BG61643B1 - Method for the preparation of benzylamine products having antifungal activity - Google Patents

Abstract

By the method the following is produced:N-methyl-N-(4'-tert-butylbenzyl)-1-naphhyl-methylaminehydrochloride, N-isopropyl-N-(4'-tert-butylbenzyl)-1-naphthylaminehydrochloride,N-alyl-N-(4'-tert-butylbenzyl)-1-naphthylmethylaminehydrochloride, N-methyl-N-(4'-isopropylbenzyl)-1-naphylmethylaminehydrochloride which can be applied in human and veterinarymedicine, in the house and in agriculture making use of accessibleand cheap raw material. Work is easy and safe, and also highyields are produced during the different stages with lowproduction costs. Synthesis is effected by reduction alkylation of1-naphthadehyde with low molecular primary amines in methanol inthe presence of activated aluminium shavings until the productionof a secondary amine. The latter is alkylated by4'-tert-butylbenzylbromide or 4'-isopropylbenzylbromide inmethylchloride in the presence of dry sodium carbonate ortriethylamine. The tetriary amine produced, dissolved in acetone,is acidified by concentrated hydrochloric acid until hydrogenchloride salt is produced. High-yield benzylbromides are producesby radical bromination of the respective toluenes in a two-phasesystem in the presence of perhydrol and lumination by an ordinarylamp with visible light.

Description

(54) METHOD OF PREPARATION OF BENZYLAMINE PRODUCTS WITH ANTI-MUSHROOM ACTIVITY

The invention relates to the preparation of: N-methyl-L- (4-tert-butylbenzyl) -1naphthylamine hydrochloride; N-isopropyl-N- (4-tert-butylbenzyl) -1-naphthylamine hydrochloride; B1-allyl-N- (4-tert-butylbenzyl) -1-naphthylmethylamine and N-methyl-N- (4-isopropylbenzyl) -1-naphthylmethylamine hydrochloride, which are used in human and veterinary medicine as antifungal agents, and in the home - as antiseptic antifungal additives to paint and wood materials, wallpaper, leather and more.

There are two major patents for the synthesis of such benzylamine products in the literature.

The basic and latest patent (1) states the preparation of benzylamine derivatives by the alkylation reaction of N-methyl-N (1-naphthylmethyl) -amine with 4-tert-butylbenzyl bromide in dimethylformamide and in the presence of dry sodium carbonate . This is a conventional reaction that is used in a variety of cases aimed at producing a tertiary amine.

The second patent (2) uses the same basic reaction, but here is how the secondary amines are prepared in different cases. In a single case, 4-tert-butylbenzyl bromide was mentioned as a reagent without specifying a method for its preparation.

As a disadvantage of the two patents cited, it can be noted that it is not stated how the benzyl halides used are synthesized. Syntheses of the intermediate reagents are more important throughout the scheme: benzyl halides and secondary amines, from which the final products are obtained.

It is an object of the invention to provide a simplified and industrially applicable method for the synthesis of benzylamine products with antifungal biological activity that utilizes accessible raw materials, soft and safe working conditions, good yields in the various steps.

The problem is solved by bromination in a two-phase system of 4-tert-butyltoluene and 4-isopropyltoluene with hydrobromic acid in the presence of perhydrol and by illumination with a visible-spectrum lamp, followed by alkylation of the corresponding secondary amines with the obtained benzyl bromide sulfides. carbonate or triethylamine, the tertiary amines obtained after isolation being dissolved in acetone and, by acidification with concentrated hydrochloric acid, converted into hydrochloric salts, which are pharmaceutical products.

Phase I

C (CH3> c

The advantages of the invention lie in the fact that an improved method for the synthesis of benzylamine antifungal products has been devised which offers a soft working environment with good yields and is industrially applicable.

For the first time, the preparation of benzyl halides by high-yield photochemical radical reaction and subsequent alkylation of the secondary amines, resulting in the final products, is proposed.

The invention is illustrated by the following examples

Example 1. 1.8 ml of 4-tert-butyltoluene were dissolved in 35 ml of methylene chloride, 0.6 ml of hydrogen peroxide (30%) was added and 1.8 ml of hydrobromic acid (48%) were added after illumination of the flask. After the reaction is complete, 100 ml of water are added and the layers are separated. The aqueous layer was extracted with 2 x 15 ml of methylene chloride. The organic extracts were combined, dried with anhydrous sodium sulfate, filtered and used for the next reaction without isolation. This solution contains 2.3 g of 4-tert-butylbenzyl bromide (97%) relative to the parent 4-tert-butyltoluene.

Bromination of 4-isopropyltoluene was similarly carried out, giving 1.6 g of starting material 2.0 g of 4-isopropylbenzyl 5 bromide (91%) relative to the parent 4-isopropyltoluene.

Example 2. In 40 ml of dry methylene chloride containing 2.3 g of 4-tert-butylbenzyl bromide were added 1.7 g of N-methyl-1-naphthylmethylamine and 10 2.0 g of dry sodium carbonate. The mixture was stirred at reflux until the amine was consumed (about 2 h). It is then cooled and 100 ml of water are added. The mixture was stirred and acidified with hydrochloric acid (1: 1) to pH = 2 - 3, separated, the aqueous layer basified to pH 9-10 and extracted with 2 x 25 ml of methylene chloride, the solvent distilled off, the residue was evacuated. 30 ml of acetone were added and acidified with concentrated hydrochloric acid, leaving the product as a hydrochloric salt under cooling.

Yield: 2.4 g = 83%.

The products described in the table below are similarly obtained.

Table

No Reagents Product Amen Bromide View ” Quantity (8) % Type ⁺ Quantity Kind ~ Quantity 1. 1 2.1 4 3.5 6 2.2 86 2. 2 2.4 4 3.5 7 3.1 80 3. 3 2.4 4 3.5 8 3.2 82 4. 1 2.1 5 3.3 9 2.9 85

* 1. N-methyl-1-naphthylmethylamine hydrochloride

2. N-isopropyl-N-naphthylmethylamine hydrochloride

3. No. allyl-1-naphthylmethylamine hydrochloride * 4. 4-tert-butylbenzyl bromide

5. 4-Isopropylbenzyl bromide *** 6. N-methyl-N- (4-tert-butyl benzyl) 1-naphthylmethylamine hydrochloride, m.p. 200 202 ° C.

7. N-isopropyl-N- (4-tert-butylbenzyl) -! -naphthylmethylamine hydrochloride, m.p.

82-84 ° C.

8. No. allyl-No. (4-tert-butylbenzyl) -1naphthylmethylamine (oil).

9. No. methyl-No. (4-isopropylbenzyl) -1naphthylmethylamine hydrochloride, m.p. 177 -

180 ° C.

Claims (1)

Claims Process for the preparation of benzylamine 50 antifungal products including No. methyl-No. (4-tert-butyl benzyl) -1-naphthylmethylamine hydrochloride, No. Isopropyl-No. (4-tert-butylbenzyl) -1-naphthylmethylamine hydrochloride, N -al-yl- N - (4-tert-butylbenzyl) -1-naphthylmethylamine hydrochloride and N-meth.tN (4-isopropylbenzyl) -1-naphthylmethylamine hydrochloride, characterized in that the synthesis is carried out by radical bromination of 4 -tert-butyltoluene and 4-isopropyltoluene in a two-phase system and in the presence of 48% hydrobromic acid and 30% hydrogen peroxide and visible spectrum branching, subsequent alkylation of the described secondary naphthylamines in methylene chloride and the presence of dry sodium carbonate, isolation of the resulting tertiary amines, dissolution in acetone, and acidification with concentrated hydrochloric acid to give the hydrochloride end products.