KR800001630B1 - Process for the preparation of benzylamines - Google Patents

Abstract

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Description

Method for preparing benzylamine

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

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 carboalkoxy group,

R ₄ and R ₅ are the same or different and are a hydrogen atom, a C ₁ -C ₅ straight or branched alkyl group which may be substituted with one or two hydroxy groups, a C ₂ -C ₄ alkenyl group, one or two hydrides hydroxy 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 A campidine ring is shown.

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

Novel Compounds of the Invention A compound of formula (II) is prepared by reacting with a compound of formula (III).

From the stomach

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

B is a carboxyl group or a functional derivative thereof.

From the stomach

R ₁₀ is a lower alkyl group,

C is a hydroxyl group or a halogen atom.

Particularly preferred as functional derivatives defined for B are anhydrides, acid halides, amides, amidines, esters or nitriles.

The reaction is carried out in the presence of a solvent such as ethanol, tetrahydrofuran, dioxane or in excess of the compound of formula (III), optionally in the presence of an alcoholate such as sodium epoxide or in the presence of an acid such as ethanol hydrochloric acid. It is convenient to carry out at a temperature of < RTI ID = 0.0 > The hydrolysis of the iminoester formed in the middle is carried out using water, and the next deacylation is carried out using the corresponding alcohol and acid.

This compound is necessary if, by the above method, a compound of formula (I) is obtained, except that R ₁ is a hydrogen atom and R ₂ , R ₃ , R ₄ and R ₅ contain a reactive hydrogen atom. As a result, acylation is performed next. 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 to 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, allic acid or fumaric acid are suitable.

Compounds of formula (II) used as starting materials can be prepared, 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 anti-ulcer activity, secretion and antitussive effect, stimulating effect on the production of alveolar surfactant or dysfunction factor.

As an example the following compounds were investigated for their physiological action.

A = 2-Amino-3-bromo-5-carethoxy-N, N-diethyl-benzylamine-hydrochloride

1. Secretion effect

An anesthetic test was performed on the anesthetized mormot.

Test substances were 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.

The circulatory effect was measured by intravenously administering test substances 2,4 and 8 mg / kg, respectively, to three rats anesthetized with chloralose-yoretan.

Test for Mormot:

2. Antiulcer activity

The action of the test substance on ulceration was determined by the method of Takagi et al. (Jap. J. Pharmac. 19,418 (1969)). The embryos of female rats weighing 220-250 g, anesthetized with eterl, split off and protruded over the stomach. Next, 0.05 ml of 5% acetic acid solution was injected between the gastric mucosa and the submucosal tissue. After injection the belly was re-sewed. After 3-5 days, the ulcers formed on the mucosa were treated by mixing 50 mg of test substance and 100 mg / kg (6 mice / dose) with food for 3 weeks. 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%).

When test substance A was administered orally at a dose of 50 mg / kg, 52% of the ulcers were reduced compared to the control value, and 79% of the ulcers were reduced when the dose of 100 mg / kg was administered.

3. Acute Toxicity

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

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

The following examples are intended to illustrate the invention.

Example 1

2-Amino-3-bromo-5-carethoxy-N, N-diethyl-benzylamine

5 g of 2-amino-3-bromo-5-carboxy-N, N-diethyl-benzylamine were dissolved in 150 ml of anhydrous ethanol. The solution was saturated with hydrogen chloride, heated to boiling for 1 hour and then evaporated to dryness in vacuo. The residue was crystallized in ethynol to give a hydrochloride with a melting point of 165-168 ° C.

Example 2

2-Amino-3-bromo-5-carethoxy-N, N-diethyl-benzylamine

0.7 g of 2-amino-3-bromo-5-carbethoxy-N, N-diethyl-benzylamine are dissolved in 75 ml of anhydrous ethanol, 0.02 g of sodium hydroxide is added, the mixture is boiled for 15 minutes and vacuum Evaporate until dry. The residue was partitioned between water and chloroform, then the chloroform solution was dried and evaporated to dryness. The residue was converted to hydrochloride with melting point 165-168 ° C. by etheric hydrochloric acid.

Example 3

2-Amino-3-bromo-5-carethoxy-N, N-diethyl-benzylamine

3 g of 2-amino-3-bromo-5-carboxy-N, N-diethyl-benzylamine were heated with 9 ml of thionyl chloride in 30 ml of toluene together with 9 ml of thionyl chloride for about 1 hour until the mixture was dried in vacuo. Evaporate until dry. The 4-amino-3-bromo-5- (N, N-diethyl) -aminomethyl-benzoylchloride-hydrochloride thus obtained was stirred for 3 hours in a solution in which 1 g of sodium was dissolved in 20 ml of anhydrous ethanol. . After evaporation of the solution to dryness in vacuo, the residue was partitioned between chloroform and water, the chloroform solution was dried and the mixture was evaporated until dryness. The residue was dissolved in ethanol and etheric hydrochloric acid was added to give a hydrochloride with a melting point of 165-168 ° C.

Example 4

2-Amino-3-bromo-5-carethoxy-N, N-diethyl-benzylamine

After 1.1 g of 2-amino-3-bromo-5-carbamoyl-N, N-diethyl-benzylamine was dissolved in 30 ml of anhydrous ethanol, the solution was saturated with hydrogen chloride and boiled for 6 hours. The mixture was evaporated to dryness and the residue partitioned between chloroform and dilute ammonia. The chloroform solution was evaporated and the residue was purified by chromatography on silica gel (eluent, toluene: acetone = 4: 1). The residue obtained by evaporating the eluate was dissolved in ethanol and etheric hydrochloric acid was added to give a hydrochloride having a melting point of 165-168 ° C.

Claims (1)

A method for producing benzylamine of the general formula (I) by reacting a compound of the general formula (II) with a compound of the general formula (III) as described above.

Wherein 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 carboalkoxy group, and R ₄ and R ₅ are the same or different and are hydrogen C ₁ -C ₅ straight or branched alkyl groups, optionally substituted with one or two hydroxy groups, alkenyl groups with C ₂ -C ₄ , C ₅ -C ₇ optionally substituted with one or two hydroxy groups Cycloalkyl group, benzyl, morpholinocarbonylmethyl group, or nitrogen atom together with pyrrolidine, piperidine, hexamethyleneamine, morpholine, N-methyl-piperazine or campidine ring, B represents a carboxyl group or It is a functional derivative, R ₁₀ is a lower alkyl group, C is a hydroxyl group or a halogen atom.