CA2126416A1 - Process for the preparation of indoles - Google Patents

Abstract

Abstract The invention relates to a new process for the preparation of indoles by decarboxylation of correspond-ing indole-2-carboxylic acids, characterized in that these acids are treated with formic acid.

Description

212b~ ~ 6 Merck Patent Gesellschaft mit beschrankter Haftung 6100 D a r m s t a d t Process for the preparation of indoles The invention relates to a new process for the preparation of indoles by decarboxylation of correspond-ing indole-2-carboxylic acids.
Indole-2-carboxylic acids have been conventional-ly decarboxylated by heating them, dissolved in a high-boiling tertiary amine, at reflux (cf. e.g. ~ouben-Weyl/
M~ller, Methoden der organischen Chemie [Methods of Organic Chemistry]; 1952, volume 8, page 486).
For instance, 4-(5-methoxy-3-indolyl)butyric acid (I), an intermediate for the synthesis of roxindol, has previously been prepared by heating a solution of 3-(3-carboxypropyl)-5-methoxyindole-2-carboxylic acid (II) in N,N-dimethylaniline or N,N-tiethylaniline at 190~ for 24 hours.
Disadvantages here are the high reaction tempera-ture and the apparatus-related problems which it entails, permitting production in only a few plants, and also the long reaction time and the consequently high consumption of energy.
The object of the invention was to find a new process for the preparation of indoles, especially I, in which the abovementioned disadvantages are greatly reduced or totally absent.
It has been found that I is obtained in a high yield if a solution of II in formic acid is heated. This is surprising inasmuch as indoles are generally con-sidered to be highly labile with respect to acids. This has also been demonstrated in attempts to replace formic acid by other acids, such as acetic acid, dilute aqueous sulfuric acid or dilute aqueous hydrochloric acid. Either there was no reaction at all or I was obtained in only a low yield with the formation of by-products.
The process can be transferred with a high degree of success to other indole-2-carboxylic acids.

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The invention relates to a process for the preparation of indoles by decarboxylation of correspond-ing indole-2-carboxylic acids, characterized in that these acids are treated with formic acid.
In this process, the formic acid used may ex-pediently contain about 0-50 % water. The reaction temperatures are between 20 and 107 and preferably between ao and 107 C. The reaction times required at the higher temperatures are between about 1 and 10 hours, preferably between 2 and 4 hours, while those required at the lower temperatures are corresponding longer.
The percentages given below are percentages by volume.

Example 1 A mixture of 14.2 g of II and 120 g of 77.4 %
formic acid is boiled for 3 houxs and then evaporated under reduced pressure. Dilute sodium hydroxide solution is added to the residue, clarification is carried out briefly with activated carbon at 40, and the product is precipitated with hydrochloric acid to pH 1.5. The precipitated I is filtered off, washed with water and dried under reduced pressure at 50. Yield: 10.9 g.

Example 2 The procedure is as indicated in Example 1 but using 100 % formic acid with a reaction time of 2 hours.

Example 3 The procedure is as indicated in Example 1 but using 50 % formic acid; reaction time: 5 hours.

Example 4 The procedure is as indicated in Example 1, but at 80; reaction time: 30 hours.

Example 5 Indole is obtained from indole-2-carboxylic acid, analogously to Example l.

Claims

Patent claim Process for the preparation of indoles by de-carboxylation of corresponding indole-2-carboxylic acids, characterized in that these acids are treated with formic acid.