KR800000539B1 - Process for the preparation of amino-pheny-ethanolamines - Google Patents

Abstract

Title compds. (I, R1 = H, F, Cl, Br, I, CN; R2 = F, C1-5 alkyl hydroxyalkyl, aminoalkyl, CF3, alkoxy, nitro, CN, COOH, carbalkoxy, carbamoyl; R3 or R4 = H, C1-6 alkyl, alkenyl, hydroxyalkyl, cycloalkyl, alkinyl, substtuted aralkyl) and their acid-addition salts having pharmaceutical properties and suspected or protective activity against β- acceptor were prepd. by reacting compd. by reacting compds. II(Z =Cl, Br, I, p-toluene-sulfonyloxy) with aminess(III).

Description

Method for preparing amino-phenyl-ethanolamine

The present invention relates to a process for the preparation of the novel amino-phenyl-ethanolamine of general formula (I) and to a process for producing the physiologically compatible acid addition salts produced by the reaction of the compounds of the general formula (I) with inorganic or organic acids.

Wherein R ₁ represents hydrogen, fluorine, chlorine, bromine, an iodine atom or a cyano group, and R ₂ represents a fluorine atom, an alkyl group having 1-5 carbon atoms with a chain or branch, hydroxyalkyl, aminoalkyl, di Alkylamino alkyl, trifluoromethyl, alcooxy, nitro, cyano, carboxyl, carbalcooxy or carbamoyl groups, R ₃ or R ₄ are the same or different and represent a hydrogen atom, a chain or branched group -Alkyl atom having 6 carbon atoms, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl or optionally substituted aralkyl.

Compounds of general formula (I) have valuable pharmaceutical properties, in particular have pseudo-active activity against β ₂ -receptors (sensory organs) and / or protective activity against β ₁ -receptors, In addition, it has analgesic activity against analgesia, uterine spasms and angular muscles, where one or another activity is predominant by their substitution.

d (+)-compounds have selective activity, in particular for β ₁ -receptors (sensor organs), and l (-)-compounds have selective activity for β ₂ -receptors.

The novel compounds can be prepared by the following procedure.

The compound of formula (II) is reacted with the amine of formula (III).

In the above formula, R ₁ and R ₂ are as described above.

Z represents a chlorine, bromine, iodine atom or P-toluene-sulfonyloxy group.

In the above formula, R ₃ and R ₄ are as described above.

The reaction proceeds suitably under an excess of the used amine of the general formula (III) in a solvent such as methanol, ethanol, chloroform, carbon tetrachloride and dioxane. But the reaction also proceeds without solvent.

The compounds of the general formula (I) obtained are, if desired, incidentally separate their optically active vehicle by separation of the racemate or by separation of the subcarrier mixture of general formula (IV), if R ₆ represents an acyl group and R ₄ If R represents an optionally substituted benzyl group, groups R ₇ , R ₆ and R ₄ are incidentally removed.

In the above formula, R ₁ , R ₂ , R ₃ and R ₄ are as described above.

R ₆ represents a hydrogen atom or an acyl group, and R ₇ represents a chiral acyl group.

As the chiralacyl group R ₇ , for example optically protected α-amino-acyl groups such as N-benzyl-oxacarbonyl-L-alanyl-groups or optical activities such as (-)-methyloxycarbonyl-groups Terphenyl-oxycarbonyl-groups can be particularly contemplated.

Separation of the partial vehicle mixture of the general formula (IV) above into the pure partial vehicle compound is appropriately by fractional crystallization and / or column chromatography on an inert carrier.

Incidental removal of groups R ₆ and R ₇ is effectively effected by hydrolysis corresponding to the respective solvolysis in the presence of a suitable alcohol, such as water or methane, optionally with a temperature of 0-100 ° C. in the presence of acids or bases. Is done in

Removal of the groups R ₇ is also effected effectively by complex metal hydrides such as aluminum hydride in a suitable solvent such as ether, tetrahydrofuran or dioxane and at moderate temperatures -20-20 ° C. _{If 2} represents a cyano group, these groups will be reduced at the same time, depending on the nature of the substituents R ₆ and R ₇ , their removal is effectively carried out in several steps or in one step.

If R ₄ represents an optionally substituted benzyl group, the removal of this group is suitable in the presence of a suitable catalyst such as palladium on coal or barium sulfate in compounds where R ₂ does not represent nitro groups. By hydrogenolysis in a solvent, optionally at a temperature of 20-50 ° C. under elevated hydrogen pressure, optionally by addition of a mineral acid such as hydrochloric acid.

If R ₂ represents a cyano group in formula (IV), these groups are reduced simultaneously. Removal of groups R ₄ takes place effectively before or after groups R ₆ and R ₇ are removed.

The racemate removal of the d, l-form of the compound of general formula (I) is D (-)-tartrate, L (+)-tartrate, dibenzoyl-D-tartrate, dibenzoyl-L-tartrate, (+)- Their subcarts using optically active acids, such as camphor-10-sulfonic acid, L (-)-nungumic acid, L (+)-mandelic acid, d-α-bromocamphor-II-sulfonic acid or l-kininic acid It is preferably carried out by fractionating a mixture of salts. However, racemate removal is effectively accomplished by column-chromatography, for example using an optically active carrier such as acetylcellulose.

If a compound of formula (I) in which R ₂ represents a cyano group is obtained, this compound may be converted to the corresponding carbamoyl compound and / or carbamoyl or carboalcooxy compound and this compound is subject to hydrolysis. If a compound of formula (I) is obtained which can be converted to the corresponding carbalcooxy compound of formula (I) and / or wherein R ₃ or R ₄ represents a hydrogen atom, By reaction with an aldehyde may be converted to the corresponding oxazolidine.

In the above formula, R ₅ represents a hydrogen atom or a chain or branched alkyl group.

The reaction with aldehydes of formula (V) is suitably carried out in a solvent such as ethanol, benzene, toluene or dioxane under dehydration conditions, for example in the presence of anhydrous copper (II) sulfate, for example at a temperature of 20-100 ° C. The reaction is carried out at the boiling temperature of the solvent used but the reaction can also be carried out without solvent. The reaction is particularly preferred using a device that introduces a water separation funnel in the presence of a solvent such as benzene or toluene.

The compound of general formula (I) obtained can be converted to physiologically compatible acid addition salts using molar equivalents of 1,2,3 times the corresponding inorganic or organic acid, if desired. As the acid, hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, lactic acid, manic acid, tartaric acid, maleic acid and fumaric acid have been found to be suitable.

Compounds used as starting materials are obtained by methods known from the references.

Compounds of formula (II) used as starting materials are obtained, for example, by reacting the corresponding phenylethylene glycol with P-toluenesulfonic acid chloride or reducing the corresponding amino-phenacylhalide with sodium borohydride.

Starting compounds do not need to be purified in all cases and they can also be used as crude products.

As already mentioned above, the compounds of general formula (I) have valuable pharmacological properties, in particular have pseudo-activities for β ₂ -receptors (sensory organs) and / or for β ₁ -receptors. They have paralytic activity and one or the other activity predominates by their substitution.

d (+)-compounds exhibit selective activity, in particular for β ₁ -receptors and l (−)-compounds have preferential activity for β ₂ -receptors.

The following materials were tested for their activity on β-receptors.

의 증가에 있어서 평균감소 %로부터 ED₅₀이 도표 외삽법에 의해 결정된다(표 Ⅱ와 Ⅲ을 참조).β ₁ -Paralytic activity is tested as antagonism against tachycardia in anesthetized cats induced by a standard dose of 1.0γ / kg sulfate N-isopropyl-noradrenaline. Heart rate obtained by various doses of the compound of interest caused by sulfuric acid N-isopropyl-noradrenaline

From the average decrease in% increase, ED ₅₀ is determined by graphical extrapolation (see Tables II and III).

방법에 의해 마취된 기니돼지에서 체중 kg당 20γ의 아세틸콜린을 정맥주사에 의해 유발된 기관지 경련에 대한 길항작용으로 테스트된다. 본 발명 화합물의 여러가지 투여에 의해 생긴 기관지 경련의 평균감소 %로부터 ED₅₀이 도표 외삽법에 의해 결정된다(표 1 참조).β ₂ -pseudo activity is referred to the intravenous administration of the compound of the present invention,

20 acetylcholine per kg body weight in guinea pigs anesthetized by the method is tested for antagonism of bronchial spasms caused by intravenous injection. ED ₅₀ is determined by graphical extrapolation from the average percent reduction in bronchial spasms resulting from various administrations of the compounds of the present invention (see Table 1).

의 시험방법에 의해 황산 N-이소프로필-노라드레날린을 체중 1kg당 5γ의 투약에 의해 관찰되는 기관지활성에 대한 길항작용으로 테스트된다(표 Ⅲ 참조).β ₂ -Paralytic Activity Induces Bronchial Spasm Caused by Standard Dosing of 20γ / kg of Acetylcholine Using Anesthetized Guinea Pigs

N-isopropyl-noradrenaline sulfate is tested by antagonism for bronchial activity observed by dose of 5γ per kg of body weight (see Table III).

Acute toxicity of the substance is investigated and determined in 10 rats.

The dose LD ₅₀ administered intravenously within 14 days after 50% of animals died is calculated by Lifchfield and Wilcoxon's method (see Tables II and III).

TABLE I

n ₁ = number of animals

number of doses taken into account to calculate n ₂ = ED ₅₀

TABLE II

n ₁ = number of animals / dose

n ₂ = frequency of administration

TABLE III

n ₁ = number of animals

n ₂ = Animal dose tested Number of doses tested

The novel compounds of formula (I) may optionally be combined with other active substances to synthesize compounds having conventional pharmaceutical compositions. Only one dose is 1-100γ but preferably 5-50γ.

The following examples illustrate the invention.

Example 1

[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 are dissolved in 25 ml of tertiary butylamine and left at room temperature for 20 hours. Excess tertiary butylamine is removed in vacuo and the residue is dissolved in ether. The ethereal solution was washed with water, dried over magnesium sulfate and evaporated in vacuo. The evaporated residue is purified by chromatography on a column of silica gel (chloroform: methanol: concentrated ammonia = 90: 10: 1).

The combined fractions with the desired material thus obtained are evaporated to dryness in vacuo. The residue is dissolved in ether and the solution is adjusted to pH 4 with isopropanolic hydrochloric acid.

1- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert-butylamino-ethanol-hydrochloride crystallizes and it is aspirated, washed with ether, 205-207 ° C. (decomposition) Melt in

Example 2

[1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert-butylamino-ethanol]

Melting Point of Hydrochloride: 205-207 ° C (Decomposition)

Prepared from 1- (4-amino-3-chloro-5-trifluoro methyl-phenyl) -2- (P-toluenesulfonyloxy) -ethanol and excess tertiary butylamine as in Example 1.

The following compounds were prepared as in Examples 1 and 2.

Example 3

[1- (4-Amino-3-bromo-5-carbamoyl-phenyl) -2-dimethylamino-ethanol]

2 g of 1- (4-amino-3-bromo-5-cyano-phenyl) -2-dimethyl-amino-ethanol are boiled for 4 hours with a solution of 5 g sodium hydroxide in 120 ml of 50% ethanol. Ethanol was distilled off and the remaining aqueous solution was washed with 100 ml of water and extracted three times with chloroform. The chloroform layer is dried over sodium sulfate and evaporated in vacuo. The obtained residue is recrystallized from chloroform.

Melting Point:〉 93 ℃ (Decomposition)

Example 4

[1- (4-Amino-3-bromo-5-carboxy-phenyl) -2-dimethylamino-ethanol]

2 g of 1- (4-amino-3-bromo-5-cyano-phenyl) -2-dimethylamino-ethanol are boiled in 120 ml of 50% ethanol with 5 g of sodium hydroxide solution for 4 hours. Ethanol was distilled off and the remaining aqueous solution was diluted with 100 ml of water and extracted three times with chloroform.

The aqueous layer is neutralized, evaporated to dryness, the residue is treated with ethanol, suction filtered and the filtrate is evaporated.

The obtained residue is again treated with ethanol and suction filtered. After evaporation of the last filtrate, residues of 1- (4-amino-3-bromo-5-carboxy-phenyl) -2-dimethylamino-ethanol are obtained. It melts at 240-250 ° C (decomposition) and its structure has been demonstrated by IR- and UV-spectrum.

IR (potassium bromide): COO- at 1,620 cm ^-1 , NH ⁺ at 2,000-3,500 cm ^-1

UV (ethanol): maximum at 220 nm and 330-340 nm, shoulder at 250 mm

Example 5

[l-1- (4-amino-3-fluoro-phenyl) -2-tert-butylamino-ethanol and d-1- (4-amino-3-fluoro-phenyl) -2-tert-butylamino -ethanol]

a) l-1- (4-acetylamino-3-fluoro-phenyl) -2- (N-benzyl-N-tert-butyl) -amino-0- (N-carbobenzooxy-L-alanyl ) -Ethanol and d-1- (4-acetyl amino-3-fluoro-phenyl) -2- (N-benzyl-N-tert-butyl) -amino-0- (N-carbobenzooxy-L- Alanyl) -ethanol

To a solution of 15 g of N-carbozenzooxy-L-alanyl dissolved in 300 ml of anhydrous tetrahydrofuran, 14.5 g of N, N'-carbonyl-diimidazole is added and stirred at room temperature for 3 hours.

Incidentally, 10 g of d, l-1- (4-acetyl amino-3-fluoro-phenyl) -2- (N-benzyl-N-tertbutyl) -amino-ethanol dissolved in 200 ml of anhydrous tetrahydrofuran The solution and a small piece of sodium are added and the mixture is stirred for 12 days at room temperature and evaporated to dryness in vacuo. The debris is dispersed between chloroform and water.

The chloroform layer is dried over sodium sulfate and evaporated to dryness in vacuo. The two subcarrier esters obtained in the mixture show different Rf values in thin layer chromatography (silica gel G, Merck: chloroform: acetone = 10: 1). The evaporation residue is purified on a silica gel chromatography column (500 g of silica gel; eluent: chloroform: acetone = 10: 1) without separating the optical collimator ester.

The fraction comprising the two substances is evaporated to dryness in vacuo and recrystallized from ether.

l-1- (4-acetylamino-3-fluoro-phenyl) -2- (N-benzyl-N-tertbutyl) -amino-0- (N-carbobenzooxy-L-alanyl)- Ethanol is obtained as colorless crystals.

The mother liquor obtained is evaporated to dryness in vacuo.

The optical collimator ester with a larger Rf value (R _f = 0.33) is separated in the chromatography column (100 h of silica gel: effluent: chloroform: acetone = 20: 1).

d-1- (4-acetylamino-3-fluoro-phenyl) -2- (N-benzyl-N-tertbutyl) -amino-0- (N-carbobenzooxy-L-alanyl)- Ethanol is obtained as colorless oil.

b) l-1- (4-amino-3-fluoro-phenyl) -2-tert-butylamino-ethanol

2 g of l-1- (4-acetylamino-3-fluoro-phenyl) -2- (N-benzyl-N-tert-butyl) -amino-0- (N-carbobenzooxy-L-alanyl ) -Ethanol is dissolved in 60 ml of ethanol. 20 ml of 5N sodium hydroxide solution is added and refluxed for 4 hours.

After cooling, the solution is dispersed between chloroform and water, and the aqueous layer is extracted four times with chloroform. The combined chloroform solution is dried over sodium sulfate and evaporated to dryness in vacuo.

residue containing l-1- (4-amino-3-fluoro-pepe) -2- (N-benzyl-N-tertbutyl) -amino-ethanol in 50 ml of methanol and pH 6 with etheric hydrochloric acid Acidify and add palladium on 0.2 g charcoal and hydrogenate the reaction product in a parr apparatus until all hydrogen is absorbed at a pressure of 5 atm. After the catalyst was suction filtered and the reaction product was evaporated to dryness in vacuo and the solid residue comprising l-1- (4-amino-3-fluoro-phenyl) -2-tert-butylamino-ethanol-hydrochloride was removed with ether. Crystallize from isopropanol by addition.

Melting Point: 199 = 200 ℃ (Decomposition)

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

D-1- (4-acetylamino-3-fluoro-phenyl) -2- (N-benzyl-N-tertbutyl) -amino-0- (N-carbobenzooxy-L- Alanyl) -ethanol is dissolved in 30 ml of ethanol. 10 ml of 5N sodium hydroxide solution is added and the solution is refluxed for 4 hours. After cooling, the reaction solution is dispersed between chloroform and water, and the aqueous layer is extracted four times with chloroform. The combined chloroform solution is 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-tertbutyl) -amino-ethanol is dissolved in 25 ml of methanol and acidified to pH 6 with etheric hydrochloric acid. Palladium (10%) is added over 0.1 g of charcoal and the reaction product is hydrogenated in a parr apparatus until all hydrogen is absorbed at a pressure of 5 atmospheres at room temperature. After the catalyst was filtered with hops the mixture was evaporated to dryness in vacuo and the solid residue consisting of d-1- (4-amino-3-fluoro-phenyl) -2-tert-butylamino-ethanol-hydrochloride was added by ether addition. Crystallize with isopropanol.

Melting Point: 198-200 ℃ (Decomposition)

Example 6

[d-1- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert-butylamino-ethanol and l-1- (4-amino-3-chloro-5-trifluoro Romethyl-phenyl) -2-tert-butylamino-ethanol]

a) d, l-1- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert-butylamino-0-[(-)-mentooxy-carbonyl] -ethanol

8.8 g of d, l-1- (4-amino-3-chloro) dissolved in 56.6 ml of toluene and dissolved in 0.5 ml of a solution of 0.5 mole chloro-formic acid-(-)-methylester in 50 ml of pyridine with continuous stirring at 20 ° C. Drop into a solution of -5-trifluoromethyl-phenyl) -2-tert-butylamino-ethanol. After 2 hours the solution is evaporated to dryness in vacuo. Oily debris is powdered with water, and incidentally, the solution is transferred to a separate bowl and dissolved in ether. The ethereal solution is continuously washed with water, washed with 2N ammonia (dissolves the precipitate obtained between the layers) and again with water. The ethereal solution is dried with magnesium sulfate and adjusted to pH 6 with 6N isopropane hydrochloric acid.

A mixture of the hydrochlorides of the optically-balanced compound described above precipitates as crystals. The reaction product is suction filtered and washed with ether.

In a thin layer chromatogram over butyl acetate: cyclohexane = 9: 1 and silicagen G. Merck, the crystals show approximately two points of the same concentration with R _f values of 0.45 and 0.55.

b) d- and l-1- (4-amino-3-chloro-5-tripolouromethyl-phenyl) -2-tert-butylamino-0-[(-)-mentooxy-carbonyl]- ethanol

3.0 g of the obtained d- and l-1- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert-butylamino-0-[(-)-mentooxy-carbonyl To a mixture of hydrochlorads of] -ethanol are suspended in a small amount of water, layered with ether, 5.0 ml of 2N ammonia is added and the mixture is shaken until everything is dissolved. The ether layer is separated and washed with water, dried over magnesium sulfate, silica gel column (diameter 6.5cm, length 107cm, weight 2.2kg) on the butyl acetate and cyclohexane (19: 1) mixture with R _f value of 0.55 (flow rate 120ml / hr) The fractions of pure substances are combined and the solvent is removed in vacuo.

Obtained d-1- (4-amino-3-chloro-5-trifluoro-methyl-phenyl) -2-tert-butylamino-0-[(-)-mentooxy-carbonyl] -ethanol as petroleum ether Crystallize at (boiling point: 40-60 ℃).

Melting Point: 95-96.5 ℃

The oil containing the mixture of the optobalance compound and which can be added for dichromatographic separation is removed. Fractions containing nearly pure materials with an Rf value of 0.45 are incidentally combined and evaporated in vacuo. The residue is once recrystallized from petroleum ether and chromatically pure l-1- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert-butylamino-0-[(-) -Mentoroxy-carbonyl] -ethanol.

Melting Point: 102-104 ℃

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

16 ml of 1.6 g of d-1- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert-butylamino-0-[(-)-mentooxy-carbonyl] -ethanol Dissolved in methanol and left at about 20 ° C. for 65 hours. The mixture is evaporated in vacuo and the residue is purified by column chromatography (silica gel; chloroform: methanol: concentrated ammonia = 90: 10: 1). The oil is combined with the desired material and evaporated in vacuo. The residue is dissolved in ethyl acetate and the theoretical value of 4N hydrochloric acid dissolved in isopropanol is crystallized from the hydrochloride of the above-mentioned compounds.

Melting Point:〉 194 ℃ (Slowly Decomposed)

d) l-1- (4-amino-3-chloro-5-trifluoro-methyl-phenyl) -2-tert-butylamino-ethanol

1.58 g of l-1- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert-butylamino-0-[(-)-mentooxy-carbonyl] -ethanol Solvent solubilization was carried out to prepare by chromatographic purification as in the example of the enantiomer compound.

Melting point of hydrochloride:〉 194 ℃ (slow decomposition)

Example 7

[d-1- (4-amino-3-bromo-5-fluoro-phenyl) -2-tert-butylamino-ethanol and l-1- (4-amino-3-bromo-5-fluoro -Phenyl) -2-tert-butylamino-ethanol]

205 g of d, l-1- (4-amino-3-bromo-5-fluoro-phenyl) -2-tert-butylamino-ethanol and 118 g of dibenzoyl-D-tartrate in 2.5 l of hot ethanol It is left for 1 day at room temperature to dissolve, filter and crystallize. The crude product thus obtained is recrystallized six times with methanol-ether and thus pure d-1- (4-amino-3-bromo-5-fluoro-phenyl) -2-3 having a melting point of 206-208 ° C. (decomposition). Butyl-ethanol] -dibenzoyl-D-tartrate is obtained.

The salt is dissolved while continuing heating in methanol and concentrated ammonia and the base is crystallized by the addition of water. The obtained base was dissolved in anhydrous alcohol, neutralized with anhydrous ethanol hydrochloric acid, and the addition of ether gave d-1- (4-amino-3-bromo-5-fluoro-phenyl) -2-tert-butylamino-ethanol- Crystallization of the hydrochloride takes place.

Melting Point: 234-235 ℃ (Decomposition)

The mother liquor of d- [1- (4-amino-3-bromo-5-fluoro-phenyl) -2-tert-butylamino-ethanol] -dibenzoyl-D-tartrate precipitate and the precipitation of the initial recrystallization process Combine and evaporate to smaller volume and precipitate the base by addition of concentrated ammonia and water. Thus obtained 140 g of 1- (4-amino-3-bromo-5-fluoro-phenyl) -2-tert-butylamino-ethanol (in deep-L form) was dissolved in 1.8 L of anhydrous ethanol and 500 ml of anhydrous A solution of 82 g of dibenzoyl-tartrate dissolved in ethanol is added and the mixture is allowed to evaporate to volume 1 L and left at room temperature for 3 days to crystallize. The obtained product is recrystallized six times with methanol / ether. L- [1- (4-Amino-3-bromo-5-fluoro-phenyl) -2-tert-butylamino-ethanol] -dibenzoyl-L-tartrate is obtained in pure form.

Melting Point: 204-206 ° C (Decomposition)

The salt is dissolved while continuing heating in methanol and concentrated ammonia and the base is precipitated by the addition of water. The obtained base was dissolved in anhydrous ethanol, neutralized with anhydrous ethanol hydrochloric acid, and ether was added to l-1- (4-amino-3-bromo-5-fluoro-phenyl) -2-tert-butylamino-ethanol-hydrochloride. Crystallize by

Melting Point: 218-220 ℃ (Decomposition)

Example 8

[d-1- (4-amino-3-chloro-5-fluoro-phenyl) -2-tert-butylamino-ethanol]

Melting point of hydrochloride: 210-211 ° C (decomposition)

From d, l-1- (4-amino-3-chloro-5-fluoro-phenyl) -2-tert-butylamino-ethanol by fractional crystallization of dibenzoyl-D-tin salt as in Example 7 Manufacture.

l-1- (4-amino-3-chloro-5-fluoro-phenyl) -2-tert-butylamino-ethanol

Melting point of hydrochloride: 209-210 ° C (decomposition)

From d, l-1- (4-amino-3-chloro-5-fluoro-phenyl) -2-tert-butylamino-ethanol by fractional crystallization of dibenzoyl-L-tin salt as in Example 7 Manufacture.

Example 9

[d-1- (4-amino-3-chloro-5-cyano-phenyl) -2-tert-butylamino-ethanol]

Melting point of hydrochloride: 197-199 ° C (decomposition)

From d, l-1- (4-amino-3-chloro-5-cyano-phenyl) -2-tert-butylamino-ethanol by fractional crystallization of dibenzoyl-D-tin salt as in Example 7 Manufacture.

l-1- (4-amino-3-chloro-5-cyano-phenyl) -2-tert-butylamino-ethanol

Melting point of hydrochloride: 199-202 ° C (decomposition)

Prepared from d, l-1- (4-amino-3-chloro-5-cyano-phenyl) -2-tert-butylamino-ethanol by fractional crystallization of dibenzoyl-L-tin salt as in Example 7. do.

Claims (1)

A method for producing an amino-phenyl-ethanol amine of the general formula (1), wherein the compound of the general formula (II) and the amine of the general formula (III) are reacted as described above in the text.

In the above formula, R ₁ represents hydrogen, fluorine, chlorine, bromine or iodine or cyano group, and R ₂ represents fluorine atom, a chain or branched alkyl group having 1-5 carbon atoms, hydroxyalkyl, aminoalkyl, di Alkylaminoalkyl, trifluoromethyl, alcooxy, nitro, cyano, carboxycarbalcooxy or carbamoyl groups, and R ₃ and R ₄ may be the same or different and are hydrogen atoms, 1-6 A chain or branched alkyl group having 4 carbon atoms, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl or an optionally substituted aralkyl group.

In the above formula, R ₁ and R ₂ are as described above, and Z represents a chlorine, bromine or iodine atom or a P-toluene sulfonyloxy group.

In the above formula, R ₃ and R ₄ are as described above.