SU337987A1 - METHOD OF OBTAINING ALKANOLAMINE DERIVATIVES - Google Patents

Description

The invention relates to a method for producing oxyamino compounds not described in the literature, which are biologically active substances and can be used in medicine.

A method of producing alkanolamine derivatives is known, based on the reaction of reacting a compound of the general formula

RzHN - SNONY - GI; lRtNRil :,

i

where Ri is a hydrogen or an alkyl radical, which may be substituted by one or more substituents selected from: the numbers of hydroxyl, alkoxy, aryl or aryloxyl radicals; cycloalkyl or alkenyl radical;

R2 is an acyl radical;

Rs is an alkyl radical;

4 and RS may be the same or different and represent hydrogen atoms or alkyl radicals; Re is a radical capable of hydrogenation.

substituents whose position in the molecule is not fixed.

A method for the preparation of alkanolamine derivatives of the formula

RgRjNCO

OSSG - SION - CHgNHRi

where RI is a hydrogen atom or an alkyl group containing up to 6 carbon atoms, which may be substituted with a hydroxy group, phenyl, or phenoxyl, or cycloalkyl having up to 8 carbon atoms;

Ra is a hydrogen atom or an alkyl containing up to 4 carbon atoms;

RS is alkyl, oxyalkyl or a -loxyl, each of which includes up to 10 carbon atoms, or cycloalkyl, including up to 8 carbon atoms, or aryl or aralkyl, each of which includes up to 12 carbon atoms and can be substituted in the aromatic core with one or a large number of substituents such as hydrogen, alkyl or alkoxy;

up to 4 carbon atoms, or acyl, including up to 6 carbon atoms, or nitro group, or thioalkyl, alkoxyl, each of which includes up to 5 carbon atoms.

The method is that the compound of the general formula

RjRiNCO,

OCHF-SNON - CHzNRiRs

where RI, R2, Ra and R4 have the indicated meanings;

Rs, a radical capable of reducing to alcohols by the action of hydrogen (for example, benzyl), is hydrogenated in the presence of a catalyst, for example palladium on carbon, in a neutral diluent or solvent, for example ethanol or an aqueous solution of ethanol. This process can be accelerated or completed as a result of the presence of an acid catalyst, such as hydrochloric or oxalic acid, and can proceed at room temperature and at atmospheric pressure. Separation of the racemic alkanolamine derivative into its optically active isomers is produced by the interaction of racemic alkanolamine derivatives with an optically active acid, followed by fractional crystallization of the diastereoisomeric mixture of the salts or solvent, thus obtained, of ethanol, resulting in an optically active alkanol derivative. the free state of this salt as a result of the base treatment. As an optically active acid suitable for this, for example, (+) or (-) 0,0-di-p-toluene acid can be mentioned.

Alkanolamine derivatives, obtained as a free base, can be converted to their salts by reaction with an acid in the usual way.

The proposed alkanolamine derivatives, as well as the salts of these derivatives, have pharmacological activity and can be used in medicine.

Example 1. A mixture of 1.25 parts of 1- (L-benzyl-Yisopropylamino) -3- (4-ethylcarbamoyl-hydroxy) -2-pronanol, 50 parts of ethanol, 2 parts of a saturated ethereal hydrochloric acid solution, and 0.5 a 5% catalyst (palladium on carbon) is mixed with hydrogen at room temperature and at atmospheric pressure until hydrogen consumption ceases.

This mixture is filtered and the filtrate is evaporated to dryness under reduced pressure. The precipitate is diluted with a mixture of 10 parts of an aqueous solution of hydrochloric acid and 25 parts of ethyl acetate. The ethyl acetate layer is separated, dried over anhydrous magnesium sulphate and evaporated to dryness under reduced pressure. The precipitate crystallizes out of acetone. Thus, 3- (4-ethylcarbamoylphenoxy) -1-isopropylamino-2-propanol is obtained, m.p. 128-130 ° C.

1- (M-Benzyl-S-isonropylamino) -3- (4-ethylcarbamoylphenoxy) -2-pronanol used as the starting product can be obtained as follows.

A mixture of 2.6 parts of 1-chloro-3- (4-ethylcarbamoylphenoxy) -2-propanol, 1.49 parts of N-benzyl-N-isopropylamine and 30 hours of “-propanol is heated under reflux for 18 hours. This mixture is evaporated to dryness under reduced pressure and the residue is diluted with a mixture of 25 parts of aq. 2 and. hydrochloric acid solution and 2 oh

ethyl acetate. The aqueous hydrochloric acid solution layer is separated and made alkaline with aqueous 1N. with a solution of sodium hydroxide and this mixture is extracted twice twice a portion with 50 parts of ethyl acetate with each extraction process. The combined ethyl acetate extracts are dried over anhydrous magnesium sulphate and evaporated to dryness under reduced pressure. The precipitate is 1- (L-benzyl N-isopropylamino) -3- (4-ethylcarbamoylphenoxy) -2-propanol, which is used without further purification.

Example 2. The process described in Example 1 is repeated using the corresponding 1- (1M-benzylamino) -3-phenoxy-2-propanol derivative obtained from the corresponding amine and chlorohydrin as a starting material, and the corresponding compound is then obtained.

Example 3. A solution of 1.5 parts of racemic 3- (2-chloro-4-ethylcarbamoylphenoxy) -1-isopropylamino-2-propanol in 10 parts of ethanol is added to a solution of 1.9 parts of (+) 0, 0- di - "- toluene acid in 10 parts of ethanol. The mixture is kept at minus 20 ° C for 48 hours, followed by crystallization. The mixture was filtered from ethanol and a solid precipitated out. The resulting product has so pl. 172-174 ° C (melts with decomposition). You crystallized the solid product is diluted with a mixture of 10 parts of an aqueous solution of sodium hydroxide and 10 parts of ethyl acetate, the ethyl acetate phase is separated, dried over anhydrous magnesium sulfate and evaporated to dryness

reduced pressure. The solid residue is diluted with a mixture of U 6 parts of allylamine and 12 parts of non-trace ether (with a melting point of 60-80 ° C) at room temperature for 15 minutes. The mixture is filtered and the filtrate is evaporated to dryness.

under reduced pressure. The precipitate is again diluted with 6 parts of allylamine and 12 parts of petroleum ether (with bp 60-80 ° C) for 15 minutes. The mixture is filtered and the filtrate is evaporated to dryness under reduced pressure. The precipitate was diluted with 5 parts of ether and the mixture filtered. The solid precipitate is (-) 3- (2-chloro-4-ethylcarbamoylphenoxy) -1-isopropylamino-2-pronanol, m.p. 122-124 ° C, 0 ° (, 9% in the aqueous solution of the process described above is repeated exactly the same, but instead of (+) O, O-di-toluene acid, use (-) O, O-di - / 1-toluene acid and instead of 10 parts of ethanol - only 5 hours. In this way (+) 3- (2 - chloro - 4-ethylcarbamoylphenoxy - 1 - isopropylamino-2-propanol, mp. 122-124 ° C, ab2 + 13.2 ° (with 2.1% in an aqueous solution of hydrochloric acid).

Subject invention

Claims (2)

1. A method of producing alkanolamine derivatives of the general formula K KANSO ..   OCH2 - SNON - CH zNlIRi K4 where RI is a hydrogen atom or an alkyl group containing up to 6 carbon atoms which may be substituted with a hydroxyl group, phenyl or phenoxyl, or cycloalkyl having up to 8 carbon atoms; Ra is a hydrogen atom or alkyl containing up to 4 carbon atoms; Cs is alkyl, oxyalkyl, or alkoxy, each of which includes up to 10 carbon atoms, or cycloalkyl, including up to 8 carbon atoms, or aryl or aralkyl, each of which contains up to 12 carbon atoms and can be substituted in the aromatic core with one or more the number of substituents such as hydrogen, alkyl or alkoxy; R4 is hydrogen or halo, or alkanolamine, aroylamine, alkanesulfonamide or arenesulfonamide, each of which contains up to 10 carbon atoms, or alkyl, including up to 4 carbon atoms, or acyl, including up to 6 carbon atoms, or a nitro group or thioalkyl, alkoxy, each of which includes up to 5 carbon atoms, characterized in that the compound of the general formula 15RgRsNCO, OCHF-SNON - CHjNRiRs where Ri, R2, Rs and R4 have the indicated meanings; Rs, a radical capable of reducing to alcohols by the action of hydrogen, is reacted with hydrogen in the presence of a catalyst, for example palladium carbon, in an organic solvent medium, for example ethanol, followed by isolation of the target product in a known manner as a base or salt. 2. A method according to claim 1, characterized in that the obtained racemate is divided into optically active antipodes in a known manner, for example, by treating the racemate with an optically active acid.