JPH03197482A - Production of apovincaminic acid ester - Google Patents

Abstract

PURPOSE:To obtain the subject compound, having cerebral bloodstream increasing, microcirculation improving, blood platelet agglutination inhibitory, cerebral metabolism improving, cerebral ischemic protective action, etc., and useful as an ameliorant of cerebral circulation and metabolism by reaction vincamine with a specific alcohol in the presence of a Lewis acid. CONSTITUTION:Vincamine expressed by formula I is reacted with an alcohol expressed by the formula R-OH (R is 2-8C alkyl) in the presence of a Lewis acid (preferably zinc chloride, aluminum chloride, boron trifluoride, stannic chloride, ferric chloride, zinc bromide or titanium tetrachloride), preferably at the refluxing temperature of the alcohol for 1-80hr to afford the objective compound expressed by formula II.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to a novel method for producing apovincamic acid ester.

Apovincamic acid ester is a drug that has an effect of increasing cerebral blood flow, improving microcirculation, inhibiting platelet aggregation, improving cerebral metabolism, and protecting against cerebral ischemia, and is used as an agent for improving cerebral circulation and metabolism.

BACKGROUND OF THE INVENTION Conventionally, a method for producing apovincamic acid ester using vincamine, a type of natural alkaloid, as a starting material has been known. The method is carried out by combining a step of dehydrating vincamin or vincamic acid obtained from vincamine and a step of esterifying it.

The dehydration process is as follows: (1) Heat treatment at 220°C [:Tetrahed
ron Letters, 702 (1961): l, (
2) Boiling in acetic anhydride (Hungarian Patent Specification No. 151295), (3) Reacting with sulfuric acid in dichloromethane (
Hungarian Patent Specification No. 160367), (4) boiling in phosphorus oxychloride or reaction with phosphoric anhydride or phosphorus halide (Hungarian Patent Specification No. 151295), (5) in the presence of hydrochloric acid. , method of boiling in alcohol [Chem, Zvesti,,
17, 4H1963) : ], (6) A method in which dehydration is carried out in a solvent that forms an azeotrope with water in the presence of a strong acid, and water is continuously removed by azeotropic distillation (JP-A-56
-71091) and the like are known.

The esterification process includes (1) a method of esterifying apovincamic acid with an alcohol corresponding to the desired ester in the presence of a catalyst, (2) a method of reacting apovincamine with a corresponding alcoholade, (3) a method of esterifying apovincamic acid with an alcohol corresponding to the desired ester, and (3) a method of reacting apovincamic acid with an alcohol corresponding to the desired ester. A method of reacting a salt with a halide or sulfate of a corresponding alcohol (Japanese Patent Publication No. 51-32640), (4) A method of converting vincamic acid into an acid chloride and reacting it with a corresponding alcohol (Spanish Patent No. 484651), 5) A method in which a salt of apovincamic acid is reacted with a corresponding alcohol halide or sulfate in the presence of a phase transfer catalyst (Japanese Patent Application Laid-Open No. 1983-8187), (6) A method in which a salt of apovincamic acid is reacted with diazoethane (Spain) Patent No. 525772), (7)
A method of reacting apovincamic acid with the corresponding alcohol halide in dimethylformamide in the presence of a metal hydride (German Patent No. 2421999), (8) Apovincamic acid salt with the corresponding alcohol and a halogenated sulfonyl or halogenated carbonate ester A method of reacting in the presence of (JP-A-63-93782
Publication No.) etc. are known.

Problems to be Solved by the Invention Even if conventional methods are successfully combined, converting vincamine to apovincamic acid ester requires three steps, which requires complicated operations and has a high total yield. I can't say that.

An object of the present invention is to provide a method for producing apovincamic acid ester from vincamine in substantially one step in a high yield in the same container.

Means for Solving the Problems The present invention provides vincamine represented by formula (II) and R-OH (I
II) (wherein R represents an alkyl group having 2 to 8 carbon atoms) is reacted with an alcohol represented by the formula (I) (wherein R represents an alkyl group having 2 to 8 carbon atoms) in the presence of a Lewis acid (synonymous with)).

Here, the alkyl group having 2 to 8 carbon atoms in the definition of R is
Straight or branched alkyl groups, such as ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, isoamyl, and the like.

Next, the method for producing apovincamic acid ester will be explained in more detail. In the reaction, the target compound can be obtained by reacting vincamine with the corresponding alcohol in the presence of a Lewis acid in a solvent if desired.

The alcohol to be used is the alcohol corresponding to the desired apovincamic acid ester.
00x amount is used.

Electron-accepting metal halides such as zinc chloride, aluminum chloride, boron trifluoride, stannic chloride, ferric chloride, zinc bromide, and titanium tetrachloride are used as Lewis acids, and the amount added is 10 to 200% (by weight) of vincamine can be added at the start of the reaction or in several portions. Further, in order to accelerate the reaction, two types of Lewis acids may be used in combination. When used in combination, they may be added at the same time, but it is more preferable to add them separately, and in this case also, they may be added in several portions.

The reaction is carried out at room temperature to 200° C., preferably at a temperature that is refluxing at the boiling point of the alcohol, and is usually completed in 1 to 80 hours, depending on the type of alcohol or reaction temperature.

The reaction may be carried out at normal pressure, but the reaction may also be accelerated by heating above the boiling point in a pressure-resistant reaction vessel.

The reaction is usually terminated by thin layer chromatography (TLC).
Alternatively, it can be confirmed by the disappearance of vincamine using high performance liquid chromatography (HPLC) or the like.

Isolation and purification of apovincamic acid ester from the reaction mixture can be carried out by solvent extraction using a conventional method, followed by recrystallization.

Furthermore, apovincamic acid ester can be converted into its acid addition salt if necessary. In this case, the method is selected as appropriate, but for example, an organic acid dissolved in a polar solvent such as ethanol is added to apovincamic acid ester and dissolved;
By dropping this solution into an inert solvent such as anhydrous ether while stirring, an acid addition salt of apovincamic acid ester can be obtained. Here, examples of the organic acid include tartaric acid, maleic acid, methanesulfonic acid, etc., and tartaric acid is particularly preferably used.

In this way, an apovincamic acid ester or an acid addition salt thereof represented by the formula (1) can be obtained by a simple operation using vincamine as a starting material in substantially one step in the same container.

The following examples provide a detailed explanation of the invention.

Example 1 Production of apovincamic acid ethyl ester Vincamine 5
20ml of 00mg! was dissolved in ethanol, and 250 mg of zinc chloride was added in four portions while heating under reflux. 3
After heating at reflux for 8 hours, 500 mg of aluminum chloride was added and heating at reflux was continued for an additional 8 hours. After cooling the reaction solution and concentrating the solvent under reduced pressure, 20-ethyl acetate and water were added to the residue, and the pH of the aqueous layer was adjusted to 7 with sodium hydroxide while stirring well.

The organic layer was separated, washed with saturated aqueous sodium bicarbonate and saturated brine, and concentrated under reduced pressure. The resulting pale yellow solid was recrystallized from ethanol to obtain 425 mg (yield: 84.5%) of crystals. This crystal showed a single peak on HPLC.

Specific optical rotation [αf,: −+ 118.2° (C・1.Pyridine) Mass spectrometry (m/z) 350 (M) “Example 2 Production of apovincamic acid n-butyl ester 400 mg of vincamine and 200 mg of aluminum chloride. 15-
of n-butanol was added thereto, and the mixture was heated under reflux for 6 hours. After cooling the reaction solution and concentrating the solvent under reduced pressure, 20 ml of ethyl acetate and water were added to the residue, and the aqueous layer was adjusted to pH while stirring well.
It was adjusted with sodium hydroxide so that the concentration was 7. The organic layer was separated, washed with saturated aqueous sodium bicarbonate and saturated brine, and then concentrated under reduced pressure. The pale yellow liquid obtained was purified by silica gel column chromatography (elution solvent: ethyl acetate) to produce apovincamic acid as a colorless oil. 385 mg (yield 90.2%) of n-butyl ester was obtained.

Specific optical rotation [αC・+77.5° (c=1.Pyridine) Mass spectrometry (m/z) 37B (M) “Example 3 Production of apovincamic acid n-propyl ester 0 500 mg of vincamine and 500 mg of ferric chloride 20 to 20
ml of n-propanol was added and heated under reflux for 18 hours. After the reaction solution was cooled and concentrated under reduced pressure, the same operation as in Example 2 was performed to obtain 436 mg of apovincamic acid n-propyl ester (yield: 83.8%).

Specific optical rotation [αC・+50.3° (C・1.Pyridine) Mass spectrometry (m/z) 364 (M)” Example 4 Production of apovincamic acid ethyl ester Vincamine 5
00 mg of ferric chloride and 500 mg of ferric chloride were added with 20 ml of ethanol, sealed in a pressure-resistant container, and heated at 140° C. for 6 hours. After cooling the reaction solution, the same operation as in Example 1 was carried out to obtain 392m of apovincamic acid ethyl ester.
g (yield 79.3%) was obtained.

Example 5.6 The same operation as in Example 4 was carried out using n-propanol or n-butanol alcohol instead of the ethanol used in Example 4. Apovinca can be done easily.

A pale yellow liquid was obtained by producing substantially monoemic acid ester from amine, and this was isolated and purified in the same manner as in Example 2 to obtain the results shown in Table 1.

Table 1 Example 7 Production of apovincamic acid ethyl ester Vincamine 5
20 ml of ethanol was added to 00 mg of zinc bromide and 500 mg of zinc bromide, and the mixture was sealed in a pressure-resistant container and heated at 120° C. for 6 hours. The reaction solution was cooled to about 80° C., 0.5 ml of titanium tetrachloride was added, and the mixture was heated under reflux at normal pressure for 3 hours. After cooling the reaction solution, the solvent was distilled off under reduced pressure, and the same operation as in Example 1 was performed to obtain apovincamic acid ethyl ester 385.
mg (yield 77.9%).

2

Claims (2)

[Claims] (1) Formula (II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (II) Vincamine represented by the formula (III) R-OH (III) (wherein, R is an alkyl group having 2 to 8 carbon atoms) The formula (I) is characterized by reacting an alcohol represented by A method for producing apovincamic acid ester represented by (2) Claims in which the Lewis acid is used in combination of one or two selected from zinc chloride, aluminum chloride, boron trifluoride, tin chloride, ferric chloride, zinc bromide, and titanium tetrachloride ( 1) Manufacturing method described.