CS225599B1 - 2,3,10,11-tetramethoxy-6-/4-tolyl/berbine and its hydrochloride - Google Patents

Description

The invention relates to 2,3,10,11-tetramethoxy-6- (4-tolyl) berbine of formula I

and its hydrochloride.

The compound of formula I and its hydrochloride exhibit pharmacodynamic and antimicrobial activity in biological assays, so that they can find use in therapy. The hydrochloride of Compound I (which has been pharmacologically tested as crystalline monohydrate) is almost non-toxic. Its median lethal dose to mice is greater than 2.5 g / kg. In animal tests, the substance exhibits tranquilizer properties. mice, where oral doses of 100-300 mg / kg prolong the duration of the hypnotic effect of thiopental to twice the control value, and a significant hypothermic effect in rats must also be interpreted in the same sense: oral doses of 110-100 mg / kg cause The antimicrobial effect of Compound I is mainly directed towards yeasts and inferior fungi, partly pathogenic, thus concentrations of 100 (Ug / ml of Compound I inhibit the growth of Saccharomyces pasterianus, Candida albicans and Aspergillus niger). L Units I and its hydrochloride are thus tranquilizers a specific antimicrobial treatment.

Compound I is synthetically accessible by the Pictet-Spengler reaction of the 1,2,3,4-tetrahydroisoquinoline derivative of formula II.

The reaction consists in treating aqueous formaldehyde in methanol and heating the reaction mixture with hydrochloric acid to give the hydrochloride of compound I directly. The hydrochloride is a well-crystallizing substance which, by decomposition with aqueous ammonia, also gives a base of formula I also crystalline. The starting material of formula (II) has not yet been described in the literature and its preparation is described in the following description of the synthesis. Substance I, its hydrochloride and a number of intermediates are novel substances whose identity has been established both analytically and by spectral methods (UF, IR and 1 H NMR spectra). The compound of formula I exhibits two chiral centers in the molecule and is accordingly able to exist in two racemic forms. Crystallization of the crude product yields a relatively homogeneous substance which is to be regarded as one individual racemate. Since the melting point of the analytical sample is not too far from the melting point of the crude, it is to be understood that the reaction proceeds considerably stereospecifically and that one of the racemates is the predominant product. The synthesis of compound I and its hydrochloride is described below.

6,7-Dimethoxy-1- (3,4-dimethoxybenzyl) -3- (4-tolyl) -1,2,3,4-tetrahydroisoquinoline hydrochloride (47 g) was quenched with 500 mL of 20% sodium hydroxide solution and liberated the base was isolated by extraction with chloroform. It is obtained as a clear oil in a yield of 45 g. This whole quantity is dissolved in 250 ml of methanol, 50 ml of 36% aqueous formaldehyde is added and the mixture is left at room temperature for 8 days. Then, 260 ml of 5M-HCl was added and the solution was refluxed for 50 min. After standing for an additional 14 days at room temperature, the precipitated 2,3,10,11-tetramethoxy-6- (4-tolyl) berbine hydrochloride monohydrate (I) is filtered off with suction, washed with a mixture of methanol and ether and dried. 40 g (83%) of crude product melting at 170-174 ° C are obtained. Crystallization from ethanol gave a homogeneous product (one individual racemate) melting at 176-177 ° C with decomposition. Decomposition of the hydrochloride with aqueous ammonia and extraction with ether yields the free crystalline base of formula I, which melts in a pure state at 87-91 ° C.

The starting 6,7-dimethoxy-1- (3,4-dimethoxybenzyl) -3- (4-tolyl) -1,2,3,4-tetrahydroisoquinoline hydrochloride (II) has not been described in the literature. They can be obtained by the following chain synthesis starting from the reaction of homoveratroyl chloride (Haworth R. D. et al., Chem. Soc. 125, 1686, 1924) with toluene.

To a stirred suspension of 450 g of anhydrous aluminum chloride in 700 ml of toluene, a solution of 430 g of homoveratroyl chloride in 800 ml of toluene was added dropwise over 3 hours at 15 ° C, stirred for 6.5 hours at 15 ° C, left at room temperature overnight. then decompose by pouring into a mixture of 5 L of 5M-HCl and 5 kg of ice. The mixture was stirred for 45 min. and extracted with chloroform after melting the ice. The extract is washed with water,

5% sodium hydroxide solution and water, dried over magnesium sulfate and evaporated under reduced pressure. 387 g (72%) of crude crystalline 2- (3,4-dimethoxyphenyl) -4'-methylacetophenone melting at 98-102 ° C (south of 94 ° C) is obtained. This material is sufficiently pure for further processing. For characterization, a completely pure material, m.p.

105.5 ° C. Also for characterization, a sample of the oxime can be prepared by reacting this ketone with hydroxylamine hydrochloride in boiling ethanol in the presence of sodium bicarbonate, which crystallizes from aqueous methanol and melts at 113-115.5 ° C.

A mixture of 270 g of the previous ketone, 680 g of formamide and 140 g of 98% formic acid was slowly heated until a temperature of 170-180 ° C was reached, maintaining the mixture for 12 h. The mixture was cooled to 30 ° C and the precipitated solid N- [2- (3,4-dimethoxyphenyl) -1- (4-tolyl) ethyl] formamide was filtered off with suction, washed with water and dried. It is obtained in an almost theoretical yield of 297 g and melts at 128-131 ° C. It is sufficiently clean for further work. For characterization, the sample can be purified by crystallization from aqueous methanol; it melts at 134-135 ° C.

A mixture of 297 g of the previous amide, 350 ml of ethanol and 310 g of 85% potassium hydroxide was stirred and refluxed in a 120 ° C bath for 3 h. It is then diluted with 1.5 L of water and the base is extracted with ether. The extract was dried over potassium carbonate and evaporated. 252 g (93%) of oily 2- (3,4-dimethoxyphenyl) -1- (4-tolyl) ethylamine are obtained, which is dissolved in 500 ml of ethanol, a slight excess of a solution of hydrogen chloride in ether is added, and a further 1 l of of ether. On standing and cooling 240 g (78%) of crystalline hydrochloride precipitated, melting at 228-229.5 ° C. is practically clean and suitable for further processing.

To a mixture of 62 g of the preceding hydrochloride and 300 ml of pyridine was added a solution of 58 g of homoveratroyl chloride in 100 ml of toluene, and the mixture was stirred at 60-70 ° C for 7.5 h. After cooling, it is poured into 3 l of ice water, the precipitated solid product is filtered off with suction, washed with water, dried and recrystallized from 1 l of toluene. 73 g (82%) of N- [2- (3,4-dimethoxyphenyl) -1- (4-tolyl) ethyl] -3,4-dimethoxyphenylacetamide are obtained, which melts at 152-155 [deg.] C. when heated, then it solidifies again and melts again at 163-164 ° C.

A mixture of the previous amide (90 g), toluene (400 ml), phosphorus oxychloride (300 ml) and phosphorus pentoxide (30 g) was stirred and refluxed for 5 hours. It is then evaporated under reduced pressure. The residue was dissolved in 3 L of ethanol, neutralized with 350 mL of 5M-NaOH and stirred with stirring for 30 min. slowly add 30 g of sodium borohydride. The mixture was refluxed for 3 h, evaporated under reduced pressure, basified with 5M-NaOH and extracted with benzene. The extract is shaken with excess 1M-HCl and the precipitated 6,7-dimethoxy-1- (3,4-dimethoxybenzyl) -3- (4-tolyl) -1,2,3,4-tetrahydroisoquinoline hydrochloride (II) is isolated by suction , washing with a mixture of ethanol and ether and drying.

61 g (65%) of m.p.

218.5 ° C with decomposition, which is suitable as a raw material for the last stage of synthesis. For characterization, recrystallization from 80% ethanol gave a pure material melting at 220-221 ° C with decomposition.

Claims (2)

SUBJECT 2,3,10,11-tetramethoxy-6- (4-tolyl) berbin of formula I YNÁLEZU and its hydrochloride,