CS262284B1 - 5p-10tt-1-Formyl-8α-formYlamino-2,3-dihydro-6-methylergoline and a process for its preparation - Google Patents

Abstract

5β,10A-1-formyl-8-<t-formylamino-2.,3- -dihydro-6-proethylergoline of formula I and a process for its preparation by the reaction of terguride with formic acid under catalysis by a palladium catalyst.

Description

The invention relates to 5beta, 10α-1-formyl-8α-formyl * mino-2,3-dihydro-6-methylergoline of formula I

and a method for producing the same.

The compound of formula I, 5beta, 10alpha-1-formyl-8alpha-formylamino-2,3-dihydro-6-methylergoline shows potent prolactin secretion in animals.

5beta, 10alpha-1-formyl-8alpha-formylamino-2,3-dihydro-6-methylergoline of formula I contains four chiral centers in the molecule, asymmetric carbons in the 3, 5, 8 and 10 positions, their spatial arrangement is as follows: hydrogen atom on C (3) has alpha or beta position (3R or 3S configuration), hydrogen atom on C (5) has beta position (5R configuration), formylamino group on C (8) has alpha position (8S configuration) and hydrogen atom on C (10) is in alpha position (10R configuration).

According to the invention, 5beta, 10alpha-1-formyl-8alpha-formylamino-2,3-dihydro-6-methylergoline can be produced by reacting the starting precursor terguride (formula II) with catalysis of palladium catalysts. .

The starting terguride of formula II can be prepared by known methods (e.g., AO 245 200).

The reaction of the starting terguride is preferably carried out in such a way that an excess of 80% or more of formic acid is added to its solution. in a mixture of formic acid with a protic solvent such as alcohols or a polar aprotic solvent such as tetrahydrofuran, dioxane or 1,2-dimethoxyethane or dimethylformamide is added under stirring, preferably under an inert atmosphere such as nitrogen or argon, a palladium catalyst such as palladium black or palladium on a suitable support, for example, on a Norit or alumina, or other suitable sorbent or palladium hydroxide on or without a suitable support, in an amount of 1% to 200% by weight with or without tertiary amine such as triethylamine, N-ethyl-N, N-diisopropylamine or also 1,2,2,6,6-pentamethylpiperidine. It is also possible to add directly palladium (II) chloride or a solution thereof in water to the solution of terguride in formic acid or in the above solvent mixture.

The resulting reaction mixture is then allowed to react for 10 minutes to 16 hours with stirring at room temperature to reflux until the starting substrate has reacted. Advantageously, ultrasonic irradiation of the resulting reaction mixture, e.g. at a frequency of 50 kHz, with a power proportional to the volume of the reaction mixture, e.g. 35 W, may also be used.

After the reaction, the mixture is worked up by methods customary in ergoline derivative chemistry, for example by filtering off the catalyst, distilling off most of the solvent in vacuo, basifying the residue to about pH 7.5, shaking the product into a water-immiscible solvent, chromatography and / or crystallization from a suitable solvent such as ethyl acetate.

The obtained 5beta, 10alpha-1-formyl-8alpha-formylamino-2,3-dihydro-6-methylergoline is a colorless, crystalline substance of m.p. 219-223 ° C, slightly basic, forming addition salts with inorganic and organic acids. For therapeutic purposes, water-soluble salts with pharmaceutically acceptable acids such as hydrochloric, sulfuric, methanesulfonic, acetic, maleic, tartaric, citric and the like are suitable.

Said salts can be prepared by treating at least 1 mole equivalent of acid to 1 mole equivalent of 5beta, 10α-1-formyl-8α-formyl-amino-2,3-dihydro-6-methylergoline in a suitable inert solvent such as methanol, ethanol, acetone, water or mixtures thereof .

The process for the preparation of 5β, 10α-1-formyl-8α-formyl-amino-2,3-dihydro-6-methylergoline is illustrated by the following non-limiting examples.

The structure of the substance was confirmed by infrared, ultraviolet and NMR spectra, composition by elemental analysis.

Example 1

To 17.0 g (50 mmol) of terguride and 10 g of 20% palladium hydroxide on Norite was slowly added dropwise with stirring at room temperature 100 ml of 99% formic acid and then over 5 minutes with 10 ml of triethylamine. The mixture was stirred at room temperature for 4 hours, then gently refluxed for 5 minutes. It is then cooled, filtered and the filter cake is washed thoroughly with formic acid. Of the combined sc solutions, most of the formic acid was evaporated in vacuo, the residue was poured into 100 ml of water and basified with conc. aqueous ammonia to pH 7.5 to 8. The product is extracted with 5 x 100 ml dichloromethane, the extracts are dried over sodium sulfate and evaporated to dryness in vacuo. Crystallization of the residue from ethyl acetate gave 10.88 g (73%) of product.

At. clade 2

To a solution of 1.27 g (3.74 mmol) of terguride in a mixture of 10 mL of 99% formic acid and 1 mL of trlethylamine was added 750 mg of 20% palladium hydroxide on Norit and the mixture was irradiated with ultrasound (50 kHz, 35 W) under nitrogen. ) for 10 minutes. The mixture was then diluted with 10 mL of dist. water, the catalyst is filtered off, the filter cake is washed with 75% aqueous methanol. The combined filtrates were basified without cooling with conc. aqueous ammonia to pH 7.5, water is added to the warm solution to turbidity and the mixture is allowed to crystallize. The product obtained is suction filtered, washed with 75% methanol. 1.06 g (95% of theory) of the product is obtained.

Claims (4)

1. 5beta, 10alpha-1-formyl-Balpha-formylamino-2,3-dihydro-6-methylergoline of formula I A process for the preparation of 5beta, 10alpha-1-formyl-8alpha-formylamino-2,3-dihydro-6-methylergoline of formula X, according to claim 1, characterized in that the terguride of formula II (IX) is reacted with formic acid under catalysis palladium catalyst. 3. A process according to claim 2 wherein the reaction mixture is added with a tertiary amine 4. Process according to claim 2 or 3, characterized in that the reaction is carried out under the action of an ultrasonic field on the reaction mixture.