CS272944B1 - Method of benzylamine's new derivatives and their salts preparation - Google Patents

Abstract

The invention concerns synthesis of medicaments. Its subject is the method of preparations of new derivatives of benzyl amine of general formula I, where R represents (OH)n, where n is the number 1 or 2, and in the case that n is 2, the hydroxy groups are in arbitrary position.R<1> and R<2> are either the same and represent an atom of hydrogen, ethyl, propyl or isopropyl, or they are different, in which case R1 is 2-dimethylaminoethyl and R<2> an atom of hydrogen or methyl, and their salts with pharmaceutically safe inorganic or organic acids. The substances according to the invention are intermediate products of the synthesis of pharmacodynamic active substances and their salts have anti-microbial action in vitro. The method of preparation according to the invention is based on the demethylation of the given methoxy compounds, whereas demethylation can be carried out (a) by heating with pyridine hydrochloride, (b) by reaction with boron bromide and (c) by heating with 48 % hydrogen bromide. The invention also includes preparation of the salts of the substance of formula I.<IMAGE>

Description

The invention relates to a process for the preparation of novel benzylamine derivatives of the general formula I,

CD, i

Wherein R represents one or more hydroxyl groups at any position of the benzene ring, R ¹ and R ² are either the same and denote hydrogen, ethyl, n-propyl or isopropyl, or are different, in which case R ¹ is 2- dimethylamino and R ² is hydrogen or methyl, -a salts thereof with pharmaceutically acceptable organic or inorganic acids,

The compounds of formula (I) are intermediates for the preparation of pharmacodynamically active substances and their salts show antimicrobial effects in in vitro tests, which make them potential chemotherapeutic agents. Their acute toxicity in mice when administered orally is relatively low. Specific activity and toxicity values are listed below for the following substances:

2- (2,5-Dihydroxyphenylthio) benzylamine (hydrogen maleate) / substance A / 2- (3,4-Dihydroxyphenylthio) benzylamine (hydrobromide) / substance B / N, N-Dietbyl-2- (3-hydroxyphenylthio) benzylamine (hydrochloride) / substance C / βΙ, β-Diethyl-2- (4-hydroxyphenylthio) benzylamine (hydrochloride) / substance D / N, N-Dipropyl-2- (3-hydroxyphenylthio) benzylamine (hydrochloride) / substance E / N, N-Dipropyl -2- (4-hydroxyphenylthio) benzylamine (hydrochloride) (substance P)

Ν ', N-Di (isopropyl) -2- (2-hydroxyphenylthio) benzylamine glycol hydrochloride) (substance 6)

N, N-Di (isopropyl) -2- (3-hydroxyphenylthio) benzylamine (hydrochloride) / substance H / N, N-Di (isopropyl) -2- (4-hydroxyphenylthio) benzylamine (hydrochloride) / substance J / N- Methyl N- (2-dimethylaminoethyl) -2- (3-hydroxyphenylthio) benzylamine (bis (hydrogen maleate)) (substance K)

Toxicological and activity data on substances A to K just mentioned:

(i) Acute oral toxicity in mice, mg / kg:

A, 598; B, 665; C, 222; D, 404; S, 1379; δ, 1 146; ´ J, 704.

(ii) In vitro antimicrobial activity; the relevant micro-organisms and minimum inhibitory concentrations in mg / l are given, if they are of low value in the region:

Streptococcus / 3-haemolyticus: A, 100; C, 16; D, 32; E, 8; P, 128; G, 16; H, 128;

J, 8; K, 128.

Streptococcus faecalis: C, 32; D, 64; E / 8; P, 64; G, 32; H, 64; J, 8.

Staphylococcus pyogenes aureus: A, 100; B, 100; C, 32; D, 32; E, 16; P, 128;

G, 64; H, 128; K, 64 *

Pseudomonas aeruginosa: A, 50; B, 50; C, 64; D, 64; E, 64; G, 128; J, 64.

Proteus vulgaris; A, 50; B, 25; C, 64; B, 64; P, 128; G, 128; H, 128,

Eacherichia coli: 0.64; G, 128,

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Trichophyton mentagrophytes: 50; B, 50; D, 50; F, 50; H, 50.

The process for the preparation of the compounds of the formula I according to the invention consists in the demethylation of the compounds of the formula II,

(II) in which r 'denotes one or two methoxy groups at any positions of the benzene ring 19, ra and R and R denote the same as in formula I.

The demethylation can be carried out in various ways, in particular the following are the subject of the invention:

(i) Heating with pyridine hydrochloride to 200-220 ° C.

(ii) Reaction with boron tribromide in chloroform, dichloromethane or chlorobenzene at room temperature; (iii) Heating with refluxing 48% hydrobromic acid, i.e. at 120 to 130 ° C.

The starting materials, i.e. the benzylamine derivatives of the formula II, are novel and methods for their preparation from the known compounds are described in the examples. All of the novel compounds described in the invention have been provided by conventional analytical and spectral methods in terms of identity. The end products, i.e. the amines of formula I, are crystalline or oily and, by neutralization with pharmaceutically acceptable acids, provide crystalline salts, the process of which is true, forming part of the invention. The examples illustrate the possibilities of the invention. They do not describe all the possibilities of the invention.

Example 1

2- (2-Hydroxyphenylthio) benzylamine

A mixture of 5.8 g of 2- (2-methoxyphenylthio) benzylamine and 14 g of pyridine hydrochloride is heated to 210-215 ° C under stirring for 30 min. After cooling, it is diluted with 300 ml of water and the precipitated crystalline hydrochloride of the desired substance is filtered off with suction, washed with a little water and dried in vacuo; 4.1 g (65%), mp 256-258 ° C (ethanol-petroleum ether). The base is liberated by treatment with aqueous ammonia and isolated by extraction with chloroform, m.p. 150-150.5 ° C (ethanol). Neutralization with maleic acid in ethanol and addition of ether gave crystalline hydrogen maleate, mp 187-187.5 ° C (ethanol).

The required starting 2- (2-methoxyphenylthio) benzylamine is a novel compound which is prepared from the known 2- (2-methoxyphenylthio) benzoic acid (Šindelář K. et al .: Collect. Czech. Chem. Commun. 47, 1367 (1982)) Czech Author's Certificate No. 202 241) as described below;

To a stirred mixture of 26 g of 2- (2-methoxyphenylthio) benzoic acid, 250 ml of benzene and 2 drops of dimethylformamide was added dropwise 39.3 g of thionyl chloride, and the mixture was refluxed for 2 hours. The benzene and thionyl chloride residues are completely removed by evaporation, the warm residue is dissolved in 65 ml of cyclohexane and the solution is left to crystallize in a refrigerator for 2 h;

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25.9 S (93%) of 2- (2-methoxyphenylthio) benzoyl chloride, mp 96.5 ° C (cyclohexane).

A solution of 25 g of the preceding chloride in 250 ml of benzene is added dropwise to the solution of 150 ml of 25% aqueous ammonia at 10 [deg.] C. with vigorous stirring over 25 minutes. The mixture was stirred for 1 h at room temperature. The precipitated 2- (2-methoxyphenylthio) benzamide was filtered off with suction, washed with water and dried in vacuo (22 g, 95%), m.p. 131 DEG C. (ethanol).

A solution of 9.4 g of lithium aluminum hydride in 200 ml of ether was added dropwise with stirring to a suspension of 20.9 g of the previous amide in 600 ml of ether. The mixture was then refluxed for 7 hours with stirring. After cooling to 0 [deg.] C., it is decomposed with stirring by the slow addition of 10 ml of water, 10 ml of 15% sodium hydroxide solution and 30 ml of water. Stir for 30 min and filter off the solid. 8.1 ml of conc. hydrochloric acid, the mixture was stirred for 10 min and left in the refrigerator for 2 h. The precipitated crystalline 2- (2-methoxyphenylthio) benzylaraine hydrochloride is filtered off with suction, washed with ether and dried in vacuo. 17.5 g (77%), mp 213-214 ° C (ethanol). Decomposition with aqueous ammonia liberates the base, which is isolated by extraction with benzene. The extract is worked up as a crystalline substance, m.p. 50-51 ° C (cyclohexane).

Example 2

II, K-Diethyl 1-2- (2-hydroxyphenylthio) benzylamine Similar to Example 1, 9.0 g of N, N-diethyl-2- (2-methoxyphenylthio) benzylamine are demethylated by heating with 30 g of pyridine hydrochloride for 30 min. 220 DEG. After cooling, the mixture was diluted with water, basified with sodium bicarbonate and the liberated base isolated by extraction with 1,2-dichloroethane. Work-up of the extract gave 5.4 g as an oil in a crude state. Neutralization with hydrogen chloride in ethanol and addition of ether gave 3.0 g of the hydrochloride (31.55) of the title compound, m.p. 166-168 ° C (ethanol ether).

The starting N, N-ethyl-2- (2-methoxyphenylthio) benzylamine, which is new, is prepared as follows:

To a solution of 10.5 g of diethylamine in 100 ml of benzene was added a solution of 20.0 g of 2- (2-methoxyphenylthio) benzoyl chloride (see Example 1) in 200 ml of benzene with stirring at 0 ° C. The mixture was stirred at room temperature for 2 h, the precipitated diethylamine hydrochloride was removed by filtration, the benzene filtrate was washed with 5% sodium hydroxide solution and water, dried and evaporated under reduced pressure, oily residue -N, N-diethyl-2- (2- methoxyphenylthio) benzamide is induced to crystallize by trituration with petroleum ether; 20.5 g (91%), mp 87-89 ° C (aqueous ethanol).

Similar to Example 1, a reduction of 6.5 g of the previous amide in a mixture of 50 ml of benzene and 200 ml of ether is carried out with 6.0 g of lithium aluminum hydride in 500 ml of ether. It is obtained

10.2 g (74.55) of oily N, N-diethyl-2- (2-methoxyphenylthio) benzylamine, which affords crystalline hydrochloride melting at 182-184 ° C (ethanol-ether).

Example 3

N, N-Dipropyl-2- (2-hydroxyphenylthio) benzylamine

As in Example 1, by heating 10.0 g of N, N-dipropyl-2- (2-methoxyphenylthio) benzylamine with 23.0 g of pyridine hydrochloride at 215 ° C, 5.5 g (52%) of the hydrochloride of the desired compound crystallizes. ethanol / ether and melts at 225-227 ° C.

The necessary starting N, N-dipropyl-2- (2-methoxyphenylthio) benzyl amine (base oily hydrochloride, m.p. 173-175 ° C (ethanol ether)) was prepared similarly to Example 2 from 2- (2-methoxyphenylthio). benzoyl chloride (Example 1) via N, N-dipropyl-2- (2-methoxyphenylthio) benzaraid (oil).

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Example 4

N, N-Di (isooryl) -2- (2-hydroxyphenylthio) benzylamine

To a solution of 9.2 g of N, N-di (isopropyl) -2- (2-methoxyphenylthio) benzylamine in 80 ml of chlorobenzene was added dropwise a solution of 10.6 g of boron tribromide in 30 ml of chlorobenzene at 10 ° C with stirring over 30 min. The mixture was stirred at room temperature for 7 h, allowed to stand overnight and then a solution of 4.0 g of methanesulfonic acid in 60 ml of water was added with stirring.

Stir vigorously for 30 min and then leave to rest for 12 h. The separated oil layer at the bottom is separated, basified with 20% sodium hydroxide solution, 150 ml of ethanol are added and the mixture is refluxed for 4 hours. The ethanol was distilled off, the residue was adjusted to pH 8.5 with acetic acid and the desired product precipitated was filtered off with suction; 4.2 g (51%), m.p.

to 85 ° C (aqueous methanol). Neutralization gives crystalline hydrochloride, t, t.

198 DEG-200 DEG C. (ethanol-ether).

The starting N, N-di (isopropyl) -2- (2-methoxyphenylthio) benzylamine used (base is oily; hydrochloride, mp 182-184 [deg.] C.) was obtained in analogy to Example 2 from 2- (2-methoxyphenylthio) benzoyl chloride, see Example 1, via crystalline N, N-di (isopropyl) -2- (2-methoxyphenylthio) benzamide, mp 121-123 ° C (cyclohexane).

Example 5

2- (3-Hydroxyphenylthio) benzylamine

Similar to Example 1, demethylation of 11.0 g of 2- (3-methoxyphenylthio) benzylamine was performed by heating with 26 g of pyridine hydrochloride at 210-215 ° C for 30 min. After cooling, it is dissolved in 300 ml of water, basified with 20% sodium hydroxide and filtered with charcoal. The filtrate is acidified with acetic acid and the pH of the mixture is adjusted with sodium bicarbonate to eliminate the maximum of the product which is isolated by extraction with chloroform. Working up the extract yielded 9.6 g (93%) of the crude product which crystallized after trituration with a 2: 1 mixture of petroleum ether and ether, m.p. 127-128 ° C (ethanol-petroleum ether). Neutralization with maleic acid in ethanol and addition of ether gave crystalline hydrogen maleate, m.p. 144.5 ° C (ethanol-ether).

The required starting 2- (3-methoxyphenylthio) benzylamine is prepared similarly to Example 1 from the known 2- (3-methoxyphenylthio) benzoic acid (Bartl V. et al .: Collect. Czech. Chem. Commun. 38, 2301 (1973)). ) through the following intermediates:

2- (3-Methoxyphenylthio) benzoyl chloride, m.p. 101-101.5 ° C (cyclohexane);

2- (3-methoxyphenylthio) benzamide, mp 120.5 ° C (ethanol).

2- (3-methoxyphenylthio) benzylamine itself is oily; 161-162 ° C (ethyl acetate).

Example 6

N, N-Diethyl-2- (3-hydroxyphenylthio) benzylamine

As in Example 1, 5.3 g of N, N-diethyl-2- (3-methoxyphenylthio) benzylamine was demethylated by heating with 12.0 g of pyridine hydrochloride at 215 ° C (under a nitrogen atmosphere). Workup yielded 3.3 g of the hydrochloride of the title compound, m.p. 155-157 ° C (ethanol-ether). The respective base is oily.

The necessary starting N, N-diethyl-2- (3-methoxyphenylthio) benzylamine (oily base, m.p. 160-162 ° C) was prepared similarly to the previous examples from 2- (3-methoxyphenylthio) 5.

Of benzoyl chloride, see Example 5, via oily N, N-diethyl-2- (3-methoxyphenylthio) benzamide.

EXAMPLE 7 11, 11-Dipropyl-2- (3-hydroxyphenylthio) benzylamine

It was obtained similarly as described in Example 4 by demethylation of N, N-dipropyl-2- (3-methoxyphenylthio) benzylamine in chloroform with boron tribromide in 72% yield.

The base is oily; hydrochloride, m.p. 204-206 (ethanol-ether).

The necessary starting 1T, N-diethyl-2- (3-methoxyphenylthio) benzylamine (oil base having 165-168 ° C / 0.13 kPa) was prepared in a similar manner to the previous examples from 2- (3-methoxyphenylthio) benzoyl chloride, cf. Example 5, via oily 3T, 1'-dipropyl-2- (3-methoxyphenylthio) benzamide.

Example 8

N, N-Di (isopropyl) -2- (3-hydroxyphenylthio) benzylamine

It is obtained, as in the previous example, by demethylation of n, N-di (isopropyl) -2- (3-methoxyphenylthio) bensylamine in chloroform with boron tribromide in a yield of 77 The base is oily; the hydrochloride is crystalline and melts at 191-193 ° C (ethanol).

The required starting 2 H, N-isopropyl) -2- (3-methoxyphenylthio) benzylamine (an oily base boiling at 172-175 ° C / 0.13 kPa) was prepared as in the previous examples from 2- (3-methoxyphenylthio). benzoyl chloride, see Example 5, via crystalline 11, N-di (isopropyl) -2- (3-methoxyphenylthio) benzamide, mp 98-100 ° C (benzene-hexane).

Example 9 1- (2-Dimethylaminoethyl) -2- (3-hydroxyphenylthio) benzylamine

A mixture of 2.55 g of N- (2-dimethylaminoethyl) -2- (3-methoxyphenylthio) benzylamine dihydrochloride and 20 ml of 48% hydrobromic acid was heated at 120 ° C for 6.5 h. After cooling, it was diluted with water, basified. with aqueous ammonia and the product was extracted with chloroform. Treatment of the extract gave an oily base which, by neutralization with maleic acid in acetone, yielded 3.5 g of crystalline bis (hydrogen maleate), mp 152.5-153.5 ° C (ethanol).

The required starting N- (2-dimethylaminoethyl) -2- (3-methoxyphenylthio) benzylamine is obtained as follows:

To a stirred solution of 12.0 g of 2-dimethylarainoethylamine in 50 ml of benzene was added dropwise a solution of 15 g of 2- (3-methoxyphenylthio) benzoyl chloride, see Example 5, in 150 ml of benzene at 10-20 ° C over 10 min. The mixture was stirred for 4 h, after standing overnight, washed with water and the benzene solution was evaporated. 17.8 g of (Theory) of N- (2-dimethylaminoethyl) -2- (3-methoxyphenylthio) benzamide are obtained, which is oily.

The whole of the crude amide was dissolved in 100 ml of tetrahydrofuran, 4.3 g of sodium borohydride was added with stirring, and 15 g of boron trifluoride etherate was added dropwise under nitrogen. The mixture was stirred at room temperature for 1 h, refluxed for 3 h, after cooling 20 ml of conc. hydrochloric acid, refluxed for 3 h, basified with 100 mL 20% sodium hydroxide after cooling, and extracted with ether. Treatment of the extract yielded an oily base which was converted to crystalline N- (2-dimethylaminoethyl) -2- (3-methoxyphenylthio) benzylamine dihydrochloride, m.p.

174 DEG-177 DEG C. (ethanol).

Example 10

N-Methyl-N- (2-dimethylaminoethyl) -2- (3-hydroxyphenylthio) benzylamine

A mixture of 3.85 g of N-methyl-N- (2-dimethylaminoethyl) -2- (3-diethoxyphenylthio) benzylamine dihydrochloride and 25 ml of 48% hydrobromic acid and refluxed at 120 ° C for 7 h. After dilution with water, it is basified with aqueous ammonia and extracted with chloroform. Treatment of the extract gave a crude oily base which, by neutralization with maleic acid in acetone, yielded 5.15 g of crystalline bis (hydrogen maleate), m.p.

M.p. 148-151.5 ° C (ethanol).

The starting amine dihydrochloride is prepared, for example, as follows:

A mixture of 15 g of oily N- (2-dimethylaminoethyl) -2- (3-methoxyphenylthio) benzylamine, 12 ml of formic acid and 18 ml of 36% aqueous formaldehyde was heated in a boiling water bath for 7 h. After cooling, it is acidified with 10 ml of hydrochloric acid, washed with ether, the aqueous solution is basified with aqueous ammonia and the product is extracted with ether. The extract was worked up to give 9.0 g of crude base which was converted to crystalline dihydrochloride (5.7 g), m.p. 168-175 ° C (ethanol-ether) by neutralization with ethereal hydrogen chloride.

Example 11

2- (4-Hydroxyphenylthio) benzylamine

As in the previous examples, 2.4 g of 2- (4-methoxyphenylthio) -henzylamine was demethylated by heating with 7.0 g of pyridine hydrochloride at 210 ° C for 30 min. Workup yielded 1.8 g (80%) of the crystalline base, m.p. 162-163 ° C (ethanol). Neutralization with maleic acid in ethanol and addition of ether yields hydrogen maleate, which crystallizes as a hemihydrate and melts at 154 ° C (ethanol-ether).

The required starting 2- (4-methoxyphenylthio) benzylamine (oily base, hydrochloride, mp 182-182.5 ° C (ethanol)) was prepared analogously to the previous examples from the known 2- (4-methoxyphenylthio) benzoyl chloride (Šindelář K. et al.). et al., Collect., Czech, Chem. Commun. 38, 1579 (1973)) via 2- (4-methoxyphenylthio) benzamide, mp 178 ° C (ethanol).

Example 12

2- (2,4-Dihydroxyphenylthio) benzylamine

As in the previous examples, 2.75 g of 2- (2,4-dimethoxyphenylthio) benzylamine was demethylated with 5.0 g of boron tribromide in 30 ml of chloroform. Workup yielded an oily base in 53% yield, which neutralized with hydrochloric acid and maleic acid to give oily salts.

Required starting 2- (2,4-dimethoxyphenylthio) benzylamine (base, mp 71-72 ° C (benzene-petroleum ether); hydrogen maleate, mp 112-113 ° C (ethanol); hydrobromide, mp 213.5 ° C (ethanol) ) is prepared from the known 2,4-dimethoxythiophenol (Suter CM, Hansen H, 1: J. Am. Chem. Soc. 55, 2080 (1933); Jacob &apos;, III et al .: J. Med, Chem. 20, 1235 (1977)), the first step being carried out as follows: To a solution of 62 g of potassium hydroxide in 570 ml of water is added successively 50 g of 2,4-dimethoxythiophenol, 72 g of 2-iodobenzoic acid and 1.5 g of copper (catalyst). ) and the mixture was refluxed under stirring for 14 h. It is then filtered after addition of 15 g of activated carbon and the cooled Be filtrate is acidified with dilute hydrochloric acid. After standing overnight, the precipitated 2- (2,4-dimethoxyphenylthio) benzoic acid is filtered off, washed with water and dried in vacuo; 81.4 g (97%), mp 215-217 ° C (ethanol).

The procedure was analogous to the previous examples and went through the following intermediates:

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2- (2,4-dimethoxyphenylthio) benzoyl chloride, m.p. 119-121 ° C (cyclohexane);

2- (2,4-dimethoxyphenylthio) benzamide, m.p. 164.5-165.5 ° C (ethanol).

Example 13

2- (2,5-Dihydroxyphenylthio) benzylamine

As in the previous examples, ae demethylation carried out 2.75 g of 2- (2,5-dimethoxyphenylthio) benzylamine with 5.0 g of boron tribromide in 30 ml of chloroform. Workup gave a 1.7 g (67%) of a crystalline base melting at 148-150 ° C (crude product without crystallization). Neutralization with maleic acid gives a crystalline hydrogen maleate, m.p. 150-151 ° C (ethanol).

The starting 2- (2,5-dimethoxyphenylthio) benzylamine is obtained analogously to the previous examples from the known 2,5-dimethoxythiophenol (Burton H., Hoggarth E .: J. Chem. Soc. 1945. 14) via the following intermediates:

2- (2,5-dimethoxyphenylthio) benzoic acid, m.p. 204-205 ° C (ethanol);

2- (2,5-dimethoxyphenylthio) benzoyl chloride, m.p. 101-102 ° C (cyclohexane);

2- (2,5-dimethoxyphenylthio) henzamide, m.p. 151-152 ° C (ethanol).

2- (2,5-dimethoxyphenylthio) benzylamine alone is a crystalline substance melting at 76-77 ° C (benzene-petroleum ether); hydrogen maleate, mp 149-151 ° C (ethanol).

. Example 14

2- (3,4-Dihydroxyphenylthio) benzylamine

As in the previous examples, 4.1 g of 2- (3,4-dimethoxyphenylthio) benzylamine was demethylated with 7.5 g of boron tribromide in 40 ml of chloroform. Workup yielded 3.55 g of the bromide of the title compound, melting at 191-192 ° C (ethanol-ether).

The base, liberated with aqueous ammonia and isolated by extraction with chloroform, melts at 139-141 ° C (without crystallization in the crude state).

The necessary starting 2- (3,4-dimethoxyphenylthio) benzylamine is obtained analogously to the previous examples - from the known 2- (3,4-dimethoxyphenylthio) benzoic acid (Roberta).

K. C., Saoiles S., J. Chem. Soc. 1929. 863) through the following intermediates:

2- (3,4-Dimethoxyphenylthio) benzoyl chloride, m.p. -133-134 ° C (benzene-cyclohexane);

2- (3,4-dimethoxyphenylthio) benzamide, m.p. 179 ° C (ethanol).

2- (3,4-dimethoxyphenylthio) benzylamine itself is a crystalline substance melting at 68-68.5 ° C (cyclohexane) which yields crystalline hydrochloride melting at 212-213 ° C (ethanol).

Example 15

N, N-Diethyl-2- (4-hydroxyphenylthio) benzylamine

Prepared as in the previous examples by demethylation of N, N-diethyl-2- (4-hydroxyphenylthio) benzylamine (as hydrochloride, 2.1 g) by heating 7.5 g of pyridine hydrochloride at 210 ° C for 35 min. Workup yielded 1.5 g of the hydrochloride of the title compound, m.p. 190-192 ° C (ethanol).

The starting N, N-diethyl 1-2- (4-methoxyphenylthio) benzylamine was prepared analogously to the previous examples from 2- (4-methoxyphenylthio) benzoyl chloride, see Example 11, via

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N, N-diethyl-2- (4-methoxyphenylthio) benzamide (oily).

N, N-diethyl-2- (4-methoxyphenylthio) benzylemine itself is oily, but yields crystalline hydrochloride melting at 151-153 ° C (ethanol-ether).

Example 16

N, N-Dipropyl-2- (4-hydroxyphenylthio) benzylamine

As in the previous examples, 13.2 g of N, N-dipropyl-2- (4-methoxyphenylthio) benzylamine are obtained by demethylation with 10 g of boron tribromide in 110 ml of chloroform to obtain 11.2 g of crude oil base which gives 9.0 by neutralization with ethanolic hydrogen chloride. g of crystalline hydrochloride melting at 225-227 ° C (ethanol-ether).

The starting N, N-dipropyl-2- (4-methoxyphenylthio) benzylamine was prepared analogously to the previous examples from 2- (4-methoxyphenylthio) benzoyl chloride, see Example 11, via oily N, N-dipropyl-2- (4-methoxyphenylthio). ) benzamide.

N, N-dipropyl-2- (4-methoxyphenylthio) benzylamine itself is oily but yields crystalline hydrochloride melting at 152-154 ° C (ethanol-ether).

Example 17

N, N-Di (isopropyl) -2- (4-hydroxyphenylthio) benzylamine

Be obtained as in the previous examples by demethylation of 13.2 g of N, N-di (isopropyl) -2- (4-methoxyphenylthio) benzylamine with 10 g of boron tribromide in 110 ml of chloroform. Workup yielded a crude oily base which was converted to 10.3 g (73%) of crystalline hydrochloride melting at 200-202 ° C (ethanol-ether).

Starting N, N-di (isopropyl) -2- (4-methoxyphenylthio) benzylamine (oily base; crystalline hydrochloride, m.p. 148-150 ° C (acetone-ether)) was obtained in analogy to the previous examples from 2- (4-methoxyphenylthio) benzoyl chloride, see Example 11, using oily N, N-di (isopropyl) -2- (4-methoxyphenylthio) benzylamine.

Claims (4)

SUBJECT OF THE INVENTION A process for the preparation of novel benzylamine derivatives of the general formula I (I), in which R represents (OH), where n is 1 or 2 and when n is 2, the hydroxyl groups are in any position, R and R are the same and are hydrogen, ethyl, n-propyl Or isopropyl, or are different, in which case R is 2-dimethylaminoethyl and R is hydrogen or methyl, and salts thereof, characterized in that the compounds of formula II (II) in which R * is (OCH) Where n is 1 or 2 and in the case where n is 2, > H &lt; 10 &gt; O are methoxy in any position, and R and R are the same as in formula dem, demethylate and neutralize the bases obtained with pharmaceutically acceptable inorganic or organic acids. F 2. The process according to claim 1, wherein the demethylation is carried out by heating and pyridine hydrochloride at a temperature of 200-220 [deg.] C. 3. The process according to claim 1, wherein the demethylation is carried out by reaction with boron tribromide, preferably in dichloromethane, chloroform or chlorobenzene, at room temperature. 4. The process of claim 1 wherein the demethylation is carried out by heating with 48% hydrobromic acid to 120-130 [deg.] C.