JPS5855133B2 - 4-amino-3,5-dihalogen-phenylethanolamine - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides 4 -Amino-3,5-dihalokene-phenyl-ethanolamines and their physiologically acceptable acid addition salts of inorganic or organic acids.

The compounds of formula (1) and their acid addition salts have valuable pharmacological properties, especially activity towards the β-receptor.

Surprisingly, it has now been found that the compound represented by formula (1) above can be produced in excellent yield by the method described below.

That is, the formula (wherein Hal is as defined above)
A novel compound represented by or a hydrate thereof is reduced in the presence of an amine represented by the formula (wherein R is as defined above).

This reaction is carried out using a solvent (e.g. methanol, ethanol,
in benzene or toluene in an apparatus equipped with a water separation funnel, or alternatively
In the excess amount of amine used in the formula, reducing agents such as hydrogen activated by a catalyst (e.g. hydrogen in the presence of Raney nickel or Raney cobalt), nascent hydrogen (e.g. activated metallic aluminum and water, ) IJum amalgam and ethanol, lead and hydrochloric acid) or alternatively metal hydride complexes (e.g. hydrogen (sodium boronate or lithium aluminum hydride), preferably at temperatures between 0 and 11
It is suitably carried out at 5° C. (e.g. up to the boiling point of the solvent used).

However, this reaction may also be carried out in such a way that the reduction is carried out using a compound of the formula (where Hal and R are as defined above) generated in situ.

If desired, the obtained compounds of formula (2) can also be converted into physiologically acceptable acid addition salts with inorganic or organic acids.

Examples of acids that have proven suitable include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, lactic acid, citric acid, tartaric acid, maleic acid or fumaric acid.

The new compounds of formula (1) used as starting materials can be obtained by oxidizing the corresponding acetophenones with selenium dioxide or the corresponding phenacyls bromides with dimethyl sulfoxide.

The method of the invention could never have been predicted.

This is because it is generally known that compounds having both an amino group and an aldehyde group are unstable and are particularly prone to self-condensation in the presence of a base.

The invention is further illustrated by the following examples.

Example A (Reference example) 4-Amino-3,5-dichlorophenyl cryoxal hydrate A solution of 200 Tll of dioxane and 22.2 S' of selenium dioxide in 6 ml of water was stirred at 60 to 70°C. So 4-amino-3,5-dichloro-acetophenone 40.8? Add little by little.

After refluxing for 4 hours, the mixture is cooled and a small amount of activated carbon is added.

The mixture is filtered and evaporated using a water pump.

This residue was dissolved in ethylbenzene acetate (1:4),
Add cyclohexane until the solution becomes cloudy.

The mixture is filtered and left at room temperature for 2 hours to slowly crystallize 4-amino-3,5-dichloro-phenylglyoxal hydrate.

Melting point: 95-98°C. Example 1 1-(4-'LE/-3.5-dichloro-phenyl)
-2-tert-butylamino-ethanol 4-amino-3,5-dichloro-phenylglyoxal hydrate in 5 oml of methanol 4. tert-butylamine 8.8P (0,1
2 mol).

When heated slightly, it initially turns into a clear solution and then precipitates out.

After stirring for 1 hour, a solution of 1.9 P (0.05 mol) of sodium borohydride in 10 ml of water is added dropwise and upon slight heating the precipitate begins to dissolve.

After stirring for 2 hours, the excess of sodium borohydride is destroyed by dropping concentrated hydrochloric acid into the solution until it becomes strongly acidic, the mixture is filtered and made alkaline with concentrated ammonia. 7mi/-3.5-dichloro-phenyl)2-tert-7'' thylamino-ethanol was obtained.

Yield: 4.8? (866% of theoretical value), melting point 110-1
18℃.

The melting point of its hydrochloride salt is 174-1755°C (decomposed).

Example 2 1-(4-7mi/-3.5-dichloro-phenyl)-2
-cyclopropylamino-ethanol melting point 125-12
7℃.

The above compound was prepared analogously to Example 1 from 4-amino-3,5-dichloro-phenylglyoxal hydrate, cyclopropylamine and sodium borohydride.

Example 3 l-(4-amino-3,5-dichloro-phenyl)-2
-Cyclobutylamino-ethanol Its hydrochloride has a melting point of 184-1845°C (decomposition).

The above compound was prepared analogously to Example 1 from 4-amino-3,5-dichloro-phenylglyoxal hydrate, cyclobutylamino and borohydride.

Example 4 l-(4-amino-3,5-dichlorophenyl)-2
-Cyclopentylamino-ethanol Its hydrochloride has a melting point of 148-150°C (decomposed).

The above compound was prepared as in Example 1 from 4-amino-3.5-dichlorophenylclyoxal Eiwa el, cyclopentylamine and sodium borohydride.

The present invention is a method for producing 4-amino 3,5-dihalogen-phenylethanolamines as claimed in the claims, and includes the following embodiments.

(1) The method according to the claims, in which the reaction is carried out in the presence of a solvent at a temperature of 0 to 115°C.

(2) The method of claim 1, wherein the reduction is performed using catalytically activated hydrogen, nascent hydrogen, or a metal hydride complex.

3. A method according to claim 1, wherein the reduction is carried out using a compound of the formula (3) in which Hal and R are as defined above.

Claims (1)

[Scope of Claims] A compound represented by the formula 1 (in the formula, Hal represents a chlorine atom or a bromine atom) or a hydrate thereof is a compound represented by the formula (in the formula, R
each represents an alkyl group or a cycloalkyl group having 3 to 5 carbon atoms), in which Hal and R are as defined above. A process for producing 4-amino-3,5-dihalogen-phenylethanolamine and its physiologically acceptable acid addition salts with inorganic or organic acids.