JPH0684375B2 - Method for producing 11-bromovincamines - Google Patents

Description

The present invention relates to the following general formula (I): (In the formula, R represents a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, or a benzyl group.) The present invention relates to a method for producing 11-bromovincamines.

11-Bromovincamine has a cerebral vasodilatory action and is widely used as a cerebral circulation metabolism improving agent.

2. Description of the Related Art Conventional methods for producing 11-bromovincamines include direct bromination of vincamine (US Pat. No. 4,146,643) and bromination after protecting the hydroxyl group of vincamine with a trimethylsilyl group. (Sho 59-80681) is known. However, the former method has low selectivity and low yield, and the latter method uses an expensive trimethylsilylating agent and requires bromination at a low temperature of about 40 ° C below zero, which is still satisfactory as an industrial manufacturing method. It wasn't possible.

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention The present invention provides a new method for producing 11-bromovincamines, which is advantageous in industrial production.

Means for Solving the Problems That is, the present invention is based on the general formula (I) (In the formula, R represents a hydrogen atom, an alkyl group having 1 to 5 carbon atoms or a benzyl group.) In the production of 11-bromovincamines represented by the general formula (II) (In the formula, R is the same as the above definition) The 16-bromovincadiformines represented by the formula Oxidized with hydrogen peroxide in the presence of general formula (III) (Wherein R is as defined above), 16-bromo-1,2-dehydro-3-hydroxyaspidospermidine-9-oxides are formed and then hydrogen-reduced in the presence of Raney nickel catalyst. General formula (IV) (Wherein R is as defined above) leading to 16-bromo-1,2-dehydro-3-hydroxyaspidospermidine, which is further heated in the presence of an acid to cause intramolecular rearrangement. And a method for producing 11-bromovincamines represented by the general formula (I).

The 16-bromovincardiformin compound of the formula (II), which is the starting material, can be easily produced by the method disclosed in the pending patent application (Japanese Patent Application No. 61-198644). That is, the 7-bromo-β-carboline compound is synthesized in good yield by subjecting the 5-bromopentanal compound to a condensation reaction in the presence of an organic carboxylic acid alkali metal salt. This can be used in either a racemic form or an optically active form.

In the first step reaction, the 16-bromovincadiformin compound was treated with hydrogen peroxide in the presence of an oxide of one or more transition metals selected from molybdenum, osmium, tungsten and vanadium or alkali metal salts of these metals. The 16-bromo-1,2-dehydro-3-hydroxyaspidospermidine-9-oxide compound of formula (III) is prepared by oxidation. The transition metal oxides referred to here are, specifically, molybdenum oxide, osmium oxide, tungsten oxide, vanadium oxide, and the alkali metal salts of inorganic oxyacids are molybdic acid, osmic acid, tungstic acid and vanadium acid. Means the sodium salt or potassium salt of. This oxidation reaction proceeds in two steps and passes through 16-bromovincardiformin-9-oxide as an intermediate, but this compound does not need to be taken out and can be produced in one pot. In this reaction, it is preferable to use a solvent miscible with water, and specifically, lower alcohols such as methanol and ethanol are suitable. A transition metal catalyst such as a tungstate, a molybdate, or vanadium oxide may be present in a very small amount. The reaction temperature is not particularly limited, but it is preferably carried out at 30 ° C. or higher, especially under reflux of the solvent, and the reaction proceeds promptly.

A known method is to carry out a similar reaction with an organic peroxide such as peracetic acid or perbenzoic acid, but the organic peroxide is expensive and is difficult to handle because of its safety. The reaction also needs to be performed at a low temperature and a low concentration, and requires a long time. Industrially, it can be said that the method of the present invention is extremely excellent.

After completion of the reaction, extraction is carried out with a solvent immiscible with water, for example, a chlorinated aliphatic hydrocarbon solvent such as methylene chloride, chloroform or trichloroethylene to obtain the compound of formula (III). This compound can be purified by recrystallization if necessary.

In the second step, the compound of formula (III) is reduced with hydrogen using Raney nickel as a catalyst in an inert solvent to reduce 9-oxide without causing debromination, and 16-bromo-1 of formula (IV) is reduced. Leads to 2,2-dehydro-3-hydroxyaspidospermidines. It is known that such a reduction reaction is carried out with a palladium-barium sulfate catalyst, but debromination is likely to occur. Although a chemical reduction method using triphenylphosphine is also known, it is difficult to industrially use it because it is difficult to treat triphenylphosphine oxide produced as a by-product. INDUSTRIAL APPLICABILITY The method of the present invention is inexpensive, easy to post-process and good in yield, and is suitable for industrialization. As the inert solvent, an alcohol solvent is preferable, and a water-containing product can also be used. Catalyst amount is 5-20
Weight% is preferable, and the reaction temperature is not particularly limited, but it is preferable to carry out hydrogen reduction at room temperature to 100 ° C. under normal pressure or increased pressure.

After completion of the reaction, the catalyst can be filtered to obtain a solution of the compound of formula (IV), but the solution can be directly used in the next reaction without isolation and purification.

In the reaction of the third step, the compound of formula (IV) is heated in the presence of an acid to cause an intramolecular rearrangement reaction, and the compound of formula (I)
Leads to bromovincamines. The product is obtained as a mixture of 11-bromo vincamine and 11-bromo-14-epi vincamine. As the acid, any of mineral acids such as hydrochloric acid, sulfuric acid and perchloric acid and organic acids such as acetic acid can be used. As a simple reaction method, an acid is added to the reaction solution in the first stage so as to have a pH of 1 to 3, heated to about 10 to 50 ° C. and stirred for about 5 to 50 hours, whereby the rearrangement reaction proceeds rapidly.

After the rearrangement reaction, sodium hydroxide, sodium carbonate, ammonium hydroxide, etc. are added to make the reaction solution alkaline,
11-Bromovincamines are freely precipitated, and the desired product can be obtained by filtration or solvent extraction.

This product can be easily isolated and purified by a conventional means such as liquid chromatography or recrystallization. For example, 11-bromovincamines can be obtained in high purity by recrystallization using an alcohol solvent such as methanol, ethanol or isopropanol. The remaining 11-bromo-14-epivincamines can be converted to medically useful 11-bromovincamines by treatment with alkali and epimerization.

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto.

Example 1 (1) Preparation of 16-bromo-1,2-dehydro-3-hydroxy-3-methoxycarbonylalpidospermidine-9-oxide 16-bromovincadiformin methyl ester 10.0 g was dissolved in methanol 50 ml. Then, add 0.20 g of sodium molybdate dihydrate and stir. To this, 13.0 g of 30% hydrogen peroxide solution was gradually added dropwise at room temperature over 30 minutes. Precipitation of crystals of 16-vincadiformin-9-oxide was observed as it was added dropwise, but the mixture was heated as it was and reacted under reflux for 8 hours. After confirming the disappearance of raw materials and intermediates by thin layer chromatography, the reaction solution was cooled, 50 ml of water was added, and the mixture was extracted twice with 25 ml of methylene chloride. The solvent was distilled off to obtain 10.3 g of a viscous oily substance. This was recrystallized with a mixed solvent of methylene chloride and ether to obtain 7.9 g of the title aspidospermidine derivative (yield 73.4%). The melting point was 158-160 ° C.

(2) Production of 11-bromovincamine and 11-bromo-14-epivincamine 10.0 g of the aspidospermidine compound obtained by the above reaction
Was placed in a 200 ml autoclave together with 100 ml of methanol and 1 g of Raney nickel, and after hydrogen substitution, reduction was started by injecting hydrogen up to a hydrogen pressure of 50 kg / cm ² . The reaction temperature was kept below 40 ° C. and the reaction was carried out for 6 hours. After the absorption of hydrogen was stopped, the contents were taken out and the catalyst was filtered. The raw material disappeared by thin layer chromatography and instead the formation of 16-bromo-1,2-dehydro-3-hydroxy-3-methoxycarbonyl-aspidospermidine was observed. Hydrochloric acid was added to this solution to adjust the pH to 1, heated to 50 ° C. and stirred for 4 hours.
Then, the mixture was cooled to room temperature, neutralized with a 10% sodium carbonate aqueous solution, concentrated under reduced pressure, and further made alkaline to precipitate crystals. The crystals are collected by filtration, washed with water and dried,
6.8 g (70% yield) of crystals consisting of -bromovincamine and 11-bromo-14-epivincamine were obtained.

Example 2 (1) 16-Bromo-1,2-dehydro-3-hydroxy-
Preparation of 3-ethoxycarbonyl-N-oxyaspidospermidine 10.0 g of 16-bromovincadiformin ethyl ester is dissolved in 50 ml of methanol, 0.20 g of sodium tungstate dihydrate is added and stirred. To this, 13.0 g of 30% hydrogen peroxide solution was gradually added dropwise at room temperature over 30 minutes. There was heat generation at the time of dropping, and white turbidity of the reaction liquid due to the formation of 16-bromovincadiformin-N-oxide was observed. After the dropping was completed, the reaction was carried out under reflux for 8 hours. After confirming the disappearance of raw materials and intermediates by thin layer chromatography, the reaction solution was cooled, 50 ml of water was added, and the mixture was extracted twice with 25 ml of methylene chloride. By removing the solvent by evaporation, a viscous oil 10.2
got g. This was recrystallized from a mixed solvent of methylene chloride and ether to give 7.6 g of the title aspidospermidine derivative.
(Yield 70.0%) was obtained. The melting point was 159-161 ° C.

(2) 11-Bromovincamine ethyl ester and 11-
Preparation of bromo-14-epivincamine ethyl ester 10.0 g of aspidospermidine compound obtained in the above reaction
Was placed in a 200 ml autoclave together with 100 ml of methanol and 1 g of Raney nickel, and after hydrogen substitution, reduction was started by injecting hydrogen up to a hydrogen pressure of 50 kg / cm ² . The reaction temperature was kept below 40 ° C. and the reaction was carried out for 6 hours. After the absorption of hydrogen was stopped, the contents were taken out and the catalyst was filtered. The material disappeared by thin layer chromatography and instead the formation of 16-bromo-1,2-dehydro-3-hydroxy-3-ethoxycarbonyl-aspidospermidine was observed. Hydrochloric acid was added to this solution to adjust the pH to 3, and the mixture was stirred at room temperature for 16 hours. afterwards
Neutralization with a 10% sodium carbonate aqueous solution, concentration under reduced pressure, and further alkalinization caused precipitation of crystals. The crystals were collected by filtration, washed with water and dried to obtain 6.9 g (yield 71.5%) of crystals consisting of 11-bromovincamine ethyl ester and 11-bromo-14-epivincamine ethyl ester.

Effects of the Invention According to the present invention, 11-bromovincamine can be obtained without using expensive vincamine as a raw material.

Claims (1)

[Claims] 1. A general formula (I) (Wherein R represents a hydrogen atom, an alkyl group having 1 to 5 carbon atoms or a benzyl group), in the production of 11-bromovincamines represented by the general formula (II) (In the formula, R is the same as the above definition.) The 16-bromovincadiformines represented by the formula Oxidized with hydrogen peroxide in the presence of general formula (III) (Wherein R is as defined above), 16-bromo-1,2-dehydro-3-hydroxyaspidospermidine-9-oxides are formed and then hydrogen-reduced in the presence of Raney nickel catalyst. General formula (IV) (Wherein R is as defined above) leading to 16-bromo-1,2-dehydro-3-hydroxyaspidospermidine, which is further heated in the presence of an acid to cause intramolecular rearrangement. The method for producing the 11-bromovincamines represented by the general formula (I) above.