CS246643B1 - Process for the preparation of substituted lysergic amides and derivatives thereof - Google Patents

Abstract

Method for preparing substituted amides of rylamidochloride and tertiary amine, lysergic acid and their derivatives of the general formula I R, - R2- r3- R, - denotes a hydrogen atom, an alkyl group with 1 to 4 carbon atoms or a 1-hydroxy- -2-alkyl group with 2 to 4 carbon atoms, denotes a hydrogen atom or an alkyl group with 1 to 2 carbon atoms, denotes an alkyl group with 1 to 4 carbon atoms, denotes a hydrogen atom or an alkyl group with 1 to 4 carbon atoms. According to the invention, amides of lysergic acid and its substituted derivatives are produced. They are physiologically active substances, in particular S-(+)-1-butsnol-z-amide of lysergic acid (methylergometrine) is of great therapeutic importance. According to the process according to the invention, these substances are produced by condensation of lysergic acid or its substituted derivatives ■ with an amine in the presence of phenyl-N-phenylphospho

Description

Process for the preparation of substituted amides of rylamidochloride and tertiary amine, lysergic acid and their derivatives of the general formula I

R @ 1, R @ ₂ R @ ₃ R @ 1 denotes hydrogen, C1 -C4 alkyl or 1 - hydroxy C2 -C4 alkyl, denotes hydrogen or C1 -C2 alkyl; C1-C4alkyl denotes hydrogen or C1-C4alkyl.

According to the invention, lysergic acid amides and their substitution derivatives are prepared. They are physiologically active substances, in particular lysergic acid S - (+) - 1-butsnol-z-amide (methylergometrine) is of great therapeutic importance.

According to the process of the invention, these compounds are produced by condensation of lysergic acid or its substitute derivatives with an amine in the presence of phenyl-N-phenylphospho246643

246643 2

The invention relates to a novel process for the preparation of substituted lysergic amides and their derivatives of general formula 1

(I) in which

R1 represents a hydrogen atom, an alkyl group having from 1 to 4 carbon atoms or a hydroxy-2-alkyl group having from 2 to 4 carbon atoms,

Rg - represents a hydrogen atom or an alkyl group of 1 to 2 carbon atoms,

R1 represents an alkyl group and 1 to 4 carbon atoms,

R ^ denotes a hydrogen atom or an alkyl group and 1 to 4 carbon atoms.

The aforementioned maids have significant pharmacodynamic effects and some find use in therapeutic practice. Methods for the preparation of these amides have received considerable attention in the past (see, for example, review articles: J. Org. Chem. 24, 368 (1959), Eur. J, Med. Chem. 13, 373 (1978)), a desirable simple method that yields high yields.

The starting material for the preparation of the above amides is d-lyaergic acid and its derivatives. For the condensation of lysergic acid and amines have been suggested by various authors.

azide method (Helv. Chim. Aeta 38, 421 (1955)) chloride method (Experimentia 17, 206 (1961)) mixed sulfuric anhydride method (J. Org. Chem. 24, 368 (1959)) mixed trifluoroacetic anhydride method (U.S. Pat. No. 27 36,728) carbonylimidazole method (Coll. Czech. Chem. Commun. 27, 1565 (1962)) dicyclohexylkerbodiimide method (Planta Med. 6, 395 (1958)) chloroformate (Belg. pat. 633 683) oxalyl chloride method (Pat. HSR 25 57 792) of the dicyclohexylcarbodimide-N-hydroxybenztrlazole method (Experimentia 33, 881 (1977)) and other methods.

All give unsatisfactory results, especially when carried out on a larger scale. This is sometimes caused by sensitive reaction conditions, such as the chloride and loaded anhydrides method. These methods provide satisfactory yields only in the case of dihydrolysergic acid, which is much more extreme. Alternatively, the cause is the difficulty of removing the by-product from the condensing agent (dicyclohexylcarbodiimide, carbonylimidazole) or the need to use a solvent which is difficult to remove from the reaction mixture (dimethylformamide).

It has now been found that, for the preparation of the substituted amides of the above-mentioned acids, phenyl-N-phenylphosphorylaidea chloride of the formula III can be advantageously used as condensing agent

Cl

This agent is readily available from cheap and common raw materials (see Synthesis 1976, 185) and has been used to prepare carboxylic acid anhydrides (Synthesis 1981, 218) and peptides (Synthesis 1982, 288).

The advantage of using the reagent of formula III to prepare substituted lysergic amides is that it is possible to work in conventional low-boiling solvents at room temperature, and that the by-product resulting from the condensation agent is an acid that can be easily removed by extraction with aqueous hydroxide solution.

According to the process according to the invention, the acid of the general formula II

in which R1, R2 are as defined above, suspended or dissolved in a suitable organic solvent (dichloromethane, chloroform, acetone, acetonitrile), at least two equivalents of a suitable base (triethylamine, pyridine), at least one equivalent of an amine of the formula IV / 1 HN \ wherein R, and R ^ ^m výěe význsm above, and at least one ekvivhlent agent of formula III.

The reaction may be carried out at a temperature between 0 ° C and the boiling point of the solvent used, but preferably at room temperature.

After the reaction and the reaction mixture is worked up in a conventional manner.

The following examples illustrate the process according to the invention.

Example 1 g of lysergic acid is suspended in 10 ml of dichloromethane, 10 ml of triethylamine are added and the suspension is stirred at room temperature for 10 minutes. Then 12 g of phenyl-N-phenylphosphorylamido chloride and 4 g of S - (+) - 2-amino-1-butanol are added.

After stirring for 1 hour, the reaction mixture was extracted twice with 50 ml of 5% aqueous sodium hydroxide solution and once with 20 ml of water. The organic phase is dried over sodium sulphate and concentrated to a residue. 12.5 g of crude methylergometrine are obtained, which is purified by conventional means.

Example 2 g of lysergic acid is suspended in 100 ml of acetone, 10 ml of triethylamine are added and the suspension is stirred for 10 minutes at room temperature. Then 12 g of phenyl-N-phenylphosphorylamidochloride and 10 ml of 26% aqueous ammonia are added.

After stirring for 1 hour, the solution is concentrated to a honey-like residue which is dissolved in 50 ml of chloroform and extracted twice with 50 ml of 5% aqueous sodium hydroxide solution and once with 20 ml of water. The organic phase is dried and concentrated to a residue. 10.2 g of crude lysergic acid amide are obtained, which is purified in a conventional manner.

Example 3 g of lysergic acid is suspended in 100 ml of dichloromethane and condensed according to the procedure of Example 1 and diethylamine.

After isolation and purification, 8.6 g (72% of theory) of lysergic acid dlethylamide are obtained.

Example

According to the procedure of Example 1, 2.8 g (10 mmol) of 6-ethyl lysergic acid are condensed with 10 mmol of S - (+) - 2-amino-1-butanol.

Yield: 1.9 g (57.6% of theory) of 6-ethyl methylergometrine.

Example 5

Following the procedure of Example 1, 0.56 g (2 mmol) of 1-methyl lysergic acid and 2 mmol + 2a-aminopropanol were condensed to give 1-methyl-ergometrine. Obtained 0.42 g (64.6% of theory)

Claims (5)

1. A process for the preparation of substituted lysergic amides of formula (1) is hydrogen, (C1-C4) alkyl or (C1-C4) -hydroxy-2-alkyl, (C1-C4) alkyl. C 1 -C 4 -alkyl, C 1 -C 4 -alkyl, C 1 -C 4 -alkyl, characterized in that the acid of formula (II) in which R 1 and R 2 are as defined above, is reacted in a solvent and phenyl-K-phenylphosphorylamidochloride of formula XII / yOP-NH (IIIJ Cl and an amine of formula IV HN ^R 1 (IV) wherein R 1 and R 8 are as defined above in the presence of a base, 2. The process of claim 1 wherein the base is a tertiary organic amine such as triethylamine or pyridine. 3. The process of claim 1 wherein the solvent is dichloromethane, chloroform, acetone or acetonitrile, or a mixture thereof. 4. Process according to claim 1, characterized in that the reaction is carried out in a temperature range of 0 DEG C. to the boiling point of the solvent used, preferably at room temperature. 5. A process according to claim 1, wherein the reaction is carried out using reaction components II, III and IV and a tertiary organic amine in a molar ratio of I and 1.1 with 1.1: 2.2 to 3.3.