JPS5938234B2 - Method for producing dihydrobenzofuran derivatives - Google Patents

Description

Detailed Description of the Invention The present invention uses benzyl, phenethyl, etc., which may have a substituent such as the general formula trifluoromethyl, and arylthioalkyl refers to halogen, lower alkyl, lower alkoxy, trifluoromethyl, etc. phenylthioethyl (optionally having a substituent).

According to the method of the present invention, the compound of general formula [I] can be prepared by the following 1
It can be manufactured by the following methods. 1 General formula [Each symbol in the formula has the same meaning as above.

] A method for reducing the compound represented by

This reduction is carried out by (a) catalytic hydrogenation, that is, hydrogenation in the presence of a catalyst such as platinum, palladium on carbon, etc., in a solvent such as methanol, ethanol, tetrahydrofuran, dioxane, etc., at normal or elevated pressure, at room temperature or under heating. or (b) using a complex metal hydride, such as sodium borohydride, in a solvent such as methanol, ethanol, tetrahydrofuran (preferably in a mixed solvent of methanol and tetrahydrofuran), 0
This can be carried out by processing at ~30°C.

2. General formula halo or this reaction amine: Excessive use of amine of general formula [] to also serve as a deoxidizing agent, or presence of potassium carbonate, sodium carbonate, caustic potash, caustic soda, triethylamine, pyridine, etc. as a deoxidizing agent. done below.

3 General formula Ha [Each symbol in the formula has the same meaning as above.

] and the general formula [wherein R'', R', R', R'' have the same meanings as above, and X represents halogen (chlorine, bromine, etc.).

] and the general formula [In the formula, R5 has the same meaning as above.

] A method of reacting with a compound represented by

, this reaction is carried out in a suitable solvent. This is carried out by heating under reflux for about 5 to 20 hours. Any solvent that does not inhibit the reaction can be used, including ethanol,
Isopropanol, benzene, toluene, dioxane and the like are advantageously used. [In the formula, R5 has the same meaning as above. ] A method of reacting with a compound represented by

This reaction is carried out in a suitable solvent at room temperature or under reflux of the solvent used.

Any solvent that does not inhibit the reaction may be used, but alcoholic solvents such as methanol, ethanol, and isopropanol are advantageously used. Among them,
Heating at reflux in ethanol for 1 to 10 hours is the preferred method of practice. Raw material compounds in methods 1 to 3 [],
[] and [V] can be prepared by the following method.

(1) How to prepare a compound of the general formula [] [In the formula, each symbol has the same meaning as above.

This reaction is carried out in a suitable solvent such as methanol, ethanol, isopropanol, benzene, toluene, dioxane, etc., generally under reflux of the solvent.

(2) Method for preparing the compound of general formula [I] [In the formula, each symbol has the same meaning as above.

] 1 This reaction is carried out by treating the compound [ ] with sodium borohydride in methanol or tetrahydrofuran at temperatures below 0°C. (3)
Method for preparing a compound of general formula [V] [In the formula, each symbol has the same meaning as above.

] This reaction is carried out in ethyl ether or tetrahydrofuran in the presence of caustic potash or caustic soda under refluxing of the solvent.

General formula [1] shall include all possible stereoisomers and mixtures thereof.

The compound of general formula [1] has at least one asymmetric center within its molecule. The derivative is therefore a racemic mixture, and in some cases exists in the form of two diastereoisomers. These racemic diastereoisomers can be separated from each other, if necessary, by, for example, fractional crystallization. A pharmaceutically acceptable acid addition salt of the dihydrobenzofuran derivative represented by the general formula [1] produced by the above method can be produced by a conventional method.

The acid for producing the acid addition salt can be appropriately selected from inorganic acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid, and organic acids such as maleic fumaric acid and citric acid. The thus obtained compound of general formula [1] and its acid addition salt have anti-inflammatory, analgesic, and antihypertensive effects, and are useful as pharmaceuticals or intermediates thereof.

Next, the present invention will be explained in more detail with reference to Examples.

Example 1 10.5 t of 2,3-dihydro-2-methyl-5-[(4-(3-chlorophenyl)-1-piperazinyl)acetyl]benzofuran was dissolved in a solvent consisting of TOO ml of methanol and 50 ml of tetrahydrofuran, and the mixture was cooled with water. 4.0 t of sodium borohydride was gradually added to the solution.

After addition, the resulting crystals were collected by leaving them at room temperature overnight and recrystallized from isopropanol, resulting in a melting point of 140-141C0.
I-(2,3-dihythro-2-methylbenzofuran-5
-yl)-2-(4-(3-chlorophenyl)
9.0 t of -1-piperazinyl)-1-ethanol are obtained. When this is treated with 30 dihydrochloric acid and isopropanol and the resulting crystals are recrystallized from a mixed solvent of ethanol and isopropyl ether, a monohydrochloride with a melting point of 131-132C is obtained. Example 2 1-(2,3-dihythro-2-methylbenzofuran-
5-yl)-2-chloro-1-ethanol 4.2y, phenylpiperazine 3.91, and triethylamine 5ml were refluxed in 100ml of isopropanol for 10 hours.
Concentrate under reduced pressure Extract with ethyl acetate Wash with water, then dehydrate and dry over magnesium sulfate.

The oil obtained by concentrating under reduced pressure was crystallized under ice-cooling and recrystallized from ethanol to give 1.
-(2,3-dihythro-2-methylbenzofuran-5
5.5y of 2-(4-phenyl-1-piperazinyl)-1-ethanol are obtained. 30% to this
When the crystals to which isopropanol hydrochloride is added are recrystallized from isopropanol, a dihydrochloride salt having a melting point of 152°C (decomposed) is obtained. Example 3 1-(2,3-dihydro-2-methylbenzofuran-5-yl)ethylene oxide 3.5y, 4-(
5.0 t of 4-chlorobenzyl)piperazine is added to 50 ml of ethanol and refluxed for 5 hours.

When the crystals obtained by concentration under reduced pressure are recrystallized from benzene, 1-(2,3-dihytro-2-methylbenzofuran-5-yl)-2-( with a melting point of 170.5-171°C) is obtained.
60 tons of 4-(4-chlorobenzyl)-1-piperazinyl)-1-ethanol are obtained. When this is treated with 30% hydrochloric acid-isopropanol and the resulting crystals are recrystallized from isopropanol, a dihydrochloride having a melting point of 272°C is obtained.

For example, the following compounds can be produced using the same method.

Claims (1)

[Scope of Claims] 1. A dihydrocarbon compound represented by the general formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ characterized by subjecting a compound represented by the following to a reduction reaction. A method for producing a benzofuran derivative or a pharmaceutically acceptable acid addition salt thereof. [In the above formula, R^1 and R^2 are the same or different and represent hydrogen or lower alkyl, R^3 represents hydrogen, lower alkyl, halogen or lower alkoxy, R^4 represents hydrogen or lower alkyl, R ^5 represents lower alkyl, hydroxy lower alkyl, aryl, arylcarbonyl, aralkyl or arylthioalkyl. ] 2 A compound represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ and a compound represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. are available ▼ are reacted.
A method for producing dihydrobenzofuran derivatives represented by the general formula ▲Mathematical formulas, chemical formulas, tables, etc.▼ or pharmaceutically acceptable acid addition salts thereof. [In the above formula, R^1 and R^2 are the same or different and represent hydrogen or lower alkyl, R^3 represents hydrogen, lower alkyl, halogen or lower alkoxy, R^4 represents hydrogen or lower alkyl, R ^5 represents alkyl, hydroxy lower alkyl, aryl, arylcarbonyl, aralkyl or arylthioalkyl, and X represents halogen. ]3 A compound represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ and a compound represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. are available ▼ are reacted.
A method for producing dihydrobenzofuran derivatives represented by the general formula ▲Mathematical formulas, chemical formulas, tables, etc.▼ or pharmaceutically acceptable acid addition salts thereof. [In the above formula, R^1 and R^2 are the same or different and represent hydrogen or lower alkyl, R^3 represents hydrogen, lower alkyl, halogen or lower alkoxy, R^4 represents hydrogen or lower alkyl, R ^5 represents lower alkyl, hydroxy lower alkyl, aryl, arylcarbonyl, aralkyl or arylthioalkyl. ]