GB2122185A

GB2122185A - Process for the preparation of alkyl-3-oxotetrahydrothiophene- carboxylates

Info

Publication number: GB2122185A
Application number: GB08218261A
Authority: GB
Inventors: David Richard Waring
Original assignee: Kodak Ltd
Current assignee: Kodak Ltd
Priority date: 1982-06-24
Filing date: 1982-06-24
Publication date: 1984-01-11

Abstract

Disclosed in an improved process for the preparation of alkyl-3-oxotetrahydrothiophene carboxylates which comprises treating an ???,???%- dicarboalkoxymethylethyl sulfide with an alkali metal alkoxide in the presence of a solvent comprising tetrahydrofuran. In an especially preferred embodiment the title compounds are prepared by conducting the reaction in the presence of a solvent comprising tetrahydrofuran and a hydrocarbon solvent such as benzene, toluene, xylene, n-hexane and n-heptane, wherein the weight ratio of tetrahydrofuran to diester sulfide reactant is at least about 1:1 and the weight ratio of hydrocarbon solvent to tetrahydrofuran is about 3-6:1.

Description

SPECIFICATION Process for the preparation of alkyl-3-oxotetrahydrothiophenecarboxylates This invention relates to an improved process for the preparation of alkyl-3-oxotetrahydrothiophenecarboxylates which are useful intermediates in the preparation of pharmaceuticals.

Alkyl-3-oxotetrahydrothiophenecarboxylates have been prepared by treating an cg,p'-dicarbo- alkoxymethylethyl sulfide (also known as alkyl-3-[(2-alkoxy-2-oxoethyl)thio]propanoate) with an alkali metal alkoxide in the presence of an organic solvent. See Woodward et al, J. Am. Chem. Soc. 68, 2229 (1946) and Wynberg et al, J. Am. Chem. Soc 79, 1972 (1957). The solvents most commonly used are diethyl ether, toluene and methanol. The use of those solvents is disadvantageous for various reasons.

The flammability of diethyl ether renders it undesirable for commercial scale operations. Toluene was found to be unsatisfactory because its use at high temperatures required the use of a large amounts of alkali alkoxide to achieve complete reaction which resulted in the formation of a considerable amount of tarry by-products. In cold toluene the reaction mixture becomes unstirrable due to the precipitation of the sodium salt of the diester. The use of methanol at high temperatures produced unsatisfactory yields while at or below room temperature the reaction was difficult to complete.

By the process of my invention the problems attendant with the prior art processes are overcome. Alkyl-3-oxotetrahydrothiophenecarboxylates are obtained in good yield and in relatively short reaction time without the use of extreme reaction temperatures, flammable solvents or excessive amounts of reactants, which therefore renders the process more attractive for commercial operation.

The process of the present invention is an improvement in the preparation of alkyl-3-oxotetrahydrothiophenecarboxylates. In accordance with the invention, an cr,P'-dica rboalkoxym ethylethyl sulfide is treated with an alkali metal alkoxide in the presence of a solvent comprising tetrahydrofuran to obtain alkyl-3-oxotetra hydrothiopheneca rboxylates.

According to the process of the invention alkyl-3-oxotetrahydrothiophenecarboxylates having the formula

are obtained by treating a diester sulfide having the formula RCH2SCH2CH2R Ii with an alkali metal alkoxide in the presence of a solvent comprising tetrahydrofuran.

In the above formulae R is independently selected from alkoxycarbonyl of 2-5 carbon atoms which in formula I is positioned at the 2 or 4 position.

The starting material wherein R in formula Ii is methoxycarbonyl can be prepared according to the procedure described in J. Am Chem. Soc. 79, 1972 (1957). Compounds of formula Il wherein R represents other groups, i.e., alkoxycarbonyl of C3-C5, can be obtained from procedures analagous to that disclosed in the literature.

Unlike prior art processes which require large amounts of base to drive the reaction to completion the present process can effectively be carried out with as little as 1 mole of alkali metal alkoxide per mole of the diester sulfide reactant. Of course a greater amount may be employed if desired but generally use of greater than about a 2:1 mole ratio confers no particular advantage. Of the alkali metal alkoxides employed, the sodium alkoxides are preferred with sodium methoxide and sodium ethoxide being most preferred. It will be readily apparent that essentially anhydrous conditions will be employed.

The tetrahydrofuran solvent may effectively be employed in combination with one or more conventional hydrocarbon solvents such as toluene, benzene, xylene, n-hexane, n-heptane and the like, or in neat form, i.e., tetrahydrofuran is uncombined with any other solvent. Iri neat form the weight ratio of solvent to diester sulfide reactant will ordinarily be about 4:1. For purposes of economy and to aid in the separation of the products the use of one or more hydrocarbon solvents in combination with tetrahydrofuran is advantageously employed. As a combination solvent the weight ratio of tetrahydrofuran to diester sulfide will generally be at least about 1:1 which the upper range limited only by economic considerations. Ordinarily a weight ratio of up to about 10:1 will be sufficient.The amount of hydrocarbon solvent employed with the tetrahydrofuran can be varied within wide range but normally a weight ratio of hydrocarbon solvent to tetrahydrofuran of about 1-10:1 will be suitable and preferably about 3-6:1. An especially preferred embodiment of my process comprises treating ,p'-dicarbomethoxymethylethyl sulfide with sodium methoxide in tetrahydrofuran and toluene to produce 2- and 4-methyl-3-oxotetra hydrothiophenecarboxylate.

Advantageously the reaction is carried out without the use of extreme temperatures. Generally, the temperature of reaction can be varied between about 0 to 30"C. with about 15 to 300 C.

normally preferred.

Particularly attractive with this process is the relatively short reaction time required for completion of the reaction. On a laboratory scale, upon addition of the diester sulfide reactant, the reaction is essentially complete in as few as 1 5 minutes with the use of tetrahydrofuran uncombined with any additional hydrocarbon solvent. When conducted in the presence of tetrahydrofuran combined with additional hydrocarbon solvent the reaction is essentially complete in as few as 30 minutes. Upon completion of the reaction the final product may be isolated in accordance with established procedures, such as by treating the reaction mixture with concentrated sulfuric acid followed by diethyl ether, removing the aqueous layer and distilling off the solvent from the upper layer.

By the process of this invention alkyl-3-oxotetrahydrothiophenecarboxylates are prepared economically, in good yield, up to about 92% in the case of 2- and 4-methyl-3-oxotetrahydrothiophenecarboxylate and in relatively short reaction times.

The following examples are given to further illustrate the invention, but it is to be understood that the invention is not to be limited in any way by the details described therein.

Experimental Example 1 Using tetrahydrofuran in neat form Sodium methoxide (27.9 g) was added to tetrahydrofuran (230 ml) cooled in a water bath at 250C. "S'- Dicarbomethoxymethylethyl sulphide (57.6 g) was added dropwise in 1 hour at < 300C.

After 15 minutes a cold solution of concentrated sulphuric acid (18 ml) in water (50 ml) was added, followed by diethyl ether (100 ml). The lower aqueous layer was removed and the solvent removed from the upper layer to give a mixture of 2- and 4-methyl-3-oxotetrahydrothiophenecarboxylate (49.6 g), which assays at 87.7% and corresponds to an assay yield of 91%.

Experimental Example 2 Using tetrahydrofuran and toluene Sodium methoxide (6.1 g) was suspended in tetrahydrofuran (10 ml) and toluene (30 ml) at < 1 50C. and cL,P'-dicarbomethoxymethylethyl sulphide (19.2 g) added dropwise in 30 minutes. After stirring for 30 minutes the reaction was complete and a solution of concentrated sulphuric acid (10 g) in water (40 ml) added at < 250C. The aqueous layer was removed and distillation of the organic layer gave a 92.6% assay yield of 2- and 4-methyl-3-oxotetrahydrothiophenecarboxylate.

The invention has been described in detail with particular reference to preferred embodiments thereof, but it will be understood that variations and modifications can be effected within the spirit and scope of the invention.

Claims

1. In a process for preparing alkyl-3-oxotetrahydrothiophenecarboxylates having the formula

by testing a diester sulfide having the formula RCH2SCH2CH2R II with an alkali metal alkoxide, the improvement comprising conducting the reaction in the presence of a solvent comprising tetrahydrofuran wherein R is independently selected from alkoxycarbonyl of 2-5 carbon atoms which in formula I is positioned at the 2 or 4 position.

2. Process according to Claim 1 wherein the mole ratio of diester sulfide to alkoxide is at least about 1:1 and the alkali metal alkoxide is sodium methoxide or sodium ethoxide.

3. Process according to Claim 1 wherein the weight ratio of solvent to diester sulfide is about 4:1.

4. Process according to Claim 1 wherein the reaction is conducted at a temperature of about 0 to about 300 C.

5. Process according to Claim 1 wherein the reaction is conducted in a solvent further comprising a hydrocarbon.

6. Process according to Claim 5 wherein the hydrocarbon solvent is selected from the group consisting of toluene, benzene, xylene, n-hexane and n-heptane.

7. Process according to Claim 5 wherein the weight ratio of tetrahydrofuran to diester sulfide is at least about 1:1 and the weight ratio of hydrocarbon solvent to tetrahydrofuran is about 1-10:1.

8. Process according to Claim 5 wherein the weight ratio of tetrahydrofuran to diester sulfide is about 1-10:1 und the weight ratio of hydrocarbon solvent to tetrahydrofuran is about 3-6:1.

9. Process for the preparation of alkyl-3-oxo-tetrahydrothiophenecarboxylate having the formula

which comprises treating a diester sulfide having the formula RCH2SCH2CH2R with an alkali metal alkoxide in the presence of a solvent comprising tetrahydrofuran and a hydrocarbon wherein R is independently selected from alkoxycarbonyl of 2-5 carbon atoms which in formula I is positioned at the 2 or 4 position, and wherein the reaction is carried out at a temperature of about 150 to 300 C., the weight ratio of tetrahydrofuran to diester sulfide is at least about 1:1 and the weight ratio of hydrocarbon to tetrahydrofuran is about 3-6:1.