JPH04120078A - Production of apovincaminic acid ester - Google Patents

Abstract

PURPOSE:To industrially obtain the subject compound, having cerebral blood flow increasing, microcirculating, blood platelet agglutination inhibitory, cerebral ischemic protective action, etc., and useful as an ameliorant for cerebral circulation by dehydrating a vincaminic acid ester in the presence of an alkylsulfonic acid. CONSTITUTION:A vincaminic acid ester expressed by formula I (R is 1-8C alkyl) is dehydrated in the presence of an alkylsulfonic acid expressed by the formula R<1> SO3H [R<1> is (halogen-substituted) 1-8C alkyl)], preferably at the boiling point of the solvent (e.g. alcohols) used for 4-6hr to afford the objective compound expressed by formula II.

Description

[Detailed description of the invention] Industrial applications The present invention relates to a method for producing apovincamic acid ester.

Apovincamic acid ester has the effect of increasing cerebral blood flow, micro@
It has a synthetic effect, a platelet aggregation inhibitory effect, a cerebral metabolism improving effect, a cerebral ischemia protective effect, etc., and is useful as an agent for improving cerebral circulation and metabolism.

Conventional technology Traditionally, vincamine, a type of natural alkaloid,
A method for producing apovincamic acid ester using vincamic acid ester (IJ), especially a methyl ester (called vincamine) as a starting material is known. The method is usually carried out by appropriately combining an esterification step and a dehydration step.

In the esterification process, vincamic acid or apovincamic acid is obtained by hydrolyzing vincamine or apovincamic acid ester, which is obtained by dehydrating vincamine, especially the methyl ester is called apovincamine. A method of esterifying vincamine or a method of directly transesterifying vincamine or apovincamine is known. As a transesterification method, a method of reacting a corresponding alcohol with an alkali metal alcoholade is disclosed in Japanese Patent Publication No. 51-32640.

As a dehydration step, for example, a method of azeotropically dehydrating vincamic acid ester in the presence of a strong acid is disclosed in JP-A-56410.
No. 91 (with descriptions of other dehydration methods).

Problems to be Solved by the Invention Many of the known methods require vincamic acid or apovincamic acid as a raw material in the esterification step, and therefore require a step of decomposing the vincamic acid or apovincamic acid extract. In addition, even in the above-mentioned direct transesterification method (1), it is necessary to use a metal alcoholade which is preferable as an industrial production method.

The present invention provides a new method for producing apovincamic acid ester, which comprises a simple and advantageous transesterification step and dehydration step on an industrial scale.

Means for Solving the Problems The present invention uses formula (II) 6-port as a dehydration step. A vincamic acid ester represented by R C,II5 (wherein R represents an alkali having 1 to 8 carbon atoms) is converted into a vincamic acid ester represented by the formula (I[l)R'5O3
Formula H) characterized by dehydration in the presence of an alkylsulfonic acid represented by H(III) (wherein R1 represents an alkyl having 1 to 8 carbon atoms which may be substituted with a halogen atom) -・□/-3 10:', 1 Vゝ゛・・〜," ,,/N・-1, (I)7ku1,7
Furthermore, as a method for producing apovincamic acid ester or an acid addition salt thereof represented by / father / C(]2RC2L (wherein R has the same meaning as above) and a transesterification step, the formula (IIa
) ′・〜／゛1.・~, (IlallO ゝ( cc2cH3c2H5 ) Vincamine and an alcohol represented by the formula (■) Ra-OH (■) (in the formula, R' represents an alkyl having 2 to 8 carbon atoms) are combined into the formula (~ ′) Ti (OR)
-(～゛) (In the formula, R represents an alkyl having 1 to 8 carbon atoms) Formula (Il b) CO2R' 口2H5 (Formula (wherein, P has the same meaning as above) or a method for producing a vincamic acid ester or acid addition salt represented by formula (I a) C020H3C21b and apovincamine represented by formula (1'V) R'-OH
(rV) (wherein II' has the same meaning as above) and the alcohol represented by the formula (V) Ti (OR
), (V) (in the formula, R has the same meaning as above). , have the same meanings as above) The present invention relates to a method for producing an apovincamic acid ester or an acid addition salt thereof represented by the following.

In the definitions of the above formulas, alkyl having 1 to 8 carbon atoms refers to straight or branched methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 5ec-butyl, te
Examples include rt-butyl, pentyl, inopentinopehexyl, heptyl, octyl, and the like. Also, the number of carbon atoms is 2~
The alkyl in 8 is also exemplified by a group obtained by removing methyl from the above alkyl.

Examples of the alkylsulfonic acid represented by formula (II[) include methanesulfonic acid and ethanesulfonic acid f>, and examples of the halogen atom include 1 to 3 substituted fluorine,
Chlorine, bromine, etc. are included, and a specific example is trifluoromethanesulfonic acid. Specific examples of the orthotitanate represented by formula (V) include tetraethyl titanate, tetrapropyl titanate, tetraisopropyl titanate, and tetrabutyl titanate. Further, acid addition salts of apovincamic acid ester include hydrochloride, sulfate, tartrate, maleate, methanesulfonate, and the like.

Each step of the manufacturing method will be explained in detail below.

l) Transesterification process Vincamine (IIa) is produced by dehydrating vincamine, apovincamine (Ia), and alcohols (rV
) in the presence of orthotitanate (V) as a catalyst, the corresponding vincamic acid ester (IIb) or apovincamic acid ester (Ib) can be obtained.

Compound (rV) is the starting material compound (IIa) or (I
The amount used is 5 to 200 times that of a).

In addition, in order to improve the solubility of the raw materials, halogenated hydrocarbons such as chloroform and dichloroethanat,
Esters such as ethyl acetate and butyl acetate; ethers such as tetrahydrofuran and dioxane; aromatic hydrocarbons such as benzene and toluene; ~200 times more! It can also be added.

The catalyst is used in an amount of 10 to 300% (weight ratio) based on the raw materials, and is added at the start of the reaction or in several portions during the reaction.

The reaction is carried out under pressure or normal pressure at room temperature to 200°C, preferably at a temperature that refluxes at the boiling point of the alcohol used in the reaction, and is usually completed in 1 to 80 hours.

11) Dehydration step Apovincamic acid ester (I) (containing apovincamine) can be obtained by dehydrating vincamic acid ester (■) (containing vincamine) in the presence of an alkylsulfonic acid (III).

Compound (III) is 0.5 to 0.5 to compound (II)
5 equivalents are used, preferably 1 to 3 equivalents.

As the reaction solvent, the alcohols or various solvents mentioned above in the transesterification step can be similarly used.

The reaction is completed in 4 to 6 hours at 50-120°C, preferably at the boiling point of the solvent used.

The target compound can be isolated and purified from the reaction mixture by conventional methods such as extraction, washing, drying, a-condensation, recrystallization, and various chromatography. Alternatively, it can be isolated as an acid addition salt if desired; for example, the product is crystallized by adding an acid dissolved in a polar solvent such as ethanol, or the solution is added to an inert solvent such as anhydrous ether to crystallize the product. It can be crystallized and isolated. Furthermore, it is also possible to use the intermediate as it is for the next reaction without isolation.

According to the present invention, apovincamic acid ester can be produced more easily and efficiently than vincamine by appropriately combining the production steps 1) and U) above.

The following examples provide a detailed explanation of the invention.

Example 1 Production of vincamic acid ethyl ester In a mixed solution of 40 ml of dioxane containing 5 g of vincamine and 30 ml of ethanol, 3.
After adding 2 g, the mixture was heated under reflux for 8 hours. Cool the reaction solution,
The solvent was distilled off under reduced pressure, and 35 g of 1N hydrochloric acid was added to the resulting residue, followed by stirring at room temperature for 3 hours.

The precipitated crystals were separated and added to 40 mR of chloroform and 40 mR of a saturated aqueous solution of hydrogen carbonate, followed by stirring and dissolving. The chloroform layer was separated, dried over anhydrous magnesium sulfate, and the residue was recrystallized from ethanol to obtain 468 g (yield: 90%) of the target compound.

Melting point 2438℃ Elemental analysis・C22H2,N 203 HN Calculated value (%) 71.71 7.66 7.60
Actual value (%) 71,92 7.88 7.47
Example 2 Production of apovincamic acid ethyl ester (1) 2.86 g of apovincamic acid ethyl ester was mixed with 63 g of anhydrous ethanol.
In addition to m1, 205 g of methanesulfonic acid was added, and the mixture was heated under reflux for 4 hours. The reaction solution was cooled, the solvent was distilled off under reduced pressure, and the resulting residue was added with chloroform and saturated hydrogen carbonate.
75 g of each aqueous solution was added and stirred. The chloroform layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was recrystallized from 30 ml of absolute ethanol to obtain 2.18 g (yield: 80.2%) of the desired metal product.

Melting point: 150.3°C, 20° α, = + 129.8° (c=
l, dimethylformamide) + D Elemental analysis/C22H26N 202 HN Calculated value (%) 75.40 7,48 7.99
Actual value (%) 75.31 7,55 8.05
Example 3 Production of apovincamic acid ethyl ester (2) 40m of dioxane containing 5g of apovincamine and 3 ethanol
Tetraethyl heorthotitanate in a mixed solution of 0-3.6
g was added thereto, and the mixture was heated under reflux for 30 hours.

The reaction solution was cooled, and the solvent was distilled off under reduced pressure. To the resulting residue were added 50 g of 1N hydrochloric acid and 50 g of chloroform, and the mixture was stirred. Separate the chloroform layer, wash with saturated hydrogen carbonate, dry with anhydrous sulfuric acid, and reduce pressure; aNl
-ta. The obtained residue was recrystallized from 100 ml of ethanol to obtain 479 g (yield 92%) of the target compound.

Melting point: 150.1℃ 3α ==-130,3@ (c=1
, dimethylformamide) +0 Elemental analysis: C22H2GN202 HN Calculated value (%) 75.40 7.48 7.99
Actual value (%) 75.23 7,52 8.01
Example 4 '31 m of apovincamic acid ethyl ester (3)
In a mixed solvent of 32 ml of ethanol and 43 cm of dioxane containing 5.32 g of vincamine, 3.42 g of tetraethyl orthotitanate was added and heated under reflux for 16 hours. Next, 5.80 g of methanesulfonic acid was added, and heating and refluxing was continued for an additional 5 hours. The reaction solution was cooled, the solvent was distilled off under reduced pressure, and the resulting residue was chloroform and saturated hydrogen carbonate.
50 ml of each IJum aqueous solution was added and stirred. The chloroform layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was recrystallized from 20 ml of ethyl acetate to obtain 3.99 g (yield 76%) of the target compound.

Melting point: 150.3℃ -20, α = -130,0' (c=1
Elemental analysis: C22i-(2,N,O.

CHN Calculated value (%) 75.40? , 48 7.9
9 Actual measurement value (%)? 5.33 7,44 7.9
7 Example 5 Production of vincamic acid isopropyl ester Vincamine 5
Dioxane containing 40 g and isopropyl alcohol 3
4.0 g of tetraisopropyl heorthotitanate was added to 0 ml of the mixed solution, and the mixture was heated under reflux for 40 hours. The reaction solution was treated in the same manner as in Example 1 to obtain 4.32 g (yield: 80%) of the target compound.

Elemental analysis' C23H3oN203 HN Calculated value (%) 72,22 7.91 7.32
Actual value (%) 1250 7.98 7.15 Example 6 After adding 3.6 g of tetraisopropyl orthotitanate to a mixed solution of 40 ml of dioxane and 30 mm of isopropyl alcohol containing 5 g of apovincamic acid isopropyl ester/apovincamine tartrate. The mixture was refluxed for 48 hours. The reaction solution was cooled, and the solvent was distilled off under reduced pressure. To the resulting residue were added 50 ml of 1N hydrochloric acid and 50 ml of chloroflume, and the mixture was stirred. The chloroform layer was separated, washed with a saturated aqueous solution of hydrogen carbonate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. A solution of anhydrous ethanol 35- containing an equimolar amount of tartaric acid to apovincamine was added to the resulting residue, and a solution was added dropwise into anhydrous ether 350-. rate 8
9%) of the target compound was obtained.

Melting point: 108.3°C m-20 α = -63,4° (C = 1, pyridine)'D Elemental analysis C27H34N20 s CHN Calculated value (%) 63,02 6.66 544 Actual value (%) 62, 88 6,72 5. Effects of a 50-shot bow The present invention makes it possible to easily and efficiently produce apovincamic acid ester on an industrial scale.

Claims (3)

[Claims] (1) Formula (II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) (In the formula, R represents an alkyl having 1 to 8 carbon atoms) Vincamic acid ester is converted to the formula (III) R^1SO_
3H(III) (wherein R^1 represents an alkyl having 1 to 8 carbon atoms which may be substituted with a halogen atom) I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) A method for producing apovincamic acid ester or its acid addition salt represented by (in the formula, R has the same meaning as above). (2) Formula (IIa) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (IIa) Vincamine represented by and Formula (IV) R^a-OH (IV) (In the formula, R^a is a carbon number of 2 to 8 (representing an alkyl group) in the presence of an orthotitanate ester represented by the formula (V) Ti(OR)_4(V) (wherein R represents an alkyl group having 1 to 8 carbon atoms). Formula (IIb) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(IIb) (In the formula, R^a has the same meaning as above) of vincamic acid ester or acid addition salt represented by Manufacturing method. (3) Formula (I a) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ ( I a) Apovincamine represented by and formula (IV) R^a-OH (IV) (In the formula, R^a is the number of carbon atoms 2 ~8 alkyl) and an orthotitanate ester represented by the formula (V) Ti(OR)_4(V) (wherein R represents an alkyl having 1 to 8 carbon atoms). Apovin camic acid ester or A method for producing its acid addition salt.