KR870000865B1 - Prpeparation process of substituted benzoic acid derivatives - Google Patents

Abstract

Substd. benzoicv acid derivs. or its HCl salts having for mula (I) are prepd. by (1) reacting hydrofuran with substd. halo benzoic acid in the presence of catalyst, (2) condensing with (II) in th epresence of NaI. The rxn. such as e.g. dissolves of 3,4-dimethoxybenzaldehyde in MeOH, gaseous bubbling into rxn. container, fractional distn. under reduced pressure to produce title compds. (I) are useful for spasmolytics and atonies.

Description

Method for preparing substituted benzoic acid derivatives

The present invention relates to an improved process for the preparation of substituted benzoic acid derivatives represented by formula (1).

The compound of formula (1) is a compound well known as antispasmodic and relaxing agent, and Lindyn et al. Among beta indolyl ethylamine derivatives and betaphenyl ethyl amine derivatives synthesized in 1961 by substituting part of the chemical structure of tesselpin by Kralt et al. The compound represented by the structural formula (1) has been found to have a very good hardening action, and it was recognized that it is major in various types of digestive diseases in clinical terms, and it is especially attracting attention as a digestive system drug.

These conventional manufacturing methods are known in the United Kingdom Patent No. 893088, 914783, 1009082, Korean Patent Publication No. 811, etc. A variety of manufacturing methods are introduced as follows.

First method: Production method by esterification between the following compounds.

2nd method: The manufacturing method by condensation between following compounds.

Third method: A manufacturing method by condensation between the following compounds.

Fourth method: Production method by condensation between the following compounds.

Fifth method: Production method by reduction of the following compound.

6th method: The manufacturing method by condensation between the following compounds.

(Wherein R ₁ and R ₂ are hydroxy, an alkoxy group having 1 to 3 carbon atoms, M is K, Na, Ca, Mg and X is halogen in the metal)

Schematic of the third method of the above production method is as follows.

Structural Formula (1) Compound

As shown in the above scheme, the yield of the reaction using the expensive intermediate 3.4-dimethoxy benzoic acid, metal sodium and 1.4-dichlorobutane is low at 60% and has a disadvantage of requiring a long time (90 hours).

In addition, the yield from the starting material to the compound of formula (1) is very low (30-35%), resulting in a very high production cost of the compound of formula (1). Therefore, the researchers have already invented a new method for the preparation of the compound of formula (1) and registered it as Patent No.14978, which is an improved method of the acid chloride by halogenating 3.4-dimethoxy benzaldehyde which is cheaper than 3.4-dimethoxy benzoic acid. After condensation with the detra hydrofuran here, the process is simpler than the known manufacturing method and more economical.

That is, in the preparation of the compound of formula (1), which is a substituted benzoic acid derivative, 3.4-dimethoxy benzaldehyde is directly chlorolated, followed by condensation of tetrahydrofuran in the presence of a catalyst, followed by reaction of the compound of formula (2) directly. Troublesome operations such as isolation from the series can be avoided and the compound of formula (1) can be easily obtained in high yield.

The present invention is schematically illustrated as follows.

(X: halogen)

The starting material 3.4-dimethoxybenzaldehyde in the above scheme is a known compound and can be prepared simply from vanillin.

Since this compound has no hydrogen at its alpha position, it is easily converted to an acid halide compound (3) by free radical type by treatment with chlorine (or sulfuryl chloride, tertiary chloro butoxide, etc.).

The compound (3) was reacted with tetrahydrofuran, anhydrous zinc chloride, and anhydrous aluminum chloride (such as Lewis acid) for about 5 hours, followed by condensation with sodium iodide and condensation with N-ethylparamethoxyphenyl isopropyl amine. Phosphorus (1) compound is obtained.

Meanwhile, the reaction mechanism of the present invention will be described schematically as follows.

The following examples illustrate the present invention in more detail, but the scope of the present invention is not limited thereto.

Example 1.

3.4 Preparation of Dimethoxybenzoyl Chloride

16.7 grams (0.1 mole) of 3.4-dimethoxy benzaldehyde is dissolved in 80 ml of anhydrous methanol, and 3.6 grams of dried chlorine gas is continuously injected over 5 hours. After the completion of the chlorine injection, the reaction solution was fractionally distilled under reduced pressure to obtain 16.9 grams of the title compound.

(Yield 84%) C ₉ H ₉ O ₃ Cl MW = 200.6

Elemental analysis

Element Name C H O Cl

division

Theoretical 53.9 4.5 23.9 17.7

Found 53.8 4.5 24.0 17.6

[Example 2.]

3.4-Dimethoxy benzoic acid 4- (ethyl (2- (4-methoxyphenyl-1-methylphenylethyl) amino) butyl ester

20.1 grams (0.1 mole) of compound obtained in Example 1, 7.3 grams (0.1 mole) of re-distilled tetrahydrofuran and 7 grams of anhydrous zinc chloride were added to a three-necked flask and refluxed for 5 hours, followed by cooling with ice water. Dissolve the precipitate in 70 ml of acetone. 15 grams (0.1 mol) of dry sodium iodide and 19.4 grams (0.1 mol) of N-ethyl P-methoxyphenyl isopropylamine were added and refluxed for 10 hours, and then the resulting solids were removed and 100 ml of diluted hydrochloric acid and 50 ml of benzene were added. The separated aqueous layer is alkaline with potassium hydroxide and then extracted twice with 50 ml of chloroform.

Hydrogen chloride gas is poured into the mixture and stirred for 1.5 hours to form crystals. The resulting product is filtered and dried to obtain 34.5 grams of the target substance.

(74% yield)

M.P 129 ~ 131 ℃

Elemental analysis

Element Name Cl H N O

Classification

Theoretical 7.6 7.7 3.0 17.2

Found 7.6 7.8 2.9 17.4

Claims (1)

In preparing a substituted benzoic acid derivative of formula (1), an acid halide of formula (3) and tetrahydrofuran are reacted in the presence of a catalyst and condensation reaction with a compound of formula (2) in the presence of sodium iodide ( The method of manufacturing the substituted benzoic acid derivative of 1), and its hydrochloride.

(X = halogen)