KR790001517B1 - Process for preparation of benzylamines - Google Patents

Abstract

Benzylamines [I; R1 = H, C1 or Br, R2 = morpholinocarbonyl methyl, C3-C5 branched alkyl substd. by 1-3 OH, etc. R4 = C1-C4 linear or branched alkyl, C2-C4 alkenyl, C3-C4 cyclo-alkyl, etc., Hal = C1 or Br, l = 1,2 were prepd. by the reaction of compd. II with compd. III or corresponding formamide at 50≰-250≰C in the presence of formic acid. I are used as antitussive and expectorant agents.

Description

Method for preparing benzylamine

The present invention relates to novel benzylamines represented by the general formula (I) or a method for producing physiologically mild inorganic or organic acid addition salts thereof.

In the above formula

Hal represents a chlorine or bromine atom;

R ₁ is hydrogen, chlorine or bromine atom;

R ₂ is morpholinophenyl-carbonyl group, one to three hydroxyl groups are optionally branched alkyl group of the substituted C ₃ ~ C ₅ or formula,

However, in the above formula

R ₃ represents a hydrogen atom, a hydroxyl group or a C ₁ -C ₄ alkyl group,

n is 0, 1 or 2, A and B are hydrogen atoms or taken together

Where R ₅ represents a hydrogen atom or a lower alkyl group of C ₁ -C ₂ , and m represents a number of 1 or 2.

Represents a group represented by;

R ₄ is a C ₁ -C ₄ straight or branched alkyl group, a C ₂ -C ₄ alkenyl group, a C ₃ -C ₄ cycloalkyl group, or R ₃ is not hydrogen, or R ₂ is 1 to 3 hydroxyl groups. Assuming a substituted C ₃ to C ₅ branched alkyl group, a hydrogen atom is represented, and l represents a number of 1 or 2.

The compounds of general formula I and their physiologically mild inorganic or organic acid addition salts have useful pharmacological properties, in particular the effect of promoting the production of surfactants or the swelling of the alveolar, on phlegm promoting and antitussive effects. These compounds can be manufactured according to the following manufacturing method.

The aldehyde of formula II is reacted with an amine of formula III or the corresponding formamide in the presence of formic acid.

In the above formula

R ₁ , Hal and 1 are as defined initially.

However, in the above formula

R ₂ and R ₄ are as defined initially.

The reductive amination reaction is preferably carried out by immediately evaporating the water produced in the solvent in the temperature range of 50 ° to 250 ° C. However, it is much better to use a solvent by reacting the amine and / or formic acid of general formula III. When R <_4> represents a hydrogen atom in the compound of general formula III, the obtained reaction mixture is refluxed with dilute acid, such as 2n- hydrochloric acid, after reaction.

The compound of the general formula II-III used as starting material in the above-mentioned manufacturing method is partially known and can be manufactured by a well-known method.

For example, the aldehyde of formula II is obtained by halogenating the corresponding benzylaldehyde.

The compound of general formula (I) thus obtained can be converted into a physiologically compatible salt with an inorganic or organic acid. Hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid, lactic acid, tartaric acid or maleic acid have been found to be suitable for this purpose.

As first mentioned, the new compounds of formula I possess useful pharmacological properties. In addition to the surfactant production promoting effect or incomplete alveolar swelling effect, they exhibit phagocytosis and antitussive ability in particular.

compound

A = N-ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine-hydrochloride,

B = N-ethyl-N-cyclohexyl-3,5-dibromo-4-hydroxy-benzylamine-hydrochloride,

C = 3,5-dibromo-4-hydroxy-N- (cis-3-hydroxycyclohexyl) -benzylamine-hydrochloride,

D = 3-bromo-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine-hydrochloride,

E = 3-bromo-5-chloro-N-cyclohexyl-4-hydroxy-N-methyl-benzylamine-hydrochloride,

F = 3,5-dibromo-2-hydroxy-N- (trans-4-hydroxycyclohexyl) -benzylamine-hydrochloride,

G = 3,5-dibromo-N- (dihydroxy-third-butyl) -2-hydroxy-benzylamine-hydrochloride,

H = 3,5-dichloro-N- (dihydroxy-third-butyl) -4-hydroxy-benzylamine-hydrochloride and

I = 3,5-dibromo-2-hydroxy-N-third-phenyl-benzylamine-hydrochloride was investigated for their biological activity.

1) Jinhae Ability

Irradiated substance was orally administered to 10 rats at a rate of 50 mg / kg. These mice were sprayed with an aqueous 7.5% citric acid solution to cause coughing. The average cough count was measured 30 minutes after the administration of the irradiated substance and compared with 10 controls. (See Enghornhorn and Puschmann in Arzneimittel for schung 13 , 474-480 (1963)).

2) phlegm promotion effect

The sputum test was performed by orally administering 8 mg / kg of the irradiated substance to 8 to 10 anesthetized rabbits or 5 anesthetized guinea pigs. The increase in secretion was calculated for 2 hours before and after material administration.

The blood circulation effect of the irradiated material was observed by intravenous injection of the irradiated material into a cat anesthetized with chloralose-urethane. (3 per test)

Rabbit experiment:

Guinea Pig Experiment:

3) Acute Toxicity

Acute toxicity was determined by oral administration from 500 mg / kg to 5,000 mg / kg in 5 rats, respectively. (Observation time: 72 hours)

The compound of general formula (I) prepared according to the present invention may be prepared as a conventional pharmaceutical preparation by arbitrarily formulating with other active ingredients, and a single dosage of 1-20 mg or 2-10 mg is suitable.

The following examples are intended to illustrate the present invention.

Example 1

N-cyclohexyl-3,5-dibromo-2-hydroxy-N-methyl-benzylamine-hydrochloride

21 g of 3,5-dibromo-salicyaldehyde, 56.5 g of N-methyl-cyclohexylamine and 23 g of formic acid were heated to 70-80 ° C. for 6 hours. After cooling the reaction product was added to chloroform and diluted ammonia water and shaken. The chloroform layer was separated and evaporated to dryness. The residue was purified by chromatography on 800 g of silica gel and ethyl acetate / chloroform (1: 1). 0.5 L in the first run and 0.5 L in the next run were evaporated to dryness. The residue was dissolved in 50 ml of ethanol and acidified with ethanol hydrochloric acid. N-cyclohexyl-3,5-dibromo-2-hydroxy-N-methyl-benzylamine-hydrochloride having a melting point of 189-191 占 폚 (decomposition) was precipitated.

Example 2

3,5-Dibromo-2-hydroxy-N- (trans-4-hydroxycyclohexyl) -N-methyl-benzylamine

Melting point of hydrochloride; 120 ℃ (decomposition)

In a similar manner to Example 1, prepared from 3,5-dibromo-salicyaldehyde and trans-4-methyl-amino-cyclohexanol and formic acid.

Example 3

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

Melting point of hydrochloride; 194-197 ℃

In a similar manner as in Example 1, prepared from 5-bromo-salicyaldehyde, N-methyl-cyclohexylamine and formic acid

Example 4

N-ethyl-5-bromo-N-cyclohexyl-2-hydroxy-benzylamine

Melting point of hydrochloride; 175-178 ℃

In a similar manner as in Example 1, prepared from 5-bromo-salicyaldehyde, N-ethyl-cyclohexylamine and formic acid.

Example 5

N-ethyl-5-bromo-2-hydroxy-N- (trans-4-hydroxycyclohexyl) -benzylamine

Melting point of hydrochloride; 190-193 ° C (decomposition)

In a similar manner as in Example 1, prepared from 5-bromo-salicyaldehyde, trans-4-ethylamino-cyclohexanol and formic acid.

Example 6

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

Melting point of hydrochloride; 166-169 ° C (decomposition)

In a similar manner as in Example 1, prepared from 5-bromo-salicyaldehyde, N-propyl-cyclohexylamine and formic acid.

Example 7

5-Bromo-N-cyclohexyl-2-hydroxy-N-isopropyl-benzylamine

Melting point; 90-93 ℃

In a similar manner as in Example 1, prepared from 5-bromo-salicyaldehyde, N-isopropyl-cyclohexylamine and formic acid.

Example 8

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

Melting point of hydrochloride; 194-198 ℃

In a similar manner as in Example 1, prepared from 5-chloro-salicylaldehyde, N-methyl-cyclohexylamine and formic acid.

Example 9

N-ethyl-5-chloro-N-cyclohexyl-2-hydroxy-benzylamine

Melting point of hydrochloride; 169-171 ℃

In a similar manner as in Example 1, prepared from 5-chloro-salicylaldehyde, N-ethyl-cyclohexylamine and formic acid.

Example 10

5-Chloro-N-cyclohexyl-2-hydroxy-N-propyl-benzylamine

Melting point of hydrochloride; 140-142 ℃

In a similar manner to Example 1, prepared from 5-chloro-salicylaldehyde, N-propyl-cyclohexylamine and formic acid.

Example 11

5-Chloro-N-cyclohexyl-2-hydroxy-N-isopropyl-benzylamine

Melting point; 85-88 ℃

In a similar manner to Example 1, prepared from 5-chloro-salicylaldehyde, N-isopropyl-cyclohexylamine and formic acid.

Example 12

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

7 g of 3,5-dibromo-salicyaldehyde, 17.5 g of dihydroxy-thi-butylamine and 7.7 g of formic acid were heated at 70-80 ° C. for 6 hours. The reaction mixture was then mixed with 2n-ammonia and shaken vigorously to precipitate the resulting precipitate. The residue was dissolved in ethanol, acidified with ethanol hydrochloric acid and ether added to precipitate the product. Recrystallization melting point from anhydrous ethanol / ether: 187-189 ° C

Example 13

N-third-butyl-3,5-dibromo-2-hydroxy-benzylamine

Melting point of hydrochloride; 216-220 ℃ (decomposition)

In a similar manner to Example 12, prepared from 3,5-dibromo-salicyl aldehyde-thi-butylamine and formic acid.

Claims (1)

As described above in the text, benzylamines represented by the following general formula (I) characterized by reacting an aldehyde of the following general formula (II) with an amine of the following general formula (III) or a corresponding formamide in the presence of formic acid How to prepare.

Food, Hal represents a chlorine or bromine atom, R ₁ represents hydrogen, chlorine or bromine atom, R ₂ represents a morpholinocarbonylmethyl group, a C 3-5 branched alkyl group optionally substituted by 1-3 hydroxyl groups, or a group of the following general formula (A),

(A) In the food, R ₃ represents a hydrogen atom, a hydroxyl group or an alkyl group having 1 to 4 carbon atoms, n represents a number of 0, 1 or 2, radicals A and B represent a hydrogen atom or together represent a group of the following general formula (B),

(B) In the food, R ₅ represents a hydrogen atom or a lower alkyl group having 1 or 2 carbon atoms, m represents a number of 1 or 2, R ₄ represents a straight or branched alkyl group having 1 to ₄ carbon atoms, an alkenyl group having 2 to 4 carbon atoms or a cycloalkyl group having 3 to 4 carbon atoms, or when R ₃ does not represent a hydrogen atom, or R ₂ represents 1- When the C 3-5 branched alkyl group optionally substituted with three hydroxyl groups is represented, a hydrogen atom is further represented, L represents the number of one or two.