CS218536B1 - Method of preparation of the d-6-methyl-8 beta-/2-kyanethyl/ergoline - Google Patents

Description

According to the invention, a compound of formula I wherein R is cyano is prepared by reacting D-6-methyl-8- (2-hydroxyethyl) ergolin-I of formula I where R is hydroxy by reaction with methanesulfochloride or p. -toluenesulfochloride to the corresponding methanesulfonyloxy- and resp. a p-toluenesulfonyloxy compound of the formula I wherein, in place of the substituent R, methane is 22,536 sulfonyloxy- and p-toluenesulfonyloxy; p-toluenesulfonyloxy and the compounds thus obtained by treatment with an alkali metal cyanide in dimethylsulfoxide or dimethylformamide give a compound of formula I wherein R is cyano.

The D-6-methyl-8 / 3- (2-hydroxyethyl) ergolin-I used was previously described. No. 165,619. The preparation of a compound of formula I wherein R is cyano is disclosed in U.S. Patent No. 3,985,752. According to said U.S. patent, the compound is prepared by the reaction of D-6-methyl-8/2-bromomethylergoline-I or the corresponding An 8β-chloromethyl- or 8β-iodomethyl- or 8S-methanesulfonyloxymethyl compound with acetonitrile in the presence of butyllithium in anhydrous tetrahydrofuran at -60 ° C. As is apparent from the comparison of the two processes, the process of our invention is considerably less demanding both in terms of reagents, solvents and reaction conditions. According to our invention, the chromatographic pure product is obtained from D-6-methyl-8 / 3- (2-methanesulfonyloxyethyl) ergoline-I in almost quantitative yield (up to 98% of the theoretical amount) as opposed to the above U.S. Pat. to give an oily product which must be purified by florisil column chromatography.

Further details of the process for the preparation of D-6-methyl-8 / 3- (2-cyanethyl) ergoline-I of the general formula I, in which R represents cyano and intermediates for its preparation are given in the examples.

Example 1

D-6-Methyl 1-8 / 3- (2-trimethylsulfonyloxyethyl) ergolin-1

To a suspension of 2.7 g (0.01 mol) of D-6-methyl-8 / 3- (2-hydroxyethyl) ergoline-I in 70 ml of pyridine was added dropwise a mixture of 2.02 ml (0.026 mol) of methanesulfochloride and 60 ml. ml of pyridine at 20 ° C and under a nitrogen atmosphere. After 1 hour, the reaction mixture was poured into 500 mL of saturated sodium bicarbonate solution and diluted with an additional 2000 mL of water. Crystallization of the precipitated product is completed by standing in a refrigerator at -5 ° C overnight. The precipitated product is filtered off with suction and washed with water; yield 2.76 g (80%), mp 140-142 ° C. The product recrystallized from ethanol has mp 144-146 ^° C, [α] _D 20 -89.9 ° (c 0.5, pyridine).

Example 2

D-6-Methyl-8- [2- (p-toluenesulfonyloxyethyl) ergolin-1

A mixture of 2.7 g (0.01 mol) of D-6-methyl-8 / 3- (2-hydroxyethyl) ergoline-I, 135 ml of pyridine and 9 g (0.47 mol) of p-toluenesulfo chloride was stirred at room temperature for 4 hours. 20 ° C under nitrogen atmosphere. After standing at room temperature for 24 hours, the mixture was poured into 45 ml of water, basified with saturated sodium bicarbonate solution and diluted with 1800 ml of water. Crystallization is completed by standing in the refrigerator at +5 ^P G overnight. The precipitated product is filtered off with suction and washed with water; yield 2.95 g (70%), mp 125-130 ° C. Recrystallization from methanol the product has mp 129-130 ° C _T [fringe ²⁰ -48.4 ° (c 0.15, pyridine).

Example 3

D-6-Methyl-8 / 3- (2-cyanethyl) ergolin-1

A mixture of 3.48 g (0.01 mol) of D-6'-methyl-8 / 3- (2-methanesulfonyloxyethyl) ergoline-1,3 g (0.16 mol) of sodium cyanide in 50 ml of dimethyl sulfoxide is heated with 2.5 g. hours in a silicone bath at 130 ° C, with stirring under a nitrogen atmosphere. After cooling, the reaction mixture was poured into 140 ml of water. Crystallization of the product was completed by standing in the refrigerator at -5 ° C overnight. The precipitated product is filtered off with suction and washed with water; yield 2.73 g (98%), mp 219-220 ° C. The product recrystallized from ethanol has mp 221-223 ° C, [α]. _D ²⁰ -97.3 ° (c 0.5, pyridine).

Claims (1)

A process for the preparation of D-6-methyl 1-8 / 3- (2-cyanethyl) -ergoline-I of formula I OF THE INVENTION wherein R represents a cyano group, characterized in that D-8-methyl 1-8 / 3- (2-hydroxymethyl) ergolin-I corresponding to the general formula I, wherein at the place of R is hydroxy, is first converted by reaction with methanesulfochloride or p-toluenesulfochloride to give a methanesulfonyloxy- or p-toluenesulfonyloxy compound corresponding to the general formula I, where R is methanesulfonyloxy- or p-toluenesulfonyloxy and is reacted with an alkali metal cyanide, in an inert solvent or dimethylsulfide, for example dimethylsulfide .