CS202219B1 - Method of producing 8-beta-amino ethylergolines-i - Google Patents

Description

The invention relates to a process for the preparation of 8-O-aminoethylergolines-I of the general formula I

wherein R ¹ is hydrogen or C 1 -C 3 alkyl and R ² is C 1 -C 4 alkyl.

The compounds of formula (I) are, on the one hand, substances with a hypotensive, prolactininhibiting and anti-inflammatory effect (see Czechoslovakian author's certificate No. 171 480), and on the other hand, they are important intermediates for the production of others pharmacologically. D-6-methyl-8- (O-isopropylamino-ethyl) ergoline-I, which can be used to regulate the sexual cycles of livestock (cf. Czechoslovakian Patent Number 177,530).

According to the above-mentioned Czechoslovakian copyright certificate number 171480, D-6-methyl-8-0-aminoethylergolin-I and its

The 1-methyl derivative can be prepared by catalytic hydrogenation of the corresponding 8-cyanomethylergoline-I with hydrogen at a pressure of 0.2 to 10 MPa and at a temperature of 20 to 120 ° C, preferably at a pressure of 5.5 to 10 ° C.

6.5 MPa and 55 to 60 ° C, in the presence of Raney nickel.

The present inventors have now unexpectedly found that the hydrogenation of the 8-cyanomethylergolines-I to the 8-O-aminoethylergolines-I of formula I proceeds smoothly and in very good yields already at atmospheric pressure and at room temperature, the desired product being obtained in high purity. The hydrogenation process represents a significant simplification and thus an economical preparation of the compounds of the formula I in comparison with the known process, since it is more gentle on sensitive ergoline derivatives and does not require expensive pressure hydrogenation autoclaves.

According to the invention, the D-8-O-aminoethylergolines-I of the formula I can be produced by the process of D-8-cyanomethylergolines-I of the formula II

202 219

202 219 wherein R ¹ and R ² are as defined above, catalytically hydrogenate with hydrogen in an indifferent solvent environment at atmospheric pressure at 10 to 40 ° C, preferably at room temperature, in the presence of a catalyst.

A suitable medium for catalytic hydrogenation is, for example, methanol, ethanol or dioxane, and mixtures thereof with water, preferably in the presence of 20 to 120 moles of ammonia per 1 mol of the cyander derivative of the formula II.

Platinum, palladium either alone or on a suitable support such as activated carbon or barium sulfate, Raney nickel and the like; particularly preferred is Raney Nickel prepared by treating a 20% sodium hydroxide solution with an aluminum alloy of 40 to 50% nickel at a temperature not exceeding 20 ° C.

Preferably, the catalytic hydrogenation of the compounds of formula II is carried out in 80% aqueous methanol containing about 20 moles of ammonia per mole of starting cyander derivative, at atmospheric pressure and room temperature, in the presence of Raney nickel, with vigorous shaking of the mixture. The hydrogenation time depends on the amount and activity of the catalyst; in the case of Raney nickel prepared as described above, about the same amount of catalyst is used as the weight of catalyst. amount of starting cyander, the hydrogenation time is about 6 to 10 hours.

The D-8- (3-aminoethylergolines-I) of the formula I can be isolated from the reaction mixture after the hydrogenation is complete by conventional means, for example by filtering off the catalyst and distilling off the solvent or solvents. Crude amino compounds which are sufficiently pure for most applications can be purified, for example, by precipitation with ammonia from an aqueous solution of a suitable salt, for example tartrate or hydrogen maleate, or by crystallization, or by conversion to a salt, for example bishydrogen maleate.

The process for the preparation of the 8-O-aminoethylergolines of formula (I) is illustrated by the following non-limiting Examples. The melting points of the compounds are determined on the Kofler block and are given, as with other temperature data, in ° C. Specific rotation values given refer to solvent-free substances.

Examples

Example 1

D-6-Methyl-8- (3-aminoethylergoline-1)

To a suspension of 25.0 g of D-6-methyl-8-cyanomethylergoline-I in a mixture of 600 ml of methanol with 150 ml of concentrated aqueous ammonia is added about 30 ml of Raney nickel (settled aqueous suspensions) and hydrogenated with shaking in a The catalyst was filtered off, washed with 90% aqueous methanol and the solvents were distilled off under reduced pressure to obtain 25.6 g of a colorless product containing 7.3% of a crystalline solvent. (94% yield). Purification of the crude product by dissolving it in an aqueous (700 mL) solution of malelic acid (26 g) and liberating the base with ammonia gave pure D-6-methyl-8-β-aminoethylergoline-I of 175-176. [Α] _D ²⁰ = -80 ° (c = 0.5, 90% aqueous ethanol).

Bishydrogenmaleinan base prepared by mixing one equivalent of the amino product with 2.2 equivalents of maleic acid in ethanol, has mp 162-163 ° and [a] ²⁰ _D - 34 ° (c = 0.5, water).

Example 2

In the same manner as in Example 1, but using D1-diinethylene-cyanomethylergoline-I or D-6-n-propyl-8-cyanomethylergoline-I, instead of D-6-methyl-8-cyanomethylergoline-I, prepare:

D 1, 6-dimethyl-8-d-aminoethylergoline-1, mp ^101-103 °, [ ^α ] ^{D 20} = -83 ° (c = 0.5, 90% aqueous ethanol); bishydrogen maleate base mp 150-152 ° (from ethanol), [α] D ²⁰ = -37 ° (c = 0.5, water); D-6-n-propyl-8- (3-aminoethylergoline-I, amorphous substance, [.alpha.] D @ ²⁰ = -78 DEG (c = 0.5, 90% aqueous ethanol).

FIXED DESCRIPTION OF THE INVENTION TO AUTHORIZATION CERTIFICATE No. 202 219/51 / Int. Cl 3 c 07 D 457/02

In the description of the invention for the author's certificate no. 202 219 the first author's name was not printed and the second author's name was misspelled.

Correctly also Černý Antonín RNDr., CSc.,

Semonský Miroslav doc., Dr., Ing., DrSc., Prague

INVENTORY AND DISCOVERY OFFICE

Claims (2)

A process for the preparation of 8- (S) -aminoethylergolines-I of the general formula I in which R ¹ represents a hydrogen atom or a C 1 -C 3 alkyl group and R ² represents a C 1 -C 4 alkyl group, characterized in that The D-8-cyanomethylergolines-I of formula II wherein R ¹ and R ² are as defined above, catalytically hydrogenate with hydrogen in the presence of an indifferent solvent at atmospheric pressure at 10 to 40 ° C, preferably at room temperature, in the presence of a catalyst. 2. A process according to claim 1, wherein the indifferent solvent used is methanol, ethanol, dioxane or mixtures thereof with water, preferably in the presence of 20 to 120 moles of ammonia per 1 mol of cyander derivative of the formula II.