was re-slurried in a mixture of 28.2 g of N(C₂H5)3 and 75 g of water. The product was filtered and washed twice with 30 mL of methanol. The product was dried over P₂0₅ 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). Ή NMR (400 MHz, DMSO-i/₆): δ = 1.29 (t, J= 7.2 Hz, 3H), 4.39 (q, J= 7.2 Hz, 2H), 6.75 (s, 1H), 7.25-7.36 (m, 17H).

¹³C NMR (100 MHz, DMSO- ₆) δ = 14.5, 62.1, 91.6, 109.6, 127.9, 128.3, 128.8, 141.6, 144.0, 148.2, 163.4, 169.4.

Example 2

Preparation of (Z)-(2-aminothiazol-4-yl)triphenylmethyloxyiminoacetic acid 97.5 mL of water and 1 1.25 g (0.170 mol) of KOH were charged into a reactor at 25 ± 5 °C. Then 39 g (0.085 mol) of the ethyl (Z)-(2-aminothiazol-4-yl)triphenylmethyloxyiminoacetate obtained in Example 1 and 97.5 mL of ethanol were added at 25 ± 5 °C. The reaction mixture was refluxed at 70 °C until the ethyl (Z)-(2-aminothiazol-4-yl)triphenylmethyloxyiminoacetate reached <1.0 area% on HPLC (about 3.5 h). The mixture was cooled to 10 °C and 97.5 mL of water was added. Then 15.36 g of acetic acid was added to adjust the pH within the range of 4 to 5. The product was filtered and washed four times with 97.5 mL of water and once with 97.5 mL of ethanol. The product was dried for 15 h at 60 °C and 25 mbar to obtain 32.4 g of the title product as a light yellow solid (96.07% HPLC purity, 90.3% yield). Ή NMR (400 MHz, DMSO-efe): 6 = 6.69 (s, 1H), 7.23-7.35 (m, 17H).

¹³C NMR (100 MHz, DMSO-ifc) 6 = 91.1, 108.9, 127.7, 128.2, 129.1, 142.2, 144.3, 149.6, 165.0, 169.2. Example 3

Preparation of (Z)-(2-aminothiazol-4-yl)triphenylmethyloxyiminoacetic acid diethoxythio- phosphoryl ester

30 g (0.070 mol) of (Z)-(2-aminotmazol-4-yl)triphenylmethyloxyiminoacetic acid obtained in Example 2, 0.08 g (1 mmol) of DABCO^® and 150 mL of CH₂C1₂ were charged into a reactor at 25 ± 5 °C. The reactor was inerted with N₂, and then 19.42 g (0.105 mol) of tributyiamine was added dropwise during 15 min at 25 ± 5 °C. The reaction mixture was stirred for 5 min and cooled to 2 °C. Then, 19.76 g (0.105 mol) of diethyl chlorothiophosphate was added over a period of 30 min. After the addition was completed, the reaction mixture was stirred until (Z)-(2-aminothiazol-4-yl)triphenylmethyloxyiminoacetate reached <1.0 area% on HPLC (about 4 h).

To the above mixture, 150 mL of water was added over a period of 45 min at 2 °C. The mixture was stirred for 15 min and the aqueous phase was removed. 150 mL of «-hexane was added at 2 °C during 40 min. The suspension was stirred at 2 °C for 1 h, and then the product was filtered and washed with a solution of 135 mL of «-hexane and 45 mL of dichloromethane in 3 portions. The product was filtered and dried for 15 h at 25 °C and 25 mbar to obtain 36.4 g of the title product as a white product solid (98.38% HPLC purity, 89.0% yield). 1H NMR (400 MHz, DMSO-d₆): 5 = 1.26 (dt, J= 7.2 Hz, 6H), 4.21^.27 (m, 4H), 6.71 (s, 1 H), 7.27-7.36 (m, 17H).

¹³C NMR (100 MHz, DMSO-d₆) δ = 16.0, 16.1, 66.5, 66.6, 92.4, 110.1 , 128.0, 128.3, 129.0, 140.5, 143.7, 146.0, 157.5, 169.7.

Claims

1. A process for preparing a (2-aminothiazol-4-yl)-triarylmethyloxyiminoacetic acid of the formula I or an ester thereof of the formula II

(I) (Π) wherein R¹, R² and R³ independently are optionally substituted phenyl groups and R⁴ is Ci-_ό alkyl, said process comprising:

wherein R⁴ is as defined above, with an alcohol of the formula R¹R²R³COH, wherein R¹, R² and R³ are as defined above, in the presence of BF₃ to form a (2-aminothiazol-4-yl)triarylmethyloxyiminoacetic acid ester of the formula II, and, optionally,

(b) subjecting the (2-aminothiazol-4-yl)triarylmethyloxyiminoacetic acid ester of the formula II to hydrolysis to obtain the (2-aminothiazol-4-yl)triarylmethyloxy- iminoacetic acid of the formula I.

2. The process of claim 1 , wherein R⁴ is ethyl.

3. The process of claim 1 or claim 2, wherein R , R and R each is a phenyl group. The process of any one of claims 1 to 3, wherein BF₃ is used in the form of a BF₃ adduct.

The process of claim 4, wherein the BF₃ adduct is an etherate.

The process of claim 5, wherein the etherate is BF₃-(C₂H₅)₂0.

The process of any one of claims 1 to 6, wherein step (a) is carried out in an organic solvent.

The process of claim 7, wherein the organic solvent is selected form the group consisting of acetic acid, acetonitrile, acetone, dioxane, ethyl acetate, and mixtures thereof.

The process of any one of claims 1 to 8, further comprising the step of

(c) reacting the (2-aminothiazol-4-yl)triarylmethyloxyiminoacetic acid of the formula I obtained in step (b) with a chlorothiophosphate of the formula V

wherein R⁵ is C₁-4 alkyl, to form the (2-aminothiazol-4-yl)-triarylmethyloxy- iminoacetic acid dialkoxythiophosphoryl ester of the formula IV

wherein R¹, R², R³ and R⁵ are as defined above.