SU768177A1 - Method of producing (s)-(-)-or (r)-(+)-1-methyl-1,2,3,4-tetrahydroisoquinoline - Google Patents

Abstract

, THE METHOD OF OBTAINING (S) - (-) OR (R) - (+) - 1-METHYL-1,2,3,4-TETPAHYDROIZOHINOLINA based on fatty-aromatic amine, characterized in that, in order to ensure process, as a fatty aromatic amine use (S) - (-) - or (R) - (+) - 1-phenylethylamine and condense it with ethylene chlorohydrin, the resulting H-

Description

About 00

h

Ichobretenno not related to the new method of obtaining optically active 1-methyl-1,2,3,4-tetrahydroisohisolines.

Tetrahydroisohynolinop derivatives have physiological activity and are part of drug preparations.

The four-step synthesis of (-1) -1-methyl-1,2,3, 4-tet15 hydroxy quinoline l is known, consisting in the acylation of 1-benzylethylamine followed by cyclization of the resulting N-acetyl-1-benzyl-1-methyl , 3,4-tetrahydroisoquinoline, the latter is cleaved with D-tartaric acid and after four salt crystallizations, (-) - 1-methyl-1, 2,3,4-tetrahydroisoquinoline is isolated from it. Outputs on none of the stages are not specified. Based on the literature data for the individual stages, it is possible to calculate approximately the yield of the final product, which will not exceed, calculated on the initial 1-benzylethyl amine.

The disadvantage of the method is its complexity due to the stage of splitting the final product into knowledge-isomers, as well as the use of the initial substance, which is not produced by the industry.

The aim of the invention is to increase the yield of the target product and to simplify the method of synthesizing the optically active 1-methyl-1,2,3,4-tetrahydroisoquinoline L by reducing the number of stages and using the optically active 1-phenylethylamine as the starting material, which is an industrial preparation . In addition, the proposed method allows the synthesis of both enantiomers of 1-methyl-1,2,3,4-tetrahydroisoquinoline, since both enantiomers of 1-phenylethylamine are available.

According to the invention, the method of producing (S) - (- 1) - or (K) - (+) - 1-methyl-1, 2,3,4-tetrahydroisoquinoline OJ is that (S) - (-) - or (K) - (+) - 1-Fensch1Etilamine is subjected to condensation with ethylene chlorohydrin, the resulting H- (2-oxystil) -1-phenylstilamine is boiled with thionyl bromide into N- (2-bromoethyl) -1-phenylethylamine bromide which is cyclized without further purification in the presence of chloride

aluminum in 1-methyl-1,2,3,4-tegrahydroisoquinoline (I), the total yield, based on the source 1-fenstatyuaminamine, 30-40%, From (3) - (-) - 1-phenyleptim do not receive (- ) -1-methyl-1,2,3,4, -tetrachdroisoquinoline lj. Since all reactions proceed without affecting the asymmetric center, (-) - 1 also has the S configuration.

Similarly, from (R) - (+) - 1-phenylethylamine, (I) - (+) - 1-methyl-1, 2,3,4-tetrahydroisoquinoline is obtained.

Example 1, K- (2-Hydroxyethyl) -1-phenylethylamine.

12.1 g (0.1 mol) of (-) - 1-phenylethylamine (4l, without solvent), 4.1 g (0.05 mol) of ethylene chlorohydrin and 10 ml of water are heated for 5 hours, alkalinized with 40% NaOH solution extracted with benzene (4 times 30 ml each time), dried with KjCOj, benzene was distilled off and excess (-) - 1-phenylethylamine, the residue was distilled in vacuum to give / - (2-hydroxyethyl) -1-phenylthylamine, yield 87%, t .kip. 39 0 ° C / 9 mm / h 1.5520.

Found,%: C 72.6; 72.5, H 9.1, 9.1. .

C, oH, 5NO

Calculated,%: C, 72.7; H, 9.2.

Bromohydrate (-) - N- (2-broeth1) -1-phenyle tylamine.

11.6 g (0.06 mol, 4.3 ml) are added dropwise to 7.3 g (0.04 mol) of (-) - H- (2-o1XIztil) 1-phenylethylamine in 15 ml of absolute benzene. thionyl bromide in 15 ml of absolute benzene, heated for 1 h in a water bath. The precipitate formed is filtered, the yield is 11.3. G (83%), so pl. 179-180 0, and purified by presidenial with absolute ether from a methanol solution, so pl. 206-210 s.

Found,%: C 39.1, 39.0, H 5.1, 5.1.

,,, NBr.,

Calculated,%: C 38.9, H 4.9.

(-) - 1-Netil-1,2,3,4-tetrahydroisoquinoline fij .. h

11.3 g (0.034 mol) of crude (-) - to - (2-bromoethyl) -1-phenylethylamine hydrobromide, 13.4 g of AlClj and 280 ml of decalin are heated at 145150 C for 1-2 h, decomposed with ice and hydrochloric acid the aqueous layer is extracted with ether, made basic, extracted with ether, the ether extracts dried with NaOH, the ether is distilled off, the residue

distilled in vacuo, i.e. Kim. Os / mm. 2.92 g of (-) - -methyl-, 2,3,4-tetrahydroisoquinoline are obtained, yield 54.5%. Total vpsod 39, A%, counting on the initial (-) - 1-phenylethylamine. ) - 76.7 (with 0.4, isooctane).

(-) - 1-Methyl-1,2,3,4-tetrahydrbisoquinoline hydrochloride, m.p. 213 ° C

FoundD: C 65.0 65, / N 7.9 /

7.7.

-

Calculated,%: C 65.4, H 7.7, Example 2. Analogously to example 1 from 12.1 g (0, 1 mol) (+) - 1-phenipethylamine (З, +40.6, without solvent) 2.63 g of (+) - 1-me. methyl-1, g, 3,4-tetrahydyroisoquinoline are obtained.

68177 .4

yield 36%. Hydrochloride (+) - 1-methyl-1, 2,3,4-tetrahydroisoquinoline, T..PL. 212, (decomp.).

Found,%: C 65.3; 65.4 H 7.5, 5 7.8.

 , C, o.H, 4NCl

Calculated,%: C 65.4, H 7.7.

Thus, the proposed method allows to increase the yield of the target product by more than 2 times, to simplify the method by reducing the number of stages, eliminating the most laborious stage of splitting the final product into enantiomers and

carrying out the last stage without further purification of the intermediate product.

Claims (1)

METHOD FOR PRODUCING (S) - (-) ~ or (R) - (+) - 1-METHYL-1,2,3,4-TETPAHYDROISOCHINOLINE based on a fatty aromatic amine, characterized in that, in order to increase the yield and simplify the process, as a fatty aromatic amine, (S) - (-) - or (R) - (+) - 1-phenylethyl amine is used and it is condensed with ethylene chlorohydrin, the resulting N- (1-hydroxyethyl) -1-phenylethylamine is boiled with. ..thionyl bromide and N- (2-bromoethyl) -1-phenylethylamine bromide are cyclized in the presence of aluminum chloride. ® ω 's .05 00 m