JPH0262846A - Method for producing carboxylic acid phenyl esters - Google Patents

Abstract

PURPOSE:To obtain the title compound useful as an intermediate for drugs in a short time, simply and in high yield without requiring heating operation in reacting a phenol corresponding to the aimed compound with a carboxylic acid anhydride by adding a small amount of an inorganic acid to the reaction system. CONSTITUTION:1 equivalent compound shown by formula I (R1 to R3 are H or substituent group) is reacted with usually 1-2 equivalent, preferably 1.2-1.8 equivalent carboxylic acid anhydride such as acetic anhydride, propionic anhydride, n-butyric anhydride or benzoic anhydride in the presence of usually 0.001-0.5 equivalent, preferably 0.005-0.1 equivalent of an inorganic acid based on the compound shown by formula I such as sulfuric acid, phosphoric acid or phosphoric anhydride, especially sulfuric acid usually at 0-180 deg.C, preferably 0-100 deg.C, especially 0-70 deg.C to advantageously give the aimed compound shown by formula II (R4 is H or hydrocarbon group) by simple purification and further to give efficiently moxisylyte hydrochloride (drug for circulatory organ base).

Description

DETAILED DESCRIPTION OF THE INVENTION [Object of the Invention] (Industrial Field of Application) The present invention relates to a method for producing carboxylic acid phenyl esters.

(Prior art and its problems) A phenol represented by the following formula (A): (In the formula, R1, R2 and Ichang represent a hydrogen atom or a substituent) in the presence of a small amount of an inorganic acid, The following formula (+) is characterized by reacting with a carboxylic acid anhydride in an inert solvent. A method for producing carboxylic acid phenyl esters represented by (representing a hydrogen group).

The substituted aminoethoxycarhachlor derivative represented by is useful as a peripheral vasodilator, an antihypertensive agent, an agent for improving cerebral circulation and metabolism, and an anti-asthmatic agent, for example, 1? ,=Il,=l
I, 4(N-monoaralkylaminoethoxy)carvacrol having the structure of R7-aralkyl group was disclosed in JP-A No. 5
It is disclosed in Japanese Patent No. 6-100745. Also, R1
=acetyl group, R6=R? -Moxisilito hydrochloride, which has a methyl group structure, is known as a compound useful as a drug for the cardiovascular system.

In the manufacturing method of these pharmaceuticals, phenols represented by the chemical formula (■) (R+, L, R3 are the tA
It is M. ) may be important. In particular, in the process of producing the hydrochloride of moxysilito, the raw material thymol (structural formula (II)
Step of acylating R+-isopropyl, Rz=hydrogen, 113=methyl, 5-(2-dimethylaminoethoxy)
-Rylhachlor (structural formula (II) R, = methyl, R2
= 2-dimethylaminoethoxy, [? .

= isopropyl] to produce moxysilito, and it is necessary to carry out esterification in a high yield, high purity, and in an industrially advantageous method.

Up to now, various methods for such esterification have been proposed, but they can be roughly divided into two types. One method is to use an acid halide, for example, as described in JP-A-58-121251, acetyl chloride was added at 1.2
- A method for reacting in dicycloethane or benzene is disclosed. Further, JP-A-58-167551 discloses a method in which the acetylation is carried out in chlorobenzene.

However, in these methods, it is necessary to use a corrosion-resistant reaction vessel because the acid halide generates corrosive chlorine gas outside the system as the reaction progresses. Furthermore, the acid halide itself reacts violently with water to generate hydrochloric acid gas, making it a difficult substance to industrially prepare, making this method disadvantageous from an industrial perspective.

Another method is to use an acid anhydride, which is inexpensive and easy to extract, and is industrially advantageous because it does not generate hydrochloric acid gas during the reaction. However, it has slightly lower reactivity than acid halides, and it is necessary to accelerate the reaction with heating or additives, especially when esterifying a phenolic hydroxyl group.

JP-A-57-206643, JP-A-604155
No. 55 discloses a method of adding acetic anhydride and heating. On the other hand, when using additives, acetates, organic bases, and acids are used.

Examples of using acetate as an additive include Org, Syn
th, 1,285 (1941), and it is necessary to add about 30 to 40 mol % of the amount to the raw material, and heating is also necessary at the same time.

On the other hand, an example of using an organic base as an additive is JP-A-49-45029.

In this example, heating is usually not necessary, but as the reaction progresses, it is necessary to add at least an amount equivalent to the raw material in order to remove the generated acid in the form of a salt with an organic base. Furthermore, upon completion of the reaction, an operation is required to remove by-produced salts, which is still industrially disadvantageous.

In addition, as an example of using an acid as an additive, JP-A-62539
Publication No. 47 discloses a reaction using acetic anhydride and acetic acid.
It requires operations such as heating to °C and also requires treatment to remove a large amount of acid from the reaction system, which is industrially disadvantageous. In addition, JP-A-62-111952 discloses a reaction using acetic anhydride and hydrochloric acid, but this also uses 0.9 times the mole of hydrochloric acid and is heated to 100'C, making it a difficult process. be.

As a result of intensive research to solve the various problems described above, the present inventors have found that the following formula (■): (wherein R1, R2, and R3 represent a hydrogen atom or a hydrocarbon group) phenols and carboxylic acid anhydrides in the presence of an inorganic acid,
The esterification reaction was carried out in an inert solvent, and it was found that the reaction rate, yield, and operability were all good, leading to the completion of the present invention. In particular, when a specific inorganic acid such as sulfuric acid is used, no heating operation is required and the manufacturing process can be simplified.

[Structure of the invention]

(Means for Solving the Problems) That is, the present invention provides the following formula (If): (wherein R1, R
2 and R1 represent a hydrogen atom or a substituent. ) is reacted with a carboxylic acid anhydride in the presence of a small amount of inorganic acid in an inert solvent. ? has the same meaning as above. Also, R4 represents a hydrogen atom or a hydrocarbon group.

In the formulas (I) and (II), R1, R2゜R
Examples of the substituent represented by 3 and L include an alkyl group or an aryl group. The alkyl group is usually an alkyl group having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group,
Examples include c-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, hexyl group, isohexyl group, neohexyl group, and the like.

Similarly, examples of the aryl group include phenyl, tolyl, cumenyl, xylyl, mesityl, hensyl, and the like.

The alkyl group and aryl group may be substituted with a suitable substituent. Here, the appropriate substituent refers to a substituent that is stable under the reaction conditions in the production method of the present invention, and includes, for example, a halogen atom, an alkoxy group, an alkyl group, a nitro group, a sulfo group, and the like.

The carboxylic acid phenyl esters represented by the formula (I) are produced by treating the phenol represented by the formula (II) with a carboxylic acid anhydride in the presence of an inorganic acid in an inert solvent. can do.

Examples of the carboxylic anhydride used here include acetic anhydride, propionic anhydride, n-butyric anhydride, benzoic anhydride, etc., and mixed acid anhydrides may also be used. The amount of these carboxylic acid anhydrides used is usually 1 to 2 equivalents, preferably 1.2 times the amount of the phenol represented by ni(n).
~1.8 times equivalent.

The inert solvent for the esterification reaction is a solvent that does not contain carboxyl groups, amines, etc. Specific examples thereof include acetonitrile, henzene, toluene, nitrobenzene, dichloroethane, methylene chloride, trichloroethylene, chloroform, carbon tetrachloride, Any substance may be used as long as it does not participate in the reaction, such as monochloroamine, dichloroamine, amine, and carbon disulfide.

Examples of the inorganic acid to be allowed to coexist include sulfuric acid myric acid, phosphoric anhydride, and the like. Among these, sulfuric acid is capable of proceeding with the reaction at room temperature and is capable of carrying out an industrially advantageous reaction.

The amount of inorganic acid used is usually 0.001 to 0.5 times equivalent, preferably 0.
．． 0.005 to 0.1 times equivalent.

The reaction temperature is usually 0 to 180°C, preferably 0 to 1
00''C1, more preferably 0 to 70°C.

The progress of the reaction can be monitored by analyzing a portion of the reaction solution by gas chromatography.

When the raw material phenols are consumed, the reaction is stopped and the solvent is distilled off to obtain crude carboxylic acid phenyl esters. Column chromatography, recrystallization, if necessary
The carboxylic acid phenyl esters represented by formula (1) can be obtained by purification using a distillation method.

(Examples of the Invention) Hereinafter, the present invention will be explained in more detail with reference to Examples, but the following Examples do not limit the scope of the present invention in any way.

Example 1゜ Raw material thymol (formula (II); R+=isopropyl, R
2-hydrogen, l13=methyl) 150.22g (1 mol) and acetic anhydride 132.7g (1,29 mol) in 1!
Transfer to a flask, add 150 mff1 of toluene and dissolve. To this, 2.45 g (0,025 mol) of concentrated sulfuric acid was added, and the mixture was stirred at room temperature of 20°C for 1 hour. After the reaction was completed, the reaction mixture was washed with 150 mfl of water, and the solvent was distilled off to obtain 182.20 g of crude thymol acetate as a residue. This contained 180.2 (b) of the target product (yield 93.7%).

It was purified by vacuum distillation to obtain a pure product as a colorless liquid.

Boiling point: 131-132°C/23 m+n11g The chemical structure of the compound thus obtained was confirmed by comparing the infrared spectrum with a standard sample in the same manner as in Example 1,
Formula (1) (R, -isopropyl, R2=hydrogen, I?3=
Methyl, Ra = mini methyl. ) was confirmed to be a compound shown by

Infrared absorption spectrum (cm-') 2950, 1750 (carbonyl X), 1360.
1200(-0-).

10B0.1010,890,810 [Effects of the Invention] According to the present invention, carboxylic acid phenyl esters can be obtained in a short time, without the need for heating operations, easily purified, and in high yield, and can be used as pharmaceuticals. It is possible to efficiently provide moxisilite hydrochloride useful as a compound.

Claims (1)

[Claims] (1) The following formula (II): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) (In the formula, R_1, R_2, and R_3 represent hydrogen atoms or substituents.) A small amount of inorganic The following formula (I) is characterized by reacting with a carboxylic acid anhydride in the presence of an acid in an inert solvent: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R_1, R_2 , R_3 have the same meanings as above. Also, R_4 represents a hydrogen atom or a hydrocarbon group.)
A method for producing carboxylic acid phenyl esters represented by