DE1003211B - Process for the preparation of 1-benzyl-2-methyl-1,2,3,4,5,6,7,8-octahydroisoquinolines optionally substituted in the benzyl radical and their salts - Google Patents

Description

Process for the preparation of optionally substituted in the benzyl radical 1-Benzyl-2-methyl-1, 2, 3, 4, 5, 6, 7, 8-octahydroisoquinolines and their salts The new process is used for the production of already known, possibly im Benzene nucleus substituted 1-benzyl-2-methyl -1, 2, 3, 4, 5, 6, 7, 8-octahydro-isoquinolines (R. Grewe, Angewandte Chemie, Vol. 59A [1947], pp. 194 f; 0. Schnider and A. Grüssner, Helvetica Chimica Acta, vol. 32 [1949] p. 821; 0. S chnider and J. Hellerbach, Helvetica Chimica Acta, Vol. 33 [1950], p. 1437, and Vol. 34 [1951], p. 2218).

It has been found that substitution may be made in the benzyl radical 1-Benzyl-2-methyl-1, 2, 3, 4, 5, 6, 7, 8-octahydroisoquinolines and their salts if you get N-methyl ß- [cyclohexen- (1) -yl] ethylamine in an inert solvent, preferably in the presence of an alkaline condensing agent such as potassium carbonate, with phenylacetaldehyde or a phenylacetaldehyde substituted in the nucleus, such as p-methoxyphenylacetaldehyde, or reacted with a bisulfite compound of such an aldehyde and the resultant Enamine either a) with concentrated phosphoric acid or about 50% sulfuric acid heated or b) with concentrated phosphoric acid at ordinary temperature for Brings reaction and the resulting, optionally substituted, 1 - benzyl - 2 - methyl -1, 2, 3, 4, 6, 7, 8, 9-octahydroisoquinoline heated with hydrochloric acid or c) can react with about 50% sulfuric acid at ordinary temperature and the optionally substituted 1-benzyl-2-methyl-10-hydroxy-decahydro-isoquinoline formed heated with concentrated hydrochloric acid and the resulting octahydroisoquinoline derivative if desired, converted into a salt.

The course of the reaction can be illustrated using an example as follows: In its preferred embodiment, the new process has the advantage over the previously known ones that it is one stage shorter in that the octahydroisoquinoline is obtained directly through the ring-closing reaction, while in the previously known processes the cyclization leads to a hexahydroisoquinoline, which is then used in a further process stage must be hydrogenated to octahydroisoquinoline. It was surprising to find that a secondary amine reacted with an optionally ring-substituted phenylacetaldehyde to form an enamine (cf. Karrer, Textbook of Organic Chemistry, 10th Edition, p. 189). Usually, primary amines form Schif's bases with aldehydes, secondary amines generally do not react. Furthermore, it could not be expected that the enamines would be subject to a ring closure to a 1-benzyl-2-methyl-1, 2, 3, 4, 5, 6, 7, 8-octahydroisoquinoline.

Appropriately, N-methyl-ß-cyclohexen- (1) -ylethylamine (0. Schnider and J. Hellerbach, Helvetica Chimica Acta, Vol. 34 [1951], p. 2218) in an inert Solvent, preferably ether, in the presence of an alkaline condensing agent, preferably of anhydrous potassium carbonate, with phenylacetaldehyde or a substituted one Phenylacetaldehyde, e.g. B. p-methoxyphenylacetaldehyde, 3, 4-dimethoxyphenylacetaldehyde, reacted with ice-cooling and left to stand for a few hours at room temperature. The reaction products are yellowish or crystallized oils that can be distilled in vacuo Substances that can be kept well in the absence of air, but in the air color dark soon.

The enamines are preferably obtained by heating with strong mineral acids, preferably 87% phosphoric acid or 50% sulfuric acid, cyclized, whereby a 1-benzyl-2-methyl-1, 2, 3, 4, 5 optionally substituted in the benzene nucleus, 6, 7, 8-octahydro-isoquinoline is formed. One can do the enamines with strong mineral acids also treat at room temperature. In the main, a Isomer 1-benzyl-2-methyl-octahydroisoquinoline which is optionally substituted in the benzene ring. and 1-benzyl-2-methyl-10-hydroxy-decahydro-isoquinoline; these are made by heating with strong mineral acids to the desired 1, 2, 3, 4, 5, 6, 7, 8-octahydro-isoquinolines rearranged or dehydrated.

The 1, 2, 3, 4, 5, 6, 7, 8-octahydroisoquinoline derivatives are distillable Oils and can be converted into crystallized salts. The connections serve as intermediate products for the production of therapeutically active agents. example 1,120 parts by weight of phenylacetaldehyde and 139 parts by weight of N-methyl-ß- [cyclohexen- (1) -yl] ethylamine are dissolved separately in 300 parts of space of absolute ether. Adds to the amine solution 80 parts by weight of anhydrous potassium carbonate and then left with external cooling drip the aldehyde solution into the amine solution within 15 minutes. Under more often Shaking the mixture is allowed to stand for 12 hours at room temperature. It is then filtered and, after evaporation of the ether, distilled. Boiling point of the enamine 138 ° / 0.06 mm Hg. The yield, based on N-methyl ß- [cyclohexen- (1) -yl] ethylamine, is 63 0%. _ 20 parts by weight of enamine become 87.60% phosphoric acid in 200 parts by volume Heated on a water bath for 8 hours. It is then diluted with 1500 parts by volume of water, etherified, the acidic aqueous solution made alkaline with 10% sodium hydroxide solution, the free base was taken up in ether and distilled. 1-Benzyl-2-methyl-1, 2, 3, 4, 5, 6, 7, 8-octahydroisoquinoline boils at 108 ° / 0.01 mm Hg. Yield 700/0. The picrate melts after dissolving from alcohol at 133 to 134 °, the hydrochloride at 195 °.

4 parts by weight of enamine are dissolved in 40 parts by volume of 87% phosphoric acid. The solution is left to stand for 72 hours at normal temperature, then diluted with 300 parts by volume of water, extracted with ether and the acidic aqueous solution made alkaline with dilute sodium hydroxide solution and extracted with ether. After the ether has evaporated, the residue is distilled. The fraction which passes over as a colorless oil at a bath temperature of 125 ° under 0.01 mm Hg pressure is 1-benzyl-2-methyl-1, 2, 3, 4, 6, 7, 8, 9-octahydroisoquinoline. Yield: 65 %. The picrate melts at 151 to 152 ° (from alcohol).

6.5 parts by weight of 1-benzyl-2-methyl-1, 2, 3, 4, 6, 7, 8, 9-octahydroisoquinoline are dissolved in 200 parts by volume of 2N hydrochloric acid. It becomes more concentrated with 50 parts of the room Hydrochloric acid is added and the mixture is refluxed for 4 hours. It is then diluted with Sodium hydroxide solution made alkaline and the base extracted with ether. That when evaporating of the ether remaining oil is at a bath temperature of 120 ° and below 0.01 distilled mm Hg pressure. Yield: 60%. The picrat melts after dissolving Alcohol at 133 to 134 ° and is identical to the picrate of 1-benzyl-2-methyl-1, 2, 3, 4, 5, 6, 7, 8-octahydro-isoquinolines.

3.34 parts by weight of enamine are 50% sulfuric acid in 33 parts by volume Left to stand for 20 hours at room temperature. Then 150 parts by volume become water diluted and refluxed for 1 hour. The solution is shaken out with ether and the acidic aqueous solution made alkaline with 30% sodium hydroxide solution. The excreted Oil is absorbed into ether. The tough one that remains after the ether has evaporated yellowish oil residue becomes petroleum ether in 10 parts by volume (boiling point 60 to 80 °) solved. The 1-benzyl-2-methyl-10-hydroxy-decahydro-isoquinoline separates into coarse crystals and melts after dissolving from petroleum ether at 103 to 104 °, Yield: 310/0; the picrate melts at 138 to 139 ° (from alcohol).

0.45 part by weight of 1-benzyl-2-methyl-10-hydroxy-decahydro-isoquinoline are dissolved in 10 parts by volume of concentrated hydrochloric acid and reflux for 4 hours cooked. The solution is made alkaline with 20% sodium hydroxide solution while cooling with ice and etherified. The residue remaining after the ether has been distilled off is distilled at a bath temperature of 120 ° at 0.03 mm Hg pressure. Yield: 76%. The picrat melts at 132 to 134 °. The mixed sample with the picrate of 1-benzyl-2-methyl-1, 2, 3, 4, 5, 6, 7, 8-octahydro-isoquinolines do not lower the melting point.

Example 2 18 parts by weight of p-methoxy-phenylaceta.ldehydebisulfite compound are moistened with 10 parts by volume of water and 8.5 parts by weight of N-methyl-ß- [cyclohexen- (1) -yl] ethylamine, dissolved in 500 parts of ether, overlaid. The mixture is left with stirring and cooling a solution of 20 parts by weight of potash in 40 parts by volume of water in the course one hour. The mixture is stirred, optionally with the addition of 100 parts by volume Water until everything has gone into solution. The ethereal solution is separated, dried with potash and the residue distilled in vacuo. The enamine is an oil which boils under 0.02 mm Hg pressure at a bath temperature of 182 °. The yield, based on N-methyl-β- [cyclohexen- (1) -yl] ethylamine, is 70%.

1 part by weight of the above enamine is heated with 10 parts by weight of 50% strength sulfuric acid for 8 hours on a water bath. It is diluted with water, etherified, the aqueous layer is rendered alkaline and the base which has precipitated is taken up in ether. After drying and evaporation of the ether, it is distilled in vacuo. The 4'-methoxy-1-benzyl-2-methyl-1, 2, 3, 4, 5, 6, 7, 8-octahydroisoquinoline boils at 178 ° / 0.03 mm Hg. Yield: 700%. The picrate melts at 171 '.

1 part by weight of enamine becomes 870% phosphoric acid in 6 parts by weight dissolved and the solution was allowed to stand at ordinary temperature for 72 hours. Man diluted with water, shaken out with ether, makes the aqueous solution alkaline, takes the precipitated base in Ether on, evaporates and distilled. The 4'-methoxy-1-benzyl-2-methyl-1, 2, 3, 4, 6, 7, 8, 9-octahydroisoquinoline is boiling at 178 ° / 0.03 mm Hg; Yield: 57 ° / 0; the picrate melts at 149 °.

1 part by weight of the above isoquinoline derivative becomes 20 parts by volume 200% hydrochloric acid refluxed for 3 hours. The solution becomes alkaline made and etherified. The base remaining after evaporation of the ether boils at 178 ° / 0.03 mm Hg. Yield: 600%. The picrate melts at 172 ° and gives in the mixed sample with the picrate of 4'-methoxy-1-benzyl-2-methyl-1, 2, 3, 4, 5, 6, 7, 8-octahydro-isoquinolines no lowering of the melting point.

Claims (1)

PATENT CLAIM: Process for the production of optionally in the benzyl radical substituted 1-benzyl-2-methyl-1, 2, 3-4, 5, 6, 7, 8-octahydro-isoquinolines and their salts, characterized in that N-methyl-β- [cyclohexen (1) -yl] ethylamine in an inert solvent, preferably in the presence of an alkaline condensing agent, such as potassium carbonate, with phenylacetaldehyde or a phenylacetaldehyde substituted in the core, such as p-methoxyphenylacetaldehyde, or with a bisulfite compound of such Aldehyde converts and the enamine thus obtained either a) with concentrated phosphoric acid or heated about 500% sulfuric acid or b) with concentrated phosphoric acid at ordinary temperature to react and the resulting, if necessary substituted, 1-benzyl-2-methyl-1, 2, 3, 4, 6, 7-8, 9-octahydro-isoquinoline with Hydrochloric acid heated or c) with about 500% sulfuric acid at ordinary temperature can react and the optionally substituted 1-benzyl-2-methyl-10-hydroxy-decahydro-isoquinoline formed heated with concentrated hydrochloric acid and the resulting octahydroisoquinoline derivative if desired, converted into a salt. References contemplated: Organic Reactions, Vol. VI, pp. 151-190 (1951); Chem. Ber., Vol. 81, p. 285 (1948); Dear. Ann., Vol. 564, pp. 196-197 (1949); Helv. Chim. Acta, Vol. 34, p. 2221 (1951).