CZ278824B6 - Process for preparing ergoline derivatives - Google Patents

Abstract

The invention concerns a process for preparing ergoline derivatives by decyanisation of 6-cyanderivatives of ergoline by the action of sodium or potassium in an environment of liquid ammoniac, or with the addition of an inert solvent. The prepared compounds are intermediate products for production of biologically active substances used in human medicine.

Description

Technical field

The invention relates to pharmaceutical chemistry and to a process for the preparation of ergoline derivatives of the general formula I

wherein R is Ν ', Ν' -diethylureido or hydroxymethyl.

BACKGROUND OF THE INVENTION

The compounds of formula (I) as defined above R are synthetic precursors of biologically active substances used in human medicine. For example, 6-propyl-8-N ', N'-diethylureidoergoline (CS certificate 235 178) has a significant inhibitory effect on prolactin secretion and 8- (methylthio) -methyl-6-propylergoline (US Pat. 4 166 182) is used to treat Parkinson's disease.

Compounds of formula I having the above-mentioned meaning of R are known per se (see, eg, J. Org. Chem. 52, 3167 (1987) and Coll. Czech. Chem. Commun. 49., 2828 (1984)) and are prepared from: compounds of formula II,

wherein R is Ν ', Ν' -diethylureido or hydroxymethyl, in organic chemistry by generally known methods such as reduction or hydrolysis procedures. Reductive cleavage of the cyano group from position 6 of the ergoline system is accomplished, for example, with zinc in acetic acid at elevated temperature, or hydrogenolytically in a suitable inert solvent such as dimethylformamide in the presence of catalysts such as Raney nickel with hydrogen at normal or elevated pressure. The disadvantages of these processes are the use of pyrophoric and / or expensive catalysts, long reaction times, difficult processing of the reaction mixture and the generation of environmentally harmful waste.

-1GB 278824 B6

Hydrolytic cleavage of the cyano group is generally carried out by treatment with an alcoholic or aqueous-alcoholic solution of an alkali metal or alkaline earth hydroxide at an elevated temperature, usually at the boiling point of the reaction mixture. As a result of the drastic reaction conditions, numerous by-products are formed and the desired reaction mixture must be isolated from the reaction mixture by complex separation procedures.

SUMMARY OF THE INVENTION

The present invention has surprisingly found that the cyano group can be removed by a nearly selective and quantitative reaction under mild conditions using an environmentally friendly and recyclable solvent, the products being very easy to isolate. A further advantage is the simultaneous removal of conventional acyl groups, which during the synthesis served as protecting groups for the hydroxyl group, and therefore a separate step for their cleavage is not necessary.

According to this solution, the ergoline derivatives of the formula (I) as defined above can be prepared by reacting a known compound of the formula (II) in which R is Ν ', Ν'-diethylureido, hydroxymethyl or p-toluenesulfonyloxymethyl, and sodium or potassium in an ammonia liquid medium, optionally with the addition of an inert solvent. Ethers, preferably tetrahydrofuran or 1,4-dioxane, can be used as the inert solvent. The reaction may be carried out in a temperature range from -78 ° C to the boiling point of the reaction mixture. The process for the preparation of the compounds of the formula I with the above-mentioned meaning of R is illustrated by the following examples.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

8-Hydroxymethylergoline

A solution of 8 g (25.86 mmol) of 8-acetoxymethyl-6-cyanergoline in 60 ml of tetrahydrofuran was added dropwise to the reaction mixture formed by dissolving 2.3 g (100 mmol) of sodium in 85 ml of liquid ammonia. The blue reaction mixture was then decolourised by the addition of 0.5 g ammonium chloride, ammonia was distilled off from the water bath (35 ° C) and 300 ml water was added to the residue. The precipitated product is crystallized for 16 hours at 5 DEG C., filtered off with suction and dried to constant weight at 40 DEG C. under a water pump vacuum. The title compound is obtained, mp 213-215 ° C and _x . · ...

[.alpha.] = 30 '(c = 0.2; pyridine).

Example 2

8-N ', N' -diethylureidoergoline

Using the same procedure as in Example 1, but using 8-N ', N'-diethylureido-6-cyanergoline as starting material and 1,4-dioxane

As a solvent, the title compound of m.p. 114 DEG-116 DEG C. and / .alpha. = 67 DEG (c = 0.5; pyridine).

Example 3

8-N ', N' -Diethylureidoergoline

In the same manner as in Example 2, but using potassium in the same stoichiometric ratio instead of sodium, the title compound was obtained with the above physicochemical constants.

Example 4

8-Hydroxymethylergoline

In the same manner as in Example 1, but using

a) 8-hydroxymethyl-6-cyanergoline

b) 6-cyano-8-p-totylsulfonyloxymethylergoline

c) Starting from 6-cyano-8-p-methylsulfonyloxymethylergoline, the title compound was prepared with the physicochemical constants described above.

Claims (2)

PATENT CLAIMS Process for the preparation of ergoline derivatives of the general formula I in which R represents Ν ', N'-diethylureido or hydroxymethyl, characterized in that the reaction of a compound of the general formula II is reacted. Wherein R represents,, Ν-diethylureido, hydroxymethyl, acetoxymethyl, methanesulfonyloxymethyl, or p-toluenesulfonyloxymethyl, and sodium or potassium in liquid ammonia, optionally with the addition of an inert solvent. Process according to claim 1, characterized in that tetrahydrofuran or 1,4-dioxane is used as the inert solvent.