DE908138C - Process for the preparation of 1-benzyl-2-alkyl-1,2,3,4,5,6,7,8, -octa-hydroisoquinolines and their salts - Google Patents

Description

Process for the preparation of 1-benzyl-2-alkyl-1, 2, 3, 4, 5, 6, 7, 8-octahydroisoquinolines and their salts It is known (O. Schnider and J. Hellerbach, Helv. Chim. Acta, 33, [195o], 1437) that i-benzyl-2-alkyl-octahy4roisoquinolines of the general formula IV can be prepared by condensing ß- [cyclohexen- (i) -yl] ethylamine with substituted or unsubstituted phenylacetic acids, the acid amides formed are cyclized with dehydrating agents to give the corresponding i-benzyl-3, 4, 5, 6, 7, 8-hexahydroisoquinolines and these are hydrogenated to give the octahydro compounds. The subsequent N-alkylation then gives the substituted or unsubstituted i-benzyl-2-alkyl-1, 2, 3, 4, 5, 6, 7, 8 = octahydroisoquinolines in the aromatic ring. It has now been found that the same i-benzyl-2-alkyl-i, 2, 3, 4, 5, 6, 7, 8-octahydroisoquinolines of the general formula IV and their salts can be obtained by using a phenylacetic acid halide the formula wherein X is a chlorine or bromine atom, R and R 'are each a hydrogen atom or a 0 H-, 0 C H3-, 0 - C 0 - CH, -, 0. CH Amide II can react with a dehydrating agent such as phosphorus oxychloride or phosphorus pentoxide and the corresponding i-benzylidene-2-alkyl-i, 2, 3, 4, 5, 6, 7, 8-octahydroisoquinoline of the general formula III obtained in the presence of Catalysts hydrogenated until 1 mole of the isoquinoline derivative has taken up 1 mole of hydrogen.

The new synthesis can be illustrated by the following equation: NH-alkyl - @ N-alkyl `0C I CH, - R, R II I N-alkyl @ N-alkyl CH CH @ I_ R,. 1I R, RR III IV (R and R '= H, OH, OCH3, O-CO-CH3, 0 - CH, - CBHS or 0 - CO - OC2H5). The i-alkylamino-2- [cyclohexen- (i ') - yl] ethanes I required as starting materials can, for. B. obtained by acylation of ß- [Cyclohexen- (i) -yl] ethylamine and subsequent reduction. The secondary amines I are converted into the corresponding phenylacetic acid-N- [cyclohexen- (i) -ylethyl] -N-alkyl-amides II by reaction with unsubstituted or substituted phenylacetic acid halides. By treatment with dehydrating agents such as PO Cl, or P205, they can be cyclized to the unsubstituted or substituted i-benzylidene-2-alkyl-i, 2, 3, 4, 5, 6, 7, 8-octahydroisoquinolines, which in the Hydrogenation provide the corresponding benzyl compounds.

The new synthesis differs in principle from the known one in that the isoquinoline compound III with the formation of a semicyclic double bond arises. The compounds of the general formula IV are therefore formed by hydrogenation a C-C double bond.

The products of the present process can be used as intermediates find for the production of N-Alky lmorphinanen use.

Example i To a well stirred solution of 278.5 parts by weight of i-methylamino-2- [cyclohexen- (i ') - yl] -ethane (prepared by reducing i-formylamino-2- [cydohexen- (i') - yl ] -ethane with lithium aluminum hydride) in 400 parts by volume of absolute benzene are added dropwise at 0 ° C 154.6 parts by weight of phenylacetic acid chloride in 45o parts by volume of absolute benzene, and the mixture is left to stand for 3 hours at room temperature. The condensation product is washed in sequence with 3N hydrochloric acid, water, 3N soda and water. After the solvent has been distilled off, the phenylacetic acid-N- [cyclohexene-(i)] remains. yl-ethyl] -N-methyl-amide as a pale yellow viscous back 01, which can be distilled, but is directly suitable for further use.

257.3 parts by weight of phenylacetic acid-N-7cyclohexen- (i) -yl-ethyl] -N-methyl-amide are absolute with 30o, 6 parts by weight of phosphorus oxychloride in 300 parts by volume Benzene heated to 95 ° C for 2 hours, and the reaction mixture is then in Poured water. After the addition of ether, the phosphoric acid salts are through Shaking transferred to the water and this washed repeatedly with ether. -The Ice-cold, aqueous solution is then carefully mixed with concentrated sodium hydroxide and takes up the deposited base in ether, which after washing with water is dried and distilled off. The remaining i-benzylidene-2-methyl-i, 2, 3, 4, 5, 6, 7, 8-octahydroisoquinoline is dissolved in iof the amount of methanol and in the presence of 60 parts by weight of Raney nickel at room temperature and normal pressure hydrogenated. After taking up the amount of hydrogen calculated for 1 mole, one breaks the hydrogenation and the catalyst is filtered off. The one after evaporation of the methanol the residue that remains is i-benzyl-2-methyl-i, 2, 3, 4, 5, 6, 7, 8-octahydroisoquinoline is, the hydrochloride melts at 195 to 196 ° C. Example 2 278 parts by weight i-Methylamino-2- [cyclohexen- (i ') - yl] ethane in 140o parts by volume of absolute benzene slowly with ice-cooling and stirring with a solution of 185 parts by weight of p-methoxyphenyl-acetic acid chloride mixed with absolute benzene in 45o parts by volume. The reaction mixture is left on Stand at room temperature for 1 hour and then heat it for 15 minutes on the water bath. When working up according to Example i you get p-Methoxy-phenylacetic acid-N- (cyclohexenyl-ethyl) -N-methyl-amide, which is light yellow colored oil is processed further without further purification.

287.4 parts by weight of p-methoxyphenylacetic acid-N [cyclohexen- (i) y1 ethyl] N methyl amide with 3o6 parts by weight of phosphorus oxychloride in 150 parts by volume Benzene heated to 95 ° C for 2 hours. The reaction product is then analogous to how described in example i, worked up. The remaining viscous i- (p-methoxy-benzylidene) -2-methyl-i, 2, 3, 4, 5, 6, 7, 8-octahydroisoquinoline is dissolved in iof the amount of methanol and in the presence of 60 parts by weight of Raney nickel until 1 mole of hydrogen is absorbed hydrogenated. After working up, the i- (p-methoxybenzyl) -2-methyl-i, 2, 3, 4, 5, 6, 7, 8-octahydroisoquinoline returned as an oil. It boils below 0.1 mm at 120 ° C; the oxalate (from alcohol-ether) melts at 163 to 164 ° C.

Example 3 Homoveratrum acid chloride (obtained from 196.2 parts by weight Homoveratrum acid by reaction with phosphorus pentachloride in anhydrous benzene) in 100 parts by volume of absolute benzene and slowly turns this solution into a solution of 278 parts by weight of i-methylamino-2- [cyclohexen- (i ') - yl] ethane in 500 parts by volume drop in absolute benzene. The implementation and work-up according to Example r result the homoveratrumsäure-N- [cyclohexen- (i) -yl-ethyl] -N-methyl-amide.

317.4. Parts by weight of homoveratrumsäure-N-cyclohexen- (i) -yl-ethyl] -N-methyl-amide are dissolved in 100 parts by volume of absolute benzene and with 3o6 parts by weight of phosphorus oxychloride offset. The treatment according to example i leads to i- (g ', 4'-dimethoxybenzylidene) -2-methyl-i, 2, 3, 4, 5, 6, 7, 8-octahydroisoquinoline, that of those listed in Example i Conditions for 1- (3 ', 4'-Dimethoxy-benzyl) -2-methyl-1, 2, 3, 4, 5, 6, 7, 8-octahydroisoquinoline (Boiling point 135 ° C at o, ooi mm) is hydrogenated. The oxalate (from methanol) has the Melting point 125 to 127 ° C.

Claims (1)

PATENT CLAIM: Process for the preparation of i-benzyl-2-alkyl-1, 2, 3, 4, 5, 6, 7, 8-octahydroisoquinolines of the general formula wherein R and R 'are each a hydrogen atom or an OH-, OCH3, O.CO.CH $, O.CH2.CBH5 or O # CO. O Ca H5 group, and their salts, characterized in that one is a phenylacetic acid halide of the general formula where X is a chlorine or bromine atom and R and R 'have the above meaning with an i-alkylamino-2- [cyclohexen- (i') - yl] ethane, the amide formed with a dehydrating agent such as Phosphorus oxychloride or phosphorus pentoxide can react and the corresponding i-benzylidene-2-alkyl-i, 2, 3, 4, 5, 6, 7, 8-octahydroisoquinoline of the general formula obtained hydrogenated in the presence of catalysts until one mole of the isoquinoline derivative has absorbed one mole of hydrogen.