NL8004206A - Benzyl di:hydroxy tetra:hydro:isoquinoline hydrochloride prepn. - by reacting sodium tri:methoxy:phenyl glycidate with di:hydroxyphenyl ethylamine - Google Patents

Abstract

In prepn. of 1-1-(3,4,5-trimethoxy benzyl)6,7-dihydroxy-1, 2,3,4-tetrahydro isoquinoline-hydrochloride salt (I), sodium-3-(3, 4,5-trimethoxy phenyl)glycidate (II) is reacted with 3,4-dihydroxyphenyl ethylamine-hydrobromide salt (III) in the presence of L(+)tartaric acid and acetic acid. In the reaction, (II) is continuously or gradually added to the reaction mixt. of the (III) and ~(+) tartaric acid and acetic acid and the resulting reaction cpd. is purified and suspended in acetone and it is treated with a highly conc. hydrochloric acid and the hydrochloride salt is re-crystallised with a mixed solvent of methanol-ether. (I) is medically used for dilating bronchus.

Description

N / 29829-Kp / vdM j .... * - 1 - /

Process for the preparation of 1-1- (3,4,5-trimethoxybenzyl) -6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride.

The invention relates to a process for the preparation of 1-1- (3,4,5-trimethoxybenzyl) -6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride, which compound is suitable as a bronchodilator.

Japanese patent N 14,229, filed April 27, 1972, discloses a method for the preparation of 1-1- (3,4,5-trimethoxybenzyl) -6,7-dihydroxy-1,2,3,4- tetrahydroisoquinoline hydrochloride, by which method 3,4-dihydroxy-phenylethylamine is condensed with methyl, or sodium 1Q 3- (3,4,5-trimethoxyphenyl) glicidate. The condensation takes place in an aqueous medium in the presence of both L (+) tartaric and acetic acid at 40 ° C for 90 hours. During the reaction, 1- (3,4,5-trimethoxybenzyl) -6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline racemate is formed, which splits into optical antipodes under the reaction conditions due to the action of the optically active tartaric acid. Due to the difference in solubility of both diastereoisomers in the reaction mixture, there is a selective crystallization of 1-1- (3,4,5-trimethoxybenzyl) -6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline -d-tartrate in 40% yield, which compound is converted into the hydrochloride after treatment with dilute hydrochloric acid.

The object of the invention is to provide a process for the preparation of 1-1- (3,4,5-trimethoxybenzyl) -6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride in a higher yield.

The process according to the invention for the preparation of 1-1- (3,4,5-trimethoxybenzyl) -6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride by reaction of sodium-3- (3,4 . wherein 3,4-dihydroxyphenylethylamine hydrobromide, L (+) - tartaric acid and acetic acid are present, continuously or from time to time 8004206 ν'- «« - 2 - is added until time; after the purification of the thus obtained 1-1- (3,4,5-trimethoxybenzyl) -6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline d-tartrate, the compound is suspended in acetone, in which it is treated with a concentrated hydrochloric acid to yield the final product which is recrystallized from a methanol-ether mixture.

The present process is carried out by continuous or stepwise addition of the sodium 3- (3,4,5-trimethoxyphenyl) glicidate to the reaction mixture containing 3,4-dihydroxyphenylethylamine hydrobromide, L (+) tartaric acid and acetic acid , for 5-20 hours. The reaction takes place at 40-60 ° C, while the molar ratios between the sodium 3- (3,4,5-trimethoxyphenyl) glicidate and the 3,4-dihydroxyphenylethylamine hydrobromide are 1.5: 1 to 2: 1.

Stirring has been found to be very important at the beginning of the reaction.

The present method has succeeded in reducing the degree of accompanying secondary reactions by the continuous or stepwise addition of the starting sodium 3- (3,4,5-trimethoxyphenyl) glicidate. As a result of the stepwise addition, the yield of 1-1- (3,4,5-trimethoxybenzyl) -6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline d-tartrate has increased to a value 25 of 60%. The thus obtained 1-1- (3,4,5-trimethoxybenzyl) -6 ', 7-dihydroxy-1,2,3,4-tetrahydroisoquinoline d-tartrate was suspended in acetone and then treated with concentrated hydrochloric acid, then 1-1- (3,4,5-trimethoxybenzyl) -6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride was recrystallized from a methanol-ether mixture. The medium from which the final product is isolated and recrystallized exerts a positive influence on both purity and yield.

The present method is now further elucidated by the following embodiment: 59.2 g of 3,4-dihydroxyphenylethylamine hydrobromide was dissolved in 400 ml of water, after which the solution was dissolved with a 10% solution of sodium bicarbonate at a pH of 7 8004206 - 3 - • ut * -c. Then 45 g of L (+) tartaric acid was dissolved in 400 ml of water, which solution was then diluted to a total volume of 1800 ml. Then 100 g of L (+) tartaric acid was dissolved in 830 ml of water with 168 ml of acetic acid in it. The mixture was heated to 60 ° C, adding 111.6 g of sodium 3- (3,4,5-trimethoxy-phenyl) -glicidate portionwise over 20 hours. After completion of the addition, the reaction mixture was heated to 60 ° C for 30 hours. The mixture was then cooled and the crystallized reaction product was filtered and then recrystallized from water.

The yield of 1-1- (3,4,5-triemthoxybenzyl) -6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline d-tartrate was 39.3 g, making up 60% of the theory. Melting point 226-229 ° C (with decomposition); (_ q_7 ^ from -3 to -6 ° (c = 1.15 H2 O).

10 g (0.02 mol.) Of 1-1- (3,4,5-trimethoxy-benzyl) -6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline d-tartrate was suspended in 50 ml acetone. Then suddenly 4.2 ml of 35% hydrochloric acid was added, after which the suspension was stirred at room temperature until everything was completely dissolved (approx. 1 hour). The solution was then cooled to 0-5 ° C, at which temperature the solution was stored for 24 hours. The white crystalline product thus obtained was filtered off and then recrystallized from a methanol-ether mixture.

The yield of 1-1- (3,4,5-trimethoxybenzyl- (6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride) was 7.3 g, which corresponded to a yield of 95% of theory. Mp 153-157 ° C (with decomposition) / from 30 -17 to -19 ° (c = 1, H 2 O).

The following table shows the yields of 1-1- (3,4,5-trimethoxybenzyl) -6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline d-tartrate obtained by the stepwise addition of sodium -3- (3,4,5-trimethoxyphenyl) -glicidate according to the invention, compared to the yields obtained in the method according to Japanese Patent N 14,229, wherein the starting products were added simultaneously.

8004206-4 w%; v

TABLE

molar ratios of sodium 3- (3,4,5-trimethoxyphenyl) -glicidate (A) mode of up to 3,4-dihydroxy mixing time temp.

phenylethylamine of the in-yield hydrobromide (B) reagents hours ° C in% 1.5: 1 simultaneous 50 60 37 10 1.5: 1 simultaneous 90 60 33 1.5: 1 stepwise of reagent A 50 60 60 15 800 4 2 06

Claims (1)

ί '- 5 - - Μ. Process for the preparation of 1-1- (3,4,5-trimethoxybenzyl) -6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride by reaction of the sodium 3- (3,4,5 -5 trimethoxyphenyl) glicidate with 3,4-dihydroxyphenylethylamine hydrobromide in the presence of both L (+) tartaric and acetic acid, characterized in that the sodium 3- (3,4,5-trimethoxyphenyl) glicidate is continuously is added stepwise to the reaction mixture of 3,4-dihydro-10-xyphenylethylamine hydrobromide, L (+) tartaric acid and acetic acid, after which the thus obtained 11- (3,4,5-trimethoxybenzyl) -6,7-dihydroxy-1, 2,3,4-tetrahydroisoquinoline d-tartrate is purified and then suspended in acetone, being treated with concentrated hydrochloric acid to give the final product, which is recrystallized from a methanol-ether mixture. 20 8004206