NO139479B - PROCEDURE FOR THE PREPARATION OF 4-AMINO-3,5-DIHALOGEN-PHENYL-ETHANOLAMINES - Google Patents

Description

This invention relates to a new process for the production of 4-amino-3,5-dihalo-phenyl-ethanolamines of the general formula I

where Hal means a chlorine or bromine atom and

R means an alkyl or cycloalkyl radical with 3 to 5 carbon atoms,

and their physiologically compatible acid addition salts with inorganic or organic acids.

The compounds of the above general formula I and

their acid addition salts possess valuable pharmacological properties, particularly an action on the & receptors.

It has now surprisingly been found that the compounds of the above general formula I can be prepared with excellent

also change according to the following procedure:

Substitution of a new compound with the general formula

where Hal is as above, or a hydrate thereof, with an amine of the general formula III where R is as above, to a Schiff base of the general formula IV

where Hal and R are as stated above, which are then reduced.

The reaction is suitably carried out in a solvent such as methanol, ethanol, dioxane, in benzene or toluene using a water separator or in an excess of the amine of the general formula III used. The reduction of the compound of formula IV can be carried out with a reducing agent such as catalytically formed hydrogen, e.g. with hydrogen in the presence of Raney nickel or Raney cobalt, with nascent hydrogen, e.g. with activated metallic aluminum and water, with sodium amalgam and ethanol, with zinc and hydrochloric acid, or with a complex metal hydride, e.g. with sodium borohydride or lithium aluminum hydride in a suitable solvent such as methanol, ethanol, ethanol/water, ether, tetrahydrofuran, dioxane or dioxane/water and preferably at temperatures between 0 and 115°C, e.g. at temperatures up to the boiling temperature of the solvent used.

The obtained compounds of the general formula I can optionally be transferred to the physiologically compatible acid addition salts with inorganic or organic acids. Particularly suitable acids are e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, lactic acid, citric acid, tartaric acid, maleic acid or fumaric acid.

A new compound with the general formula II used as starting material gives, for example, by oxidation of a corresponding acetophenone with selenium dioxide or by oxidation of a corresponding phenyl acyl bromide with dimethyl sulphoxide.

The method according to the present invention could not be foreseen as it is generally known that compounds which simultaneously contain an amino and an aldehyde group are unstable, particularly in the presence of bases and have a tendency to self-condensate.

The following examples shall serve to further illustrate the invention.

Example A

4-amino-3, 5-dichloro-phenylglyoxal- hydrate

40.8 g of 4-amino-3,5-dichloro-acetophenone is added in portions while stirring to a 60-70°C hot solution of 22.2 g of selenium dioxide in 200 ml of dioxane and 6 ml of water. After 4 hours of boiling under reflux cooling, the mixture is allowed to cool, some activated carbon is added, filtered and evaporated in a water jet vacuum. The residue is dissolved in ethyl acetate-benzene (1:4), some cyclohexane is added to the beginning of cloudiness, filtered and allowed to stand for 2 days at room temperature for slow crystallization of the 4-amino-3,5-dichloro-phenylglyoxal hydrate.

Melting point: 95-98°C.

Example 1

1-( 4- amino- 3, 5- dichloro- phenyl)- 2- tert.- butylamino- ethanol

4.7 g (0.02 mol) of 4-amino-3,5-dichloro-phenylglyoxal hydrate in 50 ml of methanol is added to 8.8 g (0.12 mol) of tert-butylamine. Thereby, under light heating, a clear solution first occurs, and later a precipitate begins to separate. After stirring for 1 hour, a solution of 1.9 g (0.05 mol) of sodium borohydride in 10 ml of water is added dropwise, whereby the precipitate dissolves under slight heating. After stirring for 2 hours, concentrated hydrochloric acid is added dropwise to the solution to a strongly acidic reaction to split excess sodium borohydride, the solution is filtered, and to precipitate 1-(4-amino-3,5-dichloro-phenyl)-2-tert-butylamino- ethanol, the solution is made alkaline with concentrated ammonia. Yield: 4.8 g (86.6% of theory), mp: 110-118°C. Melting point of the hydrochloride: 174-175.5°C (decomposition).

Example 2

1-(4-amino-3,5-dichloro-phenyl)-2-cyclopropylamino-ethanol Melting point: 125-127°C.

Prepared from 4-amino-3,5-dichloro-phenylglyoxal hydrate, cyclopropylamine and sodium borohydride analogously to example 1.

Example 3

1-(4-amino-3,5-dichloro-phenyl)-2-cyclobutylamino-ethanol Melting point for the hydrochloride: 184-184.5°C (decomposition).

Prepared from 4-amino-3,5-dichloro-phenylglyoxal hydrate, cyclobutylamine and sodium borohydride analogously to example 1.

Example 4

1-(4-amino-3,5-dichloro-phenyl)-2^cyclopentylamino-ethanol Melting point for the hydrochloride: 148-150 C (decomposition).

Prepared from 4-amino-3,5-dichloro-phenylglyoxal hydrate, cyclopentyl amine and sodium borohydride analogously to example 1.

Claims (1)

Process for the production of 4-amino-3,5-dihalo- • phenyl-ethanolamines of the general formula I where Hal means a chlorine or bromine atom, and R means an alkyl or cycloalkyl radical with 3 to 5 carbon atoms, and their physiologically compatible acid addition salts with inorganic or organic acids, characterized in that a compound of the general formula II where Hal is as indicated above, or a hydrate thereof, is reacted with an amine of the general formula III, where R is, as indicated above, a Schiff base of the general formula IV where Hal and R have the meaning indicated above, which is then reduced, after which, if desired, the formed compound of the general formula I is transferred into a physiologically acceptable acid addition salt thereof.