JPS5817193B2 - Phenoxy Amino Probanol - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a compound of the general formula [wherein R1, R2, and R3 are the same or different and represent hydrogen or methyl.

This invention relates to a method for producing a novel phenoxy-amino-propertool derivative represented by the following formula and an acid addition salt thereof.

According to the present invention, the target compound of general formula (1) can be produced by the following methods (1) and (2).

Method■ general formula %formula%] Compound and general formula represented by %formula% Reaction with a piperidine derivative represented by

where Y is -CH-CH2 or -CH(OH)-CH
2-(Hello\.

/gen).

The reaction in method (1) above may be carried out in the presence of a solvent.

Examples of solvents include ethers such as diethyl ether, dioxane, and tetrahydrofuran, alcohols such as methanol, ethanol, furopanol, impropatol, aluminum alcohol, and inoamyl alcohol, and aromatic hydrocarbons such as benzene, toluene, and xylene. , water, dimethylformamide, dimethyl sulfoxide, and any other solvent that does not inhibit the reaction may be used.

Among them, alcohols such as methanol, ethanol, and amyl alcohol are preferred.

When reacting a compound in which Y is -CH(OH) -CH2- (halogen) with a piperidine derivative represented by the formula, an excess of piperidine derivatives may be used as a deoxidizing agent, potassium carbonate, Alkali carbonates such as sodium carbonate, caustic alkaline earth metal sodiums such as caustic potash and caustic soda, sodium hydride, sodium amide, etc., or tertiary amines such as triethylamine and pyridine may be used as deoxidizing agents.

Although the reaction generally proceeds at room temperature, it may be heated to about the boiling point of the solvent used.

Method■ general formula Compound and general formula represented by OH3 A method of reacting with a compound represented by

Here, Z represents a reactive atom or group such as a halogen atom (chlorine, bromine, etc.), aryl- or alkyl-sulfonyloxy (p-tolylsulfonyloxy, methylsulfonyloxy, etc.).

The reaction in the above method (1) is usually carried out in a solvent as described in method (2) in the presence of a deoxidizing agent.

Although the reaction proceeds at room temperature, it is preferably carried out under reflux of the solvent used.

The compound mass produced by the above method can be converted into an acid addition salt by conventional methods.

Acids used to produce acid addition salts include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, and hydrobromic acid, oxalic acid, maleic acid, fumaric acid, malic acid, o-(p-hydroxybenzoyl ) Examples include organic acids such as benzoic acid and phenolphthalin.

The compound represented by the general formula ○ has an asymmetric carbon, so it can be an optically active form or a racemic form.

Racemates can usually be resolved into optically active enantiomers by well-known methods.

Phenoxy amine propatool derivatives with the general formula and their acid addition salts are useful compounds as local anesthetics and antiarrhythmic agents.

Similar phenoxy amino/propyl derivatives are described in Japanese Patent Publication No. 48390/1983.

The present inventors further investigated the pharmacological effects of this type of compound and found that the local anesthetic effect was significantly enhanced by substituting the α-position of piperidine with one or up to four methyl groupsζ Based on this, the present invention has been completed.

Example 1 1.2-epochine-3-(2-(2-thenylmethyl)
The solution is heated under reflux for 7 hours.

After the reaction, ethanol is distilled off under reduced pressure, and the residue is dissolved in ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate.

After distilling off the solvent, it was subjected to silica gel column chromatography, and the eluted portion was dispersed with chloroform-methanol (100:2). After distilling off the solvent, it was dissolved again in chloroform and evaporated under cooling with dry hydrochloric acid gas. do.

When the chloroform was distilled off, 2.0 g of colorless crystals were obtained.

This was re-crystallized from isopropyl alcohol-ethyl acetate to give 1-(2,6-dimethylpiperidi/)-3-(2-(21-enylmethyl)phenoxycou 2-propatol hydrochloride with a melting point of 152-153°C). colorless crystal 1.7
get g.

Example 2 2.8 g of 1-chloro-3-(2-(2-thenylmethynolifenoquine)-2-propylene) and 2.3 g of 12.5-dimethylpiperidine were dissolved in 30 ml of ethanol.
Heat to reflux on a water bath for 15 hours.

Afterwards, ethanol is distilled off, and ether is added to the residue and dissolved.

Insoluble matter is washed away. Add ether solution to 10% hydrochloric acid 50aA
! Extract twice.

The aqueous layer is made alkaline with caustic soda and the liberated oil is extracted with ether.

After drying the ether layer with anhydrous potassium carbonate, the ether was distilled off and subjected to silica gel column chromatography.
Collect the portion eluted with chloroform:methanol (100:2).

When the hydrochloride is prepared in the same manner as in Example 1, the melting point is 152 to 1.
1-(2,6-dimethylpiperidine)-3-( at 53°C
2-(2-thenylmethyl); 2.1 g of colorless crystals of phenoxycou 2-propatol hydrochloride were obtained.

Example 3 2-(2-thenylmethyl)phenol 1.9g 1 anhydrous potassium carbonate 1.4g 1 acetone 30rrL 11 dimethyl
Add 1-chloro-3-(2,6-dimethylpiperidine)-2 into a 20rnl mixture of chloroformamide while stirring.
- Add 2.3 g of propatool and heat to reflux with stirring for 20 hours.

After the reaction, insoluble matter is removed in an oven, and the P solution is concentrated under reduced pressure.

Add chill to the residue to dissolve it, and dilute the ether solution with 1
Extract twice with 50 rnl of 0% hydrochloric acid.

The aqueous layer is made alkaline with caustic soda and the liberated oil is extracted twice with ether.

After drying the ether layer over anhydrous potassium carbonate, the ether was distilled off, subjected to silica gel column chromatography, and the portion eluted with chloroform:methanol (100:2) was fractionated.

Hereinafter, when it is made into a hydrochloride as in Example 1, the melting point is 152~
1-42,6-dimethylpiperidine)-3- at 153°C
(1.5 g of 2-(2-f enylmethyl)phenoxycon-2-pC-phenol hydrochloride is obtained.

For example, the following compounds are further produced in the same manner as in the above examples.

◎ 1-(2,2,6,6-tetramethylpiveridino)
-3-(2-(2-thenylmethyl)phenoxycou2)
-Propertool, hydrochloride melting point 161-162°C

Claims (1)

[Claims] 1. A method characterized by reacting a compound represented by the general formula with a compound represented by the general formula CH.
A method for producing a compound represented by the general formula %. [In the formula, R1, R2, and R3 are the same or different and represent hydrogen or methyl, and Y is -CH-CH2 or \l. A compound represented by the general formula is reacted with a compound represented by the general formula,
A method for producing a compound represented by the general formula. [In the formula, R1, R2, and R3 are the same or different and represent hydrogen or methyl, and X represents a reactive atom or group. ]