KR800000537B1 - Process for the preparation of amin-pheny-etahnolamines - Google Patents

Abstract

Title compds. (I, R1 = Cl, Br, I; R2 = F, C1-5 alkyl hydroxyalkyl, aminoalkyl, CF3, nitro, cyano, COOH, carbalkoxy, carbamoyl; R3 or R4 = H, C1-6 alkyl, hydroxyalkyl, cycloalkyl, substituted aralkyl), optical active antipodes and their acid salts having pharmaceutical properties and sustected or protective activity against β-acceptor were prepd. by halogenation of compds. II with solvent at 0-50≰C in 50-100 % acetic acid or THF in the presence of tert-org. base or heavy metal salt.

Description

Method for preparing amino-phenyl-ethanolamine

The present invention relates to a novel amino-phenyl-ethanolamine represented by the general formula (I), its optically active antipodes, and the physiologically harmonized resulting from the reaction of the compounds of the general formula (I) with inorganic or organic acids. It relates to a process for producing acid addition salts.

In the general formula (I), R ₁ represents a chlorine, bromine or iodine atom, and R ₂ represents a fluorine atom, an alkyl group having 1-5 carbon atoms on a chain or branched chain, hydroxyalkyl, aminoalkyl, dialkylamino Alkyl, trifluoromethyl, alcooxy, nitro, cyano, carboxy, carbalcooxyna, carbamoyl groups, R ₃ and R ₄ being the same or different and having a hydrogen atom, a chain or branched 1- An alkyl group having 6 carbon atoms, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, or an optionally substituted aralkyl group.

The compound represented by the general formula (Ⅰ) has pharmaceutical properties of value, in particular, β ₂ - has a protective activity for the receptor, and the pseudo-active (擬似活性) and / or β ₁ to the receptor (sensory) In addition to analgesic, uterine spasms, angeungyeong (鎭 痙) activity and has a substitution, depending on which activity is more predominant. d (+) compounds have selective activity, in particular for β ₁ -receptors, and l (−) compounds have selective activity for β ₂ -receptors.

The novel compounds may be prepared by halogenating a compound of the following general formula (II).

In the above formula, R ₂ -R ₄ is as described above.

This reaction is usually carried out at a suitable temperature of 0-50 ° C., for example chlorine, bromine, in the presence of a tertiary organic base in a solvent such as 50-100% acetic acid or tetrahydrofuran, or in the presence of a heavy metal salt such as mercury (II) oxide. By halogenating with a halogenating agent such as iodine, tribromophenol bromine, or iodide benzene dichloride. It is advantageous to use 1 mole or more of a halogenating agent relative to 1 mole of the compound of formula (II) which can be used as a base or as a salt such as mono, di, trihydro chloride. If a hydrogen halide salt is obtained during the reaction, the salt can be separated directly or the base can be further purified if necessary.

If necessary, the racemate or the diastereomeric mixture of formula (III) can be separated to transform the resulting compound of formula (I) into an optically active bogie, provided that R ₆ is an acyl group If R ₄ is an optionally substituted benzyl group, groups R ₇ , R ₆ and R ₄ are thus 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.

Examples of the chiral acyl group R ₇ include an optically active α-amino-acyl group protected with a nitrogen atom such as N-benzyloxy carbonyl-L-alanyl group or an optically active terphenyl-oxycarbonyl group such as (-)-methyloxycarbonyl group. May be specially considered.

The diastereomeric mixtures of formula (III) above are suitably separated into pure diastereomeric mixtures by fractional crystallization and / or column chromatography on inert carriers.

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 in the presence of acids or bases. It is made at ℃.

Removal of the group R ₇ is also effectively effected at a suitable temperature of -20 ° to 20 ° C. by a complex metal hydride such as lithium aluminum hydride in a suitable solvent such as ether, tetrahydrofuran or dioxane.

If R ₂ represents a cyano group in the compound of formula (III), this group will be reduced simultaneously and the substituents R ₆ and R ₇ are effectively removed in several steps or in one step depending on their respective properties.

If R ₄ represents an optionally substituted benzyl group, the removal of this group is carried out in a compound in which R ₂ does not represent a nitro group, in the presence of a suitable catalyst such as palladium on coal or barium sulfate or alcohols such as methanol or ethanol. By hydrogenolysis in the same suitable solvent, optionally by addition of an inorganic acid such as hydrochloric acid, optionally under elevated hydrogen pressure, preferably at a temperature of 20-50 ° C. If R ₂ is a cyano group in formula (III) These groups are reduced simultaneously. Removal of groups R ₄ takes place effectively before or after groups R ₆ and R ₇ are removed.

Removal of the d, l-type racemate of the compound of formula (1) is D (-) tartrate, L (+)-tartrate, dibenzoyl-D-tartrate, dibenzoyl-L-tartrate, (+) Their diastereomers using optically active acids such as camphor-10-sulfonic acid, L (-)-nungumic acid, L (+)-mandelic acid, d-α-bromocamphor-?-Sulfonic acid or 1-kininic acid It is preferably carried out by fractionally determining the mixture of. However, the removal of racemates can be effected effectively with each other by column-chromatography, for example using an optically active carrier such as acetylcellulose.

If a compound of formula (1) wherein R ₂ represents a cyano group is obtained, this compound can be converted to the corresponding carbamoyl compound and / or carbamoyl or carboalcooxy compound, which compound is hydrolyzed. Can be converted into the corresponding carboxyl compound of formula (1), and / or if a compound of formula (1) is obtained in which R ₃ or R ₄ represents a hydrogen atom, this compound It may be converted to the corresponding oxazolidine.

The compound of formula (1) obtained can be converted to physiologically compatible acid addition salts using the same amount of water as 1,2,3 times the corresponding inorganic or organic acid, if desired. Examples of suitable acids include hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, lactic acid citric acid, tartaric acid, maleic acid and fumaric acid.

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

The compound of formula (II) is obtained by reacting the corresponding 2-halogen-acetophenone with the corresponding amine and then reducing the obtained ketone with, for example, 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 formula (1) have valuable pharmacological properties, in particular have pseudo activity on β ₂ -receptors (sensory organs) and / or on β ₁ -receptors. They have protective 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.

β ₁ -protective activity is tested as an antagonist against tachycardia of anesthetized cats induced by a standard dose of 1.0γ / kg sulfate N-isopropyl-noradrenaline. ED ₅₀ from the mean reduction in the increase in heart rate obtained by various doses of the compound of interest induced by N-isopropyl-noradrenaline sulfate is determined by interpolation in this chart. (See Tables II and III).

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

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

의 시험방법에 의해 황산 N-이소프로필-노라드레드날린을 체중 1kg당 5γ의 투약에 의해 관찰되는 기관지 활성에 대한 길항작용으로 테스트된다(표 Ⅲ참조).β ₂ -protective activity of bronchial spasms caused by standard administration of 20γ / kg body weight of acetylcholine using anesthetized guinea pigs

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

Acute toxicity of the substance is investigated and determined in 10 rats. The dose LD ₅₀ administered intravenously after 50% of the animals died within 14 days is calculated by Lifchfield and Wilcoxon's method (see Tables II and III).

TABLE 1

n ₁ = equimolar number / dosage

Number of doses taken to calculate n ₂ = ED ₅₀ .

TABLE 2

n ₁ = number of animals / dose

n ₂ = frequency of administration

TABLE 3

n ₁ = number of animals

n ₂ = Animal dose tested Number of doses tested

The novel compounds of formula (1) and their salts can be combined with carriers or excipients to synthesize 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-pentylamino-ethanol-hychloride]

0.37 g of 1- (4-amino-3-trifluoromethyl-phenyl) -2-tert-pentylamino-ethanol-hydrobromide and 0.2 ml of pyridine are dissolved in 30 ml of tetrahydrofuran and cooled to 0 ° C. .

0.3 g of iodide chloride is added to the chloride and the mixture is left at this temperature for 2 hours and 0.1 g of iodide chloride is added to the chloride again.

After 20 hours, the solution was evaporated at 4 ° C. and dispersed between ethyl acetate and water, the aqueous extract was alkaline with 2N ammonia and the solution was extracted again with ethyl acetate. The organic layer is washed with water and dried, and a few drops of 4N hydrochloric acid in isopropanol is added. Precipitated chlorides of the abovementioned compounds are aspirated by filtration and washed with ether.

Melting Point: 176-178 ℃ (Decomposition)

Example 2

[1- (4-Amino-3-bromo-5-methyl-phenyl) -2-tert-butylamino-ethanol-dihydrochloride]

2.6 g of 1- (4-amino-3-methyl-phenyl) -2-tert-butylamino-ethanol-hydrochloride was dissolved in 90 ml of 50% acetic acid in 5 ml of glacial acetic acid and 0 ml of 1 ml of water. Add at -5 ° C.

After 15 minutes the excess bromine is removed with sodium hydrogen sulfite. The reaction mixture is diluted with water and insoluble byproducts are removed by filtration over charcoal. The filtrate is alkaline with cooling with sodium hydroxide solution and extracted with chloroform. After drying over sodium sulfate, the chloroform solution is filtered over charcoal and evaporated to dryness in vacuo.

The oily base thus obtained is dissolved in isopropanol and acidified with isopropanolic hydrochloric acid. After evaporation and cooling the precipitated 1-4 (amino-3-bromo-5-methyl-phenyl) -2-tert-butylamino-ethanol-dihydrochloride is suction filtered and recrystallized from isopropanol / ether.

Melting Point:〉 148 ℃ Decomposition

Example 3

[1- (4-Amino-5-bromo-3-hydroxymethyl-phenyl) -2-tert-butylamino-ethanol]

2.0 g of 1- (4-amino-3-hydroxymethyl-phenyl) -2-tert-butylamino-ethanol are dissolved in 18 ml of glacial acetic acid and 2 ml of water and 1.3 g of bromine are added dropwise. The reaction mixture is then evaporated, the residue is dissolved in water, made alkaline with 2N ammonia and extracted four times with chloroform. The organic layer is dried over sodium sulfate, evaporated and the residue is purified on a silica gel column using ethanol as the eluent.

The fractions containing the material are combined and evaporated in vacuo. After mixing the evaporation residue and the ether, the desired product precipitates into crystals after some time.

Melting point: 121-124 ° C.

Example 4

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

Melting Point: 87-92 ℃

Prepared by bromination of 1- (4-amino-3-hydroxymethyl-phenyl) -2-dimethylamino-ethanol as in Example 3.

Example 5

[1- (4-Amino-5-bromo-3-dimethylaminomethyl-phenyl) -2-tert-butylamino-ethanol]

Melting Point: 127-129 ℃

Prepared by bromination of 1- (4-amino-3-dimethylaminomethyl-phenyl) -2-tert-butylamino-ethanol as in Example 3.

Example 6

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

Produced by bromination of 1- (4-amino-3-dimethylaminomethyl-phenyl) -2-dimethylamino-ethanol as in Example 3.

Structural proof of NMR spectrum (CDCl ₃ / CD ₃ OD): 2.2 ppm only one [6 proton, N (CH ₃ ) ₂ ] 2.35 ppm only one [6 proton, N (CH ₃ ) ₂ ] 1.8- 3.0 ppm multi [2 protons, CH ₂ ] 3.45 ppm single [2 protons, CH ₂ ] 4.4-4.8 ppm multi [1 protons, CH] 6.96 ppm double, 7.4 ppm double (bidirectional) Protons).

Example 7

[1- (4-Amino-3-fluoro-5-urido-phenyl) -2-isopropylamino-ethanol-hydrochloride]

5.15 g of 1- (4-amino-3-fluoro-phenyl) -2-isopropylamino-ethanol is dissolved in 300 ml of acetic acid, 80 g of urine and 4.0 g of mercury oxide (II) are added and the mixture is heated vigorously. Stir at room temperature for 1/2 hour. The solid is incidentally filtered off and the dark brown filtrate is decolorized with saturated sodium hydrogen sulfite solution and diluted with about 1 L of water. The mixture is made alkaline with cooling with 10N sodium hydroxide solution and extracted with chloroform. The chloroform layer is dried over sodium sulfate and evaporated to dryness in vacuo. The residue is dissolved in methanol and acidified to pH 4.5 with etheric hydrochloric acid. The solution is evaporated to dryness in vacuo and the solid residue is crystallized from anhydrous ethanol. Melting Point: 203-205 ℃ (Decomposition)

Example 8

[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 urethodichloride benzene is added and the mixture is left for 2 hours at the above-mentioned temperature and 0.1 g of urethodichloride benzene is added again. After 20 hours at 4 ° C., the solution is evaporated and the residue is dispersed between ethyl acetate and water. The aqueous extract is made alkaline with 2N ammonia and extracted with ethyl acetate once more. The organic layer is washed with water, dried and evaporated in vacuo. The residue is dissolved in anhydrous ethanol, neutralized with ethanolic hydrochloric acid and the hydrochloride of the abovementioned compound is crystallized by ether addition.

Melting Point: 210-211 ℃ (Decomposition)

Example 9

[d-1- (4-amino-3-bromo-5-fluorophenyl) -2-tert-butylamino-ethanol]

0.26 g of d-1- (4-amino-3-fluoro-phenyl) -2-tert-butylamino-ethanol-hydrochloride was dissolved in 30 ml of 50% ethyl acetate and dissolved in 5 ml of ethyl acetate and 1 ml of water. 0.16 g bromine is added at 0-5 ° C. After 15 minutes the reaction mixture is evaporated and the residue is dissolved in water, made alkaline with 2N ammonia and extracted with chloroform.

The chloroform solution is dried with sodium sulfate and evaporated to dryness in vacuo. The residue is converted to hydrochloride of the abovementioned compounds by dissolving in ethanol, neutralized with ethanolic hydrochloric acid and ether is added.

Melting Point: 234-235 ℃ (Decomposition)

Example 10

[1- (4-Amino-3-chloro-5-fluoro-phenyl) -2-isopropylamino-ethanol]

Melting point of hydrochloride: 152-154 ° C. (decomposition) Prepared from 1- (4-amino-3-fluoro-phenyl) -2-isopropylamino-ethanol-hydrochloride and chlorine as in Example 1. The following compounds were prepared as in Examples 1,2 or 7.

Claims (1)

A method for producing the amino-phenyl-ethanolamine of the general formula (I) and acid addition salts thereof, wherein the compound of the general formula (II) is halogenated.

Wherein R ₁ represents a chlorine, bromine or iodine atom, R ₂ represents a fluorine atom, a chain or branched alkyl group having 1-5 carbon atoms, hydroxyalkyl, aminoalkyl, dialkylaminoalkyl, trifluoro methyl alcohol aryloxy, nitro, cyano, carboxy, carbalkoxy oxy alcohol or carboxylic display the carbamoyl group and, R ₃ and R ₄ are the same or different hydrogen atoms, having from 1 to 6 carbon atoms chain or branched alkyl group, Hydroxyalkyl, cycloalkyl, cycloalkylalkyl or an optionally substituted aralkyl group.

In the above formula, R ₂ -R ₄ is as described above except that the alkenyl and alkynyl groups are not represented.