GB2126229A

GB2126229A - 7-Cyano-ergolines

Info

Publication number: GB2126229A
Application number: GB08323224A
Authority: GB
Inventors: Luigi Bernardi; Laura Chiodini; Aldemio Temperilli
Original assignee: Farmitalia Carlo Erba SRL
Current assignee: Pfizer Italia SRL
Priority date: 1982-09-03
Filing date: 1983-08-30
Publication date: 1984-03-21
Also published as: GB2126229B; GB8323224D0

Abstract

7-Cyano-ergolines of the formula <IMAGE> R=H or CH3; R1=H or CH3 and R2=H; or R1+R2=CH2 as useful as intermediates for preparing C-7ergoline derivatives. They may be prepared by cyanation of ergoline immonium salts (formula as above, but the 6,7-ring positions thus: <IMAGE> for example with KCN, NaCN, (CH3)3SiCN or (C4H9)4N<+>CN<->.

Description

SPECIFICATION 7-Cyano-ergolines The invention relates to ergoline derivatives and to a process for their preparation.

The invention provides 7-cyano-ergolines having the general formula I

wherein R represents a hydrogen atom or a methyl group, and either (a) R1 represents a hydrogen atom or a methyl group and R2 represents a hydrogen atom or (b) R1 and R2 together represent a methylene group.

The invention further provides a process for the preparation of ergoline derivatives of general formula I as herein defined, which process comprises reacting an ergoline of the general formula (II)

wherein R, R1 and R2 are as above defined and X- represents an anion with a cyanation reagent.

Suitable cyanation reagents include potassium cyanide, sodium cyanide, trimethylsilyl cyanide and tetrabutylammonium cyanide. The reaction is preferably carried out in a solvent such as chloroform, dichloromethane, dimethylformamide or diglyme. Generally the reaction takes place at a temperature of --700C to OOC for 1 hour.

The ergoline immonium salts of formula II may be produced by either of the methods depicted in the following scheme:

Known ergoline derivatives of formula Ill wherein R, Fl1,and R2 have the above given meanings are reacted with aqueous hydrogen peroxide to give the corresponding N6-oxides which by mild treatment with a solution of mesyl chloride in dichloromethane give the immonium salts 11 (path A, see P. Potier et al., J. Am. Chem. Soc., 90, 5622, 1968).

Alternatively (path B) the known ergoline lactams of formula IV wherein R, R1 and R2 have the above given meanings are partially reduced using an appropriate agent such as diisobutylaluminium hydride in tetrahydrofuran at a temperature of 000C to -700C. The initially generated cyclic enamines (see R. Lukes and J. Kovar, Collection Czech. Chem. Commun., 19, 1227 (1954)) are converted into the immonium salts of formula II in an acidic medium.

The ergoline derivatives according to the invention are useful as intermediates for the preparation of 7-substituted ergoline derivatives.

The following Examples illustrate the invention.

Example 1 7-Cyano-6,8p-dimethylergoline Method A: A suspension of 1 g of 6.8P-dimethylergoline in 30 ml of methanol and 4.2 ml of 36% aqueous hydrogen peroxide was refluxed under stirring for 6 hours. To the cooled solution 100 mg of 10% by weight palladium-on-carbon were added slowly to destroy the excess peroxide and the stirring was continued for 1 hour. After filtration and evaporation of the methanol, the residue was dissolved in dichloromethane, dried over anhydrous sodium sulphate and evaporated to dryness to give 1.0 g of 6,8 P-dimethylergoline-N-oxide. This was dissolved in 40 ml of dichloromethane and treated at -700C with 0.91 ml of mesyl chloride and after 3 hours with 4.1 9 g of tetrabutylamonium cyanide.The mixture was stirred for 1 hour and then worked up with a saturated aqueous potassium carbonate solution. The organic layer was washed with aqueous sodium chloride, dried and evaporated to dryness. The residue was chromatographed over a silica gel column using ethyl acetate:cyclohexane (1 :1 by volume) as eluent to give 0.3 g of the title compound after crystallization from diethyl ether.

PMR spectrum (CDCl3): 1.22 (d, Me), 2.58 (s, MeN), 6.70-7.30 (m, 4H), 8.0 S (broad s, NH) IR(KBr): 3350 cm-1 (v=NH), 2220 cm-' (v=C-=) MS: m/z 265 (M+), 238 (M-HCN) Rf 0.60 (silica gel plates, cyclohexane:ethyl acetate:methanol 2:2:1 by volume).

Method B: To a suspension of 0.5 g of 6,8P-dimethylergolin-7-one in 25 ml of tetrahydrofuran, 3.93 ml of a 1.0 M diisobutyl-aluminium hydride in toluene solution were added at approximately 700 C. Stirring at -7O0C was continued for 30 minutes and then 2 ml of 1 5% sodium hydroxide solution were added.

The resulting aqueous mixture was evaporated to dryness. The residue, suspended in water and ethyl acetate, was filtered and the organic layer, dried over anhydrous sodium sulphate, was distiiled to dryness at reduced pressure. To the crude product dissolved in 20 ml of dichloromethane a stoichiometric amount of trifluoroacetic acid and 0.8 g of tetrabutylammonium cyanide were added at -1 00C. The mixture was stirred for 30 minutes and then worked up as described in method A to give 0.17 g of the title compound.

Example 2 7-Cyano4,8-dimethylergoline Operating as in Example 1 (method A), but employing 6,8a-dimethylergoline in place of 6,8p- dimethylergoline the title compound was obtained in 25% yield with Rf 0.65 (silica gel plates, cyclohexane:ethyl acetate:methanol 2:2:1 by volume).

Claims

1. An ergoline derivative of the general formula I

wherein R represents a hydrogen atom or a methyl group, and either (a) R, represents a hydrogen atom or a methyl group and R2 represents a hydrogen atom or (b) R, and R2 together represent a methylene group.

2. 7-Cyano-6,8P-dimethylergoline.

3. 7-Cyano-6,8o-dimethylergoline.

4. A process for the preparation of an ergoline derivative according to claim 1, the process comprising reacting an ergoline derivative of the general formula Il

wherein R, R, and R2 are as defined in claim 1 and X- represents an anion with a cyanation reagent.

5. A process according to claim 4 in which the cyanation reagent is potassium cyanide, sodium cyanide, trimethyl silylcyanide ortetrabutylammonium cyanide.

6. A process according to claim 5 or claim 6 in which the reaction is carried out in a solvent.

7. A process according to claim 6 in which the solvent is chloroform, dichloromethane.

dimethylformamide or diglyme.

8. A process according to any of claims 4 to 7 in which the reaction is carried out at a temperature of from -800C to OOC for 1 hour.

9. A process according to any of Claims 4 to 8 in which the ergoline derivative of the general formula Il is one prepared by reducing a lactam of the general formula IV

wherein R, R, and R2 are as defined in claim 1, and acidifying the resultant cyclic enamine.

10. A process according to claim 9 in which the reduction is effected with diisobutylaluminium hydride.

11. A process according to claim 9 or claim 10 in which the reduction is carried out in tetrahydrofuran at a temperature of from --1200 to -500C.

1 2. A process according to any of claims 4 to 8 in which the ergoline derivative of the general formula Ills one prepared by reacting with aqueous hydrogen peroxide a compound of the general formula Ill

wherein R, Rt and R2 are as defined in claim 1 and treating the resultant N-6-oxide with mesyl chloride.

13. A process according to claim 4 and claim 1 2 substantially as described herein with reference to Example 1 (Method A) or Example 2.

14. A process according to claim 4 and claim 9 substantially as described herein with reference to Example 1 (Method B).