JP2920565B2 - Method for producing 2-hydroxy-4- (3-chloropropoxy) -3-propylacetophenone - Google Patents

Description

The present invention relates to a method for producing a catechol derivative, 2-hydroxy-4- (3-chloropropoxy) -3-propylacetophenone, which is useful as a pharmaceutical intermediate. It is about.

(Prior art) It is specifically described as a conventional manufacturing method,
JP-A-60-233034 discloses that as a reaction solvent in the presence of a base, dimethylformamide, formamide, dimethylsulfoxide and ethers such as tetrahydrofuran and dioxane;
Using an alkyl halide compound such as chloroform and dichloromethane, the reaction temperature and the reaction time are not particularly limited,
It is described that the reaction is generally performed at room temperature to about 180 ° C. for about 1 to 24 hours.

(Problems to be Solved by the Invention) However, in JP-A-60-233034, when the production examples specifically described in Examples are additionally tested,
The rate of change of 2,4-hydroxy-3-propylacetophenone is 76%, and the target product, 2-hydroxy-4-
The yield of (3-chloropropoxy) -3-propylacetophenone is 43%, and the selectivity is as poor as 57%. Therefore, in order to obtain a high-quality target product, purification becomes very complicated, and further reduction in yield cannot be avoided. The reaction is extremely slow with the alkyl halogen solvents described in the above text.

In the present invention, such side reactions are controlled and a high yield and high purity of 2-hydroxy-4- (3-chloropropoxy) -3-
An object of the present invention is to provide a method for producing propyl acetophenone.

(Means for Solving the Problem) The present invention relates to a method of preparing 2,4-dihydroxy-3-prolacetophenone and 1-bromo-3-chloropropane in an aprotic polar solvent in the presence of a base at room temperature to 80 ° C. Reacting within a range, 2-hydroxy-4-
It is intended to provide a method for producing (3-chloropropoxy) -3-propylacetophenone.

As the aprotic polar solvent, any solvent capable of dissolving the raw material 2,4-dihydroxy-3-propylacetophenone can be used, but ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone, dimethylformamide, Examples thereof include ethers such as dimethyl sulfoxide, tetrahydrofuran, and dioxane.

Examples of the base include, but are not particularly limited to, organic amines such as triethylamine and alkali carbonates such as anhydrous potassium carbonate.

In the method of the present invention, the reaction is carried out at room temperature to 80 ° C, preferably
It is performed in a temperature range of 30 to 70 ° C. If the temperature is too low, the reaction slows down and the yield is unfavorably reduced.On the other hand, if the temperature is too high, a side reaction occurs and the yield decreases,
It becomes difficult to obtain high-quality 2-hydroxy-4- (3-chloropropoxy) -3-propylacetophenone. The amount of the solvent used is not particularly limited, but is usually 1 to 20 times the amount of the raw material.

The amount of the base used is preferably 1 to 2 equivalents to the raw material.

After completion of the reaction, the salt is filtered, washed with water and concentrated to obtain a purity.
90% or more of the desired product, 2-hydroxy-4- (3-chloropropoxy) -3-propylacetophenone, was added to 85%
% Or higher yield. Further, by performing a crystallization operation usually performed in an organic solvent or a mixed solvent with water, 98% or more of high-quality 2-hydroxy-4- (3-
Chloropropoxy) -3-propylacetophenone is obtained.

(Action) The cause of the decrease in the yield in the conventional method was mainly due to the decrease in the selectivity due to the by-product of the dimer represented by the formula (1).

Equation 1 That is, in order to improve the yield of 2-hydroxy-4- (3-chloropropoxy) -3-propylacetophenone, it is necessary to suppress this intermolecular reaction. Therefore, as a result of an investigation, it was found that the reaction under the conditions of the present invention, that is, under a certain temperature condition, suppressed the intermolecular reaction,
Hydroxy-4- (3-chloropropoxy) -3-propylacetophenone can be selectively and efficiently produced.

(Effects and Examples of the Invention) According to the method of the present invention, a target product can be obtained in a high yield because side reactions can be suppressed at the reaction stage.

Further, by a usual crystallization method, high-quality 2-hydroxy-4- (3-chloropropoxy) -3- is easily obtained.
Since propyl acetophenone is obtained, the method of the present invention is industrially very useful.

The high yield in this and the examples means that the yield of the desired product is 85%.
% Or more, and a high selectivity and a selectivity of the target substance of 90% or more and a dimer of 5% or less. Furthermore, high quality means that the purity of the target product is 97% or more and the dimer is 3% or less.

 The analysis method and calculation method are shown below.

 The analysis method and calculation method are shown below.

Analytical method = Liquid chromatography absolute calibration curve method What is the raw material change rate [(raw material (mol)-unreacted raw material (mol) / raw material (mol)] x 100] What is the yield [objective (mol) / raw material [Material (mol)] x 100 What is the selectivity? [Object (mol) / charged raw material (mol)-unreacted raw material (mol)] x 100 Hereinafter, the present invention will be described in more detail by comparative examples and examples. However, the present invention is not limited by these examples.

(Comparative Example-1) 2,4-Hydroxy-3-propylacetophenone (10
g), 1-bromo-3-chloropropane (8.2 g), anhydrous potassium carbonate (3.7 g) and dimethylformamide (60 m
After l) was reacted at 100 ° C. for 6 hours, the reaction solution was analyzed by liquid chromatography.
The yield of the desired product was 40% and the dimer was 16%. Further, the reaction was continued and after 15 hours, the salt was filtered off, and dimethylformamide was distilled off to obtain 15 g of a concentrate. When the concentrate was analyzed by liquid chromatography, the rate of change of the raw materials was 92.5%.
%, The yield of the target product was 51.5%, and the dimer was 21%. The selectivity was 55.7%.

Example 1 2,4-dihydroxy-3-propylacetophenone (9
7.1 g), 1-bromo-3-chloropropane (115.0 g),
After reacting anhydrous potassium carbonate (68.3 g) and acetone (625 g) under reflux for 15 hours, the salt was filtered off and the solvent was distilled off to obtain a concentrate 16
1 g was obtained. When the concentrate was analyzed by liquid chromatography, the conversion of 2,4-dihydroxy-3-propylacetophenone was 96.2%, the yield of the target product was 93.2%, and the dimer was 2.0%. 96.9%.

(Example-2) The same operation as in Example-1 was carried out except that methyl isobutyl ketone was used instead of acetone and the reaction temperature was 70 ° C, to obtain 165 g of a concentrate. The rate of change of the raw material was 94.2%, the yield of the target product was 90.0%, and the dimer was 3.1%.
Its selectivity is 95.5%.

(Example-3) The procedure of Example-1 was repeated, except that dimethyl sulfoxide was used instead of acetone and the reaction temperature was changed to 43 ° C, and the reaction was carried out for 9 hours. As a result, 163 g of a concentrate was obtained. The rate of change of the raw material is 93.1%, the yield of the desired product is 89.0%, and the dimer 3.7
%, Its selectivity is 95.6%.

(Example-4) 483 g of isopropyl alcohol and water (191 g) were added to the concentrate (161 g) obtained in Example-1, heated to 40 ° C, cooled to 5 ° C, crystallized, and filtered. The obtained wet crystals were dried under reduced pressure at 30 ° C. to obtain 93.8 g. The purity was 98.0% and the dimer was 1.9%.

Claims (1)

(57) [Claims] 1. The method according to claim 1, wherein 2,4-dihydroxy-3-propylacetophenone and 1-bromo-3-chloropropane are reacted in an organic solvent in the presence of a base at room temperature to 80 ° C. A method for producing 2-hydroxy-4- (3-chloropropoxy) -3-propylacetophenone.