DK149883B - METHOD OF ANALOGUE FOR THE PREPARATION OF BENZYLAMINES OR ACID ADDITION SALTS. - Google Patents

Description

149883

The present invention relates to an analogous process for the preparation of novel benzylamines of the general formula I: R

Hal OH

where

Hal is a chlorine or bromine atom, R 2 is a hydrogen, chlorine or bromine atom, 2 R is an optionally substituted with 1 to 3 hydroxy groups, branched alkyl group having 3-5 carbon atoms or a group of formula :

Where 3 R is a hydrogen atom, a hydroxy group or an alkyl group of 1-4 carbon atoms, and n is the number 0, 1 or 2, and is a straight or branched alkyl group of 1-4 carbon atoms or also. 3. 2 is a hydrogen atom if R is not a hydrogen atom or R is an optionally substituted with 1 to 3 hydroxy groups branched alkyl group of 3-5 carbon atoms, or their physiologically acceptable acid addition salts thereof with inorganic or organic acids, the process of which is the characteristic part of the claim stated.

The compounds of the above general formula I and their physiologically acceptable acid addition salts with inorganic or organic acids have valuable pharmacological properties, in particular in addition to an enhancing effect on the production of the surfactant or anti-electase factor of alveoli, a cytochrotolytic and cough-producing effect.

The reaction according to process a) is conveniently carried out in a solvent such as acetone, carbon tetrachloride, chloroform, ethanol, tetrahydrofuran, benzene, toluene, dioxane, tetralin or in excess of the amine of the general formula III used and, depending on the reaction ability of group R, at temperatures between -70 ° C and 200 ° C.

g

If R ° is a halogen atom, the reaction is preferably carried out at temperatures between 0 ° and 150 ° C, e.g. at the boiling temperature of the solvent used, and conveniently in the presence of a hydrogen halide binding agent, e.g. an inorganic base such as sodium carbonate or sodium hydroxide, an ion exchanger or a tertiary organic base such as triethylamine or pyridine.

Hereby, an applied tertiary organic base can also simultaneously serve as a solvent.

6 e

If R is a sulfonyloxy group such as the 4-methylphenylsulfonyloxy group, the reaction is preferably carried out at temperatures between -70 ° and 50 ° C.

g

If R is an acyloxy group such as an acetoxy or benzoyloxy group, or an alkoxy, aryloxy or aralkoxy group, the reaction is optionally carried out in the presence of an acidic catalyst such as ammonium chloride, preferably at temperatures between 0 ° and 200 ° C.

If R is a hydroxy group, the reaction is optionally carried out in the presence of an acidic catalyst such as hydrobromic acid, p-toluenesulfonic acid or butyric acid, or optionally in the presence of an alkaline catalyst such as potassium hydroxide or magnesium oxide, preferably at temperatures between 120 ° and 180 ° C. However, the reaction can also be carried out without solvent.

The reaction according to process b) is preferably carried out at temperatures between 50 ° and 250 ° C, optionally in a solvent and optionally during simultaneous distillation of the formed water. However, it is particularly advantageous, when the reaction, the amine of the general formula III and / or formic acid used simultaneously acts as a solvent. If, in a compound of general formula III, R 4 is a hydrogen atom, the reaction mixture obtained after the reaction is heated with a dilute acid such as 2N hydrochloric acid under reflux.

The reduction according to process c) is suitably carried out with catalytically activated hydrogen if R 1 is a hydrogen atom, e.g. with hydrogen in the presence of Raney nickel or Raney cobalt, with hydrogen formed in statu nascendi, e.g. with activated metallic aluminum and water, with sodium amalgam and ethanol, with zinc and hydrochloric acid, or in particular with a complex metal hydride such as lithium aluminum hydride or sodium borohydride, in a suitable solvent such as methanol, ethanol, ethanol / water, tetrahydrofuran, dioxane, dioxane / water, pyridine or ether, and at temperatures up to the boiling temperature of the solvent used, e.g. at temperatures between -50 ° and 100 ° C. If Ry in a compound of the general formula V or Va is a carboxylic acid residue, it is decomposed during the reduction with hydrogen in statu nascendi or with a complex metal hydride.

The reaction according to process d) is conveniently carried out in a solvent such as methanol, dioxane or dimethylformamide, and preferably at temperatures between -20 ° and 150 ° C, preferably at the boiling temperature of the solvent used. As indicated, methylation may also be carried out with formaldehyde, which is carried out in the presence of formic acid at elevated temperature, e.g. at the boiling temperature of the reaction mixture.

The reaction according to process e) is conveniently carried out in the presence of a solvent, such as water, methanol, ethanol or dioxane, at temperatures between 0 ° and 100 ° C, preferably at the boiling temperature of the solvent used.

The reaction may also be carried out in such a way that, if necessary, an in situ compound having the general formula Illa 4 149883 '/ * 2

Alk - O - CH, - N '. IIIa

NT

wherein 2 4 R and R have the above meanings, and

Alk is a lower alkyl group, reacted with a compound of general formula VIII.

The halogenation according to process f) is carried out with a halogenating agent, e.g. with chlorine, bromine, phenyliodine dichloride or tribromophenol bromine, preferably in a solvent, e.g. 50-100% acetic acid, in methylene chloride or in tetrahydrofuran in the presence of a tertiary organic base, and preferably at temperatures between -20 ° and 50 ° C. Per mole of a compound of the general Form IX which can be used as a base or also as a salt, e.g. as hydrochloride, conveniently 1 or 2 moles of a halogenating agent or a slight excess are used. If, during the reaction, a hydrogen halide acid salt is formed, this can be isolated directly as such or, if desired, further purified via the base.

If in the process g) X and / or Y is any acyl group, e.g. an acetyl, benzoyl or p-toluenesulfonyl group, the cleavage of this group takes place hydrolytically in the presence of a solvent, e.g. with ethanolic hydrochloric acid or with aqueous-alcoholic sodium hydroxide solution, at temperatures up to the boiling point of the solvent used.

If X and / or Y is a benzyl group, the cleavage of this group is hydrogenolytic, e.g. with hydrogen in the presence of a catalyst, preferably in a solvent such as ethanol, methanol / hydrochloric acid or water / hydrochloric acid, and at room temperature.

If Y is an alkyl, aryl or aralkyl group, the cleavage of this group preferably takes place with hydrogen bromide or hydrogen iodide at elevated temperature. However, it can also be carried out with acid halides, phosphorus oxyhalides, phosphorus pentahalides, aluminum halides, with sulfuric acid or with metal-organic compounds.

If Y is a carboxylic acid residue, such as an acetyl or benzoyl group, the cleavage of this group may also occur with complex metal hydrides, e.g. with sodium borohydride in pyridine or with lithium aluminum hydride in an inert solvent, such as ether or tetrahydrofuran, at temperatures between 0 ° G and the boiling temperature of the solvent used. If in this case X means a formyl or acetyl group, it is simultaneously reduced to a methyl or ethyl group.

5 149883

The reduction according to process h) is conveniently carried out with catalytically activated hydrogen, which is a hydrogen atom, or with hydrogen formed in statu nascendi, e.g. with an alkali metal in an alcohol, such as sodium in ethanol, at temperatures between room temperature and the boiling temperature of the solvent used. However, it is particularly advantageous to carry out the reaction with a complex metal hydride, e.g. with sodium borohydride in pyridine or with lithium aluminum. . . 4 ".

hydride in ether or tetrahydrofuran. If, in a compound of the general form XI, R is a formyl or aethyl ethyl group, at the time of reduction it is simultaneously reduced to the corresponding alkyl group, and / or if R 1 represents a carboxylic acid residue, it is cleaved during the reaction if the reaction is carried out with hydrogen. in statu nascendi or with a complex metal hydride.

The hydrolysis according to process i) is conveniently carried out in the presence of an acid such as hydrochloric or sulfuric acid, or particularly advantageously in the presence of a base such as sodium hydroxide or potassium hydroxide in a suitable solvent such as ethanol, isopropanol, tert-butanol, acetone or dioxane. , and at temperatures up to the boiling point of the solvent used.

The reaction according to process j) is conveniently carried out in a solvent such as tetralin or in an excess of the amine of general formula III used at temperatures between 100 ° and 220 ° C, however preferably at temperatures between 120 ° and 180 ° C. However, the reaction can also be carried out without solvent.

Q

In particular, the acetyl, butyryl, benzoyl or 4-chlorobenzoyl group mentioned in the definition of the group R mentioned above during the reaction is considered.

The reaction according to process k) is conveniently carried out in a solvent such as tetralin or in an excess of the amine of general formula III used at temperatures between 100 ° and 200 ° C, preferably at temperatures between 120 ° and 180 ° C. However, the reaction can also be carried out without solvent.

The subsequent hydrolysis is preferably carried out in the presence of an acid such as hydrochloric or sulfuric acid in a polar solvent such as water, ethanol / water or dioxane / water, and at temperatures up to the boiling temperature of the solvent used.

g

In particular, for the groups mentioned above by the group R above, the methyl, phenyl or benzyl group is considered.

Optionally, the hydrolysis according to method 1) is carried out in the presence of an acid such as hydrochloric, sulfuric or acetic acid, however conveniently without acid in a polar solvent such as water, methanol / water or dioxane / water, and at temperatures between 0 ° and the boiling temperature. for the solvent used.

The reaction according to process m) is conveniently carried out in a solvent such as tetralin and at temperatures between 100 ° and 250 ° C, preferably at temperatures between 120 ° and 180 ° C. However, the reaction can also be carried out without solvent.

The compounds used in the processes a) -m) as starting compounds of the general formulas II-XVIa are partly known from the literature or they can be prepared by methods known from the literature.

Thus, e.g. the benzyl halides of general formula II are prepared from the corresponding toluene derivatives by reaction with N-bromo-succinimide and halogen, respectively, under UV irradiation.

Thus, a benzyl alcohol derivative of the general formula II is obtained, e.g. by reacting a corresponding benzyl alcohol with a corresponding acid in the presence of hydrochloric acid or by reacting a corresponding benzyl halide with a corresponding alcohol in the presence of barium carbonate, and a benzyl alcohol of the general formula II by halogenating a corresponding benzyl alcohol.

The aldehydes of general formula IV are obtained e.g. by halogenating the corresponding benzaldehydes and the imines of the general formulas V and Va are obtained from the corresponding primary amines and the corresponding carbonyl compounds. By reducing a compound thus obtained with the general formula V or Va, e.g. with sodium borohydride, a compound of general formula VI is obtained.

For example, the benzylamines of general formulas IX and X are obtained. by reacting the corresponding benzyl halides with the corresponding amines and optionally subsequent acylation.

The benzamides of the general formula XI used as starting compounds may, for example, are prepared by reaction with the corresponding acid halides with the corresponding amines and optionally subsequent acylation.

The compounds of general formula XII used as starting materials are obtained e.g. by halogenating the corresponding benzoxazines.

For example, a compound of general formula XIII is obtained. by reducing the corresponding benzaldehyde with hydrogen and Raney nickel as catalyst.

A compound of general formula XIV is obtained e.g. by halogenating the corresponding compounds.

A compound of general formula XV is obtained by condensing a corresponding phenol and an amine of general formula III with excess formaldehyde.

For example, an acid amide of general formula XVI or XVIa is obtained. by reacting a corresponding acid halide with a corresponding amine in the presence of pyridine.

The compounds of general formula I obtained can be transferred into their physiologically acceptable salts with inorganic or organic acids. As acids, e.g. hydrochloric acid, phosphoric acid, hydrogen bromic acid, sulfuric acid, lactic acid, tartaric acid or maleic acid proved to be suitable.

As already mentioned, the novel compounds of the general formula I have valuable pharmacological properties, in addition to an enhancing effect on the production of the surfactant or anti-electrolytic factor, in particular a secretolytic and cough-releasing effect.

For example, the following compounds have been tested for their biological action: ΔS * N-Ethyl-N-cyclohexyl-3,5-dibromo · -2-hydroxy-benzylamine hydrochloride, B * N-Ethyl-N-cyclohexyl-3,5 dibromo-4-hydroxy-benzylamine hydrochloride, C * 3,5-Dibrora -4-hydroxy-N- (cis-3-hydroxy-cyclohexyl) -benzylamine-hydrochloride, D * 3-Bromo-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine hydrochloride, E »3-Bromo-5-chloro-N-cyclohexyl-4-hydroxy-N-methyl-benzylamine hydrochloride, F * 3,5-Dibromo-2 hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine hydrochloride, G a 3,5-Dibromo-N- (dihydroxy-tert-butyl) -2-hydroxy-benzylamine hydrochloride, H a Dichloro-N- (dihydroxy-tert.butyl) -4-hydroxy-benzylamine hydrochloride and 1a 3,5-Dibromo-2-hydroxy-N-tert-pentyl-benzylamine hydrochloride.

8 149883 1. Anti-cough effect;

In groups of every 10 waking white rats, each given 50 rag / kg p.o. of the test compound, by inhalation of a 7.5% aqueous citric acid spray, cough irritation was triggered. The mean percent change in cough rate 30 minutes after administration of the test compound compared to a control group of 10 animals was measured (see Engelhorn and Ptischmann in Arzneimittelforschung 13, 474-480 (1963)):

Compound Average percentage change in cough rate 30 minutes after administration of 50 mg / kg p.o.

A - 38 B - 34 C - 35 2. Expectorating effect:

The expectoration experiments are performed after administration of 8 mg / kg p.o each time. of the test compound on 8 to 10 narcotic rabbit cubs or on 5 narcotic guinea pig cubs. The secretion increase for 2-hour values was calculated after and before drug administration (see Perry and Boyd in Pharmakol.exp.Therap. 73, 65 (1941)).

The circulatory effects of the compounds on cats were examined in chloralose-urethane anesthesia after intravenous administration of the compounds (3 animals per dose):

Experiments on rabbit cubs:

Connection Secretion increase Circuit effect (cats) A + 81% 4 mg / kg: no change 8 mg / kg: short term low blood pressure B + 87% 8 mg / kg: no change

Guinea pig kid trials:

Connection Secretion increase D + 66% E + 65 7.

F + 70 7.

G + 88% H + 88% I + 80% 3. Acute toxicity:

The orienting acute toxicity was determined on groups of every 5 white mice after a dose of between 500 mg / kg p.o. and 5000 mg / kg p.o. per. animals (observation time: 72 hours): 9 149883

Compound Acute Toxicity A> 1,000 mg / kg p.o. (0 of 5 animals died) B> 1,000 mg / kg p.o. (0 of 5 animals died) C> 1,000 mg / kg p.o. (0 of 5 animals died) D> 500 mg / kg p.o. (0 of 5 animals died) E> 500 mg / kg p.o. (0 of 5 animals died) F> 5,000 mg / kg p.o. (0 of 5 animals died) G> 5,000 mg / kg p.o. (0 of 5 animals died)

H

I> 5,000 mg / kg p.o. (0 of 5 animals died)

The compounds of the general formula 1 according to the invention may optionally be incorporated into the usual pharmaceutical formulations in combination with other active substances, the single dose being 1-20 mg, preferably 2-10 mg.

The process according to the invention will be described in more detail by the following examples.

Obviously, the compounds of the present invention can be prepared by all the methods, taking into account the limitations set by the individual processes.

Example 1.

N-Ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine hydrochloride.

17 g of 3,5-Dibromo-2-hydroxy-benzyl bromide and 12.7 g of N-ethyl-cyclohexylamine were heated under reflux in 150 ml of ethanol. Then it was evaporated to dryness. The evaporation site was shaken with 150 ml of chloroform and 200 ml of water. The chloroform phase was separated, filtered and evaporated to dryness, the residue was dissolved in ethanol and acidified with ethanolic hydrochloric acid. Thereby crystallized N-ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine hydrochloride, m.p. 192-194 ° C (dec.).

Example 2.

N -Cyclohexy 1-3,5-dibromo-2-hydroxy-N-methyl-benzylamine hydrochloride.

21 g of 3,5-Dibromo-salicylaldehyde, 56.5 g of N-methyl-cyclohexylamine and 23 g of formic acid were heated for 6 hours at 70-80 ° C. After cooling, the reaction product was shaken with chloroform and diluted ammonia. The chloroform phase was separated and evaporated to dryness. The residue was chromatographed over 800 g of silica gel with acetic acid ethyl ester / chloroform (1: 1). After 0.5 liters, the next 0.5 liters were captured and evaporated to dryness. The residue was dissolved in 50 ml of ethanol and acidified with ethanolic hydrochloric acid. Thereby crystallized N-cyclohexyl-3,5-dibromo-2-hydroxy-N-methyl-benzylamine hydrochloride, m.p. 189-191 ° C (dec.).

149883 ίο

Example 3

3,5-Dibromo-4-hydroxy-N- (cis-3-hydroxy-cyclohexyl) -benzylamine-hydrochloride.

19 g of N- (3,5-dibromo-4-hydroxy-benzylidene) -cis-3-amino-cyclohexanol (mp 231-233 ° G (dec.)) Was slurried in 0.5 L of ethanol and added 2 g sodium borohydride. The mixture was stirred for 1.5 hours at room temperature. Then 200 ml of 2N sodium hydroxide solution was added and the ethanol was distilled off in vacuo. To the remaining solution was added ammonium chloride, which precipitated a crystalline precipitate. This was suctioned off, washed with water and dissolved in 100 ml of 2N hydrochloric acid under heating. After a short time, 3,5-dibromo-4-hydroxy-N- (cis-3-hydroxy-cyclohexyl) -benzylamine hydrochloride which was suctioned off and washed with acetone crystallized, m.p. 216-218 ° C (dec.).

Example 4

N-Cyclohexyl-3,5-dibromo-2-hydroxy-N-methyl-benzylamine hydrochloride.

3.6 g of N-Cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine, 3.6 g of sodium bicarbonate and 3.6 g of methyl iodide were refluxed in 25 ml of tetrahydrofuran and 50 ml of methanol. Then, the filtrate was evaporated and the filtrate was evaporated to dryness. The evaporation residue was shaken with chloroform and diluted ammonia, and the chloroform phase was evaporated to dryness. The residue was boiled with acetic acid ethyl ester and, after cooling, filtered from undissolved material. The filtrate was acidified with ethanolic hydrochloric acid to give the hydrochloride with m.p. 189-19 ° C (dec.) Crystallized.

Example 5

N-Cyclohexyl-3,5-dibromo-4-hydroxy-N-methyl-benzylamine hydrochloride.

7.2 g of N-Gyclohexyl-3,5-dibromo-4-hydroxy-benzylamine were dissolved in 20 ml of formic acid and 2 ml of 40% formaldehyde was added. The solution was heated for 3 hours in a boiling water bath, then diluted with water and adjusted alkaline with concentrated ammonia. The precipitated base was suctioned off, washed with water and the hydrochloride was crystallized from ethanol with the addition of ether ether, m.p.168-170 ° C (dec.).

Example 6

N-Ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine hydrochloride.

51 g of N-Ethyl-cyclohexylamine and 12 g of paraformaldehyde were dissolved in 200 ml of ethanol under heating. After cooling, 100 g of 2,4-dibromo-phenol were added, allowed to stand for 1 hour at room temperature and boiled under reflux for 7 hours. The solution was evaporated to dryness. The residue was dissolved in ether and shaken with 2N ammonia and then with water. To the ether phase, 2N hydrochloric acid was added with vigorous stirring until the mixture reacted strongly acidic. After a short time, the hydrochloride crystallized. This was suctioned off, washed with water and then with acetone. After recrystallization from methanol / ether, m.p. 193-194 ° C (dec.).

Example 7

N- (4-tert.-butyl-cyclohexyl) -3,5-dibromo-4-hydroxy-benzylamine.

Mp. of the hydrochloride: 229 ° 231 ° G (dec.).

Prepared from 3,5-dibromo-4-hydroxy-benzyl bromide and 4-tert-butylcyclohexylamine analogous to Example 1.

Example 8.

3.5-Dibromo-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine.

Mp. of hydrochloride: 212-218 ° C (dec).

Prepared from 3,5-dibromo-2-hydroxy-benzyl bromide and trans-4-amino-cyclohexanol analogous to Example 1.

Example 9

3.5-Dibromo-2-hydroxy-N- (cis-3-hydroxy-cyclohexyl) -benzylamine.

Mp. of hydrochloride: 128-136 ° C (dec).

Prepared from 3,5-dibromo-2-hydroxy-benzyl bromide and cis-3-amino-cyclohexanol analogous to Example 1.

Example 10.

3.5-Dibromo-2-hydroxy-N- (trans-3-hydroxy-cyclohexyl) -benzylamine.

Mp. : 203-204.5 ° G (dec.).

Prepared from 3,5-dibromo-2-hydroxy-benzyl bromide and trans-3-amino-cyclohexanol analogous to Example 1.

Example 11.

3.5- Dibromo-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -N-methyl-benzylamine.

Mp. of hydrochloride: 120 ° C (dec.).

Prepared from 3,5-dibromo-salicylaldehyde, trans-4-methylamino-cyclohexanol and formic acid analogous to Example 2.

Example 12.

3.5-Dibromo-2-hydroxy-N »(cis-3-hydroxy-cyclohexyl) -N-methyl-benzylamine.

Mp. of hydrochloride: 80-83 ° C (dec.).

Prepared from 3,5-dibromo-2-hydroxy-benzyl bromide and cis-3-methylamino-cyclohexanol analogous to Example 1.

Example 13

N-Ethyl-3,5-dibromo-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine.

Mp. of hydrochloride as ethanolate: 135-137 ° C (decO).

Prepared from 3,5-dibromo-2-hydroxy-benzyl bromide and trans-4-ethylamino-cyclohexanol analogous to Example 1.

149883 12

Example 14.

N-Cyclohexyl-3,5-dibroro-2-hydroxy-N-propyl-benzylamine.

Mp. of hydrochloride: 178-180 ° C.

Prepared from 3,5-dibromo-2-hydroxy-benzyl bromide and N-propyl-cyclohexylamine analogous to Example 1.

Example 15

N-Cyclohexyl-3,5-dibromo-2-hydroxy-N-isopropyl-benzylamine,

Mp: 108-110 ° C.

Prepared from 3,5-dibromo-2-hydroxy-benzyl bromide and N-isopropyl-cyclohexylamine analogous to Example 1.

Example 16.

N- (4-tert.-Butyl-cyclohexyl) -3,5-dibromo-2-hydroxy-N-methyl-benzylamine.

Mp. of hydrochloride: 209-211 ° C (dec.).

Prepared from 3,5-dibromo-2-hydroxy-benzyl bromide and N-methyl-4-tert-butyl-cyclohexylamine analogous to Example 1,

Example 17

N-Ethyl-N- (trans-4-tert-butyl-cyclohexyl) -3,5-dibromo-2-hydroxy-benzylamine.

Mp. of hydrochloride: 175-176 ° C (dec.).

Prepared from 3,5-dibromo-2-hydroxy-benzyl bromide and N-ethyl-4-tert-butyl-cyclohexylamine analogous to Example 1. The division of the isomer mixture was carried out column chromatographically.

Example 18.

N-Ethyl-N- (cis-4-tert.-butyl-cyclohexyl) -3,5-dibromo-2-hydroxy-benzylamine.

Mp. of hydrochloride: 168-169 ° C (dec.).

Prepared from 3,5-dibromo-2-hydroxy-benzyl bromide and N-ethyl-4-tert-butyl-cyclohexylamine analogous to Example 17.

Example 19.

N- (trans-4-tert.-butyl-cyclohexyl) -3,5-dibromo-2-hydroxy-N-propyl-benzylamine.

Mp. of hydrochloride: 173-174 ° C (dec.).

Prepared from 3,5-dibromo-2-hydroxy-benzyl bromide and N-propyl-4-tert-butyl-cyclohexylamine analogous to Example 17.

Example 20 N- (cis-4-tert.-butyl-cyclohexyl) -3,5-dibromo-2-hydroxy-N-propyl-benzylamine.

Mp. of hydrochloride: 148-150 ° C (dec.).

Prepared from 3,5-dibromo-2-hydroxy-benzyl bromide and N-propyl-4-tert-butyl-cyclohexylamine analogous to Example 17.

13 149883

Example 21.

N- (4-tert-butyl-cyclohexyl) -3,5-dibromo-2-hydroxy-N-isopropyl-benzylamine.

Mp. of hydrochloride: 152-154 ° C (dec.).

Prepared from 3,5-dibromo-2-hydroxy-benzyl bromide and N-isopropyl-4-tert-butyl-cyclohexylamine analogous to Example 1.

Example 22.

N-Cyclopentyl-3,5-dibromo-2-hydroxy-N-methyl-benzylamine.

Mp 61-63 ° C.

Prepared from 3,5-dibromo-2-hydroxy-benzyl bromide and N-methyl-cyclopentylamine analogous to Example 1.

Example 23

N-Ethyl-N-cyclopentyl-3,5-dibromo-2-hydroxy-benzylamine.

Mp. of hydrochloride: 124-128 ° C (dec.).

Prepared from 3,5-dibromo-2-hydroxy-benzyl bromide and N-ethyl-cyclopentylamine analogous to Example 1,

Example 24.

N-Cyclopentyl-3,5-dibromo-2-hydroxy-N-propyl-benzylamine.

Mp. of hydrochloride: 113-120 ° C.

Prepared from 3,5-dibromo · -2-hydroxy-benzyl bromide and N-propyl-cyclopentyl-amine analogous to Example 1.

Example 25

N-Cyclopentyl-3,5-dibromo, -2-hydroxy-N-isopropyl-benzylamine.

Mp, of hydrochloride: 154-157 ° C (dec.).

Prepared from 3,5-dibromo-2-hydroxy-benzyl bromide and N-isopropyl-cyclopentylamine analogous to Example 1.

Example 26

N-Cycloheptyl-3,5-dibromo-2-hydroxy-N-methyl-benzylamine.

Mp. of hydrochloride: 196-198 ° C (dec).

Prepared from 3,5-dibromo-2-hydroxy-benzyl bromide and N-methyl-cycloheptyl-amine analogous to Example 1.

Example 27

N-Ethyl-N-cycloheptyl-3,5-dibromo-2-hydroxy-benzylamine.

Mp. of hydrochloride: 180-183 ° C (dec.).

Prepared from 3,5-dibromo-2-hydroxy-benzyl bromide and N-ethyl-cycloheptylamine analogous to Example 1.

14 149883

Expende1 28.

N-Cycloheptyl-3,5-dibromo-2-hydroxy-N-propyl-benzylamine.

Mp. of hydrochloride; 134-139 ° C.

Prepared from 3,5-dibromo-2-hydroxy-benzyl bromide and N-propyl-cycloheptylamine by Example 1.

Example 29.

N-Cycloheptyl-3,5-dibromo-2-hydroxy-N-isopropyl-benzylamine.

Mp. of hydrochloride: 156-159 ° C (dec.).

Prepared from 3,5-dibromo-2-hydroxy-benzyl bromide and N-isopropyl-cyclo-heptylamine analogous to Example 1.

Example 30.

3.5-Dibromo-4-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine.

Mp. of hydrochloride: 220-225 ° C (dec.).

Prepared from 3,5-dibromo-4-hydroxy-benzyl bromide and trans-4-amino-cyclohexanol analogous to Example 1,

Example 31.

3.5- Dibromo. -4-hydroxy-N- (trans -3-hydroxy-cyclohexyl) -benzylamine.

M.p. of hydrochloride: 215-215.5 ° G (dec.).

Prepared from 3,5-dibromo-4-hydroxy-benzyl bromide and trans-3-amino-cyclohexanol analogous to Example 1.

Example 32.

N-Cyclohexyl-3,5-dibromo-4-hydroxy-N-methyl-benzylamine.

Mp. of hydrochloride: 168-170 ° C (dec.).

Prepared from 3,5-dibromo-4-hydroxy-benzyl bromide and N-methyl-cyclohexyl-amine analogous to Example 1.

Example 33

3.5-Dibromo-4-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -N-methyl-benzylamine.

Mp. of hydrochloride: 160-162 ° C (dec.).

Prepared from 3,5-dibromo-4-hydroxy-benzyl bromide and trans-4-methylamino-cyclohexanol analogous to Example 1.

Example 34.

3.5- Dibromo-4-hydroxy-N- (cis-3-hydroxy-cyclohexyl) -N-methyl-benzylamine.

Mp. 133-136 ° C.

Prepared from 3,5-dibromo-4-hydroxy-benzyl bromide and cis-3-methylamino-cyclohexanol analogous to Example 1.

15 149883

Example 35, N-Ethyl-3,5-dibromo-4-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine.

Mp. of hydrochloride: 176-178 ° C (dec.).

Made from 3.5-dibromo. -4-hydroxy-benzyl bromide and trans-4-ethylamino-cyclohexanol analogous to Example 1.

Example 36.

N-Ethyl-3,5-dibromo-4-hydroxy-N «(cis-3-hydroxy-cyclohexyl) -benzylamine.

Mp: 134-136 ° C (dec.).

Prepared from 3,5-dibromo-4-hydroxy-benzyl bromide and cis-3-ethylamino-cyclohexanol analogous to Example 1.

Example 37.

N-cyclohexyl-3,5-dibromo. -4-hydroxy-N-propyl-benzylamine.

Mp: 115-H6 ° C (dec.).

Prepared from 3,5-dibromo-4-hydroxy-benzyl bromide and N-propyl-cyclohexylamine analogous to Example 1.

Example 38

N- (4-tert.-butyl-cyclohexyl) -3,5-dibromo-4-hydroxy-N-methyl-benzylamine.

Mp, of hydrochloride: 158-159 ° C (dec.).

Prepared from 3,5-dibromo-4-hydroxy-benzyl bromide and N-methyl-4-tert-butyl-cyclohexylamine analogous to Example 1.

Example 39

N-Ethyl-N- (4-tert-butyl-cyclohexyl) -3,5-dibromo-4-hydroxy-benzylamine.

Mp. of hydrochloride: 170-170.5 ° C (dec.).

Prepared from 3,5-dibromo-4-hydroxy-benzyl bromide and N-ethyl-4-tert-butyl-cyclohexylamine analogous to Example 1.

Example 40.

N- (4-tert-butyl-cyclohexyl) -3,5-dibromo. -4-hydroxy-N-propyl-benzylamine.

Mp. of hydrochloride; 159-160 ° C (dec).

Prepared from 3,5-dibromo-4-hydroxy-benzyl bromide and N-propyl-4-tert-butyl-cyclohexylamine analogous to Example 1.

Example 41, N-Cyclopentyl-3,5-dibromo-4-hydroxy-N-methyl-benzylamine.

Mp. of hydrochloride: 185-188 ° C (dec.).

Prepared from 3,5-dibromo-4-hydroxy-benzyl bromide and N-methyl-cyclopentylamine analogous to Example 1.

16 149883

Example 42

N-Ethyl-N-cyclopentyl-3,5-dibromo-4-hydroxy-benzylamine.

Mp. of hydrochloride: 164-165 ° C (dec.).

Prepared from 3,5-dibromo-4-hydroxybenzyl bromide and N-ethylcyclopentylamine analogous to Example 1.

Example 43

N-Cyclopentyl-3,5-dibromo-4-hydroxy-N-propyl-benzylamine.

Mp. of hydrochloride: 156-158 ° G (dec.).

Prepared from 3,5-dibromo-4-hydroxy-benzyl bromide and N-propyl-cyclopentylamine analogous to Example 1.

Example 44

N-Cyclopentyl-3,5-dibromo-4-hydroxy-N-isopropyl-benzylamine.

Mp. of hydrochloride: 151-152 ° C (dec.).

Prepared from 3,5-dibromo-4-hydroxy-benzyl bromide and N-isopropyl-cyclopentylamine analogous to Example 1.

Example 45

N-Cycloheptyl-3,5-dibromo-4-hydroxy-N-methyl-benzylamine.

Mp. of hydrochloride: 175-179 ° C (dec.).

Prepared from 3,5-dibromo-4-hydroxy-benzyl bromide and N-methyl-cycloheptylamine analogous to Example 1.

Example 46

N-Ethyl-N-cycloheptyl-3,5-dibromo-4-hydroxy-benzylamine.

Mp. of hydrochloride: 176-177 ° C (dec.).

Prepared from 3,5-dibromo-4-hydroxy-benzyl bromide and N-ethyl-cycloheptylamine analogous to Example 1.

Example 47.

N-Cycloheptyl-3,5-dibromo-4-hydroxy-N-propyl-benzylamine.

Mp. of hydrochloride: 135-136 ° C.

Prepared from 3,5-dibromo-4-hydroxy-benzyl bromide and N-propyl-cycloheptylamine analogous to Example 1,

Example 48.

N-Cyclohexyl-3,5-dichloro-2-hydroxy-N-methyl-benzylamine.

Mp. of hydrochloride: 174-178 ° C.

Prepared from 3,5-dichloro-2-hydroxy-benzyl bromide and N-methyl-cyclohexyl-amine analogous to Example 1.

17 149883

Example 49.

N-Ethyl-N-cyclohexyl-3,5-dichloro-2-hydroxy-benzylamine.

Mp. of hydrochloride: 185-188 ° C (dec.).

Prepared from 3,5-dichloro-2-hydroxy-benzyl bromide and N-ethyl-cyclohexyl-amine analogous to Example 1.

Example 50

N-Ethyl-3,5-dichloro-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine.

Mp. of hydrochloride: 147-152 ° C.

Prepared from 3,5-dichloro-2-hydroxy-benzyl bromide and trans-4-ethylarainocyclohexanol analogous to Example 1.

Example 51.

N-Cyclohexyl-3,5-dichloro-2-hydroxy-N-propyl-benzylamine.

Mp. of hydrochloride: 168-170 ° G.

Prepared from 3,5-dichloro-2-hydroxy-benzyl bromide and N-propyl-cyclohexylamine analogous to Example 1.

Example 52

N-Cyclohexyl-3,5-dichloro-2-hydroxy-N-isopropyl-benzylamine.

Mp: 86-89 ° C.

Prepared from 3,5-dichloro-2-hydroxy-benzyl bromide and N-isopropyl-cyclohexylamine analogous to Example 1.

Example 53.

N-Ethyl-N-cyclohexyl-3,5-dichloro-4-hydroxy-benzylamine.

Mp. of hydrochloride: 190-191 ° C (dec.).

Prepared from 3,5-dichloro-4-hydroxy-benzyl bromide and N-ethyl-cyclohexyl-amine analogous to Example 1.

Example 54

N-Ethyl 1-3-bromo-5-chloro-N-cyclohexyl-2-hydroxy-benzylamine,

Mp. of hydrochloride: 194-197 ° C (dec.).

Prepared from 3-bromo-5-chloro-2-hydroxy-benzyl bromide and N-ethyl-cyclohexylamine analogous to Example 1.

Example 55

N-Ethyl-5-bromo-3-chloro-N-cyclohexyl-2-hydroxy-benzylamine.

Mp. of hydrochloride: 188-191 ° C (dec.).

Prepared from 5-bromo-3-chloro-2-hydroxy-benzyl bromide and N-ethyl-cyclohexylamine analogous to Example 1.

18 149883

Example 56

5-Bromo -N-cyclohexyl-2-hydroxy-N-methyl-benzylamine.

Mp. of hydrochloride: 194-197 ° C.

Prepared from 5-bromo-salicylaldehyde, N-methyl-cyclohexylamine and formic acid analogous to Example 2.

Example 57.

N-Ethyl-5-bromo-N-cyclohexyl-2-hydroxy-benzylamine.

Mp. of hydrochloride: 175-178 ° C.

Prepared from 5-bromo-salicylaldehyde, N-ethyl-cyclohexylamine and formic acid analogous to Example 2.

Example 58

N-Ethyl-5-bromo-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine.

Mp, of hydrochloride: 190-193 ° C (dec.).

Prepared from 5-bromo-salicylaldehyde, trans-4-ethylamino-cyclohexanol and formic acid analogous to Example 2.

Example 59.

5-Bromo-N-cyclohexyl 2-hydroxy-N-propyl-benzylamine,

Mp. of hydrochloride: 166-169 ° G (dec.).

Prepared from 5-bromo-salicylaldehyde, N-propyl-cyclohexylamine and formic acid analogous to Example 2.

Example 60

5-Brot -N-cyclohexyl-2-hydroxy-N-isopropyl-benzylamine.

Mp: 90-93 ° G.

Prepared from 5-bromo-salicylaldehyde, N-isopropyl-cyclohexylamine and formic acid analogous to Example 2.

Example 61.

5-Chloro-N-cyclohexyl-2-hydroxy-N-methyl-benzylamine,

Mp. of hydrochloride: 194-198 ° C.

Prepared from 5-chloro-salicylaldehyde, N-methyl-cyclohexylamine and formic acid analogous to Example 2.

Example 62

N-Ethyl-5-chloro-N-cyclohexyl-2-hydroxy-benzylamine.

Mp. of hydrochloride: 169-17l ° G.

Prepared from 5-chloro-salicylaldehyde, N-ethyl-cyclohexylamine and formic acid analogous to Example 2.

19 149883

Example 63, 5-Chloro-N-cyclohexyl-2-hydroxy-N-propyl-benzylamine.

Mp. of hydrochloride: 140-142 ° C.

Prepared from 5-chloro-salicylaldehyde, N-propyl-cyclohexylamine and formic acid analogous to Example 2.

Example 64

5-Chloro-N-cyclohexyl-2-hydroxy-N-isopropylbenzylamine.

Mp: 85-88 ° C.

Prepared from 5-chloro-salicylaldehyde, N-isopropyl-cyclohexylamine and formic acid analogous to Example 2.

Example 65

3-Bromo -N-cyclohexyl-4-hydroxy-N-methyl-benzylamine.

Mp, of hydrochloride: 165-169 ° C (dec.).

Prepared from 3-bromo-4-hydroxy-benzyl bromide and N-methyl-cyclohexylamine analogous to Example 1.

Example 66.

N- (4-tert.-butyl-cyclohexyl) -3,5-dibromo-2-hydroxy-benzylamine.

Mp: 188-191 ° C.

Prepared from 3,5-dibromo-2-hydroxy-benzyl bromide and 4-tert-butyl-cyclohexylamine analogous to Example 1.

Example 67

N-Ethyl-N-cyclohexyl-3,5-dibromo-4-hydroxy-benzylamine.

Mp, of hydrochloride; 180-181 ° C (dec.).

Prepared from 3,5-dibromo-4-hydroxy-benzyl bromide and N-ethyl-cyclohexylamine analogous to Example 1.

Example 68, N-Ethyl-2-bromo-N-cyelohexyl-5-hydroxy-benzylamine.

To 54 g of 2-bromo-5-hydroxy-benzyl bromide in 800 ml of carbon tetrachloride were added 51 g of N-ethyl-cyclohexylamine and refluxed for 1 hour. The reaction mixture was then shaken twice with water, the organic phase was dried over sodium sulfate and evaporated. The residue was purified column chromatographically over silica gel with acetic acid ethyl ester. The crude base was dissolved in acetic acid ethyl ester and acidified with absolute ethanolic hydrochloric acid, whereupon N-ethyl-2-bromo-N-cyclohexyl-5-hydroxy-benzylamine hydrochloride crystallized, mp, 183-188 ° C (dec).

20 149883

Example 69

2.4- Dibromo-5-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine.

To 3.5 g of N- (2,4-dibromo-5-hydroxy-benzylidene) -trans-4-amino-cyclohexanol in 70 ml of ethanol was added dropwise with a solution of 0.4 g of sodium borohydride in 5 ml. ml of water. After one hour of stirring, 10 ml of 2n sodium hydroxide solution and 30 ml of water were added and the solution was evaporated to ca. The half. Then saturated ammonium chloride solution was added to the solution, whereby 2,4-dibromo-5-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine precipitated. The precipitate was aspirated, suspended in acetone, heated and acidified with absolute ethanolic hydrochloric acid to dissolve the base and the hydrochloride immediately crystallized, m.p. 268-270 ° C (dec.).

Example 7Θ.

3-Bromt-5-chloro-N-cyclohexyl-4-hydroxy-N-methyl-benzylamine.

3.6 g of 3-Bromo-N-cyclohexyl-4-hydroxy-N-methyl-benzylamine hydrochloride was dissolved in 50 ml of 90% acetic acid and a solution of 0.75 g of chlorine in 15 ml of glacial acetic acid was added. ice-water cooling. After brief stirring, the solution was poured onto a mixture of ice and 10N sodium hydroxide solution, shaken three times with methylene chloride, and the organic phase was evaporated to dryness. The evaporation residue was purified by column chromatography over silica gel with acetic acid ethyl ester and the obtained 3-bromo-5-chloro-N-cyclohexyl-4-hydroxy-N-methyl-benzylaraine crystallized from ethanol ether, m.p. 136-138 ° C,

Example 71.

N-Ethyl-5-bromo-N-cyclohexyl-3-chloro-4-hydroxy-benzylamine.

2.3 g of N-Ethyl-3-chloro-N 1 -cyclohexyl-4-hydroxy-benzylamine were dissolved in 20 ml of 75% acetic acid and 1.6 g of bromine was added dropwise with stirring. The solution was diluted with water, adjusted alkaline with concentrated ammonia and shaken twice with chloroform. The organic phase was dried over sodium sulfate and evaporated. The residue was dissolved in absolute ethanol, acidified with absolute ethanolic hydrochloric acid, and N-ethyl-5-bromo-N-cyclohexyl-3-chloro-4-hydroxy-benzylamine hydrochloride was crystallized by the addition of ether, m.p. 165-168 ° C (dec.).

Example 72

N-Ethyl-3-chloro-N-cyclohexyl-2-hydroxy-benzylamine.

13 g of N-Ethyl-cyclohexylamine and 3 g of paraformaldehyde were dissolved in 100 ml of ethanol under heating, cooled again, and 13 g of 2-chloro-phenol was added, allowed to stand 1.5 hours at room temperature and finally boiled for an additional 3 hours. reflux. Then, the solution was evaporated and the residue was purified column chromatographically over silica gel with acetic acid ethyl ester. The crude base was dissolved in absolute ethanol, acidified with absolute ethanolic hydrochloric acid, and N-ethyl-3-chloro-N-cyclohexyl-2-hydroxy-benzylamine hydrochloride was crystallized by the addition of acetic acid ethyl ester, m.p. 177-178 ° C (dec.).

Example 73, 3.5-Dichloro-2-hydroxy-N - (trans-4-hydroxy-cyclohexyl) -benzylamine.

Mp, of hydrochloride: 216-222 ° C (dec).

Prepared by reduction of N- (3,5-dichloro-2-hydroxy-benzylidene) -trans-4-amino-cyclohexanol with sodium borohydride analogous to Example 69.

Example 74

3.5-Dichloro-4-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine.

Mp. of hydrochloride: 222-225 ° C (dec.).

Prepared by reduction of N- (3,5-dichloro-4-hydroxy-benzylidene) -trans-4-amino-cyclohexanol with sodium borohydride analogous to Example 69.

Example 75

3- Bromo-5-chloro-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine.

Mp, of hydrochloride: 214-221 ° C (dec).

Prepared by reduction of N- (3-bromo-5-chloro-2-hydroxy-benzylidene) -trans-4-amino-cyclohexanol with sodium borohydride analogous to Example 69.

Example 76

5- Bromo-3-chloro-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -behzylamine.

Mp. of hydrochloride: 193-197 ° C (dec).

Prepared by reduction of N- (5-bromo-3-chloro-2-hydroxy-benzylidene) -trans-4-amino-cyclohexanol with sodium borohydride analogous to Example 69.

Example 77

5- Broken. -3-chloro-4-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine.

Mp. of hydrochloride: 220-226 ° C (dec.).

Prepared by reduction of N- (5-bromo-3-chloro-4-hydroxy-benzylidene) -trans-4-amino-cyclohexanol with sodium borohydride analogous to Example 69.

Example 78

5- Bromo-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine.

Mp. of hydrochloride: 222-230 ° C (dec.).

Prepared by reduction of N- (5-bromo-2-hydroxy-benzylidene) -trans-4-amino-cyclohexanol with sodium borohydride analogous to Example 69.

Example 79

2-Bromo-5-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine.

Mp. of hydrobromide; 220-225 ° C (dec.).

22 149883

Prepared from 2-bromo-5-hydroxy-benzyl bromide and trans-4-amino-cyclohexanol according to Example 68.

Example 80.

3-Bromo-4-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine.

Mp, of hydrochloride: 225 = 227 ° C (dec.).

Prepared by reduction of N- (3-bromo-4-hydroxy-benzylidene) -trans-4-amino-cyclohexanol with sodium borohydride analogous to Example 69.

Example 81.

3-Bromo-2-hydroxy-N- (trans-4-hydroxy-cyclohexy) -benzylamine.

Mp. of hydrochloride: 194-196 ° C (dec.).

Prepared by reduction of N- (3-bromo-2-hydroxy-benzylidene) -trans-4-amino-cyclohexanol with sodium borohydride analogous to Example 69.

Example 82.

2,6-Dibromi-3-hydroxy-N- (trans-4-hydroxy-cyclohexy1) -benzylamine.

Mp. of hydrochloride: 269-271 ° C (dec.).

Prepared by reduction of N- (2,6-dibromo-3-hydroxy-benzylidene) -trans-4-amino-cyclohexanol analogous to Example 69.

Example 83

3.5-Dichloro-2-hydroxy-N- (cis-3-hydroxy-cyclohexyl) -benzylamine,

Mp. of hydrochloride: 209-214 ° C (dec.).

Prepared by reduction of N- (3,5-dichloro-2-hydroxy-benzylidene) -cis-3-amino-cyclohexanol analogous to Example 69.

Example 84

3.5-Dichloro-4-hydroxy-N- (cis-3-hydroxy-cyclohexyl) -benzylamine.

Mp. of hydrochloride: 219-224 ° C (dec.).

Prepared by reduction of N- (3,5-dichloro-4-hydroxy-benzylidene) -cis-3-amino-cyclohexanol analogous to Example 69.

Example 85.

3-Bromo-5-chloro-2-hydroxy-N- (cis-3-hydroxy-cyclohexyl) -benzylamine.

Mp. of hydrochloride: 197-20l ° C (dec).

Prepared by reduction of N- (3-bromo-5-chloro-2-hydroxy-benzylidene) -cis-3-amino-cyclohexanol analogous to Example 69.

Example 86

5-Bromo-3-chloro-2-hydroxy-N- (cis-3-hydroxy-cyclohexyl) -benzylamine.

Mp. of hydrochloride: 219-222 ° C (dec.).

Prepared by reduction of N- (5-bromo-3-chloro-2-hydroxy-benzylidene) -cis-3-amino-cyclohexanol analogous to Example 69.

23 149883

Example 87

5-Bromo-3-chloro-4-hydroxy-N- (cis-3-hydroxy-cyclohexyl) -benzylamine.

Mp. of hydrochloride: 216-218 ° C (dec ·).

Prepared by reduction of N- (5-bromo-3-chloro-4-hydroxy-benzylidene) -cis-3-amino-cyclohexanol analogous to Example 69,

Example 8.

5-Bromo-2-hydroxy-N- (cis-3-hydroxy-cyclohexyl) -benzylamine.

Mp. of hydrochloride: 148-151 ° C (dec.).

Prepared by reduction of N- (5-bromo-2-hydroxy-benzylidene) -cis-3-amino-cyclohexanol analogous to Example 69.

Example 89

2- Bromo-5-hydroxy-N- (cis-3-hydroxy-cyclohexyl) -benzylamine.

Mp. of hydrochloride: 245-250 ° C (dec.).

Prepared by reduction of N- (2-bromo-5-hydroxy-benzylidene) -cis-3-amino-cyclohexanol analogous to Example 69.

Example 90.

2,4-Dibromo-5-hydroxy-N- (cis-3-hydroxy-cyclohexyl) -benzylamine.

. Mp. of hydrochloride: 278-280 ° C (dec.).

Prepared by reduction of N- (2,4-dibromo-5-hydroxy-benzylidene) -cis-3-amino-cyclohexanol analogous to Example 69.

Example 91, 3- Bromo-4-hydroxy-N- (cis-3-hydroxy-cyclohexyl) -benzylamine.

Mp. of hydrochloride: 214-220 ° C (dec.).

Prepared by bromination of 4-hydroxy-N- (cis-3-hydroxy-cyclohexyl) -benzylamine analogous to Example 71,

Example 92, 3-Bromo-2-hydroxy-N- (cis-3-hydroxy-cyclohexyl) -benzylamine.

Mp. of hydrochloride: 163-167 ° C (dec.).

Prepared by reduction of N- (3-bromo-2-hydroxy-benzylidene) -cis-3-amino-cyclohexanol analogous to Example 69.

Example 93

· 2,6-dibromo-3-hydroxy-N- (cis-hydroxy-cyclohexyl) -benzylamine.

Mp. of hydrochloride: 255-259 ° C (dec.).

Prepared by reduction of N- (2,6-dibromo-3-hydroxy-benzylidene) -cis-3-amino-cyclohexanol analogous to Example 69, 24 149883

Example 94

N-Ethyl-2-bromo (-4-chloro-N-cyclohexyl-5-hydroxy-benzylamine).

Mp. of hydrochloride: 132.5-137 ° C (dec.).

Prepared by bromination of N-ethyl-4-chloro-N-cyclohexyl-3-hydroxy-benzylamine by Example 71.

Example 95

N-Ethyl-4-chloro-N-cyclohexyl-3-hydroxy-benzylamine.

Mp, of hydrochloride: 128-132 ° C (dec.).

Prepared from 4-chloro-3-hydroxy-benzyl bromide and N-ethyl-cyclohexylamine analogous to Example 68.

Example 96.

N-Ethyl-2-chloro-N-cyclohexyl-5-hydroxy-benzylamine.

Mp. of hydrochloride: 200-111 ° C.

Prepared from 2-chloro-5-hydroxy-benzyl bromide and N-ethyl-cyclohexylamine analogous to Example 68.

Example 97

N-Ethyl-N-cyclohexyl-2,4-dichloro-5-hydroxy-benzylamine.

Mp. of hydrochloride: 179-186 ° G (dec.).

Prepared by chlorination of N-ethyl-N-cyclohexyl-3-hydroxy-benzylamine analogous to Example 70,

Example 98.

N-Ethyl-3-bromo-N-cyclohexyl-4-hydroxy-benzylamine.

Mp. of hydrochloride: 185-190 ° C (dec.).

Prepared from 2-bromo-phenol, paraformaldehyde and N-ethyl-cyclohexylamine analogous to Example 72,

Example 99

N-Ethyl-4-chloro-N-cyclohexyl-2-hydroxy-benzylamine.

Mp. of hydrochloride: 144-146 ° C.

Prepared from 3-chloro-phenol, paraformaldehyde and N-ethyl-cyclohexylamine analogous to Example 72,

Example 100, N-Ethyl-3-bromo-N-cyclohexyl-2-hydroxy-benzylamine.

Mp. of hydrochloride: 171-173 ° C.

Prepared from 2-bromo-phenol, paraformaldehyde and N-ethyl-cyclohexylamine analogous to Example 72.

149833 25

Example ιοί.

N-Ethyl-4-bromo-N-cyclohexyl-2-hydroxy-benzylamine.

Mp. of hydrochloride: 175-177 ° C.

Prepared from 3-bromo-phenol, paraformaldehyde and N-ethyl-cyclohexylamine analogous to Example 72.

Example 102.

N-Ethyl-3-chloro-N-cyclohexyl-4-hydroxy-benzylamine.

Mp. of hydrochloride: 181-183 ° C.

Prepared by chlorination of N-ethyl-N-cyclohexyl-4-hydroxy-benzylamine analogous to Example 70.

Example 103.

N-Ethyl-2-chloro-N-cyclohexyl-4-hydroxy-benzylamine.

Mp. of hydrochloride: 165-166.5 ° G.

Prepared from 3-chloro-phenol, paraformaldehyde and N-ethyl-cyclohexylamine analogous to Example 72.

Example 104.

N-Ethyl-2-bromo-4-chloro-N-cyclohexyl-3-hydroxy-benzylamine.

Mp. of hydrochloride: 130-137 ° C (dec.).

Prepared by bromination of N-ethyl-4-chloro-N-cyclohexyl-3-hydroxy-benzylamine by Example 71.

Example 105

N-Ethyl-N-cyclohexyl-2,6-dibromo-3-hydroxy-benzylamine.

Mp. 123-126 ° C.

Prepared by bromination of N-ethyl-N-cyclohexyl-3-hydroxy-benzylamine by analogy with ex. 71st

Example 106.

N-Ethyl-N-cyclohexyl-2,4-dichloro-3-hydroxy-benzylamine.

Mp. of hydrochloride: 127-132 ° C (dec.).

Prepared by chlorination of N-ethyl-N-cyclohexyl-3-hydroxy-benzylamine analogous to Example 70.

Example 107.

N-Ethyl-N-cyclohexyl-3,5-dibromo-4-hydroxy-benzylamine.

Mp. of hydrochloride: 180-181 ° C (dec.).

Prepared from N-ethyl-N-cyclohexyl-4-hydroxy-benzylamine and bromine analogous to Example 71 · 26 149883

Example 108.

N-Ethyl-5-chloro-N-cyclohexyl-2-thydroxy-benzylamine.

3.5 g of N-ethyl-N-cyclohexyl-2-hydroxy-benzylamine hydrochloride was dissolved in 50 ml of glacial acetic acid. Under vigorous stirring, a solution of 0.85 g of chlorine was poured into 10 ml of glacial acetic acid at room temperature. Stir another 1 minute and then pour on ice, after which ION sodium hydroxide solution is added until slightly alkaline reaction and extracted twice with 100 ml of chloroform. The combined chloroform solutions were washed with water, dried over sodium sulfate and evaporated in vacuo to dryness. The oily residue was taken up in slightly absolute ethanol. After adding ethereal hydrochloric acid until a clearly acidic reaction, colorless crystals are separated. The hydrochloride was aspirated and recrystallized twice by isopropanol, m.p. 169-171 C.

Example 109.

N-Ethyl-N-cyclohexyl-3,5-dichloro-2-hydroxy-benzylamine.

3.1 g of N-Ethyl-N-cyclohexyl-2-hydroxy-benzylamine was dissolved in 100 ml of absolute tetrahydrofuran and 4 ml of pyridine. The solution was cooled to -5 ° C. At this temperature, 7.2 g of phenyliodine dichloride was introduced, with vigorous stirring, and further stirred for 2 hours at -5 ° to 0 ° G. Then it was evaporated in vacuo to dryness and the residue was extracted between water and chloroform. The combined chloroform phases were dried over sodium sulfate and evaporated in vacuo to dryness. The oily residue was dissolved in slightly absolute ethanol. After addition of ethereal hydrochloric acid until a clearly acidic reaction, colorless crystals which were extracted and recrystallized from isopropanol were separated, m.p. of hydrochloride 185-188 ° C (dec.).

Example 110.

N-Ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine.

2.7 g of N-Ethyl-N-cyclohexyl-2-hydroxy-benzylamine hydrochloride was dissolved in 50 ml of glacial acetic acid. With vigorous stirring, a solution of 1 ml of bromine in 10 ml of glacial acetic acid was slowly added dropwise at room temperature. After completion of the addition, ice was poured, made slightly alkaline with 10N sodium hydroxide solution and extracted three times with 100 ml of chloroform each time. The combined chloroform solutions were washed with water, dried over sodium sulfate and evaporated in vacuo to dryness.

The oily residue was taken up in a little absolute ethanol. After addition of ethereal hydrochloric acid until a clearly acidic reaction, colorless crystals which were extracted and recrystallized from absolute ethanol were separated, m.p. of hydrochloride: 193-194 ° C (dec.).

149883 27

Example 111.

N-ethyl-N-cyclohexy1-3,5-dibrora-.2-hydroxy-benzylamine.

3 g of N-Ethyl-N-cyclohexyl-2-hydroxy-benzylamine were dissolved in 50 ml of methylene chloride. The solution was cooled to -5 ° C. At this temperature, a solution of 10.6 g of tribromophenol bromine in 200 ml of methylene chloride was slowly added dropwise with stirring and further stirred for 2 hours and evaporated in vacuo to dryness. The evaporation residue was purified column chromatographically over silica gel with chloroform. After fractionation, the solvent was evaporated in vacuo. The residue was dissolved in slightly absolute ethanol. After addition of ethereal hydrochloric acid until a clearly acidic reaction, colorless crystals which were extracted and recrystallized from absolute ethanol were separated, m.p. of hydrochloride: 193-194 ° C (dec.).

Example 112.

N-Ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine.

0.15 g of 2-Acetoxy-N-ethyl-N-cyclohexyl-3,5-dibromo benzylamine was boiled for 1 hour with 10 ml of 4N ethanolic hydrochloric acid. It was cooled, poured on ice, made alkaline with concentrated ammonia, shaken with chloroform, and the chloroform extract dried over sodium sulfate and evaporated in vacuo. The residue was dissolved in ethanol and crystallized by the addition of ethanolic hydrochloric acid, m.p. 193-194 ° C (dec.).

Example 113, 3.5-Dibromo-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine.

4.7 g of N-Benzyl-3,5-dibromo-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine was dissolved in 350 ml of methanol and 6 ml of 2N hydrochloric acid and hydrogenated in the presence of 350 mg of palladium. (10%) on coal. Hydrogenation was discontinued after uptake of 1 mole of hydrogen. The catalyst was filtered off and the filtrate was evaporated in vacuo. The evaporation residue was recrystallized from ethanol to give 3.5-dibromo-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine hydrochloride, m.p. 212-218 ° C (dec.).

Example 114.

N-Ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine.

0.2 g of N-Ethyl-N-cyclohexyl-3,5-dibromo-2-methoxy-benzylamine hydrochloride was boiled 3 hours with 3 ml of a 40% * solution of hydrogen bromide in glacial acetic acid.

It was cooled, poured on ice, adjusted alkaline with ammonia, extracted with chloroform, and the chloroform extract dried over sodium sulfate and evaporated in vacuo. The residue was dissolved in ethanol and the hydrochloride was brought to crystallization by the addition of ethanolic hydrochloric acid, m.p. 193-194 ° C (dec.).

Example 115.

N- (4-tert-Butyl-cyclohexyl) -3,5-dibromo-2-hydroxy-benzylamine.

2.8 g of 3,5-Dibromo-2-hydroxy-benzylamine and 1.6 g of 4-tert-butyl-cyclobexanone were refluxed for 4 hours in 250 ml of toluene. After cooling, 250 ml of methanol was diluted and 2.8 g of sodium borohydride were added portionwise with stirring. After 1 hour, evaporate in vacuo to dryness. The residue was shaken with 2N sodium hydroxide solution. The product was aspirated, washed with water and recrystallized from methanol. The tsomer mixture could be partitioned by column chromatography over silica gel with chloroform / acetic acid ethyl ester (2: 1).

Mp. of cis form: 159-160 ° G

Mp. of trans form: 186-189 ° C (dec.).

Example 116.

N-Ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine.

0.4 g of N-Ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzamide was boiled 5 hours with 0.12 g of sodium borohydride in 20 ml of dry pyridine. To decompose excess sodium borohydride, some acetone was added and pyridine was distilled off in vacuo and the residue was partitioned between water and chloroform and the chloroform phase was dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed over silica gel with acetic acid ethyl ester for purification. An oil which was dissolved in ethanol and obtained by ethanolic hydrochloric acid was transferred into N-ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine hydrochloride, m.p. 193-194 ° C (dec.).

Example 117

N-Ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine.

1 g of N-Ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzamide was boiled for one hour with 0.17 g of lithium aluminum hydride in 80 ml of absolute tetrahydrofuran. Cooled, gently added water and the precipitate was separated, boiled with tetrahydrofuran, the tetrahydrofuran solutions were combined and evaporated in vacuo, and the residue was partitioned between water and chloroform, and the chloroform phase was dried over sodium sulfate and evaporated in vacuo. An oil which was dissolved in ethanol and transferred by ethanolic hydrochloric acid into N-ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine hydrochloride, m.p. 193-194 ° G (dec.).

149883 29

Example 118. N-Ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine.

2.25 g of 2-Acetoxy-N-ethyl-N-cyclohexyl-3,5-dibron. -benzamide was dissolved in 30 ml of absolute tetrahydrofuran and, with stirring, dropped to a suspension of 0.8 g of lithium aluminum hydride in 120 ml of absolute tetrahydrofuran. The mixture was boiled 75 minutes, then cooled to ca. 10 ° C and decomposed with water. The resulting precipitate was separated and washed once with tetrahydrofuran. The combined aqueous tetrahydrofuran solutions were evaporated to remove the organic solvent. The aqueous solution thus obtained was extracted three times with chloroform, the combined chloroform extracts were dried over sodium sulfate and evaporated. N-ethyl-N-cyclohexyl-3,5-dibron-2-hydroxy-benzylamine was obtained as an oil which was dissolved in ethanol and transferred to the hydrochloride by ethanolic hydrochloric acid, m.p. 193-194 ° C (dec.).

Example H9.

N-Ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine.

1.2 g of 2-Acetoxy-N-acetyl-N-cyclohexyl-3,5-dibromo-benzylamine were boiled for approx. 1 hour with 0.5 g of lithium aluminum hydride in 100 ml of absolute tetrahydrofuran. Excess lithium aluminum hydride was decomposed by careful addition of water. The resulting precipitate was aspirated and washed with tetrahydrofuran. The combined aqueous tetrahydrofuran solutions were evaporated and the remaining aqueous evaporation residue was extracted with chloroform. The chloroform solution was dried over sodium sulfate and evaporated. The oil thus obtained was dissolved in ethanol and after the addition of ethanolic hydrochloric acid, N-ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine hydrochloride, m.p. 193-194 ° C (dec.).

Example 120.

3,5-Dibromo-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine.

1.0 g of 6,8-Dibromo -3- (trans-4-hydroxy-cyclohexyl) -3,4-dihydro-2H-1,3-benzoxazin-2-one was refluxed for one hour in a mixture of 30 g. tert.-butanol and 25 ml 2N sodium hydroxide solution. Cooled, first adding 30 ml of 2N hydrochloric acid and then excess sodium bicarbonate solution. The alcohol was distilled off in vacuo and the aqueous phase was extracted twice with a mixture of tetrahydrofuran and ether (1: 1). The organic extracts were dried over magnesium sulfate and evaporated to low volume in vacuo. In the hot state, petroleum ether was added until incipient cloudiness and the title compound was allowed to crystallize in the cold, m.p. 191-193 ° C. The hydrochloride had m.p. 212-218 ° C (dec.).

30 149883

Example 121.

N-Ethyl-5-bromo-N-cyclohexyl-2-hydroxy-benzylamine.

Mp. of hydrochloride: 175-178 ° G.

Prepared from N-ethyl-N-cyclohexyl-2-hydroxy-benzylarain hydrochloride and bromine analogous to Example 110.

Example 122.

N-Ethyl 3-bromo. -5-chloro-N-cyclohexyl-2-hydroxy-benzylamine.

Mp. of hydrochloride: 194-197 ° C (dec.).

Prepared from N-ethyl-5-chloro-N-cyclohexyl-2-hydroxy-benzylamine hydrochloride and bromine analogous to Example 110.

Example 123.

N-Ethyl-N-cyclohexyl-3,5-dichloro-4-hydroxy-benzylamine.

Mp. of hydrochloride: 190-19l ° C (dec.).

Prepared from N-ethyl-N-cyclohexyl-4-hydroxy-benzylamine and chlorine analogous to Example 10S.

Example 124, 3.5-Dibromo-4-hydroxy-N- (cis-3-hydroxy-cyclohexyl) -benzylamine.

Mp. of hydrochloride: 216-218 ° C (dec.).

Prepared from 4-hydroxy-N- (cis-3-hydroxy-cyclohexyl) -benzylamine hydrochloride and bromine analogous to Example 110.

Example 125.

3.5-Dibromo-2-hydroxy- (trans-4-hydroxy-cyclohexyl) -benzylamine.

Mp. of hydrochloride: 212-218 ° C (dec.).

Prepared from 2-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine hydrochloride and bromine analogous to Example 110.

Example 126.

3.5-Dibromo-4-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine.

Mp. of hydrochloride: 215-215.5 ° G (dec.).

Prepared from 4-hydroxy-N- (trans-3-hydroxy-cyclohexyl) -benzylamine hydrochloride and bromine analogously to Example 10.

Example 127.

3.5-Dibromo-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine.

Mp. of hydrochloride: 212-218 ° C (dec.).

31 149883

Prepared by cleavage of 3,5-dibromo · -N- (trans-4-hydroxy-cyclohexyl) -2-methoxy-benzylamine hydrochloride with 40 7. * hydrogen bromide solution in glacial acetic acid analogous to Example 114.

Example 128 »3.5-Dibromo-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine.

Mp. of hydrochloride: 212-218 ° C (dec.).

Prepared from 3,5-dibromo-2-hydroxy-benzylamine-4-hydroxy-cyclohexanone and sodium borohydride analogous to Example 115.

Example 129, 3.5-Dibromo-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine.

Mp. of hydrochloride: 212-218 ° C (dec.).

Prepared by reduction of 3,5-dibromo · -2-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzamide with lithium aluminum hydride analogous to Example 117.

Example 130.

3.5-Dibromo-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine.

Mp. of hydrochloride: 212-218 ° G (dec.).

Prepared by reduction of 2-acetoxy-3,5-dibromo-N- (trans-4-hydroxy-cyclohexyl) -benzamide with lithium aluminum hydride analogous to Example 118.

Example 131.

3.5-Dibromo-4-hydroxy-N- (cis-3-hydroxy-cyclohexyl) -benzylamine.

Mp. of hydrochloride: 216-218 ° G (dec.).

Prepared by de-benzylation of N-benzyl-3,5-dibromo · -4-hydroxy-N- (cis-3-hydroxy-cyclohexyl) -benzylamine hydrochloride with hydrogen in the presence of palladium on activated carbon analogous to Example 113.

Example 132, 3.5-Dibromo-4-hydroxy-N- (cis-3-hydroxy-cyclohexyl) -benzylamine.

Mp. of hydrochloride: 216-218 ° C (dec.).

Prepared by cleavage of 3,5-dibromo-N- (cis-3-hydroxy-cyclohexyl) ~ 4-methoxy-benzylamine hydrochloride with 40 7.1s hydrogen bromide solution in glacial acetic acid analogous to Example 114,

Example 133.

3.5-Dibromo-4-hydroxy-N- (cis-3-hydroxy-cyclohexyl) -benzylamine.

Mp. of hydrochloride: 216-218 ° C (dec.).

32 149883

Prepared from 3,5-dibromo-4-hydroxy-benzylamine, 3-hydroxy-cyclohexanone and sodium borohydride analogous to Example 115.

Example 134.

3.5-Dibromo-4-hydroxy-N- (cis-3-hydroxy-cyclohexyl) -benzylamine.

Mp. of hydrochloride: 216-218 ° C (dec.).

Prepared by reduction of 3,5-dibromo-4-hydroxy-N- (cis-3-hydroxy-cyclohexyl) -benzamide with lithium aluminum hydride analogous to Example 117.

Example 135.

3.5-Dibromo-4-hydroxy-N- (cis-3-hydroxy-cyclohexyl) -benzylamine.

Mp. of hydrochloride 216-218 ° C (dec.).

Prepared by reduction of 4-acetoxy-3,5-dibromo -N- (cis-3-hydroxy-cyclohexyl) -benzamide with lithium aluminum hydride analogous to Example 118.

Example 136.

3,5-Dibromo-4-hydroxy-N- (trans-3-hydroxy-cyclohexyl) -benzylamine.

Mp. of hydrochloride: 215-215.5 ° C (dec.).

Prepared by de-benzylation of N-benzyl-3,5-dibromo-4-hydroxy-N- (trans-3-hydroxy-cyclohexyl) -benzylamine hydrochloride with hydrogen in the presence of palladium on activated carbon analogous to Example 113.

Example 137

3.5-Dibromi-4-hydroxy-N- (trans-3-hydroxy-cyclohexyl) -benzylamine.

Mp. of hydrochloride: 215-215.5 ° C (dec.).

Preparation by cleavage of 3,5-dibromo -N- (trans-3-hydroxy-cyclohexyl) -. 4-methoxy-benzylamine hydrochloride with 40% hydrogen bromide solution in glacial acetic acid analogous to Example 114.

Example 188.

3.5-Dibromo-4-hydroxy-N- (trans-3-hydroxy-cyclohexyl) -benzylamine.

Mp. of hydrochloride: 215-215.5 ° C (dec.).

Prepared from 3,5-dibromo-4-hydroxy-benzylamine, 3-hydroxy-cyclohexanone and sodium borohydride analogous to Example 115.

Example 139.

3.5-Dibromo 4-hydroxy-N- (trans-3-hydroxy-cyclohexyl) -benzylamine.

Mp. of hydrochloride: 215-215.5 ° C (dec.).

Prepared by reduction of 3,5-dibromo-4-hydroxy-N- (trans-4-hydroxy-U98S3 33 cyclohexyl) -benzamide with lithium aluminum hydride analogous to Example IIt.

Example 140.

3.5- Dibromo. -4-hydroxy-N- (trans -3-hydroxy-cyclohexyl) -benzylamine.

Mp. of hydrochloride: 215-215.5 ° C (dec.).

Preparation of reduction of 4-acetoxy-3,5-dibromo-N- (trans-3-hydroxy-cyclohexyl) -benzamide with lithium aluminum hydride analogous to Example 118.

Example 141.

3.5-Dibromo-4-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine.

Mp. of hydrochloride: 220-225 ° C (dec.).

Prepared from 4-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine hydrochloride and bromine analogous to Example 110.

Example 142.

3.5-Dibromo-4-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -N-methyl-benzylamine.

Mp, of hydrochloride: 160-162 ° C (dec.).

Prepared from 4-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -N-methyl-benzylamine hydrochloride and bromine analogous to Example 110.

Example 143.

N-Ethyl-5-bromo-3-chloro-N-cyclohexyl-2-hydroxy-benzylamine.

Mp. of hydrochloride: 188-191 ° C (dec.).

Prepared from N-ethyl-5-bromo-N-cyclohexyl-2-hydroxy-benzylamine hydrochloride and chlorine analogously to Example 108.

Example 144.

N-Ethyl-3,5-dichloro-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine.

Mp. of hydrochloride: 147-152 ° C.

Prepared from N-ethyl-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine and iphenyliodide dichloride analogous to Example 109.

Example 145.

N- (4-tert.-Butyl-cyclohexyl) -3,5-dibromo-4-hydroxy-benzylamine.

Mp. of hydrochloride: 158-159 ° C (dec.).

Prepared from N- (4-tert-butyl-cyclohexyl) -4-hydroxy-benzylamine hydrochloride and bromine analogously to Example 110.

149883 34

Example 146, N-Ethyl-5-bromo-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine.

Mp. of hydrochloride: 190-193 ° C (dec.).

Prepared from N-ethyl-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine hydrochloride and bromine analogous to Example 110.

Example 147.

5-Bromo-N-cyclohexyl-2-hydroxy-N-isopropylbenzylamine,

Mp 90-93 ° C.

Prepared from N-cyclohexyl-2-hydroxy-4-isopropylbenzylamine and bromine analogous to Example 10.

Example 148.

N-Cyclopentyl-3,5-dibromo-4-hydroxy-N-methyl-benzylamine.

Mp. of hydrochloride: 185-188 ° C (dec.).

Prepared from N-cyclopentyl-4-hydroxy-N-methyl-benzylamine hydrochloride and bromine analogously to Example no.

Example 149, N-Ethyl-N-cyclopentyl-3,5-dibromo-2-hydroxy-benzylamine.

Mp. of hydrochloride 124-128 ° C (dec.).

Prepared from N-ethyl-N-cyclopentyl-2-hydroxy-benzylamine hydrochloride and bromine analogous to Example 110.

Example 150.

N-Cycloheptyl-3,5-dibromo-4-hydroxy-N-propyl-benzylamine.

Mp. of hydrochloride: 176-177 ° C (dec.).

Prepared from N-cycloheptyl-4-hydroxy-N-propyl-benzylamine hydrochloride and bromine analogous to Example 110,

Example 151.

N-Cycloheptyl-3,5-dibromo-2-hydroxy-N-isopropyl-benzylamine.

Mp. of hydrochloride: 156-159 ° C (dec.).

Prepared from N-cycloheptyl-2-hydroxy-N-isopropylbenzylamine hydrochloride and bromine analogous to Example 110.

Example 152.

N-Ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine.

6 g of acetic acid (3,5-dibromo-2-hydroxy-benzyl) ester and 7 g of N-ethyl-N-cyclo-hexylamine were heated at 140 ° C for 1 hour. The reaction product was stirred with 2N hydrochloric acid and ether to crystallize N-ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine hydrochloride. It was extracted and washed with water and acetone, m.p. 193-194 ° C (dec.).

Example 153.

N-Ethyl-N-cyclohexyl-3,5-dibromo <-2-hydroxybenzylamine.

7 g of 3,5-Dibromo-2-hydroxy-benzyl alcohol and 2.8 g of sodium hydride dispersion (50% * s in oil) were refluxed for 6 hours in 150 ml of absolute tetrahydrofuran. Then, it was cooled to -60 to -70 ° C and with stirring 9.5 g of p-toluenesulfonic acid chloride was added dropwise in 100 ml of absolute tetrahydrofuran. The reaction mixture was allowed to warm to -30 ° C and again cooled to -70 ° C. Then 12.7 g of N-ethyl-cyclohexylamine was added dropwise into 100 ml of ether. Stirring was continued and the reaction mixture was allowed to slowly warm to room temperature and was shaken twice with 200 ml of water. The combined aqueous phases were shaken once with chloroform. The chloroform phase was combined with the ether-tetrahydrofuran phase and evaporated to dryness. For purification, chromatography was coated over a silica gel column with chloroform-acetic acid ethyl ester (9: 1). The fractions in question were pooled and evaporated to dryness. The residue was stirred with 2N hydrochloric acid and ether to crystallize N-ethyl-N-cyclohexyl-3,5-dibromo · 2-hydroxy-benzylamine hydrochloride. It was extracted and washed with water and acetone, m.p. 193-194 ° C (dec.).

Example 154.

N-Ethyl "N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine.

1.3 g of 2-Benzoyloxy-3,5-dibromo-benzyl alcohol and 1.3 g of N-ethyl-cyclohexylamine were heated at 140 ° C for 1 hour. The reaction product was stirred with 2N hydrochloric acid and ether to crystallize N-ethyl-N-cyclohexyl-3,5-dibromo · -2-hydroxy-benzylamine hydrochloride. It was extracted and washed with water and acetone, m.p. 193-194 ° C (dec.).

Example 155, N-Ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine.

2.8 g of 3,5-Dibromo-2-hydroxy-benzyl alcohol and 3.8 g of N-ethyl-cyclohexylamine were heated for 1 hour at 140 ° C. The reaction product was stirred with 2N hydrochloric acid and ether to crystallize N-ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine hydrochloride. It was extracted and washed with water and acetone, m.p. 193-194 ° C (dec.).

149883 36

Example 156, N-Ethyl-N-cyclohexyl-3,5-dibromo · -2-hydroxy-benzylamine.

2.8 g of 3,5-dibromo-2-bydroxy-benzyl alcohol, 3.8 g of N-ethyl-cyclohexylamine and 1.2 ml of 48% rs of hydrogen bromic acid were heated at 140 ° C for 1 hour. The reaction mixture was shaken with chloroform and water, the chloroform phase was separated and evaporated to dryness. The residue was stirred with 2N hydrochloric acid and ether to crystallize N-ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine hydrochloride. It was extracted and washed with water and acetone, m.p. 193-194 ° C (dec.).

Example 157.

N-Ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine.

5.6 g of 3,5-Dibromo-2-hydroxy-benzyl alcohol, 8.8 g of butyric acid and 12.7 g of N-ethyl-N-cyclohexylamine were heated for 1 hour at 140 ° C and then cooled, dissolved in 200 ml of ether. and shaken four times with water. The organic phase was dried over sodium sulfate and evaporated. The residue was dissolved in some absolute ethanol, and the solution was acidified with ethanolic hydrochloric acid and the crystallization of N-ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine hydrochloride was completed by the addition of ether, m.p. 193-194 ° C (dec.).

Example 158.

N-Ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine.

5.6 g of 3.5 Dibromo-2-hydroxy-benzyl alcohol, 12.7 g of N-ethyl-N-cyclohexylamine and 0.4 g of magnesium oxide were heated for 8 hours at 120 ° G, then ether and water were added, acidified with 2N hydrochloric acid and again adjusted alkaline with concentrated ammonia. The mixture was shaken, the organic phase was separated, washed four more times with water, dried with sodium sulfate and evaporated. The residue was dissolved in absolute ethanol, acidified with ethanolic hydrochloric acid, and by the addition of ether, N-ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzyl-amine hydrochloride was crystallized, m.p. 193-194 ° C (dec.).

Example 159.

3,5-Dibromo-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine.

0.9 g of 6,8-Dibromo-2-methyl-1,3-benzdioxane and 1.0 g of trans-4-amino-cyclohexanol were heated for 17 hours at 140 C. Then the reaction product was boiled with 100 ml of diluted hydrochloric acid. The solution was treated with activated charcoal and evaporated in vacuo to ca. 5 ml. Thereby crystallized 3,5-dibromo-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine hydrochloride. It was suctioned off, washed with water and acetone and dried at 80 ° G in vacuo, m.p. 212-218 ° C (dec.).

149883 37

Example 160.

N-Ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine.

2.9 g of 3,5-Dibromo-eC-methoxy-o-cresol and 3.8 g of N-ethyl-cyclohexylamine were heated for 1 hour at 140 ° C. The reaction product was stirred with 2N hydrochloric acid and ether to crystallize N-ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine hydrochloride. It was extracted and washed with water and acetone, m.p. 193-194 ° C (dec.).

Example 161.

N-Cyclohexyl-3,5-dibromo-2-hydroxy-N-methyl-benzylamine.

1.4 g of 3,5-Dibromo-2-hydroxy-benzyl alcohol and 11.5 g of N, N *, N ,, - tricyclohexyl-N, N *, NN-trimethyl-phosphoric acid triamide were heated for 10 hours at 150 ° C and the reaction product was chromatographed over a silica gel column with chloroform acetic acid ethyl ester (1: 1). The fractions in question were collected and evaporated and the residue was dissolved in petroleum ether, acidified with ethanolic hydrochloric acid, shaken, and the solution was decanted. The oily residue was dissolved in slightly absolute ethanol and ether was added, whereupon N-cyclohexyl-3,5-dibromo-2-hydroxy-N-methyl-benzylamine hydrochloride crystallized, m.p. 189-191 C.

Example 162, 3.5-Dibromo-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine.

2 g of 6,8-Dibromo · -3,5-dihydro-3- (trans-4-hydroxy-cyclohexyl) -2H-1,3-benzoxazine was dissolved at room temperature in 20 ml of methanol and 5 ml of water was added. . After 15 minutes, an additional 10 ml of methanol was added and the crystalline precipitate formed was extracted and washed with methanol. The base was dissolved in absolute ethanol and acidified with ethanolic hydrochloric acid to crystallize 3,5-dibromo-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine hydrochloride, m.p. 212-218 ° C (dec.).

Example 163.

3.5-Dibromo-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine,

Mp. of hydrochloride: 212-218 ° C (dec.).

Prepared from acetic acid (3,5> -dibromo-2-hydroxy-benzyl) ester and trans-4-amino-cyclohexanol analogous to Example 152,

Example 164.

N-Ethyl-N-cyclohexyl-3,5-dibromo-4-hydroxy-benzylamine.

Mp. of hydrochloride: 180-181 ° C (dec.).

Prepared from acetic acid (3,5-dibromo-4-hydroxy-benzyl) ester and N-ethyl-N-eyclohexylamine analogous to Example 152.

Example 165.

3,5-Dibromo-4-hydroxy-N- (cis-3-hydroxy-cyclohexyl) -benzylamine.

Mp. of hydrochloride: 215-215.5 ° C (dec.).

Prepared from acetic acid (3,5-dibromo-4-hydroxy-benzyl) ester and cis-3-amino-cyclohexanol analogous to Example 152.

Example 166.

N-Ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine.

Mp. of hydrochloride: 193-194 ° C (dec.).

Prepared from benzoic acid (3,5-dibromo-2-hydroxy-benzyl) ester and N-ethyl-N-cyclohexylamine analogous to Example 152.

Example 167.

3.5-Dibromo-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine.

Mp. of hydrochloride: 212-218 ° G (dec.).

Prepared from 2-benzoyloxy-3,5-dibromo-benzyl alcohol and trans-4-amino-cyclohexanol analogous to Example 154.

Example 168.

N-Ethyl-N-cyclohexyl-3β-dibromo-4-hydroxy-benzylamine.

Mp. of hydrochloride: 180-181 ° G (dec.).

Prepared from 4-acetoxy-3,5-dibromo-benzyl alcohol and N-ethyl-N-cyclohexylamine analogous to Example 154.

Example 169.

3.5-Dibromo-4-hydroxy-N- (cis-3-hydroxy-cyclohexyl) -benzylamine.

Mp. of hydrochloride: 215-215.5 ° G (dec.).

Prepared from 4-acetoxy-3,5-dibromo-benzyl alcohol and cis-3-amino-cyclohexanol analogous to Example 154.

Example 170.

3.5- Dibromo. -2-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine.

Mp. of hydrochloride: 212-218 ° C (dec.).

Prepared from 3,5-dibromo-2-hydroxy-benzyl alcohol and trans-4-amino-cyclohexanol analogous to Example 155

Example 171.

3.5-Dibromo-4-hydroxy-N- (cis-3-hydroxy-cyclohexyl) -benzylamine.

39 149883

Mp. of hydrochloride: 215-215.5 ° C (dec.).

Prepared from 3,5-dibromo-4-hydroxy-benzyl alcohol and cis-3-amino-cyclohexanol analogous to Example 155,

Example 172.

N-Ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine.

Mp. of hydrochloride: 193-194 ° C (dec.).

Prepared from 3,5-dibromo-2-hydroxy-benzyl alcohol, N-ethyl-N-cyclohexylamine and p-toluenesulfonic acid analogous to Example 156.

Example 173, N-Ethyl-N-cyclohexyl-3,5-dibromo-4-hydroxy-benzylamine.

Mp. of hydrochloride: 180-181 ° C (dec.).

Prepared from 3,5-dibromo-4-hydroxy-benzyl alcohol, N-ethyl-N-cyclohexylamine and butyric acid analogous to Example 157.

Example 174, 3.5-Dibromo-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine.

Mp. of hydrochloride: 212-218 ° C (dec.).

Prepared from 3,5-dibromo-2-hydroxy-benzyl alcohol, butyric acid and trans-4-amino-cyclohexanol analogous to Example 157.

Example 175.

3.5-Dibromo-4-hydroxy-N- (cis-3-hydroxy-cyclohexyl) -benzylamine.

Mp. of hydrochloride: 215-215.5 ° C (dec.).

Prepared from 3,5-dibromo-4-hydroxy-benzyl alcohol, cis-3-amino-cyclohexanol and butyric acid analogous to Example 157.

Example 176.

3.5-Dibromo-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine.

Mp. of hydrochloride: 212-218 ° C (dec.).

Prepared from 3,5-dibromo-2-hydroxy-benzyl alcohol, trans-4-amino-cyclohexanol and magnesium oxide analogous to Example 158.

Example 177.

N-Ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine.

Mp. of hydrochloride: 193-194 ° C (dec.).

Prepared from 3,5 dibromo-2-hydroxybenzyl alcohol, N-ethyl-N-cyclohexylamine and potassium hydroxide analogous to Example 158.

149883 40

Example 178.

3.5-Dibromo-4-hydroxy-N- (cis-3-hydroxy-cyclohexyl) -benzylamine.

Mp. of hydrochloride: 215-215.5 ° G (dec.).

Prepared from 3,5-dibromo-4-hydroxy-benzyl alcohol, cis-3-amino-cyclobexanol and magnesium oxide analogous to Example 158,

Example 179, N-Ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine.

Mp. of hydrochloride! 193-194 ° C (dec.).

Prepared from 6.8 dibromo-2-methyl-1,3-benzdioxane and N-ethyl-N-cyclobexylamine analogous to Example 159.

Example 180.

3.5-Dibromo-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine.

Mp. of hydrochloride! 212-218 ° C (dec.).

Prepared from 3,5-dibromo-oC-methoxy-o-cresol and trans-4-amino-cyclohexanol analogous to Example 160.

Example 181.

N-Ethyl-N-cyclohexyl-3,5-dibromo-4-hydroxy-benzylamine.

Mp. of hydrochloride! 180-181 ° C (dec.).

Prepared from 3,5-dibromo-α-methoxy-β-cresol and N-ethyl-N-cyclohexylamine analogous to Example 160,

Example 182.

3.5- Dibromo-4-hydroxy-N- (cis-3-hydroxy-cyclohexyl) -benzylamine.

Mp. of hydrochloride: 215-215.5 ° C (dec.).

Prepared from 3,5-dibromo> -C-methoxy-β-cresol and cis-3-amino-cyclohexanol analogous to Example 160.

Example 183.

N-Cyclohexyl-3,5-dibromo-2-hydroxy-N-methyl-benzylamine.

Mp. of hydrochloride: 189-191 ° C.

Prepared from 3,5-dibromo-2-hydroxy-benzyl alcohol and N-cyclohexyl-N-methyl-acetic acid amide analogous to Example 161.

Example 184.

3.5- Dibromo -N- (dihydroxy-tert.-butyl) -2-hydroxy-benzylamine.

5.6 g of 3,5-dibromo-2-hydroxy-benzyl alcohol and 6.3 g of dihydroxy-tert-butyl-amine were heated for 1 hour at 140 ° C, after which the melt was dissolved in absolute ethanol, acidified with ethanol. hydrochloric acid, and 3,5-dibromo · -N- (dihydroxy-tert.-butyl) -2-hydroxy-benzylamine hydrochloride was crystallized by the addition of ether, m.p. 187-189 ° G (of absolute ethanol ether).

Example 185

3.5- Dibromo. -N- (tert-dihydroxy-butyl) -2-hydroxy-benzylamine.

To 21.6 g of 3,5-dibromo-2-hydroxy-benzyl bromide dissolved in 0.5 l of carbon tetrachloride was added a solution of 26.4 g of dihydroxy-tert.-butylamine in 100 ml of ethanol, and was refluxed for 30 minutes. This precipitated a precipitate which was aspirated and washed with carbon tetrachloride and water. The crude product was dissolved in absolute ethanol and the solution was acidified with ethanolic hydrochloric acid, and 3,5-dibromo-N- (dihydroxy-tert.-butyl) -2-hydroxy-benzylamine hydrochloride was crystallized by the addition of ether, m.p. . 187-189 ° C.

Example 186

3.5- Dibromo -N- (dihydroxy-tert.-butyl) -2-hydroxy-benzylamine.

4.0 g of acetic acid (3,5-dibromo-2-hydroxy-benzyl ester) and 4.0 g of dihydroxy tert. -butylamine was heated at 140 ° C for 1 hour. The reaction product was dissolved in absolute ethanol, acidified with ethanolic hydrochloric acid, and 3,5-dibromo-N- (dihydroxy-tert.-butyl) -2-hydroxy-benzylamine hydrochloride was crystallized by the addition of ether, m.p. 187-189 ° G.

Example 187, 3.5-Dibromo-2-hydroxy-N-tert.-pentyl-benzylamine.

3.5 g of 3,5-dibromo-2-hydroxy-benzyl alcohol and 1.4 g of sodium hydride dispersion (507 ° s in oil) were refluxed for 6 hours in 100 ml of tetrahydrofuran. Then, it was cooled to -60 ° to -70 ° C and with stirring 4.8 g of p-toluenesulfonic acid chloride in 50 ml of tetrahydrofuran was added dropwise. The reaction mixture was allowed to warm to -30 ° G and then cooled again to -70 ° G. Then, 4.4 g of tert-pentylamine in 50 ml of ether was added dropwise and stirred until the reaction mixture slowly warmed to room temperature. Then, it was shaken twice with water, the aqueous phase was extracted with chloroform, the organic phases were combined and evaporated. After column chromatographic purification of the crude product over silica gel with chloroform-acetic acid ethyl ester (2: 1), 3,5-dibromo-2-hydroxy-N-tert-pentyl-benzylamine hydrochloride of acetone-ether crystallized after acidification with ethanolic hydrochloric acid, m.p. 202-206 ° C (dec., Of water).

42 149883

Example 188.

3.5- Dibromo -N- (dihydroxy-tert.-butyl) -2-hydroxy-benzylamine.

2.9 g of 3,5-Dibromo-2-hydroxy-benzyl-methyl ether and 3.3 g of dihydroxy-tert-butylamine were heated at 140 ° G for 1 hour. The crude product was dissolved in absolute ethanol, acidified with ethanolic hydrochloric acid, and ether was added until initial crystallization of 3,5-dibromo-N- (dihydroxy-tert-butyl) -2-hydroxy-benzylamine hydrochloride, m.p. 187-189 ° G.

Example 189.

3.5- Dibromo -N- (dihydroxy-tert.-butyl) -2-hydroxy-benzylamine.

7 g of 3,5-Dibromo-salicylaldehyde, 17.5 g of dihydro-tert-butylamine and 7.7 g of formic acid were heated for 6 hours at 70-80 ° C. Then 2N ammonia was added, vigorously shaken and the precipitate was aspirated. This was dissolved in absolute ethanol, acidified with ethanolic hydrochloric acid and ether was added for crystallization. After recrystallization from absolute ethanol / ether, 3,5-dibromo-N- (di-hydroxy-tert-butyl) -2-hydroxy-benzylamine hydrochloride had m.p. 187-189 G,

Example 190.

3.5- Dibromo -N- (dihydroxy-tert.-butyl) -2-hydroxy-benzylamine.

7.3 g of N- (3,5-dibromo-2-hydroxy-benzylidene) dihydroxy-tert-butylamine was stirred for 2 hours with 1 g of sodium borohydride in 200 ml of ethanol. Then, some acetone was added to decompose excess sodium borohydride, acidified with 2N hydrochloric acid and evaporated to low volume. After the addition of 2N ammonia to the alkaline reaction, the yellowish precipitate was aspirated. The suction residue was dissolved in absolute ethanol, acidified with ethanolic hydrochloric acid, and ether was added until crystallization of 3,5-dibromo-N- (dihydroxy-tert-butyl) -2-hydroxy-benzylamine hydrochloride, m.p. 187-189 ° C.

Example 191.

3.5- Dibromo-2-hydroxy-N-isopropyl-benzylamine.

To 16 g of N-isopropylidene (3,5-dibromo-2-hydroxy-benzylamine) in 120 ml of ethanol were added 2 g of sodium borohydride, stirred for 3 hours, then filtered, 40 ml of 2N sodium hydroxide solution and 200 ml of water were added and evaporated to dryness. half the volume. To the solution was then saturated aqueous ammonium chloride solution. whereby the crude product precipitated. The precipitate was aspirated and washed well with water. The product was dissolved in acetone and acidified with ethanolic hydrochloric acid. Thereby crystallized 3,5-dibromo-2-hydroxy-N-isopropyl-benzylamine hydrochloride, m.p. 195-199 ° G (dec.).

149883 43

Example 192.

3,5-Dibromo-N- (dihydroxy ter to butyl) -2-hydroxybenzylamine.

4.2 g of dihydroxy-tert.-butylamine and 1.2 g of paraformaldehyde were dissolved under heating in 20 ml of absolute ethanol, and at room temperature 10 g of 2.4-dibromo-phenol were added and after standing for 1 hour an additional 7 hours under reflux. The reaction solution was then acidified with ethanolic hydrochloric acid and, with the addition of ether, 3,5-dibromo-N- (dihydroxy-tert.-butyl) -2-hydroxy-benzylamine hydrochloride was crystallized, m.p. 187-189 ° C (of absolute ethanol ether).

Example 193, 3.5-Dibromo -N- (dihydroxy-tert-butyl) -2-hydroxy-benzylamine.

2.5 g of N- (dihydroxy-tert.-butyl) -2-hydroxy-benzylamine hydrochloride was dissolved in 50 ml of glacial acetic acid and 5 ml of water, and with stirring 3.2 g of bromine was added dropwise in 10 ml of glacial acetic acid. Then, the reaction mixture was diluted with water, adjusted alkaline with concentrated ammonia, and the precipitated crude base was suctioned. The base was dissolved in absolute ethanol, acidified with ethanolic hydrochloric acid, and ether was added to initial crystallization of 3,5-dibromo-N- (dihydroxy-tert-butyl) -2-hydroxy-benzylamine hydrochloride, m.p. 187-189 ° C (of absolute ethanol ether).

Example 194.

3.5- Dibromo -N- (dihydroxy-tert.-butyl) -2-hydroxy-benzylamine.

2.5 g of N-benzyl-3,5-dibromo-N- (dihydroxy-tert.-butyl) -2-hydroxy-benzylamine hydrochloride was dissolved in 200 ml of methanol and hydrogenated in the presence of ca.

0.1 g palladium (10%) on charcoal. After taking up the calculated amount of hydrogen, hydrogenation was quenched, the catalyst was filtered off and the solution was evaporated. After two recrystallizations of absolute ethanol ether, pure 3.5-dibromo-N- (dihydroxy-tert-butyl) -2-hydroxy-benzylamine hydrochloride was obtained, m.p. 187-189 ° C.

Example 195.

3.5- Dibromo-2-hydroxy-N-tert.-pentyl-benzylamine.

0.8 g of 3,5-Dibromo-2-hydroxy-N-tert.-pentyl-benzamide was refluxed for 5 hours with 0.3 g of sodium borohydride in 30 ml of dry pyridine. To decompose excess sodium borohydride, some acetone was added and pyridine was distilled off in vacuo. The residue was taken up in hot 2N hydrochloric acid, filtered, adjusted alkaline with 2N ammonia and shaken three times with chloroform.

The organic phase was dried over sodium sulfate and evaporated. For further purification, the crude product was chromatographed over silica gel with chloroform-acetic acid ethyl ester (2: 1). The obtained base was dissolved in slightly acetone, acidified with ethanolic hydrochloric acid, and 3,5-dibromo-2-hydroxy-tert.-pentyl-benzylamine hydrochloride was crystallized by the addition of ether, m.p. 202-206 ° C (dec., Of water).

Example 196, 3.5-Dibromo-N- (dihydroxy-tert.-butyl) -2-hydroxy-benzylamine.

1.8 g of 6,8-Dibromo-3,4-dihydro-3- (dihydroxy-tert.butyl) -2H-1,3-benzoxazin-2-one was refluxed for 1 hour in a mixture of 50 ml of tertiary compound. butanol and 40 ml of 2N sodium hydroxide solution. Cooled, 50 ml of 2N hydrochloric acid was added, the alcohol was distilled off in vacuo, and excess sodium bicarbonate solution was added. The precipitated base was aspirated and washed with water.

The residue was dissolved in absolute ethanol, acidified with ethanolic hydrochloric acid, and 3,5-dibromo-N- (dihydroxy-tert.-butyl) -2-hydroxy-benzylamine hydrochloride was crystallized by the addition of ether, m.p. 187-189 ° C.

Example 197

3.5- Dibromo -N- (dihydroxy-tert.-butyl) -2-hydroxy-benzylamine.

0.9 g of 2-Benzoyloxy-3,5-dibromo-benzyl alcohol and 0.6 g of dihydroxy-tert-butylamine were heated at 140 ° C for 1 hour. The reaction product was dissolved in absolute ethanol, acidified with ethanolic hydrochloric acid, and ether was added to crystallize 3,5-dibromo-N- (dihydroxy-tert-butyl) -2-hydroxy-benzylamine hydrochloride, m.p. 187-189 ° C (of absolute ethanol ether).

Example 198.

3.5- Dibromo -N- (dihydroxy-tert.-butyl) -2-hydroxy-benzylamine.

1.8 g of 6,8-Dibromo-2-methyl-1,3-benzdioxane and 1.8 g of dihydroxy-tert-butylamine were heated for 20 hours at 140 ° C. Then, the reaction product was boiled with 100 ml of 2N hydrochloric acid, which was added with activated carbon, filtered and evaporated. Evaporation residue was purified twice by absolute ethanol ether to purify 3,5-dibromo-N- (dihydroxy-tert.-butyl) -2-hydroxy-benzyl-amine hydrochloride. 187-189 ° C.

Example 199

3,5 - Dibromo -N- (dihydroxy-tert-butyl) - 2-hydroxy-benzylamine.

3 g of 6,8-Dibromo-3,4-dihydro-3- (dihydroxy-tert-butyl) -2H-1,3-benzoxazine was dissolved in 30 ml of methanol and 10 ml of water was added. This precipitated a precipitate. After 1 hour, the precipitate was aspirated and washed with some methanol. The base was dissolved in some absolute ethanol, acidified with ethanolic hydrochloric acid, and ether was added to crystallize 3,5-dibromo-N- (dihydroxy-tert-butyl) -2-hydroxy-benzylamine hydrochloride, m.p. 187-189 ° G.

Example 200.

3.5- Dichloro-2-hydroxy-N-isopropyl-benzylamine.

Mp. of hydrochloride: 188-189.5 ° G.

Prepared from 3,5-dichloro-2-hydroxybenzyl bromide and isopropylamine analogous to Example 185.

Example 201.

N-tert.-Bytyl-3,5-dibromo-4-hydroxy-benzylamine.

Mp. of hydrochloride: 234-236 ° C (dec.).

Prepared from 3,5-dibromo-4-hydroxy-benzyl bromide and tert-butylamine analogous to Example 185.

Example 202, N-tert-Butyl-3,5-dichloro-2-hydroxy-benzylamine.

Mp: 172-174 ° C.

Prepared from 3,5-dichloro-2-hydroxy-benzyl bromide and tert-butylamine analogous to Example 185,

Example 203.

N-tert.-Butyl-3,5-dichloro-4-hydroxy-benzylamine.

Mp. of hydrochloride: 222-223 ° C (dec.).

Prepared from 3,5-dichloro-4-hydroxy-benzyl bromide and tert-butylamine analogous to Example 185.

Example 204, 3.5-Dibromo-4-hydroxy-N-tert.-pentyl-benzylamine.

Mp. of hydrochloride: 176-180 ° C (dec.).

Prepared from 3,5-dibromo-4-hydroxy-benzyl bromide and tert-pentylamine analogous to Example 185.

Example 205.

3.5- Dichloro-4-hydroxy-N-tert.-pentyl-benzylamine.

Mp. of hydrochloride: 203-207 ° C (dec.) »

Prepared from 3,5-dichloro-4-hydroxy-benzyl bromide and tert-pentylamine analogous to Example 185.

Example 206, 3.5-Dibromo-2-hydroxy-N- (hydroxy-tert-butyl) -benzylamine.

46 149883

Mp. of hydrochloric !:

Prepared from 3,5-dibromo-2-hydroxy-benzyl bromide and hydroxy-tert-butylamine analogous to Example 185.

Example 207.

3.5-Dibromo-4-hydroxy-N- (hydroxy-tert-butyl) -benzylamine.

Mp. of hydrochloride: 200-202 ° C.

Prepared from 3,5-dibromo-4-hydroxy-benzyl bromide and hydroxy-tert-butylamine analogous to Example 185.

Example 208.

3.5-Dichloro-4-hydroxy-N- (hydroxy-tert-butyl) -benzylamine.

Mp. of hydrochloride: 208-212 ° C (dec.).

Prepared from 3,5-dichloro-4-hydroxy-benzyl bromide and hydroxy-tert-butylamine analogous to Example 185.

Example 209, 3.5- Dibromo -N- (dihydroxy-tert.-butyl) -4-hydroxy-benzylamine.

Mp. of hydrochloride: 182-183.5 ° C.

Prepared from 3,5-dibromo-4-hydroxy-benzyl bromide and dihydroxy-tert-butylamine analogous to Example 185,

Example 210.

3.5-Dibromo-4-hydroxy-N- (trihydroxy-tert.-butyl) -benzylamine.

Mp. of hydrochloride: 189-191.5 ° C.

Prepared from 3,5-dibromo-4-hydroxy-benzyl bromide and trihydroxy-tert-butylamine analogous to Example 185.

Example 211.

3-5-Dichloro-N- (dihydroxy-tert-butyl) -4-hydroxy-benzylamine.

Mp. of hydrochloride: 166-169 ° C (dec.).

Prepared from 3,5-dichloro-4-hydroxy-benzyl bromide and dihydroxy-tert-butylamine analogous to Example 185.

Example 212.

3.5-Dibromo-2-hydroxy-N- (trihydroxy-tert.-butyl) -benzylamine.

Mp. of hydrochloride: 185-187 ° G (dec.).

Prepared from 3,5-dibromo-2-hydroxy-benzyl bromide and trihydroxy-tert-butylamine analogous to Example 185.

47 149883

Example 213, 3.5-Dichloro-4-hydroxy-N- (trihydroxy-tert-butyl) -benzylamine.

Snip. of hydrochloric acid: 170-174 ° C (dec.).

Prepared from 3,5-dichloro-4-hydroxy-benzyl bromide and trihydroxy-tert-butylamine analogous to Example 185.

Example 214.

N-tert.-Butyl-3,5-dibromo-2-hydroxy-benzylamine.

Mp. of hydrochloride: 216-220 ° C (dec.).

Prepared from 3,5-dibromo · -salicylaldehyde, tert-butylamine and formic acid analogous to Example 189,

Example 215.

3.5- Dibromo-4-hydroxy-N-isopropyl-benzylamine.

Mp. of hydrochloride: 229-233 ° C (dec.).

Prepared by reduction of N- (3,5-dibromo-4-hydroxy-benzylidene) -isopropylamine with sodium borohydride analogous to Example 190.

Example 216, 3.5-Dichloro-4-hydroxy-N-isopropyl-benzylamine.

Mp. of hydrochloride: 223-231 ° C (dec.).

Prepared by reduction of N- (3,5-dichloro-4-hydroxy-benzylidene) -isopropyl-amine with sodium borohydride analogous to Example 190.

Example 217.

3,5 Dichloro-2-hydroxy-N-tert.-pentyl-benzylamine.

Mp. of hydrochloride: 2ll-213 ° C (dec.).

Prepared by reduction of N- (3,5-dichloro-2-hydroxy-benzylidene) tert-pentylamine with sodium borohydride analogous to Example 190.

Example 218, 3.5-Dichloro-2-hydroxy-N- (hydroxy-tert-butyl) -benzylamine.

Mp. of hydrochloride: 200 ° -204.5 ° C (dec.).

Prepared by reduction of N- (3,5-dichloro-2-hydroxy-benzylidene) -hydroxy-tert-butylamine with sodium borohydride analogous to Example 190.

Example 219.

3.5- Dichloro-N- (dihydroxy-tert.-butyl) -2-hydroxy-benzylamine.

Mp. of hydrochloride: 184-188 ° C (dec.).

Prepared by reduction of N- (3,5-dichloro-2-hydroxy-benzylidene) -dihydro-

Claims (2)

149883 droxy-tert.-butylamine with sodium borohydride analogous to Example 190. Example 220, 3,5-Dichloro-2-hydroxy-N- (trihydroxy-tert.-butyl) -benzylamine. Mp. of hydrochloride 172-176 ° C (dec). Prepared by reduction of N- (3,5-dichloro-2-hydroxy-benzylidene) -trihydroxy-tert.-butylamine with sodium borohydride analogous to Example 190. Example 221. 5- Bromo · -N-tert-butyl 2-hydroxy-benzylamine. Mp. of hydrochloride 255-258 ° C (dec.). Prepared by reduction of N- (5-bromo-2-hydroxy-benzylidene) -tert-butylamine with sodium borohydride analogous to Example 190. Analogous process for the preparation of benzylamines of general formula I: R 2 OH where Hal is a chlorine or bromine atom, R 2 - is a hydrogen, chlorine or bromine atom, 2 R is an optionally substituted with 1-3 hydroxy groups, branched alkyl group having 3-5 carbon atoms or a group of formula: γ (0Η2) "Η where 3 R is a hydrogen atom, a hydroxy group or an alkyl group of 1-4 carbon atoms, and nine is the number 0, 1 or 2, and 4 R is a straight or branched alkyl group of 1-4 carbon atoms or also 149883 . 3. 2 is a hydrogen atom if R is not a hydrogen atom or R is an optionally substituted with 1 to 3 hydroxy groups branched alkyl group having 3-5 carbon atoms or their physiologically acceptable acid addition salts with inorganic or organic acids, characterized in that a) compound of the general formula II: CHO - R6 X fY r-- n Hal OH wherein R and Hal have the meanings set forth above and 6 R is a hydroxy group, a chloro, bromo or iodo atom, an acyloxy, sulfonyloxy , alkoxy, aryloxy or aralkoxy group, is reacted with an amine of general formula III: H - III 2 4 wherein R and R have the above meanings, or b) an aldehyde of general formula IV:. (^ y'cw R1-- IV M Hal OH where R * and Hal have the above meanings are reacted with an amine of the general formula III: ~ h - rrf in N, 4 where R and have the above meanings, respectively with the corresponding formamide, in the presence of formic acid, or 149883 c) for the preparation of compounds of the general formula I, wherein is a hydrogen atom, a compound of the general formula V: CH = NV v W7 Hal OR or a compound of the general formula Va: '.CH - N = Z in R-- Va Hal OR in which formulas: 1 2 R, R and Hal have the above meanings, Z is one optionally with a hydroxy or an alkyl group of 1-4 carbon atoms. substituted cyclohexylidene group or a branched alkylidene group having 3-5 carbon atoms and R 1 is a hydrogen atom or a carboxylic acid residue is reduced, or d) to prepare compounds of general formula I wherein R 2 is not a hydrogen atom and R is not one substituted with a hydroxy group, a compound of the general formula VI: γγ0 "2-" O R1-- VI AK Hal OH where R 1 and Hal have the above meanings and 2 'R is an alkyl group having 1-4 carbon atoms or, with the exception of the branched alkyl groups having 3-5 carbon atoms and those substituted with hydroxy groups, they have for 2 R the meanings set forth above are alkylated with a compound of the general formula VII: R 4 'R - W VII wherein R 1' is a branched alkyl group having 3-5 carbon atoms or a cyclohexyl group, o in λ '4 when R is alkyl of 1-4 carbon atoms, or R has those for R, except hydrogen, as defined above when R is different from alkyl of 1-4 carbon atoms and 4 'W is a halogen atom or a sulfonic acid group, or R - W can, when the alkyl ring is a methylation, represent CH 2 O, or e) a phenol of the general formula VIII: in XX E v vm M Hal OH where R and Hal have the above meanings wherein one of the groups Hal is present in 2- position of the compound of general formula VIII, reacted with formaldehyde or paraformaldehyde and an a min of the general formula III: vR 2 H - <4 111 R where 2 4 R and R have the above meanings, or f) a compound of the general formula IX: X V 1 IX R-- SX OH wherein 12 4 R, R and R have the above meanings are halogenated, or g) the protecting groups present are split off from a compound of the general formula X: ^ v "2 -" 0 1__ 7 * 1 Hal OY 149883 where 1 2 R, R and Hal have the above meanings, 4 X is a protecting group for an amino group or has the meanings for R above, Y is a protecting group for a hydroxy group or a hydrogen atom, wherein at least one of the groups X or Y is a protecting group for an amino or hydroxy group, or h) a compound with. the general formula XI: 0 2 »/ R c - ΓΓ 1 ^ R4" R-- R XI X, Hal OR wherein 1 2 R, R and Hal have the above meanings, 4 "4 R is a formyl or acetyl group or have the meanings for R above and R / is a hydrogen atom or a carboxylic acid residue, is reduced, or i) to produce compounds of general formula I wherein the hydroxy group is in the 2-position and R hydrogen atom, a compound of the general formula XII:, - R2 R - I XII Hal wherein 1 2 R, R and Hal have the above meanings, are hydrolyzed, or j) a compound of the general formula XIII: XIII R —- In Hal OR where 149883 R · * · and Hal have the above meanings, and R ° is an organic acyl group, is reacted with an amine of the general formula III: R2 H - Ν '"III \ r4 2 4 where R and R have the above meanings, or k) for the preparation of compounds of the general formula I wherein the hydroxy group is in the 2-position, a compound of the general formula flour XIV: / VC “2X ° * --- In xiv χΛο / 01 R Hal where R 2 and Hal have the above meanings and R 9 is an alkyl, aryl or aralkyl group, is reacted with an amine of the general formula III : H - NC 111 24 where R and R have the above meanings and the resulting reaction product is then hydrolyzed, or l) to produce compounds of general formula I wherein R 1 is a hydrogen atom and the hydroxy group is in the 2-position , a compound of the general formula XV: R1 - iol XV XAo / H2 Hal wherein 1 2 R, R and Hal have the above meanings, are hydrolyzed, or, 2 m) to prepare compounds of the general formula I wherein R is a cyclohexyl group and R 1 is a methyl group, a compound of the general formula IIa: