HU183594B - Process for producing 11-methoxy-vincamone - Google Patents

Abstract

A process for the preparation of alkoxyvincamone derivatives of the formula (I> <IMAGE> (wherein R<1> and R<2>, which may be the same or different, each represents an alkyl group having from 1 to 6 carbon atoms) comprising reacting a halovincaminic acid ester of the formula (II> <IMAGE> (wherein R<2> is as defined above R<3> represents an alkyl group having from 1 to 6 carbon atoms, and X represents a halogen atom) with an alkali metal alkanoate of the formula R<1>-OMe, (wherein R<1> is as defined above and Me represents an alkali metal atom), in the presence of a catalyst. Compounds of formula I other than (-)-vincinone are also claimed.

Description

The present invention relates to a novel process for the preparation of 11-methoxy-vincamine of formula I, wherein R * is methyl, R ² is ethyl, by reacting a halo-vincamic acid ester of formula II, wherein R ² is R ³ is C 1 -C 4 alkyl and X is bromo at the 11-position in the presence of a catalytic amount of a monovalent copper ion with an alkali metal alkanolate of the formula R ¹ -MMe - in which R ² is of the formula I and Me is an alkali metal atom.

The compounds of formula I, on their own, are biologically active in themselves, namely, having a vasodilating effect and, on the other hand, are valuable starting materials for the preparation of other therapeutic compounds of eburnan backbone.

The compounds of Formula I are novel except for (-) - vinquinone, which is a narrower group of compounds of Formula I, wherein R ² is ethyl at the α-position R ¹ is methyl and R ¹ is O. and the hydrogen atom is also in the α-position. Synthetic preparation of (-) - vincinone is an alkaloid found in Vinca minor (Tetrahedron Letters 75, 1805-1806 (1968)), Bull. Soc. Chim. Belg. 88, 93 (1979), the (-) - vincamone is nitrated, the yield of nitration is 77%, the 11 nitro-vincamone obtained is reduced, the yield of the reduction is 80%, the resulting 11-aminocycamone is diazotized, followed by the diazonium salt is converted, without isolation, to 11-hydroxy-vincamone, without isolation, in a yield of 50%, and the resulting 11-hydroxy-vincamone is reacted with diazomethane to give (-) - vincinone in a yield of 3%. The overall yield of 5-step synthesis is only 9.2%.

It has been found that reacting the halo-vincamic acid ester derivatives of formula II in the presence of a suitably selected catalyst with an alkali metal alkanolate of formula R'-OMe corresponding to the alkoxy group R'O to be introduced into the molecule in a single step The alkoxyquincamone derivatives of the formula I can be prepared in a yield of 1%.

In the general formulas of the compounds of this invention, R ^{3 as C} 1-4 alkyl is linear or branched, namely methyl, ethyl, η-propyl, isopropyl, η-butyl, sec-butyl, tertiary butyl, preferably methyl or ethyl.

Exemplary starting compounds of formula II are disclosed in U.S. Patent No. 2,036,732. Great Britain and No. 178702; can be prepared according to the procedure described in Hungarian Patent Specification.

In the process of the present invention, the inorganic salt containing a monovalent copper ion may be used as a catalyst for the reaction of the compounds of formula II with the alkali metal alkanolate of formula R'-OMe. These include copper (I) iodide, copper (I) rhodanide, copper (I) chloride, copper (I) bromide, etc., preferably copper (I) iodide. Suitable solvents for the reaction include alkanol R'-OH corresponding to alkanolate R'-OMe and dimethylformamide. The reaction may be carried out at a temperature of from 25 to 140 ° C. The alkanolates of the formula R'-OMe may be used in an amount of 3 to 15 equivalents, and the copper (I) salts may be used in an amount of 0.5 to 4 moles per compound of formula II.

The invention is illustrated by the following non-limiting examples.

Example (-) - Vincinone [(-) - 11-methoxy-vincamone]

0.12 g (5.21 mmol) of sodium metal are dissolved in 1.6 ml of absolute methanol under a nitrogen atmosphere. To the solution, 2.5 ml of absolute dimethylformamide and 0.25 g (1.31 mmol) of copper (I) iodide followed by 0.20 g (0.46 mmol) of (+) - 1-bromo-vincamine (Hungarian Patent Application 178,702). The reaction mixture was maintained at ⁰ to 110 ° C for 1.5 hours with stirring under nitrogen. After cooling, the mixture was poured into ice water (7 ml), shaken with ethyl acetate (5 ml) and the inorganic precipitate was filtered off. The organic layer was separated from the filtrate, and the aqueous portion was extracted with ethyl acetate (3 x 5 mL). The combined ethyl acetate layers were shaken with water (2 x ²⁵ mL), the organic layer was dried over anhydrous magnesium sulfate, filtered and the solvent removed in vacuo. The residual oil was crystallized from 1 ml of methanol to give 0.10 g of the title compound. Yield: 66%.

Melting point: 168-170 ° C (from methanol). 161-162 ° C (from acetone) (Bull. Soc. Chim. Béig. 88, 93, 1979). Czech.

³⁵ Chem. Commun. 29, 447 (1964)].

IR (KBr): 1700 (lactam CO); 1620 cm -1 (aromatic).

MS m / e (%): 324 (M ⁺ , C ₂₀ H ₂₄ N ₂ O ₂ , 100); 323 (80); 296 (12); 295 (26); 294 (8.8); 293 (8.3); 267 (18); 254 (20); 252 (8.3): 197 (9.4).

⁴⁰ [α] D = - 112.2 °; [α] ₂₅ D = -137.7 ° (c = 0.70, chloroform). [Literal rotation: [α] _D = -107 ° (c = 0.37; chloroform) (Bull. Soc. Chim. Bee. 88, 93, 1979), [α] _D = -118 ° (Tetrahedron Letters, 1968, 1805.)].

Claims (2)

1. Procedure I 11-methoxy-vinkamon formula - wherein R 'is methyl, R ² present in ⁵⁰ of ethyl - preparation, characterized in that a II haloalkyl vincaminic acid ester of formula - wherein R ² represents the formula 1 R ³ is C 1 -C 4 alkyl and X is 11-position 55 Br - salt containing a catalytic amount of a divalent copper ion in the presence of an alcoholate R'-OMe alkali formula - wherein R 'are as defined for formula I and Me is an alkali metal - ⁶⁰ is reacted. 2. A process according to claim 1, wherein the solvent is an alkanol of the formula R'-OH, wherein R ¹ is as defined in claim 1, and dimethylformamide. 1 figure