FI60858C - NYTT FOERFARANDE FOER FRAMSTAELLNING AV 4-AMINO-3,5-DIHALOGEN-FENYL-ETANOLAMINER - Google Patents

Description

ί * ϊ5 £ Ζ * 1 Γηΐ CONSULTATION PUBLICATION cnoca JK »W« "'uTlAGGNINOSSIUIFIF 60858 C ^ 45) Pateulti ayonnetty 13 04 1982 Patent aeddelat (51) Kv.lk?/Int.CI.3 c 07 G 91/40 ENGLISH— FINLAND (21) P »t * nttlh» kemu * - PttMttnseknlnf 2736/7 * + (22) Htkemlspilvl - An * ttknln (tdag 19 · 09 · 7 * + '' (23) Alkupiivi - Glltlfhctsdag 19.09-7 * + ( 41) Become Public - Bllvlt offmtllf 03.05.75

Patent and Registration Office .... .... .... .....

__. . . . (44) Date of issue and date of issue. -

Patent and registration authorities Ansttktn utlagd och utl.tkriften publfcarad 31.12.8l (32) (33) (31) Pyydetty etuoikeui - Begird prlorltet 02.11.73

Federal Republic of Germany Förbundsrepubliken Tyskland (DE) P 235 * + 959-9 (71) Dr. Karl Thomae Gesellschaft mit beschränkter Haftung, D-7950 Biberach / Riss, Federal Republic of Germany-Förbundsrepubliken Tyskland (DE) (72) Johannes Keck, Bi Riss, Gerd Kruger, Biberach / Riss, Helmut Pieper, Biberach / Riss, Klaus-Reinhold Noll, Warthausen-0berhöfen, Federal Republic of Germany-Förbundsrepubliken iy skland (DE) (7 * 0 Leitzinger Oy (5 * 0 New method l- for the preparation of amino-3,5-dihalo-phenylethanolamines - Nyt förfarande för framställning av h-amino-3,5-dihalogen-phenyl-ethanolaminer

The present invention relates to a new process for the preparation of 4-amino-3,5-dihalo-phenylethanolamines of general formula I.

OH

, 1 CH - CH, - N (I)

XJ

h2n T

Shark where

Hal is a chlorine or bromine atom and R is an alkyl or cycloalkyl group each having 3 to 5 carbon atoms, and their physiologically acceptable acid addition salts with inorganic or organic acids.

The compounds of the above general formula I and their acid addition salts have valuable pharmacological properties, in particular their action on fluorescent receptors.

2 60858

It has now surprisingly been found that the compounds of the above general formula I can also be prepared in excellent yields by the following method:

Compound of general formula II 0

II

HALV ^ X / C "CH0

XX

h2n

Hai wherein Hai is as defined above, or a hydrate thereof is reacted with an amine of general formula III H "V (III) wherein R is as defined above, and the compound of formula Ha thus obtained is 0, 1

Hai where Hai and R have the same meaning as above are reduced.

The reaction is conveniently carried out in a solvent such as methanol, ethanol, dioxane, benzene or toluene using a water separator or an excess of an amine of general formula III with a reducing agent such as catalytically activated hydrogen, e.g. hydrogen in the presence of Raney nickel or Raney hydrogen with water, sodium amalgam and ethanol, zinc and hydrochloric acid, or a complex metal hydride, for example sodium borohydride or lithium aluminum hydride in a suitable solvent such as methanol, ethanol, ethanol / water, ether, tetrahydrofuran, dioxane or water at 0 ° C and , for example up to the boiling point of the solvent used at temperatures.

The compounds of the general formula I obtained can, if desired, be converted into their physiologically acceptable acid addition salts by means of inorganic or organic acids. Hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, lactic acid, citric acid, tartaric acid, maleic acid and fumaric acid have proved to be suitable acids.

The novel compound of general formula II used as starting material is obtained, for example, by oxidizing the corresponding acetophenone with selenium dioxide or by oxidizing the corresponding phenacyl bromide with dimethyl sulfoxide.

The process of the present invention could not be foreseen, as it is generally known that compounds containing both an amino and an aldehyde group are unstable, especially in the presence of bases, and tend to condense.

The following examples further illustrate the invention:

Example A

4-Amino-3,5-dichloro-phenylglyoxal hydrate 40.8 g of 4-amino-3,5-dichloro-acetophenone are added portionwise with stirring to a solution of 22.2 g of selenium dioxide at 60-70 ° C, 200 ml of dioxane and 6 ml of water.

Boil at reflux for 4 hours, allow to cool, add a little activated carbon, filter and evaporate to dryness in a water pump vacuum. The residue is dissolved in ethyl acetate-benzene (1: 4), a little cyclohexane is added until the solution begins to cloud, filtered and allowed to stand for 2 days at room temperature to initiate slow crystallization of 4-amino-3,5-dichlorophenylglyoxal hydrate.

Melting point: 95-98 ° C.

Example 1 1- (H-Amino-3,5-dichloro-phenyl) -2-tert-butylamino-ethanol 8.8 g (0.12 mol) of tert-butylamine are added to 4.7 g (0, 02 moles) of 4-amino-3,5-dichlorophenylglyoxal hydrate in 50 ml of water. This causes some warming and a clear solution is formed at first, but later a precipitate begins to separate. Stir for 1 hour and add dropwise a solution of 1.9 g (0.05 mol) of sodium borohydride in 10 ml of water, whereupon the precipitate dissolves and some heating occurs. Stir for 2 hours and add concentrated hydrochloric acid dropwise until the reaction is strongly acidic to remove excess sodium borohydride, filter and make alkaline 1- (4-amino-3,5-dichlorophenyl) -2-tert-butylaminoethanol with alkaline ammonia. to precipitate.

Yield: 4.8 g (86.6% of theory), melting point: 110-118 ° C Hydrochloride melting point: 174-175.5 ° C (decomposes).

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

Prepared according to Example 1 from 4-amino-3,5-dichloro-phenyl-glyoxal hydrate, cyclopropylamine and sodium borohydride.

Example 3 1- (4-Amino-3,5-dichloro-phenyl) -2-cyclobutylamino-ethanol

Hydrochloride melting point: 184-184.5 ° C (decomposes).

Prepared according to Example 1 from 4-amino-3,5-dichloro-phenyl-glyoxal hydrate, cyclobutylamine and sodium borohydride.

60858 5

Example U

1- (H-amino-3,5-dichloro-phenyl) -2-cyclopentylamino-ethanol Melting point of the hydrochloride: m8-150 ° C (decomposes).

Prepared according to Example 1 from 4-amino-3,5-dichloro-phenylglyoxal hydrate, cyclopentylamine and sodium borohydride.

Claims (2)

A process for the preparation of 4-amino-3,5-dihalo-phenylethanolamines of the general formula I OH Hdlx ^ N ^ CH-CHo-N XX ^ is an alkyl or cycloalkyl group having 3 to 5 carbon atoms, and their physiologically acceptable acid addition salts with inorganic or organic acids, characterized in that the compound of the general formula II is reacting with an amine of general formula III H-N (ui) wherein R is as defined above, and the compound of formula IIa thus obtained is 0 md II Hai c 1. H (Ha) H2N Hai where Hai and R have the same meaning as above, are reduced.