GB2235193A - Improved process for the preparation of aryl and heteroaryl beta -keto esters - Google Patents

Abstract

A process for the preparation of a beta -keto ester of the general structure: <IMAGE> [where R1 is a substituted or unsubstituted aryl or heteroaryl @ group R2 is hydrogen, alkyl, aryl, alkoxy, halogen, or @ unsubstituted or substituted phenoxy; and R3 is alkyl] comprises condensing a ketone of the general structure: R1COCH2R2 with an ester of the general structure: <IMAGE> in the presence of potassium t-butoxide. beta -Keto esters are useful intermediates in a wide variety of organic syntheses, eg in the synthesis of photographic couplers.

Description

IMPROVED PROCESS FOR THE PREPARATION OF ARYL AND HETEROARYL ss-KETO ESTERS The present invention relates to the preparation of aryl and heteroaryl B-keto esters and more particularly to the preparation of such esters in the presence of potassium t-butoxide.

The literature contains many methods for the preparation of B-keto esters, for example those involving the reaction of an aromatic ketone such as acetophenone with an ester such as diethyl carbonate using a base to effect the condensation. Bases which have been used include sodium ethoxide, sodium amide and sodium hydride. GB-A-1450485 claims improved yields and purity of ss-keto esters can be obtained by a process in which an arylmethyl ketone is added to excess dialkylcarbonate in the presence of sodium or potassium methoxide or ethoxide. In the process disclosed, it is however necessary to distill off the alcohol formed in the reaction and also to add arylmethyl ketone over at least 90 minutes.

In accordance with the present invention there is provided a process for the preparation of a 8-keto ester of the general structure:

where R1 is a substituted or unsubstituted aryl or heteroaryl group; R2 is hydrogen, alkyl, aryl, alkoxy, halogen or unsubstituted or substituted phenoxy; and R3 is alkyl, comprising condensing a ketone of the general structure: R1 COCH2R2 with an ester of the general structure:

in the presence of potassium t-butoxide.

The group of R1 may be phenyl, thienyl, thiazolyl, isothiazolyl, pyridyl, furyl, imidazolyl, thiadiazolyl, oxadiazolyl, benzoxazolyl, benzothiazolyl, benzisothiazolyl, pyrazolyl, triazolyl and pyrimidinyl, which group may be unsubstituted or substituted by one or more groups R4 defined below.

The alkyl and alkoxy groups of R2 preferably each have up to 20 carbon atoms. The phenoxy group of R2 may be substituted by one or more groups R4 defined below.

The alkyl group of R3 preferably has up to 6 carbon atoms.

R4 can be any one of the commonly used substituents such as alkyl, alkoxy, halogen, cyano, carboxy, carboalkoxy, carbonamido, sulphonamido, alkylsulphonyl, nitro, alkylamido and acyl. Where there is an alkyl group in R4 it may be straight chain or branched and preferably contains up to 24 carbon atoms.

The reaction is best carried out using an excess of ester (typically 3 moles excess), with or without an inert solvent such as toluene.

The 8-keto ester is formed in high purity and high yield (up to 100% yield has been obtained).

The ss-keto ester is easily isolated from the reaction mixture and can be used without further purification.

The present invention is further illustrated by the following examples: EXAMPLE 1: Methyl 4-methoxvbenzovl acetate Potassium t-butoxide (120g, 1.07 moles) was added with stirring at 400C to diethyl carbonate (317g, 2.68 moles). The mixture was stirred at 700C for 15 minutes, cooled to 600C and a solution of 4-methoxyacetophenone (100g, 0.66 moles) in toluene (160 ml) was added over 5 minutes keeping the temperature below 750C. Some ice-bath cooling was used. The mixture was then stirred at 75-800C for one hour, cooled to 300C, and sodium chloride solution (600 ml) plus ethyl acetate (300 ml) added. The organic layer was washed with sodium chloride solution and dried over magnesium sulphate.The solvents were removed on a rotary evaporator to give the product, ethyl 4-methoxybenzoyl acetate, as an oil. The yield was 148g (100%), purity by H.P.L.C. 99%.

EXAMPLE 2: Lethal 4-dodecvloxvbenzovl acetate This was prepared by the method of Example 1 except that the 4-dodecyloxyacetophenone was added as a solid, followed by the same amount of toluene used in Example 1. This was because 4-dodecyloxyacetophenone is not as soluble in toluene as 4-methoxyacetophenone. The yield of the B-keto ester was 97%, purity by H.P.L.C. 99%. NB. When this B-keto ester was prepared using sodium hydride as base the purity varied from 87% to 92%.

The use of potassium t-butoxide gives improved yields and purity of product as compared to the use of the bases mentioned above as being known in the prior art, such as sodium ethoxide, sodium hydride and sodium amide. In particular, potassium t-butoxide gives markedly better yields and purity than sodium or potassium methoxide or ethoxide.

Sodium hydride also gives better yields and purity than sodium ethoxide but potassium t-butoxide is even better than sodium hydride in this respect.

Furthermore, potassium t-butoxide is less hazardous to use than sodium hydride which has a significant fire risk.

The process using potassium t-butoxide can be readily scaled up. However, when sodium hydride is used as base, an unpredictable induction period occurs which reduces the controllability of the reaction on a larger scale.

ss-keto esters are useful intermediates in a wide variety of organic syntheses. One of the uses is as an intermediate in the preparation of photographic couplers.

Claims (13)

1. A process for the preparation of a ss-keto ester of the general structure:

where R1 is a substituted or unsubstituted aryl or heteroaryl group; R2 is hydrogen, alkyl, aryl, alkoxy, halogen or unsubstituted or substituted phenoxy; and R3 is alkyl, comprising condensing a ketone of the general structure: R1COCH2R2 with an ester of the general structure:

in the presence of potassium t-butoxide.

2. A process according to claim 1 wherein the group of R1 is phenyl, thienyl, thiazolyl, isothiazolyl, pyridyl, furyl, imidazolyl, thiadiazolyl, oxadiazolyl, benzoxazolyl, benzothiazolyl, benzisothiazolyl, pyrazolyl, triazolyl or pyrimidinyl, which group may be unsubstituted or substituted by one or more of the groups alkyl, alkoxy halogen, cyano, carboxy, carboalkoxy, carbonamido, sulphonamido, alkylsulphonyl, nitro, alkylamido and acyl.

3. A process according to claim 1 or 2 wherein the phenoxy group of Rz is substituted by one or more of the groups alkyl, alkoxy, halogen, cyano, carboxy, carboalkoxy, carbonamido, sulphonamido, alkylsulphonyl, nitro, alkylamido and acyl.

4. A process according to claim 2 or 3 wherein when there is an alkyl group in the substituent in Rl or the substituent in the phenoxy group of R2 it may be straight chain or branched and contains up to 24 carbon atoms.

5. A process according to claim 1, 2, 3 or 4 wherein the alkyl group of R2 has up to 20 carbon atoms.

6. A process according to any one of the preceding claims wherein the alkoxy group of R2 has up to 20 carbon atoms.

7. A process according to any one of the preceding claims wherein the alkyl group of R3 has up to 6 carbon atoms.

8. A process according to claim 1 wherein the ss-keto ester is ethyl 4-methoxybenzoyl acetate.

9. A process according to claim 8 wherein the ketone and ester used in the process are respectively 4-methoxyacetophenone and diethyl carbonate.

10. A process according to claim 1 wherein the B-keto ester is ethyl 4-dodecyloxybenzoyl acetate.

11. A process according to claim 10 wherein the ketone and ester used in the process are respectively 4-dodecyloxyacetophenone and diethyl carbonate.

12. A process according to claim 1 substantially as hereinbefore described with reference to any of the specific Examples.

13. A ss-keto ester whenever prepared by the process according to any one of claims 1 to 12.