CS275769B6 - Target. butylated derivatives of elymoclavine and process for their production - Google Patents

Abstract

The solution relates to tert. butyl derivatives of elymoclavin of the general formula I and a method for their production, characterized in that elymoclavin, an excess of trifluoroacetic anhydride and 2-methyl-2-propanol are introduced into the reaction, optionally in an inert solvent environment. These compounds are intermediates in the preparation of pharmaceutically usable substances.

Description

The invention relates to tert-butyl derivatives of elymoclavine of the general formula I, ch ₂ or ³

in which R ¹ and R ³ denote a hydrogen atom and R 3 denotes a target, a butyl group, when R 1 denotes a target, a butyl group and R ³ denotes a hydrogen atom or R ^{3 denotes a hydrogen atom and R 3} denotes a target, a butyl group, or R ¹ denotes a target , butyl and R 1, R 2 and R ³ represent a hydrogen atom, when R represents a hydrogen atom or a target, a butyl group.

Said compounds are derivatives of ergot alkaloids which are known (see, for example, B. Berde, HO Schild (Editors): Handbook of Experimental Pharmacology, Vol. 49 »pp. 87-196) to have biological activities on their own, optionally after suitable derivatization. which are useful in human or veterinary medicine. The target, butyl group in these compounds by its spherical action blocks the reactivity in adjacent positions of the skeleton of the molecule. The result is an increase in the differentiation of reactivity in the compounds of the formula I, which thus represent preferred synthetic intermediates in the field of ergot alkaloids.

According to the invention, the compounds of the formula I as defined above R ¹ to R ^{3 are} prepared by reacting elymoclavine, an excess of trifluoroacetic anhydride and 2-methyl-2-propanol, optionally in an inert solvent at temperatures from 0 ° C. C to the boiling point of the reaction mixture.

The excess of trifluoroacetic anhydride and 2-methyl-2-propanol is in the range from 5 to 100 molar equivalents, based on the elymoclavin used.

Examples of inert solvents which can be used are chlorinated aliphatic hydrocarbons, preferably dichloromethane or ethers, preferably tetrahydrofuran or 1,4-dioxane, or mixtures of these solvents, which usually dissolve the starting elymoclavine better.

ζ

Target, butyl derivatives of the formula I as defined above R to R ³ are crystalline substances of a basic nature which are isolated from the reaction mixture by methods known per se, preferably by a combination of extraction, chromatography and crystallization. They form salts with stronger inorganic and organic acids, which are also useful for the isolation and purification of these derivatives.

Process for the preparation of compounds of the formula I as defined above for R ¹ to R ³ . is explained in more detail in the following exemplary embodiment, which, however, does not limit the scope of the invention in any way.

CS 275 769 B6 2

Example

Target, butyl derivatives of elymoclavine

To a stirred suspension of elymoclavine (1.27 g, 5 mmol) in 2-methyl-2-propanol (20 g, 0.265 mol) ae with vigorous stirring and cooling to 10 ° C was added trifluoroacetic anhydride (47.6 g, 0.227 mol) dropwise. ). The reaction mixture was then stirred at 20 ° C for 90 h, then the volatiles were evaporated under a water pump vacuum at 35 ° C, the residue was partitioned between dichloromethane (100 ml) and saturated aqueous sodium bicarbonate solution and the organic layer was separated. . Evaporation under a water pump vacuum at 35 ° C gave a residue which was chromatographed on a silica gel column with 7% methanol in ethyl acetate as eluent. The homogeneous fractions are combined, the solvent is evaporated off under a water pump vacuum and the evaporators are crystallized. This gives compounds with the following physicochemical properties:

2,13-di-tert-butylelymoclavine, mp 255-260 ° C (ethyl acetate / hexane) [α] D ⁰ - 75.08 ° (c 0.2, chloroform)

2,14-di-tert-butylelymoclavine, m.p. 115-118 ° C (dichloromethane / hexane)>> 14.88 ° (c 0.2, chloroform)

1,0-di-tert-butylelymoclavine, m.p. 214-216 ° C (ethyl acetate / hexane)

- 62.62 ° (c 0.2, chloroform)

1-tert-butylelyraoclavine, m.p. 105-108 ° C (dichloromethane / hexane) [.alpha.] D @ 20 -89.84 DEG (c 0.2, chloroform)

Claims (4)

PATENT CLAIMS 1. Target, butyl derivatives of elymoclavine of general formula I ch ₂ or ³ (I) wherein R ¹ and R ³ represent a hydrogen atom and R ² represents a target, a butyl group, when R ⁴ represents a target, a butyl group and R ³ represents a hydrogen atom or R represents a hydrogen atom and R represents a target, a butyl group, or R 3 represents a tert, butyl and R ² , n 1 and R 8 denote a hydrogen atom when R ³ denotes a hydrogen atom or a target, butyl. 3 OS 275 769 B6 2. A process for the preparation of compounds of the formula I having the meanings given above R ¹ to R 2 according to claim 1, which comprises reacting elymoclavine and an excess of trifluoroacetic anhydride and 2-methyl-2-propanol, optionally in an inert environment. solvents at reaction temperatures from 0 ° C to the boiling point of the reaction mixture, then the mixture of elymoclavine derivatives obtained is separated by chromatography and / or crystallization, 3. The process according to item 2, characterized in that the excess of trifluoroacetic anhydride and 2-methyl-2-propanol is in the range of 5 to 100 molar equivalents, calculated on the elymoclavin used. 4. The process according to item 2, characterized in that chlorinated aliphatic hydrocarbons, preferably dichloromethane, or ethers, preferably tetrahydrofuran or 1,4-dioxane, or mixtures of said solvents are used as inert solvents.