HU185815B - Process for preparing ester derivatives of racemic and optically active 10-halogen-vincaminic acid - Google Patents

Abstract

The present invention relates to a novel process for the preparation of racemic or optically active 10-halo-vincamic acid esters of formula I wherein R and R2 are C1-C4 alkyl and X is halogen, such that a novel racemic or optically active compound is present. An eburnan of Formula VIII is an alkali metal tertiary alcohol in an alcoholic medium of formula R, OH. treated. The 10-halo-vincamic acid esters of the formula I have valuable therapeutic properties, namely, for the treatment of behavioral disorders caused by the damage and calcification of cerebral vessels in the old age, and also for the treatment of cognitive disorders resulting from cranial injuries. The novel process of the present invention has the advantage of producing a completely pure, pure 10-halo-apoincinnamic acid-free 10-halo-vincamic acid ester from a single step of synthesis from a single, readily prepared starting material. -1-

Description

The present invention relates to a novel process for the preparation of racemic and optically active JO-1-allyl-vincamic acid esters of formula I wherein R 1 and R ₂ are C 1 -C 4 alkyl and X is halogen by reacting a novel racemic or optically active 10-halo-4,15-dioxo-E-hotno-eburryl of the formula wherein R ₂ and X are as defined above in an alcoholic medium of formula R 1 -OH wherein R 1 is of formula I as described above - treated with an alkali metal tertiary alcoholate.

In the compounds of Formula I, R ₁ and R _{2 as} alkyl may be straight or branched C 1 -C 4, for example methyl, ethyl, n-propyl, i-propyl, π-butyl, i- butyl and tert-butyl groups.

X as halogen may be fluorine, chlorine, bromine or iodine.

The t0-halo-vincamic acid esters of Formula I have valuable therapeutic effects, namely, on the one hand, in the treatment of behavioral disorders caused by damage and cerebral vascularization in old age, and, on the other hand, in the treatment of consciousness disorders caused by cranial injuries.

Some of the compounds of formula I are known from German Patent No. 2,458,164. According to this, a mixture of 10-halo-vincamine and 10-halo-apovincamine is prepared from 3- [1-ethyl-9

- halooctahydroindoloquinolizin-1-yl] - 2

- methoxypropenoic acid methyl ester by acid cleavage. At the end of the reaction, the mixture must be further selected from the O-halogenated vinegar. The starting material is prepared from the corresponding halo-tryptamine and diethylacetates of ethyl [3- (p-toluenesulfonyloxy) prop-1-yl] -malealdehyde acid via a five-step synthesis, through complex intermediates.

z \ is novel according to the new process of the present invention. 10-halo-apovincaminic acid ester-free 10-halo-vincaminic acid esters can be obtained in one step synthesis from a readily prepared starting material in one step.

The starting materials of the general formula Vili are disclosed in Hungarian Patent Application Publication No. T / 26,331 and U.S. Patent No. 182,432. can be prepared according to the method described in Hungarian Patent Publication No. 4,123,198.

Compounds of formula Vili are reacted with an alkali metal tertiary alcoholate such as lithium, potassium or sodium tert-butyl in the presence of an alcohol of the ester group R 1 -OH to be introduced into the molecule.

In the process according to the invention, the reaction mixture can be processed in a manner known per se from the starting materials, the final product, the solvent, and the like. depending, for example, if the product precipitates at the end of the reaction, it is isolated by filtration, if the product remains in solution, the solution is evaporated to dryness, preferably under vacuum. The evaporated material is crystallized with a suitable inert organic solvent such as petroleum ether. The choice of solvent depends on the solubility and crystallization properties of the material to be crystallized. The reaction mixture may be worked up by treating the reaction product with a suitable inert organic solvent such as dichloromethane, dichloroethane and the like. The organic solvent solution is dried and evaporated, and the residue is crystallized if desired. The desired mixture (coins) can be precipitated from the reaction mixture with an inert organic solvent, such as ether, and the precipitated material can then be isolated by filtration.

The racemic or optically active compounds of the formula I obtained by the process of the invention may, if desired, undergo further purification, such as recrystallization. Suitable solvents for the recrystallization include, for example, aliphatic alcohols such as methanol, isanes and isomonanol; aliphatic ethers such as diethyl ether and the like.

The compounds of the present invention can also be purified by preparative layer chromatography. Suitable adsorbents are preferably Merck Fr _{2M 3-5} silica gel and various solvent combinations such as benzene-methanol, preferably 14: 2 or 14: 3, preferably aliphatic ethers such as diethyl ether, aliphatic, are used. ketones such as aeeton are used.

The compounds of formula I obtained by the process of the present invention contain an asymmetric carbon atom. The process of the present invention involves the preparation of both optically active and racemic compounds.

The process of the present invention provides compounds of the general formula (I) in high yield, well identifiable form, with good elemental analysis, calculated location of the bands of the characteristic groups measured by infrared spectroscopy, unambiguous nuclear magnetic resonance signals and mass spectral measurements. structure.

The invention is illustrated in more detail by the following non-limiting example.

Pclda (±) -10-Bromo-vincamine

0.12 g (0.26 mmol) of (±) -10-bromo-l4-oxo-E-homo-15hidroxiimino eburnánt (3aH, 17üC ₂ H ₅₎

Dissolve 2.4 ml of glacial acetic acid and add 0.24 g of anhydrous p-toluenesulfonic acid and 0.36 g of paraformaldehyde. The reaction mixture was heated at 110 ° C to 30 ° C for 3 hours and half-hour, and was poured into ice-cold water, basified to pH 9 with concentrated aqueous ammonium hydroxide, and the (±) -cis-10-bromo-14,15-dioxo precipitated. -E-homo eburnánt (3aH! 7ctC ₂ H ₅₎ was filtered, washed with water and dried over phosphorus (V) oxide in a desiccator. The product (84 mg) (m.p. 184 'C (decomposed), IR (KBr): 1720 cm' (CO), 1690 cm '(acid amide CO)) was carried on to the next step without purification, i.e. 4 m. dichloromethane, filtered, and the filtrate was filtered under reduced pressure

185,815 are removed. To the residue was added 0.4 ml of a solution of 0.10 g of potassium tert-butylate in 4 ml of absolute methanol. The mixture was warmed to 40 ° C and allowed to stand at room temperature for 2 hours. The precipitated crystals are filtered off, washed with a little cold methanol and dried.

38 mg of the title compound are obtained.

Yield: 33%.

Melting point: 196-197 ° C (decomposed).

IR (KBr): 1738 cm @ -1 (ester CO).

MS m / e (%): 432 (M ⁺ , 100), 431 (47), 373 (56), 330 (89).

1 H-NMR (CDCl 3): 807.68-6.85 (3H, m, aromatic protons), 4.50 (1H, interchangeable, OH), 3.80 (3H, s, CO 2 CH 3), 0.89 ppm (3H, t, CH ₂ CH ₂ ).

The mother liquor was purified by preparative thin-layer chromatography (A1 ₂ O-PF ₂₅₄ , _w ; dichloromethane-methanol 100: 1, R _f title compound> (±) -1-O-bromo-14-epivincamine> 14,15-dioxoE-). homc-eburnan, eluting with dichloromethane-methanol 20: 4). During processing, a further 5 mg (total yield: 43 mg; 39%) of the title compound and 5 mg (4%) of (±) -10-bromo-14-epi-vincamine with a melting point of 138-189 ° C were isolated. methanol).

Ms m / e (%); 432 (M \ 83), 431 (53), 385 (33), 373 (52), 330 (96).

Claims (1)

A process for the preparation of racemic and optically active 10-halo-vincamic acid esters of formula I wherein R 1 and R ₂ are C 1 -C 4 alkyl and X is halogen, characterized in that a novel racemic or optically active compound of formula VIII -halo-14,15-dioxo-E-homo-ebuman, wherein R ₂ and X are as defined above, in an alcoholic medium of formula R 1 -OH, wherein R 1 is as defined for formula I, an alkali metal tertiary alcohol.