KR800001677B1 - Process for the preparation of benzylamines - Google Patents

Abstract

Benzylamines ≮I; R1 = H, aliphatic or substituted aromatic acyl; R2 = H, Cl, Br; R3 = carboxyl groupl; R4, R5 = H C1-5 alkyl; C2-4 alkenyl, hydroxy group substituted C5-7 cycloalkyl, benzyl; A = carboxyl group derivs. (e.g. amide, aminoester, ester, or nitril)≉, having excretion effect and anti ulcer activity, were prepd. by hydrolysis of compd. (II). Thus, N-ethyl-2-amino-3-bromo-5-carbethoxy-N-cyclohexyl-ben-zylamine l3 g and 6N-HCI 100 ml was reacted for 1 hr, dried, and recrystallized to give N-methyl-2-amino-3-bromo-5-carboxy-N-cyclohexyl-benzylaminehydrochloride (m.p. 227-2290C).

Description

Method for preparing benzylamine

The present invention relates to a process for preparing benzylamine of the following formula (I).

In the common sense,

R ₁ is a hydrogen atom, an aliphatic or an optionally substituted aromatic acyl group,

R ₂ is hydrogen, chlorine or bromine atom,

R ₃ is a carboxyl group.

R ₄ and R ₅ are the same or different and are hydrogen atom, C ₁ -C ₅ straight or branched alkyl group C ₂ -C ₄ alkenyl group, one or two hydroxy, which may be substituted with one or two hydroxy groups group optionally substituted cycloalkyl group of C ₅ -C _7, benzyl, morpholino carbonyl group, or blood, together with the nitrogen atom pyrrolidine, piperidine, hexamethylene amine, morpholine, N- methyl-piperazine or kampi A din ring is shown.

Compounds of formula (I) have valuable pharmacological properties, in particular anti-ulcer activity, secretory and antitussive effects, stimulating effects on the production of surfactants or dilated factors of alveoli.

The novel compounds of the present invention are prepared by hydrolyzing the compound of formula (II).

In the common sense

R ₁ , R ₂ , R ₄ and R ₅ are the same as described above,

A is a functional derivative of the carboxyl group.

Functional derivatives defined in group A can in particular be considered amides, aminoesters, esters or nitriles.

The reaction is carried out in a solvent such as methanol, ethanol, methanol / water, ethanol / water, dioxane / water or water, in the presence of an acid such as trifluoroacetic acid or sulfuric acid or in the presence of a base such as sodium hydroxide. It is suitably carried out at a temperature of 占 폚, preferably at the boiling point of the solvent used.

When R ₁ is an acyl group, it is simultaneously separated during the reaction.

By the above method, when R ₁ is a hydrogen atom and R ₂ R ₄ and R ₅ are the same as those described above except for the group containing a reactive hydrogen atom, the compound of the formula (I) is obtained. Acylating. This reaction is conveniently carried out by reactive acid derivatives such as acid halides, acid anhydrides or mixed acid anhydrides in the presence of a dehydrating agent such as NN'-dicyclohexylcarbodiimide.

The compound of formula (I) obtained is converted into its acid addition salt with its physiologically mild inorganic or organic acid using 1,2 or 3 equivalents of the corresponding acid as required. As the acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, lactic acid, citric acid, tartaric acid, maleic acid or fumaric acid are suitable.

Compounds of formula (II) used as starting materials are prepared by known methods, for example by reacting the corresponding benzyl halides with the corresponding amines.

As mentioned above, the novel compounds of formula (I) have valuable pharmacological properties, more specifically, have anti-ulcer activity, secretion and antitussive effect, stimulating effect on the production of surfactants or factors during dilatation of alveolar .

As examples, the following compounds were investigated for their physiological action.

A = N-ethyl-2-amino-3-bromo-5-carboxy-N-cyclohexyl-benzylamine-hydrochloride,

1. Secretion effect

Anesthetic tests were performed on anesthetized morphotes or anesthetized rabbits. The test substance was administered orally to 6-8 animals at 8 mg / Kg each. It was calculated by comparing the increase in secretion within 2 hours after administration of the test substance.

Three rats anesthetized with chloralose-urethane were tested intravenously with 2,4 and 8 mg / kg of test substance, respectively, to determine the circulation effect.

Test for Mormot:

2. Antiulcer activity

The action of the test substance on ulceration was measured by the method of Takag et al. (Jap. J. Pnarmac. 19, 418 (1969)). Next, 0.05 ml of 5% acetic acid solution was injected between the gastric mucosa and the submucosal tissue, and after the injection, the stomach was re-stitched. 100 mg / kg (6 mice / dose) were mixed and administered to the food for 3 weeks, and control rats were fed only ground food.

After treatment for 3 weeks, rats were killed and stomachs were taken to measure the length and width of the ulcers. The activity of the test substance was compared with the control value (100%). Intensive administration of test substance A at a dose of 50 mg / kg resulted in a 52% reduction in ulcers compared to the control, and a 79% reduction in ulcers at a dose of 100 mg / kg.

3. Acute Toxicity

Five rats were dosed orally at 1000 or 2000 mg / kg (one time), respectively, to determine the acute toxicity of the test substance.

The novel compounds of formula (1) may be combined with other active ingredients, optionally in combination with other active ingredients, in a single dosage of 1-100 mg, preferably in conventional pharmaceutical compositions such as tablets, coated tablets, capsules, suppositories, ampoules and solutions. 4-60 mg, the daily dose is 2-300 mg, preferably 4-2000 mg. In the case of a compound having a secretory activity, the single dose is 1-20 mg, preferably 4-15 mg, and in the case of a compound having antiulcer activity, 25-100 mg, preferably 30-60 mg.

The following examples are intended to illustrate the invention.

Example 1

N-ethyl-2-amino-3-bromo-5-carboxy-N-cyclohexyl-benzylamine

13 g of N-ethyl-2-amino-3-bromo-5-carboethoxy-N-cyclohexyl-benzylamine was boiled with 100 ml of 6n hydrochloric acid for 1 hour. The solution was then decanted from the oily residue obtained and dried until dry. The residue was recrystallized from methanol. N-methyl-2-amino-3-bromo-5-carboxy-N-cyclohexyl-benzylamine hydrochloride having a melting point of 227-229 ° C. was obtained.

Example 2

2-amino-5-carboxy-N, N-diethyl-benzylamine

Melting Point of Hydrochloride: 194-198 ℃

2-Amino-5-carbethoxy-N, N-diethyl-benzylamine was prepared by saponifying similarly as in Example 1 in hydrochloric acid.

Example 3

2-Amino-3-bromo-5-carboxy-N, N-dithyl-benzylamine

Melting point of hydrochloride: 233-234 ° C. (decomposition)

2-Amino-3-bromo-5-carethoxy-N, N-diethyl-benzylamine was prepared by saponifying in hydrochloric acid similarly as in Example 1.

Example 4

2-Amino-3-bromo-N-tertbutyl-5-carboxy-benzylamine

Melting point of hydrochloride: 270-280 ° C (decomposition)

2-Amino-3-bromo-N-tertbutyl-5-carbethoxy-benzylamine was prepared by saponification in hydrochloric acid as in Example 1.

Example 5

2-Amino-3-bromo-5-carboxy-N-cyclohexyl-N-methyl-benzylamine

Melting Point of Hydrochloride: 230-240 ℃

2-Amino-3-bromo-5-carethoxy-N-cyclohexyl-N-methyl-benzylamine was prepared by saponifying similarly as in Example 1 in hydrochloric acid.

Example 6

N-ethyl-2-amino-5-carboxy-N-cyclohexyl-benzylamine

Melting Point of Dihydrochloride: 175-181 ℃

N-ethyl-2-amino-5-carbethoxy-N-cyclohexyl-benzylamine was prepared by saponifying similarly as in Example 1 in hydrochloric acid.

Example 7

N-ethyl-2-amino-5-carboxy-3-chloro-N-cyclohexyl-benzylamine

Melting Point of Hydrochloride: 228-232 ℃

N-ethyl-2-amino-5-carethoxy-3-chloro-N-cyclohexyl-benzylamine was prepared by saponifying in hydrochloric acid similarly as in Example 1.

Example 8

N-ethyl-2-amino-3-bromo-5-carboxy-benzylamine

2.7 g of N-ethyl-3-bromo-5-carbmethoxy-benzylamine was boiled with 65 ml of 6N hydrochloric acid for 35 minutes. After cooling to -15 ° C, N-ethyl-2-amino-3-bromo-5-carboxy-benzylamine-hydrochloride crystallized. This was recrystallized from ethanol / ether.

Melting point of hydrochloride: 261 ° C (decomposition)

Example 9

N- (2-Amino-5-carboxy-benzyl) -pyrrolidine

Melting point of hydrochloride: 193-194 ° C (decomposition)

Prepared according to the method sprayed with Example 8 from N- (2-amino-5-carbethoxy-benzyl) -pyrrolodine and 6n hydrochloric acid.

Example 10

N- (2-Amino-3-bromo-5-carboxy-benzyl) -pyrrolidine

Melting point of hydrochloride: 267 ° C (decomposition)

Prepared according to a method similar to Example 8 from N- (2-amino-3-bromo-5-carethoxy-benzyl) -pyrrolidine and 6n hydrochloric acid.

Example 11

2-Amino-5-carboxy-N- (trans-4-hydroxycyclohexyl) -benzylamine

Melting point of hydrochloride: 224 ° C (decomposition)

Prepared according to a method similar to Example 8 from 2-amino-5-carbethoxy-N- (trans-4-hydroxycyclohexyl) -benzylamine and 6n hydrochloric acid.

Example 12

2-Amino-3-bromo-5-carboxy-N- (trans-4-hydroxycyclohexyl) -benzylamine

Melting point of hydrochloride: 270 ° C (decomposition)

Prepared according to a method similar to Example 8 from 2-amino-3-bromo-5-carbethoxy-N- (trans-4-hydroxy cyclohexyl) -benzylamine and 6n hydrochloric acid.

Example 13

N- (2-amino-5-carboxy-benzyl) -morpholine

Melting point of hydrochloride: 222 ° C (decomposition)

Prepared according to a method similar to Example 8 from N- (2-amino-5-chamoethoxy-benzyl) -morpholine and 6n hydrochloric acid.

Example 14

N- (2-Amino-3-bromo-5-carboxy-benzyl) -morpholine

Melting Point of Hydrochloride: 286 ° C (Decomposition)

Prepared according to a method similar to Example 8 from N- (2-amino-3-bromo-5-carbethoxy-benzyl) -morpholine and 6n hydrochloric acid.

Example 15

N- (2-Amino-5-carboxy-benzyl) -hexamethyleneamine

Melting point of dihydrochloride: 121 ° C (decomposition)

Prepared according to similar protection as in Example 8 from N- (2-amino-5-carbethoxy-benzene) -hexamethyleneamine and 6n hydrochloric acid.

Example 16

N- (2-Amino-3-bromo-5-carboxy-benzyl) -hexamethyleneamine

Melting point of hydrochloride:> 224 ° C (decomposition)

Prepared according to a method similar to Example 8 from N- (2-amino-3-bromo-5-carbethoxy-benzyl) -hexamethyleneamine and 6n hydrochloric acid.

Example 17

2-amino-5-carboxy-N- (cis-3-hydroxy cyclohexyl) -benzylamine

Melting point of dihydrochloride: 162 ° C (decomposition)

Prepared according to a method similar to Example 8 from 2-amino-5-carbethoxy-N- (cis-3-hydroxy cyclohexyl) -benzylamine and 6n hydrochloric acid.

Example 18

2-Amino-3-bromo-5-carboxy-N- (cis-hydroxy-cyclohexyl) -benzylamine

Melting point of hydrochloride: 119 ° C (decomposition)

Prepared according to a method similar to Example 8 from 2-amino-3-bromo-5-carbethoxy-N- (cis-3-hydroxy cyclohexyl) -benzylamine and 6n hydrochloric acid.

Example 19

N-ethyl-2-amino-3-bromo-5-carboxy-N-cyclohexyl-benzylamine

0.6 g of N-ethyl-2-amino-3-bromo-5-carbamoyl-N-cyclohexyl-benzylamine was dissolved in 45 ml of concentrated hydrochloric acid and then boiled for 40 minutes. The precipitate obtained after cooling was suction filtered. Hydrochloride with a melting point of 227-229 ° C. (decomposition) was obtained under recrystallization from ethanol.

Example 20

N-ethyl-2-amino-3-bromo-5-carboxy-N-cyclohexyl-benzylamine

1 g of N-ethyl-2-amino-4-bromo-N-cyclohexyl-5-cyano-benzylamine was boiled with 45 ml of concentrated hydrochloric acid for 40 minutes. The reaction mixture was poured into ice, neutralized with ammonia and then filtered through a small amount of insoluble matter. The filtrate was extracted with ether, the ether extract was evaporated to dryness, the residue was dissolved in ethanol and etheric hydrochloric acid was added to give a hydrochloride having a melting point of 227-229 ° C. (decomposition).

Claims (1)

A method for producing benzylamine of formula (I) by hydrolyzing a compound of formula (II) as described above in the text.

In the above formula, R ₁ is a hydrogen atom, an aliphatic or an optionally substituted aromatic acyl group, R ₂ is hydrogen, chlorine or bromine atom, R ₃ is a carboxyl group, R ₄ and R ₅ are the same or different and are hydrogen atoms, C ₁ -C ₅ straight or branched alkyl groups, which may be substituted with one or two hydroxy groups, C ₂ -C ₄ alkenyl groups, one or two hydroxy Pyrrolidine, piperazine, hexamethyleneamine, morpholine, N-methyl-piperazine or campidine ring together with a C ₅ to C ₇ cycloalkyl group, benzyl, morpholinocarbonyl methyl group or nitrogen atom optionally substituted with a group And A is a functional derivative of the carboxyl group.