SU884563A3 - Method of preparing 2-acyloxy-(4-aminobenzyl)-derivatives or their salts - Google Patents

Description

The invention relates to a process for the preparation of 2-acyloxy- (4-aminobeneyl) derivatives of the general formula, ----, a chlorine or bromine atom; where (b, trifluoromethyl group, Rn is fluorine or chlorine atom; branched alkyl residue or cycloalkyl group, each with 3-5 carbon atoms; alkanoyl group with 1-5 C-atoms, benzoyl, nitroben zoyl or naphthalenecarbonyl group or hydrogen; Rg - - CO- or CHij-rpynna, or their salts with a bronchodilator effect. It is known that some compounds based on the structure of 2-hydroxy-2-phenylethylamine, have a bronchodilator effect. A method of obtaining 0-acyl derivatives of N-substituted amides 2-oxycarb One-time acids based on the reaction of Passerini, which consists in the interaction of carbonyl compounds with isonitriles and carboxylic acids 2 1, the purpose of the invention is to expand the means of action on the organism, and according to the method of obtaining 2-acyloxy- (4-aminobenzyl) - derivatives of general formula (I), where the above values occur, 4-amino-benzaldehyde of the general formula where R., and Rn - have the above values, are reacted with isonitrile; 1 general formula

RJ-N- C-, (1i)

where R-3 has the above recitation, and a carboxylic acid of the general formula

R - OH

V

in which R has the above meaning,

followed by the allocation of the desired product in free or in salt form or its reduction to obtain compounds of the general formula (I), where " 4 is hydrogen and -Cf +. - rpynap, and the product is isolated in free form or in salt form.

Typically, the process is carried out in a solvent at temperatures between -20 and. Moreover, the process is carried out at room temperature for several hours.

The reduction of the resulting compound is carried out with metal hydrides or complex metal hydrides.

In addition, a solution of borane in tetrahydrofuran and tetrahydrofuran as a solvent are used as the hydride.

The reaction of 4-amino-benzaldehyde with an obi. Of formula (II) with isonitriles of general formula (III) and a carboxylic acid of general formula (IV) is carried out mainly in solvents such as methylene chloride, chloroform, benzene, ether, tetrahydrofuran or dioxane .

The obtained 2-acyloxy- (4-aminobenzyl) -derivatives can be converted into their salts with the corresponding acid. Suitable acids, for example, hydrochloric, hydrobromic, sulfuric, phosphoric, lactic, tartaric, citric, fumaric or maleic, are used as the starting materials of the compound of general formula (III) and (IV) are well known.

The aldehyde of the general formula (II) used as a starting material is obtained, for example, by reducing the corresponding hydroxyhalide or 4-amino-benzoic acid ester and then oxidizing the resulting benzoyl alcohol with pyro;

Example 1, 2-acetoxy-2- (4-amino-3, 5-dichlorophenyl) -acetyl- (N-tert-butyl) -amide,

To a solution of 3.8 g (0.02 mol) of 4-amino-3,5-dichlorobenzaldehyde in 50 ml of absolute methylene chloride with stirring and room temperature for 8 hours, drop by drop at the same rate of 3.32 g (0.04 mol) of t - butyl isonitrile and 4.8 g (0.08 mol) of acetic acid from two separately installed dropping funnels.

Then the resulting solution is evaporated to half its volume and cooled. The unreacted 4-amino-3,5-dichlorobenzaldehyde, which was added during this process, was filtered off, the filtrate was again evaporated to half its volume and an equal amount of diisopropyl ether was added. The crystalline target product is filtered and washed with diisopropyl ether.

Example 2. 2-Acetoxy-2- (4-amino-3, 5-dichlorophenyl) -acetyl- (N-tert-butyl) -amide,

To a solution of 30 g (0.16 mol) of 4-amino-3, 5-dichlorobenzaldehyde in 280 ml of methylene chloride is added 45 ml of tert-butyl nitrile and then with stirring at room temperature for 16 hours, 40 ml of acetic acid are added dropwise. The reaction mixture was stirred for 4 hours and evaporated in vacuo until the first crystals separated. After cooling, unreacted 4-amino-3,5-dichlorobenzaldehyde is filtered off, the filtrate is mixed with n-hexane, the desired product precipitated is filtered off, washed with n-hexane and dried. Melting point 175-176 C.

Example 3. 1- (4-Lmino-3, 5-dichlorophenyl) -2- (N-tert-butylamino) -ethanol-1,

To a solution of 4.01 g of 2-acetoxy-2- (4-amino-3, 5-dichlorophenyl) -acetyl- (N-tert-butyl) -amide in 50 ml of absolute tetrahydrofuran is added 100 ml of 1-molar solution borane in tetrahydrofuran. After heating for two hours under reflux, the reaction mixture is evaporated, 100 ml of water is added and acidified with hydrochloric acid, the aqueous phase is washed with ethyl acetate, then basified with ammonia and extracted with methylene chloride. After concentrating the organic phase, the hydrochloride of the desired product is obtained in isopropanol by adding a solution of hydrogen chloride in ether. The melting point of the hydrochloride salt is 174-175 ° C.

Example 4. 2-Acetoxy-α-amino-3-chloro-5-trifluoromethylphenyl) acetyl- (N-tert-butyl) -amide.

To a solution of 4.47 g (20 mmol) of 4-amino-3-chloro-5-trifluoromethylbenzaldehyde in 50 ml of methylene chloride at room temperature with stirring for three hours, 3.32 g (40 mmol) of tert-butyl isonitrile and 4 , 8 g (80 mmol) of acetic acid and then the reaction mixture is stirred for 65 hours at room temperature. After removing the solvent in vacuo, the residue is dissolved in diethyl ether, washed with water and saturated sodium bicarbonate solution, dried over magnesium sulfate and evaporated in vacuo to dryness .

The residue is chromatographed on a silica gel column of methylene chloride as eluant. The fractions containing the desired product are combined, evaporated and the residue is crystallized from diethyl ether. M.p.155-15b S.

Example 5. 1- (4-Amine-3-chloro-5-trifluoromethylphenyl) -2- (H-tert-butylamino) -ethanol-1 hydrochloride.

2 g (5.4 mmol) of N-tert-butylamide 2-acetoxy-2- (4-amino-3-chloro-5-trifluoromethylphenyl) -acetic acid is dissolved in 15 ml of absolute tetrahydrofuran and 27 ml are added under nitrogen molar solution of borane in tetrahydrofuran. After 4 hours of refluxing, another 15 ml of a 1 molar solution of borane in tetrahydrofuran is added and the reaction mixture is heated under reflux for 2 hours. Then the excess borane is destroyed with acetone, the boron complex is decomposed with water and the solvent is evaporated in vacuo. The residue is acidified with 2N-hydrochloric acid to the value, alkalinized with ammonia and extracted with diethyl ether. The ether extracts are treated with 0.5N hydrochloric acid, the acidic solution is washed with ether, basified with ammonia and again extracted with diethyl ether. The ether extracts are washed with water, dried over magnesium sulfate and evaporated in vacuo. The oily residue is dissolved in diethyl ether and acidified with a solution of hydrogen in ether. The precipitated crystals are filtered and washed with diethyl ether. Mp. 192-193 ° C.

Example 6. 2-Acetoxy-2- (4-amino-3, 5-dichlorophenyl) -acetyl- (N-tert-butyl) -amide.

To a solution of 14.1 g (0.08 mol) of 4-ai "lino-3,5-dichloro-benzaldehyde in 60 ml of methylene chloride, at room temperature, 3.6 g (0.06 mol) of acetic acid and 2 , 5 g (0.03 mol) tert-butylionitrile. Then the reaction mixture is heated under reflux for three hours. The above operation (additives of acetic acid, tert-butyl isonitrile and heating under reflux) is repeated 4 times more, the reaction mixture is poured into cold 2N sodium hydroxide solution and the organic phase is separated. After washing with water and drying the organic phase over sodium sulfate, the solvent is distilled off in vacuo and the residue is crystallized from methylene chloride / hexane. M.p. 175-176 ° C.

Example 7. 2- (4-Amino-3,5-dichlorophenyl) -2-benzoyloxyacetyl- (N-tert-butyl) -amide.

The compound is prepared under conditions analogous to Example 4 from 4-amino-3,5-dichlorobenzaldehyde, tert-butyl isonitrile and benzoic acid in chloroform and at the boiling point of the solvent. T. pl. 189-192 ° C (sintering starts at 185 ° C).

Example 8. 2- (4-Amino-3,5-dichlorophenyl) -2-valeryloxyacetyl- (N-tert-butyl) -amide.

The compound is obtained from 4-amino-3, 5-dichlorobenzaldehyde, tert-butyl isonitrile and valeric acid in ana / oh example 4 conditions. M.p. 95-98s.

Example 9. 1- (4-Amino-3,5-dichlorophenyl) -2- (N-tert-butylamino) -ethanol-1.

The compound was obtained from 2- (4-amino-3, 5-dichlorophenyl) -2-benzoyloxyacetyl- (N-tert-butyl) -amide and lithium aluminum hydride in tetrahydrofuran under conditions similar to those in Example 3, m.p. hydrochloride 174-175 ° C.

Example 10. 1- (4-Amino-3,5-dichlorophenyl) -2- (N-tert-butylamino) -ethanol-1.

The compound is obtained from 4-amino-3, 5-dichlorobenzaldehyde, tert-butyl isonitrile and valeric acid, under the conditions analogous to examples 2 and 5 without isolating the resulting 2- (4-amino-3, 5-dichlorophenyl) -2-valeryloxyacetyl- (M-tert-butyl) -amide. Mp. Hydrochloride 174-175 ° C.

Under conditions analogous to the examples, the following compounds are obtained:. 1- (4-amino-3-bromo-5-fluorophenyl) -2- (N-tert-butylamino) -ethanol-1 hydrochloride. T. pl. 207-177c 1- (4-amino-3-chloro-5-fluorophenyl) -2- (M-tert-butylamino) -ethanol-1 hydrochloride. M.p. 206-208 ° С 1- (4-amio-3-chloro-5-trifluoromethylphenyl) -2- (N-cyclobutylamino) ethanol-1 hydrochloride; 1.T.pl.177178 ° C; 1- (4-amino-3-bromo-5-fluorophenyl) -2- (M-cyclobutylamino) -ethanol-1 hydrochloride. T. pl. 164-16bS-, 1- (4-amino-3-chloro-5-trifluoromethylphenyl) -2- (N-tert-pentylamino) -ethanol-1 hydrochloride "So pl. 176-178C (decomp.) 1- (4-amino-3-chloro-5-fluorophenyl) -2- (N-isopropylamino) ethanol-1 hydrochloride. T. pl. 152-154s (decomp.)) 1- (4-amino-3-6rom-5-trifluoromethylphenyl) -2- (M-diclopentylamino) -ethanol-1. M.p. 100-102.5 ° C (decomp.).

Claims (1)

1. A process for the preparation of 2-acyloxy- (4-aminobenzyl) derivatives of general formula I - ".N chlorine or bromine atom Where CL trifluoromethyl group, fluorine or chlorine atom R is a branched gkyl residue or a cycloalkyl group, each with 3-5 carbon atoms;