DK150502B - METHOD OF ANALOGUE FOR THE PREPARATION OF AMINOPHENYLETHANOLAMINES AND THEIR OXAZOLIDINES AND ACID ADDITION SALTS THEREOF - Google Patents

Description

150502

The present invention relates to an analogous process for the preparation of novel aminophenylethanolamines of the formula I as claimed in claim 1, their optically active antipodes and their physiologically acceptable acid addition salts with inorganic or organic acids.

In the general formula I, R 1 represents a hydrogen atom, a chlorine atom, a bromine atom or, a cyano group, 2 R represents a fluorine atom, a trifluoromethyl group, nitro group or a cyano group, 3 R represents an alkyl or cycloalkyl group having 3-5 carbon atoms, a hydroxy-tert.-butyl or 3,4-methylenedioxyphenyl-propyl group, and 4 4 R and A each represent a hydrogen atom or R together with A represents a group 2 of the formula / CH 2.

The compounds of the general formulas I possess valuable pharmacological properties, in addition to an analgesic, a uterine spasmolytic and an antispasmodic effect on the cross-striated muscle, in particular a P 2 mimetic or a β 2 blocking effect or both, depending on the substitution. one or the other effect comes to the fore. In particular, the d (+) - compounds exhibit a selective effect on the β 1 receptors, and the l (-) compounds preferably exhibit an effect on β2-ΓβοβρϋθΓ6Γηβ.

The present compounds are prepared according to the invention by the following methods: a) Reduction of an acetophenone by the general formula set out in claim 1. . 1 4 II, in which formula R - R has the meaning given above to form a compound of formula I wherein A represents a hydrogen atom and, if R 1 in the formula of the compound obtained represents a hydrogen atom, then, if desired, converting this to a compound of formula I wherein A, together with R 1, represents the group ^ CH 2, by reaction with CH 2 O.

The reduction is preferably carried out in a solvent such as methanol / water, ethanol, isopropanol, ether, tetrahydrofuran or dioxane, and. preferably with a complex metal hydride, such as lithium aluminum hydride or sodium borohydride, with aluminum isopropylate in the presence of a primary or secondary alcohol or with catalytically activated hydrogen and at temperatures between -20 ° C and the boiling temperature of the solvent used.

However, the reduction with complex metal hydrides is preferably carried out with sodium borohydride and at room temperature. By using a more reactively complex metal hydride, such as lithium aluminum hydride, and optionally at elevated temperature, the cyan groups mentioned by the definition of group R can be simultaneously reduced.

b) For the preparation of compounds of general formula I wherein R 1 and are as defined above and wherein R 1 represents a chlorine or bromine atom: Halogenation of a compound of the general formula III as claimed in claim 1, wherein formula R 1 - R 1 has the meaning given above.

The reaction is carried out with a halogenating agent, e.g. with chlorine, bromine, tribromophenol bromine or phenyliodide dichloride, preferably in a solvent, for example in 50-100 7 "acetic acid or in tetrahydrofuran in the presence of a tertiary organic base, optionally in the presence of a heavy metal salt such as mercuric oxide, and conveniently at temperatures between 0 and 50 ° C. moles of compound of the general formula III which can be used as a base or in the form of a salt, e.g. as mono-, di- or trihydrochloride, 1 mole of halogenating agent or a slight excess is suitably used. If, during the reaction, a hydrogen halide salt is formed, it can be isolated directly as such, or it can be further purified above the base if desired.

c) For the preparation of compounds of general formula I wherein A denotes a hydrogen atom:

Cleavage of one or more protecting groups from a compound of 12 the general formula IV of claim 1, in which formulas R, R and R are as defined above, and X represents a protecting group for a hydroxy group or a hydrogen atom, Y * represents a protecting group for an amino group or a hydrogen atom, and Y represents a protecting group for an amino group or 4 having the same meaning as indicated for the group R, with at least one of the groups X, 1 2 Y or Y being both one of the above protecting groups.

1 2 Y, Y or both denote in particular an acyl group, e.g. an acetyl group, a benzoyl group or a p-toluenesulfonyl group, or a benzyl group, and X represents in particular an acyl group, e.g. an acetyl group, a benzoyl group or a p-toluenesulfonyl group, or a trimethylsilyl group, a benzyl group or a tetrahydropyranyl (2) group.

1 2

Denotes Y or Y or both e.g. any acyl group, the cleavage of this group is carried out hydrolytically, e.g. with ethanolic hydrochloric acid or with sodium hydroxide solution at temperatures up to the boiling point of the solvent used. Hereby, in a compound of the general formula IV 2, the group R represents a cyano group, it may be simultaneously saponified to a carbamoyl group or a carboxyl group.

12

Represents X, Y or Y or both in a compound of general formula IV wherein R is not a nitro group, e.g. a benzyl group, the cleavage of this group is carried out by hydrogenolysis, e.g. with hydrogen in the presence of a catalyst such as palladium on charcoal, palladium oxide hydrate on barium sulfate, platinum or Raney nickel, preferably in a solvent such as methanol, a mixture of methanol and hydrochloric acid or ethanol, at room temperature or slightly elevated temperature and at atmospheric pressure or slight overpressure.

Denotes X e.g. any acyl group, the trimethylsilyl group or the tetrahydropyranyl (2) group, the cleavage is carried out hydrolytically, preferably in the presence of an acid and at temperatures up to the boiling temperature of the solvent used.

d) For the preparation of compounds of general formula I wherein R 1 and A each represent a hydrogen atom:

Dehalogenation of a compound of the general formula of claim 1 in which formula R, R and R have the meaning given above and Hal represents a chlorine atom, a bromine atom or an iodine atom.

The dehalogenation is preferably carried out in a solvent and suitably either with triphenylphosphine in benzene or toluene or with hydrogen in methanol, ethanol, ethyl acetate or tetrahydrofuran and in the presence of a hydrogenation catalyst. Depending on the method used, the reaction is carried out at room temperature or at elevated temperature, e.g. at temperatures between 100 and 150 ° C, and at atmospheric or slight overpressure. When using Raney nickel or palladium on coal, the dehalogenation is carried out e.g. at room temperature and atmospheric pressure.

2

If in a compound of general formula V, R is a nitro group, the dehalogenation is preferably carried out with triphenylphosphine.

e) For the preparation of compounds of general formula I wherein A represents a hydrogen atom:

Reaction of a compound of the general formula I 2 VII of claim 1 in which formulas R and R are as defined above and Z represents a chlorine atom, a bromine atom, an iodine atom or a p-toluenesulfonyloxy group, with an amine having the general formula VIII: y

H - N VIII

V

Wherein R and R are as defined above.

The reaction is conveniently carried out in a solvent such as ethanol, ethanol, chloroform, carbon tetrachloride, dioxane or in excess of the amine of general formula VIII used and preferably at temperatures between 0 and 100 ° C. However, the reaction can also be carried out without solvent.

f) For the preparation of compounds of the general formula I wherein A represents 2 a hydrogen atom and R does not represent a nitro group:

Reduction of a compound of the general formula 1 3 4 2 'IX as claimed in claim 1, in which formulas R, R and R have the meaning given above and R with 2 except for a nitro group has the meaning given for R.

The reduction is conveniently carried out in a solvent such as water, methanol, ethanol, a mixture of water and methanol or ethyl acetate, and preferably with nascent hydrogen, e.g. with zinc and glacial acetic acid or iron and hydrochloric acid, with hydrogen in the presence of a catalyst such as Raney nickel, {Latin elfer palladium on coal, with a complex metal hydride such as lithium aluminum hydride, or with stannous chloride and hydrochloric acid, conveniently at temperatures between 0 and 100 ° C.

g) For the preparation of compounds of the general formula I wherein A represents a hydrogen atom and R is not a cyano group and R is not a nitro group or cyano group:

Reduction of a compound of the general formula 3 of claim 1 wherein X is as defined above, R with the exception of a cyano group has the meaning given for R, R 2 and a cyano group have the meaning given to R and A represents a carbonyl group or a hydroxymethylene group.

The reaction is carried out in a solvent such as ether, tetrahydrofuran, dioxane or a mixture of tetrahydrofuran and benzene, preferably with a reducing agent such as a complex metal hydride, e.g. with lithium aluminum hydride, with sodium borohydride in the presence of a Lewis acid or with sodium borohydride in pyridine, e.g. at temperatures between 0 and 120 ° G and conveniently at the boiling temperature of the solvent used.

h) For the preparation of compounds of the general formula ", wherein and A is each a hydrogen atom:

Hydrolysis of an oxazolidone of the general formula 12 in XI of claim 1, in which formulas R, R and R are as defined above.

The hydrolysis is conveniently carried out in a solvent such as water, methanol, ethanol, a mixture of ethanol and water or glacial acetic acid, in the presence of an acid such as hydrochloric acid, hydrobromic acid or sulfuric acid, or in the presence of a base such as sodium hydroxide or potassium hydroxide. at temperatures between 0 and 110 ° C and depending on the nature of the hydrolyzing agent used, preferably at room temperature or at the boiling temperature of the solvent used.

i) For the preparation of compounds of the general formula wherein R 1 and A are each a hydrogen atom;

Reduction of an aldehyde by the general formula XII, 1 2 'of claim 1 wherein R and R are as defined above, or a hydrate thereof, in the presence of an amine of the general formula Villa x

H

3 wherein R is as defined above.

The reduction is conveniently carried out in a solvent such as ethanol, ethanol, ether or tetrahydrofuran, preferably with a complex metal hydride, such as sodium borohydride or lithium aluminum hydride, with nascent hydrogen or with hydrogen in the presence of a catalyst such as Raney nickel or palladium at temperatures between -20 and 100 ° C and preferably at temperatures up to the boiling temperature of the solvent used. However, the reaction can also be carried out by reducing an in situ compound formed by the general formula XIIa of claim 15, in which formula 12 3 R, R and R have the meaning given above.

J) For the preparation of compounds of the general formula I wherein R represents a nitro group and A represents a hydrogen atom; 6 150502

Nitration of a compound of the general formula 13 X XI of claim 1, in which formulas R, R and R have the meaning given above.

The reaction is carried out with a nitrating agent, preferably with nitric acid, or with a mixture of concentrated nitric acid and concentrated sulfuric acid, and suitably at temperatures between -20 and 100 ° C.

k) For the preparation of compounds of the general formula I wherein A together is 4 s.

with R represents the group CH₂ represents a compound of formula I wherein R ^ and A each represent a hydrogen atom with an aldehyde CH₂O.

The reaction with the aldehyde CH90 is conveniently carried out in a solvent such as ethanol, benzene, toluene or dioxane under water decomposing conditions, e.g. in the presence of anhydrous cupric sulfate, at temperatures between 2+ and 100 ° C, but it can also be carried out without the presence of a solvent. However, the reaction is particularly advantageously carried out by means of a water discharger in the presence of a solvent such as benzene or toluene.

The compounds of the general formula I obtained by the processes a) -j) can then, if desired, be separated into their optically active antipodes by racemate cleavage or by separating a mixture of the diasterioisomeric compounds with the general formula XIV of claim 16. , in which formula R, R, 3 4 6 R and R have the meaning given above, R represents a hydrogen atom or an acyl group, and R 7 represents a chiral acyl group, and subsequently cleavage 7 6 6 of the groups R and R, if R represents an acyl group.

As chiral acyl groups p7, especially optically active α-aminoacyl groups protected by the nitrogen atom are considered here, e.g. The N-benzyloxycarbonyl-L-alanyl group, or optically active terpenyloxycarbonyl groups, e.g. (-) - menthyloxy-carbonyl group.

The separation of a mixture of the diastereoisomeric compounds of the above general formula XIV into the pure diastereoisomeric compounds is conveniently carried out by fractional crystallization or by column chromatography on an inert carrier material or both.

The subsequent cleavage of groups R6 and R7 is conveniently carried out by hydrolysis or solvolysis in the presence of water or a suitable alcohol such as methanol, optionally in the presence of an acid or a base and at temperatures between 0 and 100 ° C.

• 7 150502

The cleavage of the group R 1 can also be carried out by a complex metal hydride such as lithium aluminum hydride, a suitable solvent, e.g. in ether, tetrahydrofuran or dioxane, and conveniently at temperatures between -20 and 20 ° C. Here, in a compound of general formula XIV, denotes a cyano group, it may be reduced simultaneously. Depending on the nature of the substituents and R 1, these can be split stepwise or in a single step.

The racemate cleavage of the d-1 form of a compound of the above general formula I is preferably carried out by fractional crystallization of a mixture of its diastereoisomeric salts with an optically active acid, e.g. D (-) - tartaric acid, L (+) - tartaric acid, dibenzoyl-D-tartaric acid, dibenzoyl-L-tartaric acid, (+) - camphor ~ 10-sulfonic acid, L (-) - malic acid, L (+) - mandelic acid, da-bromocamphor IF-sulfonic acid or 1-quinic acid. However, the racemate cleavage can also be performed by column chromatography on an optically active carrier material, e.g. acetyl cellulose.

The compounds of general formula I obtained can, if desired, be transferred with inorganic or organic acids into their physiologically acceptable acid addition salts with 1, 2 or 3 equivalents of the acid in question. As acids, for example, hydrochloric, hydrobromic, sulfuric, phosphoric, lactic, citric, tartaric, maleic and fumaric acids have proved suitable.

The compounds of starting formula II-XIV used as starting materials are obtained by methods known in the literature.

The compounds of general formula II used as starting materials are thus obtained e.g. by reacting the corresponding 2-haloacetophenones with the corresponding amines.

The compounds of general formulas III, IV and V are obtained by reacting the corresponding 2-haloacetophenones with the corresponding amines and subsequently reducing the ketones obtained, e.g. with sodium borohydride; a starting compound of the general formula IV may also be obtained by halogenating a corresponding compound or by catalytically reducing a corresponding 4-nitrophenyl compound.

An initial compound of general formula VII is obtained, for example. by reacting a corresponding phenylethylene glycol with p-toluenesulfonic acid chloride in the presence of pyridine or by reducing a corresponding aminophenacyl halide with sodium borohydride.

An starting compound of the general formula IX is obtained e.g. by reducing a corresponding ketone with sodium borohydride.

A starting compound of the general formula X is obtained, for example, by reacting a corresponding acid with a corresponding amine in the presence of a condensation brine, such as Ν, Ν'-dicyclohexylcarbodiiraid or NjN'-carbonyldiimidazole, or by activation over an acid chloride or one mixed anhydride and subsequent reaction with a corresponding amine, or also by reduction of a corresponding ketocarboxylic acid amide.

8 150502

An starting compound of the general formula XI is obtained e.g. by halogenating a corresponding oxazolidone, wherein R * represents a hydrogen atom, or by 3 alkylating a corresponding oxazolidone, wherein R represents a hydrogen atom.

An starting compound of the general formula XII is obtained e.g. by oxidation of a corresponding acetophenone with selenium dioxide or by oxidation of a corresponding phenacyibromide 'with dimethylsulfoxide.

A starting compound of general formula XIII is conveniently obtained by a process of the present invention.

The starting materials used in processes a) - k) of the general formulas II-XIII need not in all cases be prepared in pure form, but they can also be suitably used in the form of raw products.

As already discussed, the compounds of general formulas I and Ia exhibit valuable pharmacological properties, especially a P 2 mimetic or a β 2 -blocking effect, or both, one or the other of these effects being prominent depending on the substitution. d (+) - The compounds in particular exhibit a selective effect on the β1 receptors, and the l (-) compounds in particular have an effect on the β1 receptors.

For example, the following compounds were examined for their effect on receptors.

A = 1- (4-Amino-3-bromo-5-fluorophenyl) -2-tert.-butylaminoethanol hydrochloride, B = 5- (4-Amino-3-bromo-5-fluorophenyl) -3-tert. butyloxazolidine dihydrochloride, C = 1- (4-Amino-3-chloro-5-fluorophenyl) -2-cyclopropylaminoethanol hydrochloride, D = 1- (4-Amino-3-chloro-5-fluorophenyl) -2-tert -butylaminoethanol hydrochloride, E = 1- (4-Amino-3-fluorophenyl) -2-tert.-butylaminoethanol hydrochloride, F * 1- (4-Amino-3-trifluoromethylphenyl) -2-tert. -pentylaminoethanol hydrobromide, G = 1- (4-Amino-3-chloro-5-trifluoromethylphenyl) -2-tert.-butylaminoethanol hydrochloride, H = 1- (4-Amino-3-chloro-5-trifluoromethylphenyl) - 2-cyclobutylaminoethanol hydrochloride, I = 1- (4-Amino-3-chloro-5-cyanphenyl) -2-tert.-butylaminoethanol, j = 1- (4-Amino-3-bromo-5-cyanphenyl) - 2-tert-Butylaminoethanol hydrochloride, K = 1- (4-Amino-3-bromo-5-fluorophenyl) -2-cyclobutylaminoethanol hydrochloride, L = 1- (4-Amino-3-fluoro-5-iodophenyl) -2-cyclopropylaminoethanol hydrochloride, M = 1- (4-Amino-3-fluoro-5-cyanophenyl) -2-isopropylaminoethanol hydrochloride, N = 1- (4-Amino-3-fluoro-5-cyanophenyl) -2 tert-butylaminoethanol hydrochloride, 0-1- (4-Amino-3-cyanphenyl) -2-cyclobutylaminoethanol hydrobromide, ps1_ (4-Amino-3-cyanphenyl) -2-tert.-pentylaminoethanol q = 1_ ( 4-Amino-3-chloro-5-cyanphenyl) -2-propylaminoethanol hydrochloride, R = 1- (4-Amino-3-chloro-5-cyanphenyl) -2-sec-butylaminoethanol hydrochloride, S = 1- 4-Amino-3-chloro-5-cyanophenyl) -2- (hydroxy-tert.-butylamino) ethanol-hydro chloro T = 1- (4-Amino-3-chloro-5-cyanphenyl) -2-tert.-pentylaminoethanol hydrochloride, U = 1- (4-Amino-3-chloro-5-cyanphenyl) - 2-cyclopentylaminoethanol hydrochloride, V1-1- (4-Amino-3-chloro-5-cyanphenyl) -2- [1- (3,4-methylenedioxyphenyl) -2-propylamino] ethanol hydrochloride, W = 1_ ( 4-Amino-3-bromo-5-cyanphenyl) -2-cyclobutylaminoethanol hydrochloride, X = 1- (4-Amino-3,5-dicyanphenyl) -2-tert-butylaminoethanol hydrochloride, Y 1- (4-Amino -3-bromo-5-nitrophenyl) -2-tert.-butylaminoethanol and Z1-1- (4-Amino-3-chloro-5-nitrophenyl) -2-tert.-butylaminoethanol.

The β 1 -blocking effect was tested by antagonism against the tachycardia triggered on anesthetized cats by intravenous administration of a standard dose of 1.0 ftg / kg of N-isopropyl noradrenaline sulfate. From the mean value of the percentage decrease in the heart rate increase conditional on N-isopropylnoradrenaline sulfate supplementation, a graphical extrapolation determined an ED ED value (see Tables II and III).

The 3g-flimetic effect was tested by antagonism against the bronchospasm triggered by an intravenous administration of 20 µg / kg of acetylcholine on anesthetized guinea pig in the test apparatus developed by Konzett - Rossier after intravenous use. From the percentage reduction of bronchospasm obtained with different doses, by graphical extrapolation, an ED 50 was determined (see Table I).

The β1, blocking effect was tested by antagonism against the broncholytic effect observed with 5 µg / kg (intravenous) N-isopropylnoradrenaline sulfate on anesthetized guinea pigs in the test apparatus developed by Konzett - Rb's. triggers the bronchospasm with a standard amount of 20 pg / kg (intravenous) acetylcholine (see Table III).

The acute toxicity of the compounds was determined on groups of 10 mice each. LD ^, the dose that killed 50% of the animals in 14 days by intravenous administration, was calculated by the method set by Litchfield and Vilcoxon (see Tables II and III).

Table I

10 150502

Compound P ^ mimetic effect Effect time in n ^ ED 50 Vg / kg intravenous minutes A 9 5 8.3> 150 B 54 6.7> 110 C 54 24.0> 50 D 54 19.0> 120 E 6 3 18 , 0> 80 G 10 5 19.5> 130 H 5 5 6.8> 125 I 11 4 0.20> 95 J. 5 4 4.8> 40 K 6 3 58.0> 50 M 6 4 0.08> 40 N 5 3 0.32> 40 0 5 3 6.9 40 P 5 4 3.6 65 Q 5 3 27, 0 50 R 5 3 5.7> 80 S 53 10.0> 65 T 5 3 1.9> 40 U 4 4 9.8> 50 V 6 4 2.7> 65 W 5 3 20.5> 50 X 63 11.3> 65 Z 53 31.5> 80 1

Number of animals per dose ^ = Number of doses used to determine ED ^ q.

Table II

11502 11

Compound Effect on β ^ receptors ^ 50 'intrane ^ ED550 ^ § / ^ 8 intravenous venous A 35 18.5 34.5 B - - 27.2 C 45 14.0 57.0 D 45 8.0 35.1 E 45 13.5 69.2 F 35 35.0 G 55 11.5 36.5 H - - 36.3 I 55 0.74 60.0 J - - 67.0 K 44 1.5 26.4 L 6 5 1.3 45.2 M 53 0.27 66.4 N 64 0.022 58.4 0 55 0.030 61.8.

P 55 0.086 62.0 Q 65 0.76 53.4 R 66 0.32 40.4 S 54 0.76 81.8 T 54 0.45 33.7 U 64 0.70 39.1 V 64 1, 4 13.5

We 6 5 0.078 38.5 X 6 4 0.92 166.0 Y 54 2.8 35.8 Z 64 4.5 42.4 = «Number of animals per unit. dose ^ = Number of doses.

Table III

12 150502

Compound Blocking effect Blocking effect LD ^ q, mg / kg on β ^ receptors on P ^ receptors intravenous nl π2 ED5o »ni n2 E ^^ g / kg intravenous intravenous A- d (+) 7 4 8.4 5 1 > 2000 37.2 D- d (+) 6 4 6.2 5 1> 2000 34.2 E- d (+) 8 3 1.5 4 1> 2000 G- d (+) 8 4 12.5 5 1> 2000 33.2 n ^ = Number of animals.

Π2 = Number of doses tested on each animal.

Compounds related to the compounds in question are known from German publication specification No. 1,643,498. 1- (3-Amino-4-bromo-phenyl) -2-cyclopropylaminoethanol is described, and from German Publication No. 2,205,158, which relates to 1- (3-amino-5-trifluoromethyl-phenyl) ethanol amines.

However, it has been found, according to the invention, that an additional substituent is required for the appearance of broncholytic action. Furthermore, the compounds disclosed in the publication publications have quite different biological effects than those of the invention.

From Danish patent application no. 4717/67 and French patent no.

1,561,863 are further known related 1- (4-amino-dihalo-phenyl) - and 1- (4-amino-monohalo-phenyl) -ethanolamines, wherein the halogen atom is always a chlorine, bromine or iodine atom.

Compared with the compounds AZ prepared by the process of the invention, the 32-mimetic effect of the compounds AA = 1- (4-Amino-3-chloro-phenyl) -2-ethylaminoethanol hydrochloride, BB = 1- (4) was investigated. -Amino-3-bromo-phenyl) -2-isopropylamino-ethanol hydrochloride, CC = 1- (4-Amino-3-5-dibromo-phenyl) -2-n - * - propylamino-ethanol hydrochloride, DD = 1- (4-Amino-3-5-dibromo-phenyl) -2-isopropylamino-ethanol hydrochloride, BB - 1- (4-Amino-3-5-dibromo-phenyl) -2-n-butylamino-ethanol hydrochloride, FF = 1- (4-Amino-3,5-dibromo-phenyl) -2-sec-butylamino-ethanol hydrochloride, GC * 1- (4-Amino-3-dichloro-phenyl) - 2-tert-Butylamino-ethanol hydrochloride, H * in 1- (4-Amino-3,5-ylbromophenyl) -2- (β-hydroxyethylamino) -ethanol hydrochloride, II a 1- ( 4-Amino-3,5-dibromo-phenyl) -2-cyclopropylamino-ethanol hydrochloride, JJ = 1- (4-Amino-3-dichloro-phenyl) -2-n-propylamino-ethanol hydrochloride and KK = 1 - (4-Aino-315-dichloro-phenyl) -2-n-butylanino-ethanol hydrochloride in the same manner as or compounds A-Z.

The results are given in Table I below.

Table I: I 1 j · '

Compound n2 following mycogenic effect - EASY / kg iv_ AA 4 3> 5 000 E B "13> 250 CC 2 3> 5 000 OD 2 4> 5 000 DE 2 3> 5 000 tF 2 3> 5 000 GG 5 17-22 7.8 * HH 2 3> 5 000 II 2 3> 5 000 JJ 2 3> 5 000 'KK I 2 I 3 _> 5 000_

Furthermore, the β 1 -mimetic (stimulatory) effect on anesthetized guinea pig hearts was investigated for compounds A, D, E and 6 in comparison with compound GG as follows.

The study of the effect on heart rate was performed with bastard guinea pigs, both kinds weighing between 350 and 500 g, anesthetized with 1.8 g / kg urethane i.p. The heart rate was recorded using the ECG. The tested compounds were injected in increasing doses as solution in 0.9% NaCl solution (0.1 ml / 100 g). From the average maximum increase in heart rate obtained with the different doses, as far as possible by graphical extrapolation, an ED 1 was measured as the dose which led to an increase in heart rate by 25 p / min. The results are shown in Table II.

Table III

The connection ,. n «Increase of heart rates they ^ see Ί * by iv administration ED + 2j H? / kg A 8 9> 4 000 D 8 8-12> 3 000 E 7 12> 4 000 G 5 10> 4 000 m mm mm mm mm mm mm mm m mm m · mm m mm mm mm mm mm mm mm mm mm mm mm mm mm GG 5 10-13 14.0 n '= Number of doses rich = Number of animals / dose

The acute toxicity for compound GG was determined in the same way as for compounds A-Z. The result was an LD 2 Q value of 27.6 mg / kg i.v.

As can be seen by comparing Table 1 and Table I, the compounds prepared by the process of the invention exhibit superior efficacy in comparison with the known compounds. Thus, it is seen from Table 1 and Table I that all of the compounds A-Z have a stronger 32 "mimetic effect than the known compounds, except for the compound GG, which has better effect than some of the compounds A-Z. However, this compound has a much stronger side effect on the heart, cf. Table II.

The present compounds of general formula I, optionally in combination with other active compounds, are incorporated into the usual pharmaceutical composition. Hereby, an ericella dose is 1-100 µg and preferably 5-50 µg.

The process according to the invention is further illustrated by the following examples.

Example 1 1- (4-Amino-3-chloro-5-trifluoromethylphenyl) -2-tert.-butylaminoethanol hydrochloride.

80 g of 4'-amino-2-tert-butylamino-31-chloro-5'-trifluoromethylacetophenone hydrochloride (decomposes between 223 and 231 ° C) are dissolved in 500 ml of methanol and cooled to -15 ° C. 9.5 g of sodium borohydride are added portionwise with stirring over a period of 1 hour, keeping the temperature at -5-15 ° C. After an additional 1 hour at -15 ° C, acidify with 2N hydrochloric acid and remove the methanol in vacuo. The residual aqueous solution is made basic with 2N aqueous ammonia solution and extracted with ethyl acetate. The organic phase is washed with water, dried and 50 ml of 4.5 N hydrochloric acid is added in isopropanol. The precipitated hydrochloride of the above compound is aspirated and washed with ethyl acetate and ether. Mp. (decomp.): 205-207 ° C.

By concentrating the mother liquor it is possible to extract more material.

Example 2 1- (4-Amino-3-chloro-5-trifluoromethylphenyl) -2-tert.-pentylaminoethanol hydrochloride.

0.37 g of 1- (4-Amino-3-trifluoromethylphenyl) -2-tert.-pentylaminoethanol hydrochloride and 0.2 ml of pyridine are dissolved in 30 ml of tetrahydrofuran and cooled to 0 ° C. 0.3 g of phenyl iodide dichloride is added and the temperature is maintained at 0 ° C for 2 hours, then a further 0.1 g of phenyl iodide dichloride is added. After 20 hours standing at approx. At 4 ° G, the solution which is then partitioned between ethyl acetate and water is evaporated and the aqueous phase is basified with 2N aqueous ammonia solution and extracted again with ethyl acetate. The organic phase is washed with water, dried and a few drops of 4N isopropanol hydrochloric acid are added. The precipitated hydrochloride of the subject compound is aspirated and washed with ether. Mp. (decomp.): 176-178 ° C.

Example 3 1- (4-Amino-3-trifluoromethylphenyl) -2-tert.-butylaminoethanol.

5.05 g of 1- (4-acetylamino-3-trifluoromethylphenyl) -2-tert.-butylaminoethanol hydrochloride is boiled under reflux for 3 hours with a mixture of 50 ml of ethanol and 50 ml of 4N sodium hydroxide solution. The ethanol is removed in vacuo and the precipitated crystalline substance is extracted. After recrystallization from a mixture of ethanol and water, the melting point is 145-147 ° C.

For transfer into the monohydrochloride, the compound is dissolved in the calculated amount of 1N hydrochloric acid and evaporated to dryness in vacuo, whereupon the solid residue is recrystallized from a mixture of isopropanol and ether. Melting point of the hydrochloride: 172-174 ° C (decomp.).

Example 4 1- (4-Amino-3-trifluoromethylphenyl) -2- (N-benzyl-N-tert-butyl) aminoethanol.

0.45 g of 1- (4-amino-3-trifluoromethylphenyl) -2- (N-benzyl-N-tert-butyl) amino-ethanol are dissolved in 10 ml of methanol and 1.4 ml of 1 N hydrochloric acid in a hydrogenation vessel. And is hydrogenated in the presence of 50 mg of 10% palladium on coal as catalyst to take up 1 mole of hydrogen. Catalysts are separated by filtration and the solution is evaporated in vacuo, whereupon the residue is partitioned between ethyl acetate and 2N ammonia solution. The water-washed organic phase is dried and evaporated in vacuo again. The residue is crystallized by a mixture of ethanol and water. Mp: 145-147 ° G.

Example 5 1- (4-Amino-3-chloro-5-trifluoromethylphenyl) -2-tert-butylaminoethanol hydrochloride.

0.76 g of 1- (4-amino-3-chloro-5-trifluoromethylphenyl) -2- (N-benzyl-N-tert-butyl) aminoethanol is dissolved in 20 ml of methanol and 1.95 ml of 1N hydrochloric acid in a hydrogenation vessel and hydrogenated in the presence of 80 mg 10 7 The hydrogenation is then quenched, the catalyst is removed by filtration and the filtrate is evaporated to dryness in vacuo. The oily evaporator residue is purified on a silica gel column using an 80: 20sl mixture of chloroform, methanol and concentrated ammonia solution as eluent. The desired compound containing fractions are collected and freed of the solvent in vacuo. The residual crystallized base of the desired compound is transferred into the hydrochloride with the calculated amount of 1.07 N isopropanolic hydrochloric acid and recrystallized from a mixture of ethyl acetate and ether. Mp. (decomp.): 205-207 ° G.

Example 6 1- (4-Amino-3-trifluoromethylphenyl) -2-cyclopropylaminoethanol dihydrochloride.

4.1 g of 1- (4-amino-3-bromo-5-trifluoromethylphenyl) -2-cyclopropylaminoethanol is dissolved in 200 ml of methanol in a hydrogenation vessel and 2 g of 5% palladium oxide is added to barium sulfate as catalyst. Hydrogen is taken up to take up 1 mole of hydrogen, then the catalyst is filtered off and the filtrate is evaporated to dryness in vacuo. The residue is taken up in water, made basic with 2N ammonia solution, and the aqueous phase is extracted with ethyl acetate. The organic extracts are washed with water, dried and evaporated again. The solid residue is dissolved in isopropanol and 2 equivalents of 4N isopropanol hydrochloric acid are added. The crystallized dihydrochloride of the subject compound is suctioned off and washed with isopropanol and ether. Mp: 141.5-142 ° C (decomp.).

Example 7 1- (4-Amino-3-trifluoromethylphenyl) -2-tert.-pentylaminoethanol hydrobromide.

5 g of 1- (4-amino-3-trifluoromethylphenyl) -2-tert.-pentylaminoethanol hydrochloride are partitioned between ethyl acetate and 2N ammonia solution. The organic phase is dried and evaporated in vacuo. The residue base is dissolved in 100 ml of methanol in a hydrogenation vessel, 2.5% palladium oxide is added to barium sulfate as catalyst and hydrogenated until 1 mole of hydrogen is taken up. After removing the catalyst by filtration, the filtrate is evaporated in vacuo and the solid residue is recrystallized from isopropanol. The hydrobromide obtained of the subject compound melts at 174-175 ° C (during decomposition).

Example 8 5- (4-Amino-3-chloro-5-trifluoromethylphenyl) -3-tert-butyl-1,3-oxazolidine.

1.35 g of 1- (4-amino-3-chloro-5-trifluoromethylphenyl) -2-tert-butylaminoethanol are dissolved in 30 ml of benzene and 1.2 ml of 40% aqueous formaldehyde solution is added. Evaporate at normal pressure to half the volume, add approx. 35 ml of benzene and boil for 5 hours under reflux. Then an additional 1.5 ml of formaldehyde solution is added and the procedure described is repeated 3 more times. Evaporate to dryness in vacuo, dissolve in ether and filter out insoluble fluff. The filtrate is weakly acidified with ethereal hydrochloric acid and the precipitated product crystallizes upon tearing. Acetone and ether are extracted and recrystallized. The hydrochloride obtained of the above compound melts at 163-165 ° C (decomp.).

Example 9 1- (4β-Amino-3-fluoro-phenyl) -2-tert.-butylamino-ethanol *

Melting point of the hydrochloride: 196-197 ° C (Sun)

Prepared according to process a) from 4, -amino-2-tert.-butylamino-3'-fluoroacetophenone hydrochloride and sodium borohydride analogous to Example 1.

Example 10 1- (4-Amino-3-bromo-5-fluoro-phenyl) -2-tert-butylamino-ethanol.

Melting point of hydrochloride: 207-208 ° C (Sun.)

Prepared according to process a) from 4'-amino-3'-bromo-2-tert.-butylamino-5'-fluoro-acetophenone hydrochloride and sodium borohydride analogous to Example 1.

Example 11 1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-cyclobutylamino-ethanol.

Melting point of the hydrochloride: 177-178 ° C.

Prepared according to process a) from 4'-amino-3'-chloro-2-cyclobutylamino-5'-trifluoromethyl-acetophenone hydrochloride and sodium borohydride analogous to Example 2.

Example 12 1- (4-Amino-3-fluoro-phenyl) -2-cyclopropylamino-ethanol ·

Melting point of the hydrochloride: 157-158 ° C (Sunday) 18 150502

Prepared according to process c) from 1- (4-acetylamino-3-fluoro-phenyl) -2-cyclopropylamino-ethanol and sodium hydroxide solution analogous to Example 7.

Example 13 1- (4-Amino-3-fluoro-phenyl) -2-tert-butylamino-ethanol.

Melting point of the hydrochloride: 196-197 ° C (Sun)

Prepared according to process c) from 1- (4-amino-3-fluoro-phenyl) -2- (N-benzyl-N-tert-butyl) -amino-ethanol hydrochloride and catalytically activated hydrogen analogously to Example 13.

Example 14 1- (4-Amino-3-chloro-5-fluoro-phenyl) -2-isopropylamino-ethanol.

Melting point of hydrochloride: 152-154 ° C (Sun.)

Prepared according to process a) from 4'-amino-3'-chloro-5'-fluoro-2-isopropylamino-acetophenone hydrochloride and sodium borohydride analogous to Example 1.

Example 15 1- (4-Amino-3-chloro-5-fluoro-phenyl) -2-cyclopropylamino-ethanol.

Melting point of the hydrochloride: 175-177 ° C (Sun)

Prepared according to process a) from 4, -araino-3, -chloro-2-cyclopropylamino-5'-fluoro-acetophenone hydrochloride and sodium borohydride analogously to Example 1.

Example 16 1- (4-Amino-3-chloro-5-fluoro-phenyl) -2-tert-butylamino-ethanol.

Melting point of the hydrochloride: 206-208 ° C (Sun.)

Prepared according to process a) from 4, -amino-2-tert-butylamino-3'-chloro-5'-fluoro-acetophenone hydrochloride and sodium borohydride analogous to Example 1.

Example 17 1- (4-Amino-3-chloro-5-fluoro-phenyl) -2-tert.-pentylamino-ethanol.

Melting point of the hydrochloride: 187-188 ° C (Sun)

Prepared according to process a) from 4'-amino-3'-chloro-5'-fluoro-2-tert-pentylamino-acetophenone hydrochloride and sodium borohydride analogous to Example 1.

Example 18 1- (4-Amino-3-chloro-5-fluoro-phenyl) -2- [1- (3,4-methylenedioxy-phenyl) -2-propylamino] -ethanol.

Melting point of the hydrochloride: 119-121 ° G (Sun.)

Prepared according to process a) from 4, -amino-3, -chloro-5, -fluoro-2- [1- (3,4-methyl-dioxy-phenyl) -2-propylamino] -acetophenone and sodium borohydride analogous to Example first

Example 19 1- (4-Amino-3-bromo-5-fluoro-phenyl) -2-isopropylamino-ethanol.

Melting point of the hydrochloride: 171-173 ° C (Sun.)

Prepared according to process a) from 4'-amino-3'-bromo-α'-fluoro-2-isopropylamino-acetophenone hydrochloride and sodium borohydride analogously to Example 1.

Example 20 1- (4-Amino-3-bromo-5-fluoro-phenyl) -2-cyclopropylamino-ethanol.

Melting point of the hydrochloride: 185-187 ° C (Sun)

Prepared according to process a) from 4'-amino-3, -bromo-2-cyclopropylamino-5-fluoroacetophenone and sodium borohydride analogous to Example 1.

Example 21 1- (4-Amino-3-bromo-5-fluoro-phenyl) -2- (hydroxy-tert-butylamino) -ethanol.

Melting point: 122-125 ° C.

Prepared according to process a) from 4'-amino-3, -bromo-5, -fluoro-2- (hydroxy-tert-butylamino) -acetophenone hydrochloride and sodium borohydride analogous to Example 1 ·

Example 22 1- (4-Amino-3-bromo-5-fluoro-phenyl) -2-tert.-pentylamino-ethanol.

Melting point of the hydrochloride: 185-187 ° C (Sun)

Prepared according to process a) from A'-amino-S'-bromo-S'-fluoro-2-tert.-pentylamino-acetophenone hydrochloride and sodium borohydride analogous to Example 1.

Example 23 1- (4-Arnino-3-bromo-5-fluoro-phenyl) -2- [1- (3,4-methylenedioxy-phenyl) -2-propylamino] ethanol.

Melting point: 126-128 ° C.

Prepared according to process a) from 4'-amino-3'-bromo-5'-fluoro-2- [1- (3,4-methylenedioxy-phenyl) -2-propylamino] -acetophenone and sodium borohydride analogous to Example 1.

20

Example 2.4 1- (4-Amino-3-chloro-5-trifluoromethyl-1-phenyl) -2-i-sopropylamino-e thano1.

Melting point: 104-106 ° C.

Melting point of the hydrochloride: 185-187 ° C.

Prepared according to process a) from 4, -amino-3, -chloro-2-isopropylamino-5'-trifluoromethyl-acetophenone hydrochloride and sodium borohydride analogous to Example 2.

Example 25 1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-cyclopropylamino-ethanol. Melting point: 138-139 ° C.

Prepared according to process a) from 4'-amino-3, -chloro-2-cyclopropylamino-5'-trifluoromethyl-acetophenone and sodium borohydride analogous to Example 2.

Example 26 1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2- (hydroxy-tert-butylamino) -ethanol. Melting point of the hydrochloride: 219-220 ° C.

Prepared according to process a) from 4'-amino-3'-chloro-2- (hydroxy-tert.-butylamino) -5'-trifluoromethyl-acetophenone hydrochloride and sodium borohydride analogous to Example 2.

Example 27 1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert.-pentylamino-ethanol. Melting point of the hydrochloride: 176-178 ° C (Sun.)

Prepared according to process a) from 4, -amino-3, -chloro-2-tert.-pentylamino-5'-trifluoromethyl-acetophenone hydrochloride and sodium borohydride analogous to Example 2.

Example 28 1- (4-Amino-3-chloro-5-trifluoromethyl-1-phenyl) -2- [1- (3-trimethylenedioxy-phenyl) -2-propylamino] -ethanol.

Melting point of the hydrochloride: 206-207 ° G (Sun.)

Prepared according to process a) from 4'-amino-3'-chloro-2- [1- (3,4-methylene-dioxy-phenyl) -2-propylamino] -5'-trifluoromethyl-acetophenone hydrochloride and sodium borohydride analogously with Example 2.

21

Example 29 1- (4-Amino-3-bromo-5-trifluoromethyl-phenyl) -2-isopropylamino-ethanol.

Melting point: 102-103 ° C.

Melting point of the hydrochloride: 177-179 ° C (Sun.)

Prepared according to process a) from A'-amino-S'-bromo-β-isopropylamino-S'-trifluoromethyl-acetophenone hydrochloride and sodium borohydride analogous to Example 1.

Example 30 1- (4-Amino-3-bromo-5-trifluoromethyl-phenyl) -2-cyclopropylamino-ethanol.

Melting point: 141.5-142.5 ° C.

Melting point of the hydrochloride: 195-195.5 ° C (Sun.)

Prepared according to process a) from 4'-amino-3'-bromo-2-cyclopropylamino-5'-trifluoromethyl-acetophenone hydrochloride and sodium borohydride analogous to Example 1.

Example 31 1- (4-Amino-3-bromo-5-trifluoromethyl-phenyl) -2-tert-butylamino-ethanol.

Melting point: 85-87 ° G.

Melting point of the hydrochloride: 205-206 ° C (Sun.)

Prepared according to process a) from 4, -amino-3'-bromo-2-tert.-butylamino-5'-trifluoromethyl-acetophenone hydrochloride and sodium borohydride analogous to Example 1 *

Example 32 1- (4-Amino-3-bromo-5-trifluoromethyl-phenyl) -2-cyclobutylamino-ethanol

Melting point of the hydrochloride: 189-19l ° G (Sun.)

Prepared according to process a) from 4, -amino-3 * -bromo-2-cyclobutylamino-5'-trifluoromethyl-acetophenone hydrochloride and sodium borohydride analogous to Example 1.

Example 33 1- (4-Amino-3-bromo-5-trifluoromethyl-phenyl) -2-tert.-pentylamino-ethanol.

Melting point of the hydrochloride: 166.5-168.5 ° C (Sun.)

Prepared according to process a) from 4'-amino-3'-bromo2-tert.-pentylamino-5'-trifluoromethyl-acetophenone hydrochloride and sodium borohydride analogous to Example 1.

22

Example 34 1- (4-Amino-3-chloro-5-cyano-phenyl) -2-isopropylamino-ethanol.

Melting point of the hydrochloride: 185-188 ° C.

Prepared according to process a) from 4'-amino-3'-chloro-5'-cyano-2-isopropylamino-acetophenone and sodium borohydride analogous to Example 1.

Example 35 1- (4-Amino-3-chloro-5-cyano-phenyl) -2-tert-butylamino-ethanol.

Melting point: 125-133 ° C.

Prepared according to process a) from 43-amino-3, -chloro-5'-cyano-2-tert.-butylamino-acetophenone and sodium borohydride analogous to Example 1.

Example 36 1- (Amino-3-bromo-5-cyano-phenyl) -2-isopropylamino-ethanol.

Melting point of the hydrochloride: 186-189 ° C.

Prepared according to process a) from 4'-amino-3'-bromo-5'-cyano-2-isopropylamino-acetophenone and sodium borohydride analogous to Example 1.

Example 37 1- (4-Amino-3-bromo-5-cyano-phenyl) -2-tert-butylamino-ethanol.

Melting point of the hydrochloride: 213-215 ° C.

Prepared according to process a) from 4'-amino-3'-bromo-2-tert.-butyl-amino-5'-cyano-acetophenone and sodium borohydride analogous to Example 1.

Example 38

1- (4-Amino-3-fluoro-phenyl) -2-isopropylamino-e thano1.

Melting point of the hydrochloride: 156-158 ° C (Sunday) -----

Prepared according to process c) from 1- (4-acetylamino-3-fluoro-phenyl) -2-isopropylamino-ethanol and sodium hydroxide solution of Example 7.

Example 39 1- (4-Amino-3-fluoro-phenyl) -2-tert.-pentylamino-ethanol.

Melting point of hydrochloride: 153-155 ° C (Sun.)

Prepared according to process c) from 1- (4-acetylamino-3-fluoro-phenyl) -2-tert.-pentylamino-ethanol and sodium hydroxide solution analogous to Example 7.

23

Example 4 1- (4-Amino-3-trifluoromethyl-phenyl) -2-isopropylamino-ethanol.

Melting point: 136-137.5 ° C.

Prepared according to process d) from 1- (4-amino-3-bromo-5-trifluoromethyl-phenyl) -2-isopropylamino-ethanol and catalytically activated hydrogen analogously to Example 6.

Example 41 1- (4-Amino-3-cyano-phenyl) -2-isopropylamino-ethanol.

Melting point: 159-161 ° C.

Prepared according to process d) from 1- (4-amino-3-bromo-5-cyanophenyl) -2-isopropylaminoethanol and catalytically activated hydrogen analogously to Example 1.

Example 42 1- (4-Amino-3-cyano-phenyl) -2-tert-butylamino-ethanol.

Melting point: 181-185 ° C.

Prepared according to process d) from 1- (4-amino-3-bromo-5-cyanphenyl) -2-tert.-butylamino-ethanol and catalytically activated hydrogen analogously to Example 1.

Example 43 5- (4-Amino-3-bromo-5-fluoro-phenyl) -3-tert-butyl-oxazolidine.

Melting point of the dihydrochloride: 164-178 ° C (Sun.)

Prepared from 1- (4-Amino-3-bromo-5-fluoro-phenyl) -2-tert-butylamino-ethanol and 40% formaldehyde solution analogous to Example 8,

Example 44 1- (4-Amino-3-chloro-3-trifluoromethyl-phenyl) -2-tert-butylamino-ethanol.

Melting point of the hydrochloride: 205-207 ° C (Sun.)

Prepared according to process c) from 2-tert.-butylamino-1- [3-chloro-4- (p-chloro-benzoylamino) -5-trifluoromethyl-phenyl] -ethanol and sodium hydroxide solution analogously to Example 3.

Example 45 1- (4-Amino-3-fluoro-phenyl) -2-tert-butylamino-ethanol.

Melting point of the hydrochloride: 196-197 ° C (Sun)

Prepared according to process c) from 1- (4-benzoylamino-3-fluoro-phenyl) -2-tert-butylamino-ethanol and sodium hydroxide solution analogous to Example 3.

24 150502

Example 46 1- (4-Amino-3-chloro-5-fluoro-phenyl) -2-tert-butylamino-ethanol.

Melting point of the hydrochloride: 206-208 ° C (Sun.)

Prepared according to process c) from 2-tert-butylamino-1- (3-chloro-5-fluoro-4-propionylamino-phenyl) -ethanol and sodium hydroxide solution analogous to Example 3.

Example 47 1- (4-Amino-3-bromo-5-trifluoromethyl-phenyl) -2-cyclopentylamino-ethanol.

Melting point: 100-102.5 ° G (Sun.)

Prepared according to process a) from 4, -amino-3 * -bromo-2-cyclopentylamino-5'-trifluoromethyl-acetophenone hydrochloride and sodium borohydride analogous to Example 1.

Example 48 1- (4-Amino-3-bromo-5-cyano-phenyl) -2-cyclopropylamino-ethanol

To 7.5 g of 4'-amino-3'-bromo-5'-cyan-2-cyclopropylamino-acetophenone, dissolved in 200 ml of tetrahydrofuran and 100 ml of water, is added at room temperature 3 g of sodium borohydride and stirred for 1 hour; excess sodium borohydride is decomposed by the addition of acetone. The solvent is filtered off and the solvent is distilled off in vacuo; the residue is dissolved in hot isopropanol and, by the addition of isopropanol hydrochloric acid, the hydrochloride of 1- (4-amino-3-bromo-5-cyano-phenyl) -2-cyclo-propylamino-ethanol is recrystallized from isopropanol.

Mp: 190-193 ° C (Sunday).

Example 49 1- (4-Amino-3-bromo-5-fluoro-phenyl) -2-cyclobutylamino-ethanol a) 20 g of 41-amino-3'-bromo-51-fluoro-acetophenone are dissolved in 300 ml of chloroform.

While boiling with stirring, a solution of 4.3 ml of bromine in 20 ml of chloroform is slowly added dropwise. When the addition is complete, stir for another 5 minutes at boiling temperature and then cool to room temperature. To the crude solution of 4'-ami-no-3 ', 2-dibromo-5'-fluoro-acetophenone is added dropwise with continued stirring and under ice-cooling a mixture of 15 g of cyclobutylamine and 14 ml of triethylamine. After completion of the addition, heat for 2 hours at reflux temperature. After cooling, wash with water and evaporate the organic phase to dryness in vacuo. The residue consists of crude A'-amino-S'-bromo-cyclobutylamino-S'-fluoro-acetophenone.

b) The crude ketone obtained under (a) is dissolved in 30 ml of tetrahydrofuran. Water (5 ml) is added to the solution and then stirred and cooled with ice with 4.5 g of sodium borohydride. The solution is stirred under cooling for 3 hours, and then allowed to stand at room temperature overnight. Then, excess sodium borohydride with acetone is destroyed and the solution evaporated to dryness in vacuo. The residue is partitioned between water and chloroform, the organic phase is extracted 3 times, each time with 100 ml of 2N hydrochloric acid, the combined hydrochloric acid extracts are made alkaline with sodium hydroxide and extracted with chloroform. The chloroform solution is washed with water, dried over sodium sulfate and evaporated to dryness in vacuo. The residual residue consisting of crude 1- (4-amino-3-bromo-5-fluoro-phenyl) -2-cyclobutylamino-ethanol is dissolved in isopropanol and acidified with ethereal hydrochloric acid until pH 5. Upon addition of ether, crystallization occurs. The separated hydrochloride of the desired compound is recrystallized from isopropanol.

Mp: 164-166 ° G (Sunday).

Example 50 1- (4-Amino-3-cyano-phenyl) -2-cyclopropylamino-ethanol 4 g of 1- (4-amino-3-bromo-5-cyano-phenyl) -2-cyclopropylamino-ethanol are dissolved in methanol and hydrogenated after the addition of 1 g of palladium on carbon (10 7> s) at room temperature and a hydrogen pressure of 3-5 ato. After completion of the hydrogen uptake, the catalyst is filtered, the filtrate is evaporated to dryness in vacuo and the residue partitioned between dilute sodium hydroxide solution and chloroform. Evaporation of the chloroform phase gives 1- (4-amino-3-cyano-phenyl) -2-cyclopropylamino-ethanol as an oil purified by silica gel chromatography (eluent: chloroform: methanol = 9: 1) and crystallized out as dihydrochloride of isopropanol by the addition of ethereal hydrochloric acid.

Mp: 148-151 ° C (Sunday).

Example 51 1- (4-Amino-3-bromo-5-fluoro-phenyl) -2-cyclopentylamino-ethanol.

Melting point of hydrochloride: 167-170 ° C (dec.).

Prepared according to process a) from 4'-amino-3'-bromo-2-cyclopentylamino-5'-fluoro-acetophenone and sodium borohydride analog: with Example 49.

Example 52 1- (4-Amino-3-cyano-5-fluoro-phenyl) -2-cyclopropylamino-ethanol.

Mp. of the hydrochloride: 188-190 ° C (Sun.).

Prepared according to process a) from 4'-amino-3'-cyano-2-cyclopropylamino-5'-fluoroacetophenone and sodium borohydride analogous to Example 49.

26

Example 53 1- (4-Amino-3-cyano-5-fluoro-phenyl) -2-isopropylamino-ethanol

Mp. of the hydrochloride: 182-184 ° C (Sun.).

Prepared according to process a) from 4 * -amino-3'-cyano-5'-fluoro-2-isopropylamino-acetophenone and sodium borohydride analogous to Example 49.

Example 54 1- (4'-Amino-3-cyano-5-fluoro-phenyl) -2-cyclobutylamino-ethanol

Mp. of the hydrochloride: 222-224 ° C (sin ·).

Prepared according to process a) from 4'r-amino-3'-cyano-2-cyclobutylamino-5'-fluoroacetophenone and sodium borohydride analogous to Example 49.

Example 55 1- (4-Amino-3-cyano-5-fluoro-phenyl) -2-tert.-butylamino-e thano1.

M.p. of the hydrochloride: 242-243 ° C (dec.).

Prepared according to process a) from 4, -amino ~ 2-tert.-butylamino-3'-cyair-5'-fluoro-acetophenone and sodium borohydride analogous to Example 49.

Example 56 1- (4-Amino-3-cyano-5-fluoro-phenyl) -2-cyclopentylamino-ethanol.

Mp. of the hydrochloride: 184-186 ° C (dec.).

Prepared according to process a) from 4, -amino-3, -cyan-2-cyclopentylamino-5'-fluoroacetophenone and sodium borohydride analogous to Example 49.

Example 57 1- (4-Amino-3-cyano-5-fluoro-phenyl) ~ 2-tert.-pentylamino-ethanol.

Mp. of the hydrochloride: 172-175 ° C (sin ·).

Prepared according to process a) from 4'-amino-3 * -cyan-5 * -fluoro-2-tert-pentylamino-acetophenone and sodium borohydride analogous to Example 49.

Example 58 1- (4-Amino-3-trifluoromethyl-phenyl) -2-cyclopentylamino-ethanol.

Mp. of the hydrochloride: 144-145 ° C.

Prepared according to process d) from 1- (4-Amino-3-bromo-5-trifluoromethyl-phenyl) -2-cyclopentylamino-ethanol and catalytically activated hydrogen analogously to Example 50.

27502 27

Example 59 1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-cyclopentylamino-ethanol.

Mp. of the hydrochloride: 188-190 ° C (Sun).

Prepared according to process a) from 4'-amino-3 * -chloro-2-cyclopentylamino-5'-trifluoromethyl-acetophenone and sodium borohydride analogous to Example 48.

Example 6.0 1- (4-Amino-3-cyano-phenyl) -2-cyclobuty lamino-e thano 1

Mp. of the hydrobromide: from 193 ° C (sin ·) ·

Prepared according to process d) from 1- (4-amino-3-bromo-5-cyano-phenyl) -2-cyclobutylaminoethanol and catalytically activated hydrogen analogously to Example 48.

Example 61 1- (4β-Amino-3-cyano-phenyl) -2-cyclopentylamino-ethanol.

Mp: 158-160 ° C.

Prepared according to process d) from 1- (4-amino-3-bromo-5-cyanophenyl) ~ 2-cyclopentylaminoethanol and catalytically activated hydrogen analogously to Example 48.

Example 62 1- (4-Amino-3-cyano-phenyl) -2-tert.-pentylamino-ethanol.

Mp: 143 ° C.

Prepared according to process d) from 1- (4-amino-3-bromo-5-cyanphenyl) - 2-tert.-pentylamino-ethanol and catalytically activated hydrogen analogous to Example 48.

Example 63 1- (4-Amino-3-chloro-5-cyano-phenyl) -2-cyclopropylamino-ethanol.

Mp. of the hydrochloride: 175-177 ° C,

Prepared according to process a) from 4'-amino-3, -chloro-5, -cyan-2-cyclopropylamino-acetophenone and sodium borohydride analogous to Example 48.

Example 64 1- (4-Amino-3-chloro-5-cyano-phenyl) -2-propylamino-ethanol.

Mp. of the hydrochloride: 187-189 ° C.

Prepared according to process a) from 4'-amino-3'-chloro-5, -cyan-2-propylamino-acetophenone and sodium borohydride analogous to Example 48.

28 150502

Example 65 1- (4-Amino-3-chloro-5-cyano-phenyl) -2-cyclobutylamino-ethanol.

Mp of the hydrochloride: 178-180 ° C (dec.).

Prepared according to process a) from 4, -amino-3'-chloro-5, -cyan-2-cyclobutylamino-acetophenone and sodium borohydride analogous to Example 48.

Example 66 1- (4-Amino-3-chloro-5-cyano-phenyl) -2-sec-butylamino-ethanol.

Mp. of the dihydrochloride: 190-191 ° C »

Prepared according to process a) from 4, -amino-2-sec-butylamino-3 * -chloro-5'-cyano-acetophenone and sodium borohydride analogous to Example 48.

Example 67 1- (4-Amino-3-chloro-5-cyano-phenyl) -2- (hydroxy-tert.-butylamino) -ethanol.

Mp. of the hydrochloride: 228-230 ° C (Sun).

Prepared according to process a) from 4'-amino-3, -chloro-3'-cyano-2- (hydroxy-tert-butylamino) -acetophenone and sodium borohydride analogous to Example 48.

Example 68 1- (4-Amino-3-chloro-5-cyano-phenyl) -2-cyclopentylamino-ethanol.

Mp. of the hydrochloride: 138-144 ° C.

Prepared according to process a) from 4'-amino-3'-chloro-5'-cyano-2-cyclopentylamino-acetophenone and sodium borohydride analogous to Example 48.

Example 69 1- (4-Amino-3-chloro-5-cyano-phenyl) -2-tert.-pentylamino-ethanol.

Mp. of the hydrochloride: 218-220 ° C (Sun.).

Prepared according to process a) from 4, -amino-3, -chloro-5, -cyan-2-tert.-pentylamino-acetophenone and sodium borohydride analogous to Example 48.

Example 70 1- (4-Amino-3-chloro-5-cyano-phenyl) -2- [1- (3,4-methylenedioxy-phenyl) -2-propylamino] -ethanol.

Mp. of the hydrochloride: 189-192 ° G.

Prepared according to process a) from 4, -amino-3'-chloro-5, -cyan-2- [1- (3,4-methylenedioxy-phenyl) -2-propylamino] -acetophenone and sodium borohydride analogous to Example 48.

29

Example 71 1- (4-Amino-3-bromo-5-cyano-phenyl) -2-cyclobutylamino-ethanol.

Mp, of the hydrochloride: 215-216 ° C (Sunday) ·

Prepared according to process a) from 4, -amino-3'-bromo-5, -cyan-2-cyclobutylamino-acetophenone and sodium borohydride analogous to Example 48.

Example 72 1- (4-Amino-3-bromo-5-cyano-phenyl) -2- (hydroxy-tert.-butylamino) -ethanol.

Mp. of the hydrochloride: 221-222 ° C.

Prepared according to process a) from 4'-amino-3'-bromo-5'-cyano-2-hydroxy-tert-butylamino) -acetophenone and sodium borohydride analogous to Example 48.

Example 73 1- (4-Amino-3-bromo-5-cyano-phenyl) -2-cyclopentylamino-ethanol.

Mp. of the hydrochloride: 177 ° C.

Prepared from 4'-amino-3, -bromo-5, -cyan-2-cyclopentylamino-acetophenone and sodium borohydride analogous to Example 48.

Example 74 1- (4 * -Ami no-3-bromo-5-cyano-phe new 1) -2-tert.-pentylamine no-e t hano 1.

Mp. of the hydrochloride: 202-204 ° C (sin ·) ·

Prepared according to process a) from 4, -amino-3, -bromo-5, -cyan-2-tert-pentylamino-acetophenone and sodium borohydride analogous to Example 48.

Example 75 1- (4-Amino-3,5-dicyan-phenyl) -2-cyclopropylamino-ethanol.

Mp. of the hydrochloride: 222-223 ° C (Sun) *

Prepared according to process a) from 4 * -amino-2-cyclopropylamino-3 ', 5'-dicyanacetophenone and sodium borohydride analogous to Example 48.

Example 76 1- (4-Amino-3,5-dican-phenyl) -2-isopropylamino-ethanol.

Mp. of the hydrochloride: 224-226 ° C (sin ·).

Prepared according to process a) from 4f-amino-3 ', 5,5-dicyan-2-isopropylamino-acetophenone and sodium borohydride analogous to Example 48.

Example 77 1- (4-Amino-3,5-dicyan-phenyl) -2-cyclobutylamino-ethanol.

Mp. of the hydrochloride: 258 ° C (Sun.).

30 150502

Prepared according to process a) from 4, -amino-2-cyclobutylamino-3 *, 5'-dicyanacetophenone and sodium borohydride analogous to Example 48.

Example 78 1- (4-Amino-3,5-dicyan-phenyl) -2-sec-butylamino-ethanol.

Mp. of the hydrochloride: 197-199 ° C.

Prepared according to process a) from 4'-amino-2-sec-butylamino-3 ', 5'-dicyanacetophenone and sodium borohydride analogous to Example 48.

Example 79 1- (4-Amino-3,5-dicyan-phenyl) -2- tert -butylamino-ethano-1

Mp. of the hydrochloride: 251-253 ° G (Sun.).

Prepared according to process a) from 4, -amino-2-tert.-butylamino-3 ', 5-dicyanacetophenone and sodium borohydride analogous to Example 48.

Example 80 1- (4-Amino-3,5-dicyanophenyl) -2- (hydroxy-tert-butylamino) -ethanol.

Mp. of the hydrochloride: 240-241 ° C (Sun.).

Prepared according to process a) from 4'-amino-3 ', 5'-dicyan-2- (hydroxy-tert.-butylamino) -acetophenone and sodium borohydride analogous to Example 48.

Example 81 1- (4-Amino-3,5-dicyan-phenyl) -2-cyclopentylamino-ethanol.

Mp. of the hydrochloride: 214-216 ° G.

Prepared according to process a) from 4, -amino-2-cyclopentylamino-3, 15'-dicyanacetophenone and sodium borohydride analogous to Example 48.

Example 82 1- (4-Amino-3,5-dicyan-phenyl) -2-tert.-pentylamino-ethanol.

Mp. of the hydrochloride: 231-233 ° C (sin ·) ·

Prepared according to process a) from 4, -amino-3 ·, 5'-dicyan-2-tert.-pentylamino-acetophenone and sodium borohydride analogous to Example 48.

Example 83 1- (4-Amina-3,5-dicyan-phenyl) -2- [1- (3,4-methylenedioxy-phenyl) ~ 2-propylamino] -ethanol.

Mp. of the hydrochloride: 299-222 ° C (Sun.).

Prepared according to process a) from 4, -amino-3 ', 5, -dicyan-2- [1- (3,4-methylenedioxy-phenyl) -2-propylamino] -acetophenone and sodium borohydride analogous to Example 48.

- 31 150502

Example 84 1- (4R-Amino-3-chloro-5-nitro-phenyl) -2-tert-butylamino-ethanol.

Mp: 148-149 ° C.

Prepared according to process a) from 4'-amino-2-tert.-butylamino-3'-chloro-5'-nitro-acetophenone and sodium borohydride analogous to Example 48.

Example 85 1- (4-Amino-3-bromo-5-nitro-phenyl) -2-tert-butylamino-ethanol.

Mp: 151-152 ° G.

Prepared according to process a) from 4, -amino-3, -bromo2-tert-butylamino-5'-nitroacetophenone and sodium borohydride analogous to Example 48.

Example 86 5- (4-Amino-3-bromo-5-fluoro-phenyl) -3-tert-butyl-oxazolidine.

Mp. of the dihydrochloride: 164-178 ° C (Sun.).

Prepared from 1- (4-amino-3-bromo-5-fluoro-phenyl) -2-tert-butylamino-ethanol and formaldehyde analogous to Example 8.

Example 87 µl (4-Amino-3-fluoro-phenyl) -2-tert-butylamino-ethanol and d-1- (4-amino-3-fluoro-phenyl) -2-tert-butylamino-ethanol.

a) /-1-(4- Acetylamino-3- fluoro-phenyl)-2-(N-benzyl-N_tert.-butyl)-amino-0-(N- carbobenzoxy-L-alanyl) -ethanol and dl- ( 4-acetyl-amino-3-fluoro-phenyl) -2- (N-benzyl-N-tert-butyl) amino-O- (N-carbobenzpxy-L-alanyl) -ethanol.

To a solution of 15 g of N-carbobenzoxy-L-alanine in 300 ml of absolute tetrahydrofuran is added 14.5 g of Ν, Ν'-carbonyldiimidazole and stirred for 3 hours at room temperature. Then a solution of 10 gd, of 1- (4-acetylamino-3-fluoro-phenyl) -2- (N-benzy 1-N-tert-butyl) -amino-ethanol in 200 ml of absolute tetrahydrofuran is added. a pea-sized piece of sodium and stir for 12 days at room temperature. After this time period, evaporate to dryness in vacuo and partition the residue between chloroform and water. The chloroform phase is dried over sodium sulfate and evaporated to dryness in vacuo. The two diastereomeric esters thus obtained in admixture show different R ^ values by thin layer chromatography (silica gel G, Merckj chloroform: acetone - 10: 1).

The above evaporation residue is purified over a silica gel chromatography column without separating the diastereomeric esters (500 g silica gel, eluent: chloroform: acetone * 10: 1).

The substance containing fractions are evaporated to dryness in vacuo and recrystallized from ether. Colorless crystals are obtained consisting of pure / -1- (4-acetylamino-3-fluoro-phenyl) -2- (N-benzyl-N-tert-butyl) -amino-O- (N-carbobenzoxy-L alanyl) -ethanol.

= -101 ° (c = 2.0; methanol); R ^ value = 0.27.

The mother liquor obtained in the manner described above is evaporated to dryness in vacuo. The diastereomeric ester with the largest R 2 value (R 2 = 0.33) is isolated over a chromatography column (100 g silica gel; eluent: chloroform: acetone = 20: 1):

Colorless oil consisting of dl- (4-acetylamino-3-fluoro-phenyl) -2- (N-benzyl-N-tert-butyl) -amino-O- (N-carbobenzoxy-L-alanyl) ethanol .

^ - * ^ 364 = = ^ »0» methanol); R ^ value = 0.33.

b) / - 1- (4-Amino-3-fluoro-phenyl) -2-tert -butylamino-ethanol.

2 g /-1-(4- Acetylamino-3- fluoro- phenyl)-2-(N-benzyl-N-tert.-butyl)-amino-0-(N-carbobenzoxy-L-alanyl)-ethanol are dissolved in 60 ml of ethanol. 20 ml of 5N sodium hydroxide solution are added to the solution and heated for 4 hours at reflux temperature. After cooling, partition between chloroform and water, and the aqueous phase is extracted four times with chloroform. The combined chloroform solutions are dried over sodium sulfate and evaporated to dryness in vacuo. The residue, consisting of /_l_(4-amino-3-fluoro- phenyl)-2-(N-benzyl-N-tert.-butyl)-aminoethanol, is dissolved in 50 ml of methanol and acidified with ethereal hydrochloric acid to pH 6; 0.2 g of palladium on carbon (10 7 "s) is added and hydrogenated at room temperature and 5 atmospheric pressure in a Parr apparatus until hydrogen is no longer absorbed. After suction of the catalyst, evaporate to dryness in vacuo and give the solid residue consisting of [1- (4-amino-3-fluoro-phenyl) -2-tert-butylamino-ethanol hydrochloride to crystallize isopropanol after addition of ether.

Mp: 199 - 200 ° C (Sunday).

[α] 20 = -123.3 ° (c * 1.0; methanol).

c) d-1- (4-Amino-3-fluoro-phenyl) -2-tert-butylamino-ethanol.

The oily d1- (4-acetylanino-3-fluoro-phenyl) -2- (N-benzyl-N-tert.-butyl) -amino-O- (N-carbobenzoxy-L-alanyl) obtained in the above-described manner -ethanol is dissolved in 30 ml of ethanol. 10 ml of 5N sodium hydroxide solution are added to the solution and heated for 4 hours at reflux temperature. After cooling, partition between chloroform and water and extract the aqueous phase four more times with chloroform. The combined chloroform solutions are dried over sodium sulfate and evaporated to dryness in vacuo. The residue, consisting of d-1- (4-amino-3-fluoro-phenyl) -2- (N-benzyl-N-tert-butyl) -aminoethanol, is dissolved in 25 ml of methanol and acidified with ethereal hydrochloric acid until pH 6; 0.1 g of palladium on carbon (10%) is added and hydrogenated at room temperature and 5 atmospheric pressure in a Parr apparatus until hydrogen is no longer absorbed. After suction of the catalyst, evaporate to dryness in vacuo and give the solid residue consisting of dl- (4-amino-3-fluoro-phenyl) -2-tert-butylamino-ethanol hydrochloride to crystallize isopropanol after addition of ether.

Mp: 198 - 200 ° C (Sun).

364 = + 124.4 ° (c = 1.142; methanol).

150502 33

Example 88 'dl- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert-butylamino-ethanol and -1- (4-amino-3-chloro-5-trifluoromethyl-phenyl) - 2-tert-butylamino-ethanol.

a) d, - 1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert-butylamino-O - [(-) - menthoxy-carbonyl] -ethanol.

To a solution of 8.8 gd, - 1- (4-amino-3-chloro-5-trifluoro-methyl-phenyl) -2-tert-butylamino-ethanol in 50 ml of pyridine is added dropwise with stirring and at 20 56.6 ml of a 0.5 molar solution of chloroformic acid (~) ^ menthyl ester in toluene. After 2 hours, the solution is evaporated to dryness in vacuo. The oily residue is first rubbed off with water and taken up after removing the above solution in ether. The ethereal solution is washed successively with water, 2N ammonia (whereby a precipitate precipitated between the phases dissolves) and again with water. The ethereal solution dried with magnesium sulfate is brought to pH 6 with 4 N isopropanol hydrochloric acid. Thereby, the mixture of the hydrochlorides crystallizes out of said diastereomeric compounds. They are extracted and washed with ether.

In thin layer chromatogram on silica gel G, Merck, with butyl acetate: cyclohexane = 9: 1, the crystallate shows two equally strong spots with the approximate R 2 values of 0.45 and 0.55.

b) Separation of d- and /-1-(4-amino-3- chloro- 5 -trifluoromethyl- phenyl)-2-tert.-butylamino-0-[(-)-menthoxy- carbonyl]- ethanol.

3.0 g of the mixture obtained in the above-described mixture of the hydrodorides of d- and β-1- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert-butylamino-O-Γ ( -) - menthoxy-carbonyl] -ethanol is suspended in a small amount of water, covered with ether, added 5.0 ml of 2N ammonia and shaken until dissolved. The ether phase is separated, washed with water, dried over magnesium sulfate and evaporated in vacuo. The oily residue is chromatographed over a silica gel column (6.5 cm diameter, 107 cm long, 2.2 kg silica gel) with a mixture of butyl acetate and cyclohexane (19: 1) at a flow rate of 120 ml / hour). The pure matter fractions with R ^ value 0.55 are combined and freed of the solvent in vacuo. The residue is crystallized by petroleum ether (boiling point: 40-60 ° C). There is obtained d-1- (4-amino-3-chloro-5-trifluoro-methyl-phenyl) -2-tert.-butylamino-O - [(-) - menthoxy-carbonyl] -ethanol.

Mp: 95.5 - 96.5 ° C.

2Q φ [α] β64 = + 74.1 (c * 1.0; chloroform).

After separation of fractions containing mixtures of the diastereomeric compounds and can be passed on to further chromatographic separation, the fractions containing almost pure substance with the R 2 value are 0.45 and evaporated in vacuo. By a single recrystallization of the obtained residue from petroleum ether, chromatographically pure / -1- (4-amino-3-chloro-5-trifluoro-phe-new) -Leryl-outylamino-0 - [(-) - menthoxy-carbonyl] -ethanol.

Mp: 102 - 104 ° C.

[Α] D = -273.5 ° C (c = 1.0; chloroform).

c) d-1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert-butylamino-ethanol.

1.6 g of dl- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert.-butylamino-O- [(-) - menthoxy-carbonyl] ethanol are dissolved in 16 ml of methanol and let the solution stand for 65 hours at approx. 20 ° C. Evaporate in vacuo and purify the residue by column chromatography (silica gel; chloroform: methanolic concentrated ammonia = 90: 10: 1). The fractions with the desired substance are combined and evaporated in vacuo. The residue is dissolved in vinegar ester and the calculated amount of 4 L hydrochloric acid in isopropanol is added to the solution, whereby the hydrochloride of the desired compound crystallizes. Mp: above 94 ° C at slow decomposition.

[α] 20 D = + 154.9 ° (c = 1.0; methanol).

d) 1- (4-Arraino-3-chloro-5-trifluoromethyl-phenyl) -2-tert-butylamino-ethanol. The compound is prepared from 1.58 g / -1- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert-butylamino-O-Γ (-) - menthoxy-carbonyl] -ethanol by solvolysis with methanol and chromatographic purification analogous to the example of the enantiomeric compound.

Hydrochloride mp: above 194 ° G during slow decomposition.

[.alpha.] D @ 20 = -154.8 DEG (c = 1.0; methanol).

Example 89 d-1- (4-Amino-3-bromo-5-fluoro-phenyl) -2-tert.-butylamino-ethanol and 1- (4-Amino-3-bromo-5-fluoro-phenyl) -2-tert-butylamino-ethanol.

205 gd, - 1- (4-amino-3-broro-5-fluoro-phenyl) -2-tert.-butylamino-ethanol and 118 g of dibenzoyl-D-tartaric acid are dissolved in 2.5 l of warm ethanol, filtered and recommended for 1 day at room temperature for crystallization. The product obtained is recrystallized six times by methanol ether to give the pure d- [1- (4-amino-3-bromo-5-fluoro-phenyl) -2-tert-butylamino-ethanol] -dibenzoyl-D tartrate with m.p. 206-208 ° C (dec.).

364 = + 332.9 ° (c = 2.0; methanol).

The salt is dissolved in methanol and concentrated ammonia under heating and the base is crystallized by the addition of water. The obtained base is dissolved in absolute ethanol, neutralized with absolute ethanolic hydrochloric acid, and the crystallization of dl- (4-amino-3-bromo-5-fluoro-phenyl) -2-tert-butylamino-ethanol hydrochloride is completed by the addition of ether.

Mp: 234 - 235 ° C (Sunday).

364 = + · ^ 2.0 ° (c β 2.0; methanol).

The mother liquor from the precipitate of d- [1- (4-amino-3-bromo-5-fluoro-phenyl) -2-tert-butylamino-ethanol] -dibenzoyl-D-tartrate and the mother liquor from the first recrystallization are combined and is concentrated to a smaller volume and the base is precipitated by the addition of concentrated ammonia and water. 140 g of the 1- (4-amino-3-bromo-5-fluoro-phenyl) -2-tert-butylamino-ethanol (β-form concentrated) is dissolved in 1.8 L of absolute ethanol and added a solution of 82 g of dibenzoyl-L-tartaric acid in 500 ml of absolute ethanol is evaporated to a volume of 1 liter and the solution is allowed to stand for 3 days at room temperature for crystallization. The product obtained is recrystallized 6 times by methanol / ether. There is thus obtained 1- (4-amino-3-bromo-5-fluoro-phenyl) -2-tert.-butylamino-ethanol] -dibenzoyl-L-tartrate in pure form.

Mp: 204 - 206 ° C (Sunday). r Ί 20 L J364 = 330.2 ° (c = 2.0; methanol).

The salt is dissolved in methanol and concentrated ammonia under heating and the base is precipitated by the addition of water. The obtained base is dissolved in absolute ethanol and neutralized with ethanolic hydrochloric acid; 1- (4-Amino-3-bromo-5-fluoro-phenyl) -2-tert-butylamino-ethanol hydrochloride is crystallized by the addition of ether. Mp: 218 - 220 ° C (Sunday).

[Α] 30 D = 133.9 ° (c = 2.0; methanol).

Example 90 d-1- (4-Amino-3-chloro-5-fluoro-phenyl) -2-tert-butylamino-ethanol.

Hydrochloride m.p .: 210 - 211 ° C (Sun).

C “] 364 = + 139'7 ° (c" 2> 0 "methanol).

Prepared from d, - 1- (4-amino-3-chloro-5-fluoro-phenyl) -2-tert.-butyl-amino-ethanol by the fractional crystallization of the dibenzoyl-D-tartrate, analogous to Example 89.

/-1-(4-Amino-3-chlor-5-fluoro-phenyl)-2-tert.-butylarnino-ethanol The m.p. of 209 - 210 ° C (Sunday).

^ 364 = "139> 2 ° and 2> 0" methanol).

Prepared from d, - 1- (4-amino-3-chloro-5-fluoro-phenyl) -2-tert-butyl-amino-ethanol by the fractional crystallization of the dibenzoyl-L-tartrate, analogous to Example 89.

Example 91 d-1- (4-Amino-3-chloro-5-cyano-phenyl) -2-tert-butylamino-ethanol.

Hydrochloride mp: 197 - 199 ° C (Sun).

364 = + 39.9 ° = 2> ®> methanol).

Prepared from d, 1- (4-amino-3-chloro-5-cyano-phenyl) -2-tert-butylamino-ethanol by the fractional crystallization of the dibenzoyl-D-tartrate, analogous to Example 89.

150502 36 /-1-(4-Amino-3-chlor-5-cyan- phenyl)-2-tert.-butylamino-ethano1.

Hydrochloride mp: 199 - 202 ° C (Sun).

[α] 25 D = -59.85 ° (c = 2.0; methanol).

Prepared from d, - 1- (4-amino-3-chloro-5-cyano-phenyl) -2-tert-butylamino-ethanol by the fractional crystallization of the dibenzoyl-L-tartrate, analogous to Example 89.

Example 92 d-1- (4-Amino-3-chloro-5-fluoro-phenyl) -2-tert-butylamino-ethanol.

0.26 g of d-1- (4-amino-3-fluoro-phenyl) -2-tert.-butylamino-ethanol hydrochloride and 0.2 ml of pyridine are dissolved in 30 ml of tetrahydrofuran and cooled to 0 ° C. 0.3 g of phenyl iodide dichloride is added, the mixture is kept for 2 hours at said temperature and an additional 0.1 g of phenyl iodide dichloride is added. After 20 hours at approx. Evaporate the solution at 4 ° C, distribute between vinegar ester and water, make the aqueous extract alkaline with 2 N ammonia and extract again with vinegar ester. The organic phase is washed with water, dried and evaporated to dryness in vacuo. The residue is dissolved in absolute ethanol, neutralized with ethanolic hydrochloric acid and the hydrochloride of the desired compound is crystallized by the addition of ether. Mp: 210 - 211 ° C (Sunday).

^ 364 = + ~ 2.0; methanol).

Example 93 d-1- (4-Amino-3-bromo-5-fluoro-phenyl) -2-tert.-butylamino-ethanol.

Dissolve 0.26 g of dl- (4-amino-3-fluoro-phenyl) -2-tert.-butylamino-ethanol hydrochloride in 30 ml of 50% acetic acid and add dropwise at 0-5 ° C. 16 g of bromine dissolved in 5 ml of vinegar ester and 1 ml of water. After 15 minutes, the reaction mixture is evaporated, the residue dissolved in water, made alkaline with 2N ammonia and extracted with chloroform. The chloroform solution is dried over sodium sulfate and evaporated to dryness in vacuo. The residue is transferred into the hydrochloride of the desired compound by dissolution in ethanol, neutralization with ethanolic hydrochloric acid and addition of ether.

Mp: 234 - 235 ° C (Sunday).

+ 36.0 = + 132.0 ° (c = 2.0; methanol).

Example 94 1- (4-Amino-3-cyano-phenyl) -2-cyclobutylaminoethanol mp. of the hydrobromide: from 193 ° C (Sun.).

Prepared from 4'-amino-3'-cyano-2-cyclobutylamino-acetophenone hydrochloride and sodium borohydride analogous to Example 1.

The following compounds were prepared in an analogous manner: 1- (4-Amino-3-cyano-phenyl) -2-tert.-pentylamino-ethanol.

Mp: 143 ° C.

L- (4-Amino-3-trifluormethy1-pheny1) -2-tert-butylamino-ethanol ·

Mp. of the hydrochloride: 172 - 174 ° C (Sun.).

L- (4-Amino-3-trifluormethy1-phenyl) -2-tert.-pentylamino-ethanol.

Mp. of the hydrobromide: 174 - 175 ° C (Sun).

Example 95 1- (4-Amino-3-chloro-5-fluoro-phenyl) -2-isopropylamino-ethanol.

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

Prepared from 1- (4-amino-3-fluoro-phenyl) -2-isopropylamino-ethanol hydrochloride and chlorine analogously to Example 12.

The following compounds were prepared analogously to Example 2: 1- (4-Amino-3-chloro-5-fluoro-phenyl) -2-cyclopropylamino-ethanol hydrochloride.

Mp: 175 - 177 ° C (Sunday).

L- (4-Amino-3-chloro-5-fluoro-phenyl) -2-tert.-butylamino-ethanol hydrochloride.

Mp: 206-208 ° C (sin) · 1- (4-Amino-3-chloro-5-fluoro-phenyl) -2-tert.-penty-laminoethanol-hydrochloride

Mp: 187-188 ° C (Sunday).

1- (4-Araino-3-bromr5-fluoro-phenyl) -2-isopropylamino-ethanol hydrochloride.

Mp: 171-173 ° C (Sunday).

L- (4-Amino-3-bromo-5-fluoro-phenyl) -2-tert.-butylamino-ethanol hydrochloride.

Mp: 207-208 ° C (Sunday).

L- (4 * -Amino-3-bromo-5-fluoro-phenyl) -2-cyclobutylamino-ethanol hydrochloride.

Mp: 164-166 ° C (Sunday).

L- (4-Amino-3-chloro-5-cyano-phenyl) -2-propylamino-ethanol hydrochloride.

Mp: 187–189 C.

L- (4-Amino-3-chloro-5-cyano-phenyl) -2-sec-butylamino-ethanol dihydrochloride.

Mp: 190-191 ° C

L- (4-Amino-3-chloro-5-cyano-phenyl) -2-tert.-butylamino-ethanol.

Mp: 125-133 ° C.

1- (4R-Amino-3-chloro-5-cyano-phenyl) -2- (hydroxy-tert; -butylamino) -ethanol-hydrochloride.

Mp: 228-230 ° C (Sunday).

1_ (4_Amino-3-chloro-5-cyano-phenyl) -2-tert.-pentylamino-ethanol hydrochloride.

Mp: 218-220 ° C (Sunday).

1- (4-Amino-3-chloro-5-cyano-phenyl) -2-cyclopentylamino-ethanol-hydrochloride.

Mp: 138-144 ° G.

l ~ (4-Amino-3-chloro-5-cyano-phenyl) -2- [1- (3,4-methylenedioxy-phenyl) -2-propylamino] -ethano1 hydrochloride.

Mp: 189-192 ° C.

L- (4-Amino-3-bromo-5-cyano-phenyl) -2-isopropylamino-ethano1 hydrochloride.

M.p.

Mp ·; 213-215 ° G.

L- (4-Amino-3-bromo-5-cyano ~ phenyl) -2-cyclobutylamino-ethano1 hydrochloride.

Mp: 215-216 ° C (Sunday).

L- (4-Amino-3-chloro-5-trifluormethy1-pheny1) -2-isopropylamino-ethanol.

Mp: 104-106 ° C.

1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert-butylamino-ethano-1-hydrochloride.

Mp: 205-207 ° C (Sunday).

1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-cyclobutylamino-ethanol-hydrochloride.

Mp: 177-178 ° C.

1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert.-pentylamino-ethano1 hydrochloride.

Mp: 176-178 ° C (Sunday).

L- (4-Amino-3-bromo-5-trifluoromethyl-phenyl) -2-isopropylamino-ethano1 hydrochloride.

Mp: 177-179 ° C (Sunday).

L- (4-Amino-3-chloro-5-nitro-phenyl) -2-tert.-butylamino-ethanol.

Mp: 148-149 ° C.

L- (4-Amino-3-bromo-5-nitro-pheny1) -2-tert-butylamino-ethanol.

Mp: 151-152 ° C.

Example 96 1- (4-Amino-3-chloro-5-fluoro-phenyl) -2-isopropylamino-ethanol.

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

Prepared from 1- (4-acetylamino-3-chloro-5-fluoro-phenyl) -2-isopropylamino-ethanol hydrochloride analogously to Example 3 or from 1- (4-amino-3-chloro-5-fluoro-phenyl) phenyl) -2- (N-benzyl-N-isopropyl) amino-ethanol analogous to Example 4.

The following compounds were prepared in an analogous manner:] - (4-Amino-3-chloro-5-fluoro-phenyl) -2-cyclopropylamino-ethanol hydrochloride.

Mp: 175-177 ° C (sin ·).

L- (4-Amino-3-chloro-5-fluoro-phenyl) -2-tert.-pentylamino-ethanol hydrochloride.

Mp: 187-188 ° C (Sunday).

L- (4-Amino-3-bromo-5-fluoro-phenyl) -2-isopropylamino-ethanol hydrochloride.

Mp: 171-173 ° C (Sunday).

L- (4-Amino-3-bromo-5-fluoro-phenyl) -2-tert.-butylamino-ethanol hydrochloride.

Mp: 207-208 ° C (sin *) · 1- (4-Amino-3-bromo-5-fluoro-phenyl) -2-cyclobutylamino-ethanol hydrochloride.

Mp: 164 ° C 166 ° C (Sunday).

L- (4-Amino-3-trifluoromethyl-pheny1) -2-tert.-pentylamino-ethanol hydrobromide.

Mp: 174 DEG-175 DEG C. (Sunday).

L- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-isopropylamino-ethanol.

Mp: 104-106 ° C.

1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert.-butylamino-ethanol hydrochloride.

Mp: 205-207 ° C (Sunday).

1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-cyclobutylamino-ethanol hydrochloride.

Smp.:177-178°C.

1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert.-pentylamino-ethanol hydrochloride.

Mp: 176-178 ° C (sin) · 1- (4-Amino-3-bromo-5-trifluoromethyl-phenyl) -2-isopropylamino-ethanol hydrochloride. Mp: 177-179 ° C (Sunday).

Example 97 1- (4-Amino-3-chloro-5-nitro-phenyl) -2-tert-butylamino-ethanol.

Mp: 148-149 ° C.

Prepared from 1- (4-acetylamino-3-chloro-5-nitro-phenyl) -2-tert-butylamino-ethanol hydrochloride analogous to Example 3.

The following compound was prepared in an analogous manner: 1- (4-Amino-3-bromo-5-nitro-phenyl) -2-tert-butylamino-ethanol.

Mp: 151-152 ° C.

40502 40

Example 98 1- (4-Amino-3-fluoro-phenyl) -2-tert-butylamino-ethanol.

Melting point of the hydrochloride: 196-197 ° C (Sun).

Prepared from 1- (4-amino-3-bromo-5-fluoro-phenyl) -2-tert.-butylamino-ethanol analogous to Example 6, The following compound was prepared in an analogous manner: 1- (4-Amino-3 -trifluoromethyl-phenyl) -2-tert.-butylamino-ethanol.

Mp. of the hydrochloride: 172-174 ° C (Sun.).

Example 99 1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert-butylamino-ethanol 3.4 g of 1- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2 -Bromo-ethanol is dissolved in 25 ml of tert-butylamine and left for 20 hours at room temperature. Excess tert-butylamine is evaporated in vacuo and the residue is taken up in ether. The ether solution is washed with water, dried over magnesium sulfate and evaporated in vacuo. The evaporation residue is purified chromatographically over a silica gel column with the system chloroform: methanol: concentrated ammonia = 90: 10: 1. The combined fractions thus obtained with the desired substance are evaporated to dryness in vacuo. The residue is dissolved in ether and the solution is brought to pH 4 with isopropanol hydrochloric acid. Thereby 1- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert-butylaminoethanol hydrochloride crystallizes, which is filtered off and washed with ether and melts at 205-207 ° C (dec.).

Example 100 1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert.-butylamino-ethanol Hydrochloride mp: 205-207 ° C (dec.).

Prepared according to process f) from 1- (4-amino-3-chloro-5-trifluoro-methyl-phenyl) -2- (p-toluolsulfonyloxy) -ethanol and tert-butylamine in excess analogous to Example 99.

Analogously to Examples 99 and 100, the following compounds were prepared: 1- (4-Amino-3-fluoro-phenyl) -2-tert-butylamino-ethanol hydrochloride.

Mp: 196-197 ° C (Sunday).

L- (4-Amino-3-chloro-5-fluoro-phenyl) -2-isopropylamino-ethanol hydrochloride.

Mp: 152-154 ° C (Sunday).

l_ (4-Amino-3-chloro-5-fluoro-phenyl) -2-cyclopropylamino-ethanol hydrochloride.

Mp: 175-177 ° C (Sunday).

L- (4-toino-3-chloro-5-fluoro-phenyl) -2-tert.-butylamino-ethanol hydrochloride.

Mp: 206-208 ° C (Sunday).

1- (4-Amino-3-chloro-5-fluoro-phenyl) -2-tert.-pentylamino-ethanol hydrochloride. Mp: 187-188°G (Sun.).

1_ (4-Amino-3-bromo-5-fluoro-phenyl) -2-isopropylamino-ethanol hydrochloride.

Mp: 171-173 ° C (Sunday).

1- (4-Amino-3-bromo-5-fluoro-phenyl) -2-tert-butylamino-ethanol hydrochloride.

Mp ·: 207–208 ° C (Sunday).

l_ (4-Amino-3-bromo-5-fluoro-phenyl) -2-cyclobutylamino-ethanol hydrochloride.

Mp: 164-166 ° C. (Decomp.).

1- (4- Amino-3-cyano-5-fluoro-phenyl) -2-isopropylamino-ethanol hydrochloride.

Mp: 182-184 ° C. (Decomp.).

L- (4-Amino-3-cyano-5-fluoro-phenyl) -2-tert.-butylamino-ethanol hydrochloride.

Mp: 242-2424 C. (Sun.).

L- (4-Amino-3-cyano-phenyl) -2-cyclobutylamino-ethanol hydrobromide.

Mp: from 193 ° C. (Decomp.).

1- (4-Amino-3-cyano-phenyl) -2-tert.-pentylamino-ethanol.

Mp: 143 ° C.

1- (4-Amino-3-chloro-5-cyano-phenyl) -2-propylamino-ethanol hydrochloride ~.

Mp: 187-189 ° C.

L- (4-Amino-3-chloro-5-cyano-phenyl) -2-sec-butylamono-ethanol dihydrochloride.

Mp: 190-191 ° C.

L- (4-Amino-3-chloro-5-cyano-phenyl) -2-tert.-butylamino-ethanol.

Mp: 125-133 ° C.

L- (4-Amino-3-chloro-5-cyano-phenyl) -2- (hydroxy-tert.-butylamino) ethanol hydrochloride. Mp: 228-230 ° C. (Decomp.).

1_ (4-Amino-3-chloro-5-cyano-phenyl) -2-tert.-pentylamino-ethanol hydrochloride.

Mp: 218-220 ° C. (Decomp.).

1- (4-Amino-3-chloro-5-cyano-phenyl) -2-cyclopentylamino-ethanol hydrochloride.

Mp: 138-144 ° C.

1- (4-Amino-3-chloro-5-cyano-phenyl) -2- [1- (3,4-methylenedioxy-phenyl) -2-propylamino] -ethanol hydrochloride.

Mp: 189-192 ° C.

L- (4-Anino-3-bromo-5-cyano-phenyl) -2-isopropylamino-ethanol hydrochloride.

Mp: 186-189 ° C.

1- (4-Amino-3-bromo-5-cyano-phenyl) -2-tert.-butylamino-ethanol hydrochloride.

Mp: 213-215 ° C.

L- (4-Anino-3-bromo-5-cyano-phenyl) -2-cyclobutylamino-ethanol hydrochloride.

Mp: 215-216 ° C. (Decomp.).

1- (4-Amino-3,5-dicyano-phenyl) -2-tert.-butylamino-ethanol hydrochloride.

Mp: 251-253 ° C (Sunday).

1- (4-Anino-3-trifluoromethyl-1-phenyl) -2-tert-butylamino-ethano-1-hydrochloride.

Mp: 172-174 ° C. (see above).

1- (4-Anino-3-trifluoromethyl-phenyl) -2-tert-pentylaminoethanol hydrobroraid.

Mp: 174-175 ° C (Sunday).

1- (4- [Mino-3-chloro-5-trifluoromethyl-phenyl) -2-isopropylamino-ethanol hydrochloride. Mp: 185-187 ° C.

l_ (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2-cyclobutylamino-ethanol hydrochloride. Mp: 177-178 ° C.

1- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert.-pentylamino-ethanol hydrochloride. Mp: 176-178 ° C (Sunday).

1_ (4-amino-3-bromo-5-trifluoromethyl-phenyl) -2-isopropylamino-ethano1 hydrochloride.

Mp: 177-179 ° C (Sunday).

1_ (4-amino-3-chloro-5-nitro-phenyl) -2-tert.-butylamino-ethanol.

Mp: 148-149 ° C.

1- (4-amino-3-bromo-5-nitro-phenyl) -2-tert.-butylamino-ethanol.

Mp: 151-152 ° C.

Example 101 1- (4-Amino-3-bromo-5-fluoro = phenyl) -2-tert-butylamino-ethanol hydrochloride.

1.5 g of 2-tert.-butylamino-1- (3-bromo-5-fluoro-4-nitro-phenyl) -ethanol hydrochloride are dissolved in 40 ml of methanol. After the addition of 0.6 g of platinum dioxide, it is hydrogenated with shaking at room temperature and normal pressure until the theoretical amount of hydrogen is absorbed. The catalyst is removed and the solution is evaporated to dryness in vacuo. The crude solid residue of 1- (4-amino-3-bromo-5-fluoro-phenyl) -2-tert-butyl-ara-ethanol hydrochloride is partitioned between 2N sodium hydroxide solution and methylene chloride. The organic phase is separated, washed with water, dried over sodium sulfate and evaporated to dryness in vacuo. The residual oily residue is chromatographed over a chromatography column loaded with 80 g of silica gel using a mixture of chloroform and methanol = 10: 1 as the eluent. The substance-containing eluates are combined and evaporated to dryness in vacuo. The residue is taken up in a small amount of isopropanol and acidified with ethereal hydrochloric acid until pH 5. After addition of a small amount of ether, crystallization occurs. The crystals are extracted and washed with a mixture of isopropanol and ether.

Mp: 207-208 ° C (Sunday).

Analogously to Example 101, the following compounds were prepared: 1- (4-Amino-3-fluoro-phenyl) -2-tert.-butylamino-ethanol hydrochloride.

Mp: 196-197 ° C (Sunday).

(4-Amino-3-chloro-5-fluoro-phenyl) -2-isopropylamino-ethanol hydrochloride.

Mp: 152-154 ° C (Sunday).

l_ (4-Amino-3-chloro-5-fluoro-phenyl) -2-cyclopropylamino-ethanol hydrochloride.

Mp: 175-177 ° C (Sunday).

1- (4-Amino-3'-chloro-r-5-i-fluoro-phenyl) -2-tert-butylamino-ethanol hydrochloride.

Mp: 206-208 ° C (Sunday).

1- (4-Amino-3-chloro-5-fluoro-phenyl) -2-tert.-pentylamino-ethanol hydrochloride.

Mp: 187-188 ° C (Sunday).

1- (4-Amino-3-bromo-5-fluoro-phenyl) -2-isopropylamino-ethanol hydrochloride.

Mp: 171-173 ° G (Sunday).

1- (4-Amino-3-bromo-5-fluoro-phenyl) -2-cyclobutylamino-ethanol hydrochloride.

Mp: 164-166 ° C (Sunday).

L- (4-Amino-3-cyano-5-fluoro-phenyl) -2-isopropylamino-ethanol hydrochloride.

Mp: 182-184 ° C (Sunday).

1_ (4-Amino-3-cyano-5-fluoro-phenyl) -2-tert.-butylamino-ethanol hydrochloride.

Mp: 242 - 243 C (Sunday).

1_ (4-Amino-3-cyano-phenyl) -2-cyclobutylamino-ethano1 hydrobromide.

Mp: from 193 ° C (Sunday).

1- (4-Amino-3-cyano-phenyl) -2-tert.-pentylamino-ethanol.

Mp: 143 ° C.

l_ (4-Amino-3-chloro-5-cyano-phenyl) -2-propylamino-ethanol hydrochloride.

Mp: 187-189 ° C.

L- (4-Amino-3-chloro-5-cyano-phenyl) -2-sec-butylamino-ethanol dihydrochloride.

Mp: 190-191 ° C.

1- (4-Amino-3-chloro-5-cyano-phenyl) -2-tert.-butylamino-ethanol.

Mp: 125-133 ° 0.

1- (4-Amino-3-chloro-5-cyano-phenyl) -2- (hydroxy-tert.-butylamino) ethanol hydrochloride. Mp: 228-230 ° C (Sunday).

1- (4-Amino-3-chloro-5-cyano-phenyl) -2-tert.-pentylamino-ethanol hydrochloride.

Mp: 218-220 ° C (Sunday).

L- (4-Amino-3-chloro-5-cyano-phenyl) -2-cyclopentylamino-ethanol hydrochloride.

Mp: 138-144 ° C.

1- (4-Amino-3-chloro-5-cyano-phenyl) -2- [L- (3,4-methylenedioxy-phenyl) -2-propylamino] ethanol hydrochloride.

Mp: 189-192 ° C.

1- (4-Amino-3-bromo-5-cyano-pbenyl) -2-tsopropylamino-ethanol hydrochloride.

Mp: 186-189 ° C.

1- (4-Amino-3-bromo-5-cyano-phenyl) -2-tert-butylamino-ethanol hydrochloride.

Mp: 213-215 ° C.

1- (4-Amino-3-bromo-5-cyano-phenyl) -2-cyclobutylamino-ethanol hydrochloride.

Mp: 215-216 ° C.

L- (4-amino-3,5-dicyano-phenyl) -2-tert.-butylamino-ethanol hydrochloride.

Mp: 251-253 ° C (Sunday).

l - (4-Amino-3-trifluoromethyl-phenyl) -2-tert.-butylamino-ethanol hydrochloride.

Mp: 172-174 ° C (Sunday).

1- (4-Amino-3-trifluoromethyl-phenyl) -2-tert.-pentylamino-ethanol hydrobromide.

Mp: 174-175 ° G (Sunday).

L- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-isopropylamino-ethanol.

Mp: 104-106 ° C.

1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert.-butylamino-ethanol hydrochloride. Mp: 205-207 ° C (Sunday).

1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-cyclobutylamino-ethanol hydrochloride. Mp: 177-178 ° C.

1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert.-pentylamino-ethano1 hydrochloride. Mp: 176-178 ° G (Sunday).

l_ (4_Amino-3-bromo-5-trifluoromethyl-phenyl) -2-isopropylamino-ethanol hydrochloride. Mp: 177-179 ° C (Sunday).

Example 102 1- (4-Amino-3-bromo-5-fluoro-phenyl) -2-tert-butylaminoethanol.

To 4.8 g of 4-amino-3-bromo-5-fluoro-phenylglycolic acid tert-butylamide in 100 ml of absolute ether are added 1.2 g of lithium aluminum hydride and heated under stirring for 2 hours to boil. Then, excess lithium aluminum hydride is decomposed with acetic acid ethyl ester, water and 2N sodium hydroxide solution are added and the phases are separated. The aqueous layer is extracted with chloroform and the combined organic phases are dried and evaporated in vacuo. The residue is purified column chromatographically over silica gel with the system. Chloroform: methanol: concentrated ammonia = 90: 10: 1. The entrapment residue of the substance-containing fractions is dissolved in isopropanol and acidified with ethereal hydrochloric acid until pH 5. Upon addition of ether, crystallization occurs.

The separated hydrochloride of the desired compound is recrystallized from isopropanol.

Mp: 207-208 ° C (Sunday).

Analogously to Example 102, the following compounds were prepared in 1- (4-Amino-3-fluoro-phenyl) -2-tert-butylamino-ethanol hydrochloride.

Mp: 196-197 ° C (Sunday).

1- (4-Mino-3-chloro-5-fluoro-phenyl) -2-isopropylamino-ethanol-hydrochloride.

Stnp ·! 152-154 G (Sun) · 1 (4-Amino-3-chloro-5-fluoro-phenyl) -2-cyclopropylamino-ethanol hydrochloride.

Snip.! 175-177 ° C (Sunday).

l_ (4-Amino-3-chloro-5-fluoro-phenyl) -2-tert.-butylamino-ethanol hydrochloride.

Mp: 206-208 ° C (Sunday).

l_ (4-Amino-3-chloro-5-fluoro-phenyl) -2-tert.-pentylamino-ethanol hydrochloride.

Mp: 187-188 ° C (Sunday).

L- (4-Amino-3-bromo-5-fluoro-phenyl) -2-isopropylamino-ethanol hydrochloride.

Mp.! 171-173 ° C (decomp.).

1_ (4-Amino-3-bromo-5-fluoro-phenyl) -2-cyclobutylamino-ethanol hydrochloride.

Mp: 164-166 ° C (Sunday). in 1- (4-Amino-3-trifluoromethyl-phenyl) -2-tert-butylamino-ethanol hydrochloride.

Mp: 172-174 ° C (Sunday).

1_ (4-Amino-3-trifluoromethyl-phenyl) -2-tert.-pentylamino-ethanolhydrobromid.

Mp: 174-175 ° C (Sunday).

1_ (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-isopropylamino-ethanol.

MP ·! 104—106 C.

L- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert.-butylamino-ethanol hydrochloride. Mp: 205-207 ° G (Sunday).

L- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-cyclobutylamino-ethanol hydrochloride. Mp: 177-178 ° C.

1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert.-pentylamino-ethanol-hydrochloride Mp: 176-178 ° C (dec.).

l_ (4-Amino-3-bromo-5-trifluoromethyl-phenyl) -2-isopropylamino-ethanol hydrochloride. Mp: 177-179 ° C (Sunday).

Example 103. 1- (4-Amino-3-bromo-5-fluoro-phenyl) -2-tert.-butylamino-ethanol.

To 4.2 g of 4-amino-3-bromo-5-fluoro-phenylglyoxylic acid tert-butylamide in 100 ml of absolute ether is added 0.75 g of powdered lithium aluminum hydride, which is mechanically stirred and heated for 2 hours under reflux. Then 2.0 ml of water, 2.4 ml of 2N sodium hydroxide solution and 6.0 ml of water are added cautiously successively to the reaction mixture. The inorganic residue is washed off with chloroform and the combined filtrates are evaporated in vacuo. The residue is purified by chromatography on a silica gel column (eluent = chloroform: methanol: concentrated ammonia = 90; 10; 1). The evaporation residue of the desired fractions obtained by vacuum distillation of the solvent is dissolved in isopropanol, ethereal salt = acid is added to pH 5 and further ether is added. The crystallized hydrochloride of the above compound is aspirated and recrystallized from isopropanol.

Mp: 207-208 ° C (Sunday).

46

Analogously to Example 103, the following compounds were prepared: 1- (4-Amino-3-fluoro-phenyl) -2-tert-butylamino-ethanol hydrochloride.

Snip: 196-197 ° C (Sunday).

L- (4-Amino-3-chloro-5-fluoro-phenyl) -2-isopropylamino-ethanol hydrochloride.

Mp: 152-154 ° C (Sunday).

l_ (4-Amino-3-chloro-5-fluoro-phenyl) -2-cyclopropylamino-ethanol hydrochloride.

Mp: 175-177 ° C (Sunday).

L-4-amino-3-chloro-5-fluoro-phenyl) -2-tert.-butylamino-ethanol hydrochloride.

Mp: 206-208 ° C (Sunday).

L- (4-Amino-3-chloro-5-fluoro-phenyl) -2-tert.-pentylamino-ethanol hydrochloride.

Mp: 187-188 ° C (Sunday).

L- (4-Amino-3-bromo-5-fluoro-phenyl) -2-isopropylamino-ethanol hydrochloride.

Mp: 171-173 ° C (Sunday).

1_ (4-Amino-3-bromo-5-fluoro-phenyl) -2-cyclobutylamino-ethanol hydrochloride.

Mp: 164-166 ° C (Sunday).

L- (4-Amino-3-trifluoromethyl-phenyl) -2-tert.-butylamino-ethanol hydrochloride.

Mp: 172-174 ° G (Sunday).

1- (4-Amino-3-trifluoromethyl-phenyl) -2-tert.-pentylamino-ethanol hydrobromide.

Mp: 174-175 ° C (Sunday).

L- (4-Amino-3-chloro-5-trifluormethy1-phenyl) -2-isopropylamino-ethanol.

Mp: 104-106 ° C.

L- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert.-butylamino-ethanol hydrochloride. Mp: 205-207 ° C (Sunday).

1- (4 Amino-3-chloro-5-trifluoromethyl-phenyl) -2-cyclobutylamino-ethanol hydrochloride. Mp: 177-178 ° C.

L- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert.-pentylamino-ethanol hydrochloride. Mp: 176-178 ° C (Sunday).

L- (4-Amino-3-bromo-5-trifluoromethyl-phenyl) -2-isopropylamino-ethanol hydrochloride. Mp: 177-179 ° C (Sunday).

Example 104 1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert-butylamino-ethanol.

3.5 g of 5- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -3-tert-butyl-oxazolidone (2) is dissolved in 13 ml of vinegar ester, added at room temperature 13 ml of 45% bromine hydrochloric acid in glacial acetic acid and leave for 1 hour. Then poured on ice, made alkaline with concentrated ammonia and extracted with acetic acid ethyl ester. The organic phase is extracted with 2N hydrochloric acid, the acidic solution is adjusted to an alkaline reaction with concentrated ammonia and extracted again with vinegar ester. After evaporation of the organic solvent in vacuo, a crude product is left which after chromatographic purification over a silica gel column (eluent chloroform: methanol: concentrated ammonia = 90: 10: 1) gives pure 1- (4-amino-3-chloro) -5-trifluoromethyl-phenyl) -2-tert.-butylamino-ethanol. By dissolving in ether and adding isopropanolic hydrochloric acid, the hydrochloride is obtained, mp 205-207 ° C (Sunday).

Example 105 1- (4-Amino-3-bromo-5-fluoro-phenyl) -2-tert-butylamino-ethanol.

1.5 g of 5- (4-Amino-3-bromo-5-fluoro-phenyl) -3-tert-butyl-oxazolidone (2) is heated in 25 ml of 3 N hydrochloric acid for 3 hours at 90 ° C. After cooling, the slightly cloudy solution is filtered, brought to pH 9 with sodium hydroxide solution and extracted with chloroform. The chloroform phase is washed with water, dried over sodium sulfate and evaporated to dryness in vacuo. The oily residue is taken up in a small amount of isopropanol and acidified to pH 5 with ethereal hydrochloric acid. After adding a small amount of ether, crystallization occurs. The crystals are aspirated and washed with a mixture of isopropanol and ether.

Mp: 207-208 ° C (Sunday).

Example 106 1- (4-Amino-3-chloro-5-cyano-phenyl) -2-tert-butylamino-ethanol.

0.5 g of 5- (4-Amino-3-chloro-5-cyano-phenyl) -3-tert-butyl-oxazolidone (2) (mp: 115-119 ° C) is heated with 5 ml of concentrated hydrochloric acid for 30 minutes under reflux. Cool, add ice, make alkaline with sodium hydroxide solution and extract: 1- (4-amino-3-chloro-5-cyano-phenyl) -2-tert-butylamino-ethanol with chloroform. The product is purified by chromatography on silica gel (eluent chloroform: methanol = 7: 3). Mp: 131-135 ° C> m.p. of hydrochloride: 204-207 ° G.

Analogously to Examples 104 - 106, the following compounds were prepared: 1- (4-Amino-3-fluoro-phenyl) -2-tert-butylamino-ethanol hydrochloride.

Mp: 196-197 ° C (Sunday).

L- (4-Amino-3-chloro-5-fluoro-phenyl) -2-isopropylamino-ethanol hydrochloride.

Mp: 152-154 ° C (Sunday).

L- (4-Amino-3-chloro-5-fluoro-phenyl) -2-cyclopropylamino-ethanol hydrochloride.

Mp: 175-177 ° C (Sunday).

L- (4-Amino-3-chloro-5-fluoro-phenyl) -2-tert.-butylamino-ethanol hydrochloride.

Mp: 206-208 ° C (Sunday).

1- (4-Amino-3-chloro-5-fluoro-phenyl) -2-tert.-pentylamino-ethanol hydrochloride.

Mp: 187-188 ° C (sin).

1- (4-Amino-3-bromo-5-fluoro-phenyl) -2-isopropylami.no-ethanol-hydrochloric !.

Mp: 171-173 ° C (Sunday).

1- (4-Amino-3-bromo-5-fluoro-phenyl) -2-cyclobutylamino-ethanol hydrochloride.

Mp: 164-166 ° C (Sunday).

1_ (4-Amino-3-cyano-5-fluoro-phenyl) -2-isopropylamino-ethanol hydrochloride.

Mp: 182-184 ° C (Sunday).

1- (4-Amino-3-cyano-5-fluoro-phenyl) -2-tert.-butylamino-ethanol hydrochloride.

Mp: 242-243 ° C (Sunday).

1- (4-Amino-3-cyano-pheny1) -2-cyclobutylamino-ethanol hydrobromide.

Mp: from 193 ° G (Sunday).

1- (4-Amino-3-cyano-phenyl) -2-tert.-pentylamino-ethano1.

Mp: 143 ° C.

1_ (4-Amino-3-chloro-5-cyano-phenyl) -2-propylamino-ethanol hydrochloride.

Mp: 187-189 ° C.

L- (4-Amino-3-chloro-5-cyano-phenyl) -2-sec-butylamino-ethanol dihydrochloride.

- »Mp: 190_191 ° C.

1_ (4-Amino-3-chloro-5-cyano-phenyl) -2- (hydroxy-tert.-butylamino) ethanol hydrochloride. Mp: 228-230 ° C (Sunday).

1- (4-Amino-3-chloro-5-cyano-phenyl) -2-tert.-pentylamino-ethanol hydrochloride.

Mp: 218-220 ° C (sin) · 1- (4-Amino-3-chloro-5-cyano-phenyl) -2-cyclopentylamino-ethanol hydrochloride.

Mp: 138-144 ° C.

l_ (4-Amino-3-chloro-5-cyano-phenyl) -2- [L- (3,4-methylenedioxy-phenyl) -2-propylamino] ethanol hydrochloride.

Mp: 189-192 ° C.

1- (4-Amino-3-bromo-5-cyano-phenyl) -2-isopropylamino-ethanol hydrochloride.

Mp: 186–189 C.

l_ (4-Amino-3-bromo-5-cyano-phenyl) -2-tert.-butylamino-ethanol hydrochloride.

M.p .: 213-215 C (Sun.).

L- (4-Amino-3-bromo-5-cyano-phenyl) -2-cyclobutylamino-ethanol hydrochloride.

Mp: 215-216 ° C (Sunday).

1_ (4-Amino-3,5-dicyano-phenyl) -2-tert.-butylamino-ethano1 hydrochloride.

Mp: 251-253 ° C (Sunday).

1- (4-Amino-3-trifluoromethyl-phenyl) -2-tert.-butylamino-ethanol hydrochloride.

Mp: 172-174 ° C (Sunday).

1- (4-Amino-3-trifluoromethyl-phenyl) -2-tert.-pentylamino-ethanol-hydrobromide.

Mp: 174-175 ° C (Sunday).

1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-isopropylamino-ethanol.

Mp: 104 ~ 106 ° C.

1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-cyclobutylamino-ethanol hydrochloride. Mp: 177-178 ° C.

L- (4-Amino-3-chloro-5-trifluormethy1-phenyl) -2-tert-pentylamlno-ethanol hydrochloride. Mp: 176-178 ° C (dec) · 1- (4-Amino-3-bromo-5-trifluoromethyl-phenyl) -2-isopropylamino-ethanol hydrochloride. Mp: 177-179 ° C (Sunday).

1- (4-Amino-3-chloro-5-nitro-phenyl) -2-tert.-butylamino-ethanol.

Mp: 148-149 ° C.

1- (4-Amino-3-bromo-5-nitro-phenyl) -2-tert.-butylamino-ethanol.

Mp: 151-152 ° G.

Example 107 1- (4-Amino-3-cyano-5-fluoro-phenyl) -2-tert-butylamino-ethanol.

10 g of 4'-amino-3'-cyan-5'-fluoro-acetophenone are added portionwise with stirring at 60 ° C in a solution of 6 g of selenium dioxide in 36 ml of dioxane and 1 ml of water. Then heat for 4 hours at reflux temperature. To the thus prepared solution of 4-amino-3-cyano-5-fluoro-phenylglyoxal is added dropwise after cooling and under external cooling with ice 30 ml of tert.-butylamine. After the addition is complete, dilute with 150 ml of ethanol and filter from the undissolved. To the solution containing the crude 4-amino-3-cyano-5-fluoro-phenylglyoxylidene tert-butylamine is added 6 g of sodium borohydride with stirring and cooling and left to stand overnight at room temperature. Then, excess sodium borohydride is dissolved with acetone, water is added and the organic solvents removed in vacuo. The precipitated precipitate is aspirated, washed with water and taken up in 200 ml of 2N hydrochloric acid. The hydrochloric acid solution is filtered and then 10 N sodium hydroxide solution is added to obtain a pH of 6. The aqueous phase is washed with chloroform and an additional 10 N sodium hydroxide solution is added until a clear alkaline reaction. The precipitated precipitate is extracted with chloroform, the chloroform solution washed with water, dried over sodium sulfate and evaporated to dryness in vacuo. The solid residue of 1- (4-amino-3-cyano-5-fluoro-phenyl) -2-tert-butylamino-ethanol is taken up in 100 ml of absolute ethanol and acidified to pH 6 with ethereal hydrochloric acid. Already during the acidification with ethereal hydrochloric acid, the secretion of the hydrochloride in the form of colorless crystals begins. The crystallization is completed by the addition of ether. The crystals are aspirated and washed with ether.

Mp: 242-243 ° C (Sunday).

150502 50

Example 108 1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert-butylamino-ethanol.

Dissolve 0.4 g of 4-amino-3-chloro-5-trifluoromethyl-phenylglyoxal hydrate in 10 ml of methanol, add 0.23 g of tert-butylamine and leave for 3 hours at room temperature. The solution is then cooled to -20 ° C, 0.1 g of sodium borohydride is added and stirred for 20 minutes at -10 ° C to -20 ° C. Acidify with 2N hydrochloric acid to pH 2 and then bring the pH to pH 9 with 2N ammonia, dilute with water and remove the methanol in vacuo. The aqueous mixture is extracted with ether, the ether extract is washed with water, dried over magnesium sulfate and evaporated in vacuo. The oily evaporator residue is dissolved in a small amount of ether and brought to pH 4 with isopropanol hydrochloric acid. Crystalline 1- (4-amino-3-chloro-5-trifluoro-methyl-phenyl) -2-tert-butylamino-ethanol hydrochloride is obtained, which is aspirated and washed with ether. >

Mp: 205-207 ° C (sin ·).

Analogously to Examples 107 and 108, the following compounds were prepared: 1- (4-Amino-3-fluoro-phenyl) -2-tert-butylamino-ethanol hydrochloride.

Mp: 196-197 ° C (Sunday).

L- (4-Amino-3-chloro-5-fluoro-phenyl) -2-isopropylamino-ethanol hydrochloride.

Mp: 152-154 ° C (dec.).

L- (4-Amino-3-chloro-5-fluoro-phenyl) -2-cyclopropylamino-ethanol hydrochloride.

Mp: 175-177 ° G (Sunday).

l_ (4-Amino-3-chloro-5-fluoro-phenyl) -2-tert-butylamino-ethanol hydrochloride. .

Mp: 206-208 ° C (Sunday).

1- (4-Amino-3-chloro-5-fluoro-phenyl) -2-tert.-pentylamino-ethanol-hydrochloride.

Mp: 187-188 ° C (Sunday).

L- (4-Amino-3-bromo-5-fluoro-phenyl) -2-isopropylamino-ethanol hydrochloride.

Mp: 171-173 ° C (Sunday).

L- (4-Amino-3-bromo-5-fluoro-phenyl) -2-tert-butylanrino-ethanol hydrochloride.

Mp: 207–208 G (sin ·).

L- (4-Amino-3-bromo-5-fluoro-phenyl) -2-cyclobutylamino-ethanol hydrochloride.

Mp: 164-166 ° C (Sunday).

L- (4-Amino-3-cyano-5-fluoro-phenyl) -2-isopropylamino-ethanol hydrochloride.

Mp: 182-184 ° C (Sunday).

1- (4-Amino-3-cyano-pheny1) -2-cyclobutylamino-ethano1 hydrobromide.

Mp: from 193 ° C (Sunday).

(4-Amino-3-cyano-phenyl) -2-tert.-pentylamino-ethanol.

Mp: 143 ° C.

1- (4-Amino-3-chloro-5-cyano-phenyl) -2-propylamino-ethanol hydrochloride.

Mp: 187-189 ° C.

L- (4-Amino-3-chloro-5-cyano-phenyl) -2-sec-butylamino-ethanol dihydrochloride.

Mp: 190-191 ° C.

1_ (4-Amino-3-chloro-5-cyano-phenyl) -2-tert.-butylamino-ethanol.

Mp: 125-133 ° C.

1- (4-Amino-3-chloro-5-cyano-phenyl) -2- (hydroxy-tert.-butylamino) -ethanol hydrochloride · Mp: 228-230 ° C (dec.).

1- (4-Amino-3-chloro-5-cyano-phenyl) -2-tert.-pentylamino-ethanol hydrochloride.

Mp: 218-22 ° C (dec.) -1 (4-Amino-3-chloro-5-cyano-phenyl) -2-cyclopentylamino-ethanol hydrochloride.

Mp: 138-144 ° C.

1- (4-Amino-3-chloro-5-cyano-phenyl) -2- [L- (3,4-methylenedioxy-phenyl) -2-propylamino] ethanol hydrochloride.

Mp: 189-192 ° C.

1- (4-Amino-3-bromo-5-cyano-phenyl) -2-isopropylamino-ethanol hydrochloride.

Mp: 186-189 ° C.

1- (4-Amino-3-bromo-5-cyano-phenyl) -2-tert-butylaraino-ethanol hydrochloride.

Mp: 213-215 ° C.

L- (4-Amino-3-bromo-5-cyano-phenyl) -2-cyclobutylamino-ethanol hydrochloride.

Mp: 215-216 ° C (Sunday).

1- (4-Amino-3,5-dicyano-phenyl) -2-tert.-butylamino-ethanol hydrochloride.

Mp: 251-253 ° C (Sunday).

1- (4-Amino-3-trifluoromethyl-phenyl) -2-tert.-butylamino-ethanol hydrochloride.

Mp: 172-174 ° C (Sunday).

1- (4-Amino-3-trifluoromethyl-phenyl) -2-tert.-pentylamino-ethanol hydrobromide.

Mp: 174-175 ° C (Sunday).

1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-isopropylamino-ethanol.

Mp: 104-106 ° C.

1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-cyclobutylamino-ethanol hydrochloride. Mp: 177-178 ° C.

1_ (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert.-pentylamino-ethano1 hydrochloride. Mp: 176-178 ° C (Sunday).

1- (4-Amino-3-bromo-5-trifluormethy1-phenyl) -2-isopropylamino-ethanol hydrochloride. Mp: 177-179 ° C (Sunday).

L- (4-Amino-3-chloro-5-nitro-phenyl) -2-tert.-butylamino-ethanol.

Mp: 148-149 ° C.

rfl.i i '-. CC ·. - (4-Arraino-3-bromo-5-nitro-phenyl) -2-tert. butylamino-ethanol.

Mp: 151-152 ° C.

Example 109 1- (4-Amino-3-bromo-5-nitro-phenyl) -2-tert-butylamino-ethanol.

2.9 g of 1- (4-amino-3-bromo-phenyl) -2-tert-butylamino-ethanol are dissolved in 15 ml of a mixture of concentrated nitric acid and concentrated sulfuric acid. The solution is heated to 80-85 ° C for 1 minute and then poured onto ice. By the addition of ammonia, the mixture is made alkaline and then extracted with chloroform. The chloroform solution is washed with water, dried and evaporated to dryness in vacuo. The residue is chromatographed over silica gel (eluent: chloroform: methanol = 8: 2) and the crude product thus obtained is recrystallized from vinegar ester. Melting point of 1- (4-amino-3-bromo-5-nitro-phenyl) -2-tert-butylamino-ethanol 151-152 ° C.

Example 110 1- (4-Amino-3-chloro-5-nitro-phenyl) -2-tert-butylamino-ethanol.

Mp: 148-149 ° C.

Prepared from 1- (4-amino-3-chloro-phenyl) -2-tert.-butylamino-ethanol and nitric / sulfuric acid analogous to Example 109 »

Example 111 1- (4-Amino-3-chloro-5-cyano-phenyl) -2-tert-butylamino-ethanol.

0.5 g of N-acetyl-N-2-acetoxy-2- (4-amino-3-chloro-5-cyano-phenyl) ethyl] tert-butylamine (mp: 160-162 ° C) is stirred. with methanolic sodium hydroxide solution for 1/2 hour at 20 ° C. Water is added and the methanol is evaporated off in vacuo, the residual aqueous phase is extracted with chloroform, the chloroform phase is dried over sodium sulfate, evaporated to dryness in vacuo, and the residue of ethanol is crystallized.

1- (4-amino-3-chloro-5-cyano-phenyl) -2-tert-butylamino-ethanol is obtained.

Mp: 131-135 ° C, hydrochloride mp: 204-207 ° C.

Analogously to Example 111, the following compounds were prepared: 1- (4-Amino-3-fluoro-phenyl) -2-tert-butylamino-ethanol hydrochloride.

Mp: 196-197 ° (Sunday).

I- (4-Amino-3-chloro-5-fluoro-phenyl) -2-isopropylamino-ethanol hydrochloride.

Mp: 152-154 ° C (Sunday).

L- (4-Amino-3-chloro-5-fluoro-phenyl) -2-cyclopropylamino-ethanol hydrochloride.

Mp: 175-177 ° C (Sunday).

L- (4-Amino-3-chloro-5-fluoro-phenyl) -2-tert.-butylamino-ethanol hydrochloride.

Mp: 206-208 ° C (Sunday).

1- (4-Amino-3-chloro-5-fluoro-phenyl) -2-tert.-pentylamino-ethanol hydrochloride.

Mp: 187-188 ° C (Sunday).

L- (4-Araino-3-bromo-5-fluoro-phenyl) -2-isopropylamino-ethanol hydrochloride.

Mp: 171-173 ° G (Sunday).

l_ (4_Amino-3-bromo-5-fluoro-phenyl) -2-tert.-butylamino-ethanol hydrochloride.

Mp: 207-208 ° C (Sunday).

1- (4-Amino-3-bromo-5-fluoro-phenyl) -2-cyclobutylamino-ethanol hydrochloride.

Mp: 164-166 C (Sun).

L- (4-Amino-3-cyano-5-fluoro-phenyl) -2-isopropylamino-ethanol hydrochloride.

Mp: 182-184 ° C (Sunday).

L- (4-Amino-3-cyano-5-fluoro-phenyl) -2-tert.-butylamino-ethanol hydrochloride.

Mp: 242-243 ° G (Sunday).

l_ (4-Amino-3-cyano-phenyl) -2-cyclobutylamino-ethanol hydrobromide.

Mp: from 193 ° G (sin ·).

1- (4-Amino-3-cyano-phenyl) -2-tert.-pentylamino-ethanol.

Mp: 143 ° C.

L- (4-Amino-3-chloro-5-cyano-phenyl) -2-propylamino-ethanol hydrochloride.

Mp: 187-189 ° C.

L- (4-Amino-3-chloro-5-cyano-phenyl) -2-sec-butylamino-ethanol dihydrochloride.

Mp: 190-191 ° C.

1- (4-Amino-3-chloro-5-cyano-phenyl) -2- (hydroxy-tert-butylamino) -ethanol hydrochloride Mp: 228-230 ° G (dec.).

L- (4-Amino-3-chloro-5-cyano-phenyl) -2-tert.-pentylamino-ethanol hydrochloride.

Mp: 218-220 ° C (Sunday).

L- (4-Amino-3-chloro-5-cyano-phenyl) -2-cyclopentylamino-ethanol hydrochloride.

Mp: 138-144 ° C.

1- (4-Amino-3-chloro-5-cyano-phenyl) -2- [L- (3,4-methylenedioxy-pheny1) -2-propylamino] -ehtanol hydrochloride.

Mp: 189-192 ° C.

1- (4-Amino-3-bromo-5-cyano-phenyl) -2-isopropylamino-ethanol hydrochloride.

Mp: 186-189 ° C.

1- (4-Amino-3-bromo-5-cyano-phenyl) -2-tert.-butylamino-ethanol hydrochloride.

Mp: 213-215 ° C.

L- (4-Amino-3-bromo-5-cyano-phenyl) -2-cyclobutylamino-ethanol hydrochloride.

Mp: 215-216 ° C (Sunday).

1_ (4-Amino-3,5-dicyano-phenyl) -2-tert.-butylamino-ethanol hydrochloride.

Mp: 251-253 ° C (Sunday).

1- (4-Amlno-3-trifluoromethyl-phenyl) -2-tert.-butylamino-ethanol hydrochloride.

Mp: 172-174 ° C (Sunday).

1- (4-Amino-3-trifluoromethyl-phenyl) -2-tert.-pentylamino-ethanol hydrobromide.

Mp: 174-175 ° C (Sunday).

1- (4-Amino-3-chloro-5-trifluoromethyl-pheny1) -2-isopropylamino-ethano1.

• Mp: 104-106 ° C.

1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert · -buty1amino-ethanol hydrochloride. Mp: 205-207 ° C (Sunday).

L- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-cyclobutylamino-ethanol hydrochloride.

Mp: 177-178 ° G.

1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert.-pentylamino-ethanol hydrochloride. Mp: 176-178 ° C (Sunday).

L- (4-Amino-3-bromo-3-trifluoromethyl-phenyl) -2-isopropylamino-ethanol hydrochloride. Mp: 177-179 ° C (Sunday).

l_ (4-Amino-3-chloro-5-nitro-phenyl) -2-tert.-butylamino-ethanol.

Mp: 148-149.

1- (4-Amino-3-bromo-5-nitro-phenyl) -2-tert-butyl amino-ethanol.

Juice: 151-152 ° C.

Claims (21)

150502 1. Analogous process for the preparation of aminophenylethanolamines of the general formula I ° A 1 1 χ * R - CH 2 - I. R 2 represents R 2 represents a hydrogen, fluorine, chlorine or bromine atom or a cyano-2 group, R represents a trifluoromethyl, nitro or cyano group, R 3 represents an alkyl or cycloalkyl group having 3-5 carbon atoms, a hydroxy -tert-butyl-4 or 3,4-methylenedioxyphenyl-pronyl group, and P. and A each represent a hydro-4 * genome or R together with A represents a group of the formula or their optically active antipodes or physiologically acceptable acid addition salts with inorganic or organic acids, characterized in that a) a compound of the general formula II y Ε - c »2 - 4 11 i2 14 wherein R -R has the meaning given above, to form a compound of formula I wherein A represents a hydrogen atom and, if R in the formula of the compound obtained, represents a hydrogen atom and then, if desired, * A converts it to a compound of formula I wherein A together with R represents a group of formula. C1I20, or b) for preparation a are compounds of the general formula I wherein J 1 represents 34. .1 is a hydrogen atom and R and R are as defined and wherein R represents a chlorine or bromine atom halogenates a compound of general formula III OH R 3 -c "2 - V - R or c) for the preparation of compounds of general formula X, wherein A represents a hydrogen atom, one or more protecting groups are deprived of a compound of general formula IV ΟΧ, Ί1 * νχΗ - - \ S3 ί R2 12 3 wherein R, R and R have the indicated meaning, X represents a protecting group for a hydroxy group or a hydrogen atom, Y represents a protecting group for 2 an amino group or a hydrogen atom, Y represents a protecting group for an amino group or has the same meanings as indicated for the group R however, at least 12 of the groups X, Y and / or Y must represent one of the above protecting groups, or d) for the preparation of compounds of general formula I wherein R * and A each represent a hydrogen atom, the dehalogenes is a compound of general formula V. Γ / r 3 Hal CH - CH 2 _ NV vxy l2 2 4 wherein R - R is as defined and Hal represents a chlorine, bromine or iodine atom, or e) for the preparation of compounds of the general formula X wherein A represents a hydrogen atom, reacting a compound of the general formula VII in which R and R are as defined and Z represents a chlorine, bromine or iodine atom or a p-toluenesulfonyl group , with an amine of the general formula VIII H - C / VI11 34 wherein R and R are as defined, or f) for the preparation of compounds of the general formula I wherein A represents 2 a hydrogen atom and R is not a nitro group, reduces a compound of the general formula IX OR R3 r1vVnJh - CH2 - 4 π F 1 3 4 2 '2 wherein R, R and R have the meaning given and R has the meaning given for R with the exception of a nitro group, or g) for the preparation of compounds of general formula I wherein A represents 1 2 a hydrogen atom, R does not denote a cyano group and R does not denote a nitro or cyano group reduces a compound of the general formula XM g3 * 1; γΎ - = - <4 R wherein R 3 and R 4 have the indicated meaning, in * "" * ..... 2 "........... * ......... the meaning given for R, with the exception of a nitro and cyano group has 2 the meaning given for R and B represents a carbonyl group or a hydroxymethyl group, or. H) for the preparation of compounds of general formula I wherein R and A each represent a hydrogen atom hydrolyzes an oxazolidone of general formula XI 0-C - 0 VyW1- * 3 »2» y 3 wherein R, R and R are as defined, or i) for the preparation of compounds of general formula I wherein R and A each represent a hydrogen atom, reducing an aldehyde of the general formula XII R * - CHO R 1 2 wherein R and R are as defined, or a hydrate thereof, in the presence of an amine of the general formula Villa H - N Villa 3 wherein R is as defined; or 2 3. to prepare compounds of the general formula I wherein R represents a nitro group and Δ represents a hydrogen atom, a compound of the general formula XIII OH .R3 R ^^ R / V - CH - CH - XIII, Xx N 13a in which R1, RJ and R4 are as defined, or t) for the preparation of compounds of the general formula I, wherein A together with 4 to 4 R represents the group reacting a compound of formula I wherein R and A are each represents a hydrogen atom, with an aldehyde C 2 O. a compound of general formula I obtained by one of the processes a) -j) wherein A represents a hydrogen atom, if desired, is cleaved into its optically active antipodes and / or a obtained compound if desired is transferred into a physiologically acceptable acid addition salt with a inorganic or organic acid. Process according to claim 1, characterized in that the reaction is carried out in a solvent. Process according to claims 1a and 2, characterized in that the reduction is carried out with a complex metal hydride, with aluminum isopropylate or with catalytically activated hydrogen at temperatures between -20 ° C and the boiling temperature of the solvent used. 150502 Process according to claims 1b and 2, characterized in that the halogenation is carried out with chlorine, bromine, tribromophenol bromine or phenyliodide dichloride, optionally in the presence of a tertiary organic base or a heavy metal salt such as mercuric oxide, and at temperatures between 0 and 50 ° C. . Process according to claims 1c and 2, characterized in that the cleavage of one or more protecting groups is carried out by hydrolysis if 12 'X, Y and / or Y represent an acyl group or X represents a trimethylsilyl group or a tetrahydropyranyl - (2) group. Process according to claims 1c and 2, characterized in that the cleavage of a protecting group is carried out by hydrogenolysis if X, Y and / or 2 or Y represents a benzyl group. Process according to claims 5 and 6, characterized in that the reaction is carried out at temperatures up to the boiling temperature of the solvent used. 8. A process according to claims 1d and 2, characterized in that the dehalogenation is carried out with triphenylphosphine or with hydrogen in the presence of a hydrogenation catalyst and at temperatures between 0 and 150 ° C. Process according to claims 1e and 2, characterized in that the reaction is carried out at temperatures between 0 and 100 ° C. Process according to claims 1f and 2, characterized in that the reduction is carried out with nascent hydrogen, with hydrogen in the presence of a catalyst, with stannous chloride and hydrochloric acid or with a complex metal hydride and at temperatures between 0 and 100 ° C. Process according to claims Ig and 2, characterized in that the reduction is carried out with a complex metal hydride at temperatures between 0 and 120 ° G and suitably at the boiling temperature of the solvent used. Method according to claims 1h and 2, characterized in that the hydrolysis is carried out in the presence of an acid or in the presence of a base at temperatures between 0 and 110 ° C. Process according to claims 1 and 2, characterized in that an in situ formed compound of the general formula XIIa - CH = N - R3 I of XIIa H2N'AV R2123 is reduced, wherein R, R and R in the sense given. »60 150502 Process according to claims 1, 2 and 13, characterized in that the reduction is carried out with a complex metal hydride, with nascent hydrogen or with hydrogen in the presence of a catalyst at temperatures between -20 and 100 ° C, preferably at temperatures up to the boiling temperature. for the solvent used. Process according to claims 1j and 2, characterized in that the nitration is carried out with nitric acid or with a mixture of concentrated nitric acid and concentrated sulfuric acid at temperatures between -20 and 100 ° C. Process according to claim 1, characterized in that a obtained racemate of the general formula I is separated, if desired, by racemate cleavage or that a mixture of diastereoisomeric compounds of the general formula XIV OR7 R3 R Wherein R 1, R 3, R 3 and R 2 are as defined in claim 1, R 2 represents a hydrogen atom or an acyl group and R 7 represents a chiral acyl group is separated into its pure diastereoisomeric components, the group R does not denote a hydrogen atom, is cleaved. Process according to claim 16, characterized in that the racemate cleavage is carried out by fractional crystallization of the diastereoisomeric salts. Process according to claim 17, characterized in that D (-) - tartaric acid, L (+) - tartaric acid, dibenzoyl-D-tartaric acid, dibenzoyl-L-tartaric acid, (+) - camphor-10 are used as optically active auxiliary acid. -sulfonic acid, L (-) - malic acid, L (+) - mandelic acid, then-bromocamphor-JF-sulfonic acid or 1-quinic acid. ICE. Process according to claim 16, characterized in that the cleavage of a mixture of diastereoisomeric compounds of the general formula XIV is carried out by fractional crystallization and / or column chromatography on an inert carrier. Process according to claim 16, characterized in that the racemate cleavage is carried out by column chromatography on an optically active carrier material. Process according to claims 1 and 2, characterized in that the subsequent transfer of a compound of the general formula I into an oxazolidine of the general formula Ia is carried out at water decomposition conditions and at temperatures up to the boiling temperature of the solvent used, e.g. at temperatures between 20 and 100 ° G.