CS201303B1 - Method of preparing 6-substituted derivatives of d-8-ergoline-i-yl-acetamide - Google Patents

Description

The invention relates to a process for the preparation of 6-substituted D-8-ergolin-1-ylacetamide derivatives of the general formula I,

wherein R is C1-C4 alkyl, allyl, propargyl or benzyl.

The compounds of the above formula are known; causes a marked inhibition of adenohypophysial prolactin secretion in experimental animals, which is manifested in the target effects by, for example, an anti-lactation and an antinidant effect; they also have a gonadotropinstimulatory effect. The magnitude of these effects ranks these substances among tc. the most potent inhibitors of adenohypophysial prolactin secretion (U.S. Patent No. 143,170; U.S. Patent No. 195,905).

According to known methods, the 6-substituted D-8-ergolin-1-ylacetamide of formula (I) of formula (I) was prepared from cyanomethylergoline of formula (II) in which R is the same as in formula (I) by transferring the nitrile group to a hydrazide which has undergone reductive deamination, optionally by converting the hydrazide to an acid azide which, by condensation with a concentrated ammonia solution, provides the desired product. These methods represent a multi-step synthesis which is labor and time consuming and is associated with relatively low yields of the desired end products.

It has now been found that the process for the preparation of the compounds of formula I can be significantly shortened to one step in which the nitrile group is directly converted to the amide group. The principle of the novel process of the present invention is that it is not possible to react the cyanomethylergoline of formula II in which R is the same as in formula I with a quaternary ammonium or phosphonium base used in an amount of 2 to 20 mol equivalents with preferably with tetraethylammonium hydroxide or benzyltriphenylphosphonium hydroxide in an aqueous pyridine base medium, preferably in an aqueous pyridine medium, for example at a concentration of 10 to 80% by volume, at temperatures from room temperature to the boiling point of the reaction mixture.

Suitably, the quaternary ammonium or phosphonium bases prepared in the reaction mixture in the respective quaternary salt are used by alkalization, in particular by treatment with an alkali metal hydroxide. For technological and economic reasons, it is preferable to use, for example, tetraethylammonium bromide from the available selection of quaternary ammonium salts and, for phosphonium salts, benzyltriphenylphosphonium chloride, for example.

The reaction mixtures after hydrolysis are worked up in the usual manner; for example, after dilution with water, the reaction product is taken up in chloroform and the chloroform extract is concentrated for crystallization or used directly for chromatographic separation on a suitable adsorbent column, optionally evaporated to dryness and the residue purified by column chromatography from a suitable solvent mixture.

The compounds of formula (I) may also be prepared by treatment with quaternary ammonium or phosphonium bases in a two-phase medium in which these bases are phase transfer catalysts. The organic phase is formed by a mixture of pyridine with 10 to 50% by volume of a water-immiscible solvent and the second phase is water. However, this reaction also produces, in addition to the desired amides, a greater amount of their hydrolysis products, i.e. acids, in addition to a smaller amount of accompanying substances. The compounds of formula (I) may also be prepared directly from compounds of formula (II) by other methods conventional in organic synthesis for the synthesis of amides from nitrides, such as aqueous alcoholic sodium or potassium hydroxide solution in the presence of hydrogen peroxide, 100% formic acid in an autoclave. by treatment with polyphosphoric acid at elevated temperature or by using ion exchangers in θ cyk -cycles. However, these processes are less preferred in terms of yield and purity of the end product.

The starting materials of the formula II are known. Those derivatives in which R is methyl in formula II are preferably prepared according to e.g. U.S. Patent No. 132,156; R = alkyl and 2 to 4 carbon atoms according to C8-C5; No. 188 414 and the substances with R = allyl-, propargyl- or benzyl group according to the author's certificate no. Certificate No. 194 523.

The process according to the invention is considerably more advantageous compared to the known processes in terms of economy, yields and technological demands and represents a significant technical-economic benefit while maintaining the desired product quality.

Further details of the method according to the invention will be apparent from the exemplary embodiments which illustrate the method but do not limit it in any way. The temperatures indicated are expressed in degrees Celsius, the melting points of the substances were determined on the Kofler block and are not corrected. The values of specific rotations refer to solvent-free substances.

EXAMPLES Example 1

D-6-Methyl-8-ergolin-1-ylacetamide

To a solution of 5.3 g (20 mmol) of D-6-methyl-8-cyanomethylergoline-I in 260 ml of pyridine was added 50 g (275 mmol) of tetraethylammonium bromide and a solution of 15.4 g (275 mmol) of potassium hydroxide in 130 ml of water. and the heterogeneous reaction mixture with ref lux is under nitrogen for 7 hours. After cooling, the reaction mixture is diluted with 200 ml of water and shaken with 500 ml of chloroform and the chloroform extract is evaporated to dryness. The residue was dissolved in a mixture of benzene and 10% methanol and chromatographed on a silica gel column. Combine the single fractions and crystallize them to give the product, mp 236 °; [.alpha.] D @ 20 = -84.4 DEG (c = 0.6; pyridine).

Example 2

D-6-Propyl-8-ergolin-1-ylacetamide

To a solution of 5.86 g (20 mmol) of D-6-propyl-8-cyanomethylergoline-I in 260 ml of pyridine was added 58 g (275 mmol) of tetraethylammonium bromide and a solution of 15.4 g (275 mmol) of potassium hydroxide in 130 ml of water. and the reaction is carried out under the conditions of the example

1. After diluting the reaction mixture with water and removing it into chloroform, the chloroform extract is directly loaded onto a silica gel column and chromatographed using the same solvent to remove dyes and accompanying substances. The desired product is then eluted from the column using a chloroform / 20% ethanol system. Combined fractions and crystallization gave a melting point of 261-262 °; [ ^.alpha. ] ^D @ 20 -66.7 DEG (c = 0.1; pyridine).

Using the same procedure, the following were prepared:

D-6-Ethyl-8-ergolin-1-ylacetamide: mp 263-265 ° (benzene-methanol);

[.alpha.] D @ 20 -86.2 DEG (c = 0.23; pyridine).

D * 6-Butyl-8-ergolin-1-ylacetamide: mp 218-220 ° (ethanol);

[.Alpha.] D @ 20 -66.4 DEG (c = 0.1; pyridine).

D-6-Benzyl-8-ergolin-1-ylacetamide: mp 215-217 ° (benzene-ethanol);

[.Alpha.] ^D @ 20 = 85.5 DEG (c = 0.33; pyridine).

D-6-Isopropyl-8-ergolin-1-ylacetamide: mp 279-281 ° (pyridine-ethanol-water);

[.Alpha.] ^D @ 20 = -82.3 DEG (c = 0.17; pyridine).

D-6-Propargyl-8-ergolin-1-ylacetamide: mp 293-294 ° (pyridine-ethanol);

[.Alpha.] ^D @ 20 = -93.1 DEG (c = 0.22; pyridine).

Example 3

D-6-Allyl-8-ergolin-1-ylacetamide To a solution of 5.8 g (20 mmol) of D-6-allyl-8-cyanomethylergoline-I in 260 ml of pyridine was added 56.9 g (150 mmol) of benzyltriphenylphosphonium chloride and solution of 15.4 g (275 mmol) of potassium hydroxide in 130 ml of water and the reaction is carried out in the same manner as in Example 1. After diluting the reaction mixture with 200 ml of water, the reaction mixture is shaken with 2X500 ml of chloroform. By cooling the separated chloroform and water extract to 5 °, a crystalline solid is obtained, chromatographically uniform in both phases, which, after recrystallization from pyridinethanol-water (1: 1: 1), gives the desired product, m.p. 284-286 °; [Α] D = -90.5 ° (c = 0.20; pyridine).

Claims (1)

OBJECT OF THE INVENTION A process for the preparation of 6-substituted D-8-ergolin-1-ylacetamide derivatives wherein R is C1 -C4 alkyl, allyl, propargyl or benzyl, which is reacted with a cyanomethylergoline of the formula II, in which: wherein R denotes the same as in formula I, with a quaternary ammonium or phosphonium base, used in an amount of 2 to 20 mol equivalents, preferably tetraethylammonium hydroxide or benzyltriphenylphosphonium hydroxide, in an aqueous pyridine base medium, preferably in an aqueous pyridine medium, e.g. % by volume, at temperatures from room temperature to the boiling point of the reaction mixture.