DE1112516B - Process for the preparation of basic substituted derivatives of 1-benzyl-1, 2, 3, 4-tetrahydroisoquinoline - Google Patents

Description

Process for the preparation of basic substituted derivatives of 1-benzyl-1,2,3,4-tetrahydroisoquinoline Addition to patent application K 20957 IVb / l2p (Auslegeschrift 1 108 223) In patent application K 20957 IVbll 2p a process is described which leads to new Basically substituted derivatives of l-benzyl-1,2,3,4-tetrahydroisoquinoline of the general formula leads, in which R are hydrogen atoms, meth or ethoxy groups, but at least one of the alkoxy groups mentioned is present on each aromatic ring, X is hydrogen or a low molecular weight alkyl group, R1 and R2 are hydrogen atoms or low molecular weight alkyl groups or aralkyl groups optionally substituted by low molecular weight alkoxy groups and Y mean a low molecular weight, straight or branched alkylene chain.

In the further development of this process it was found that these new compounds can also be prepared in a simple manner by using derivatives of l-benzylisoquinoline of the general formula or the corresponding 3,4-dihydro compounds with haloamines of the general formula in which X, Y, R1 and R2 and R have the meaning given above, are reacted and the quaternary ammonium salts obtained are catalytically hydrogenated.

So z. B. 1- (3 ', 4'-Dimethoxybenzyl) -2- (diethylamino-p-ethyl) -6 * 7-dimethoxy- 1, 2,3,4-tetrahydro-isoquinoline obtained by adding diethylaminop-chloroethane attaches to papaverine and the quaternary ammonium salt obtained is catalytically hydrogenated. Instead of papaverine, one can also start from 3,4-dihydropapaverine.

The salt solutions of the new compounds are ahead of those of papaverine the advantage that their mixtures with blood serum remain clear while papaverine saline solutions result in a precipitation of papaverine base with serum protein with blood serum.

The new bases differ in their effect from the compounds the type of papaverine in that it has a long, narrowed blood vessel permanent spasmolysis with simultaneous lowering of blood pressure and increased tissue perfusion cause. This is particularly evident in tests on the dog's brain with the compound 1- (3 ', 4'-diethoxybenzyl) - 2 - (N - methyl - N - 3 ", 4" - dimethoxy -phenylethyl-8-aminoethyl) -6,7-diethoxy- 1,2,3,4-tetrahydroisoquinoline (= D 119) compared with papaverine according to the method von Hensel (Pflüger's Archive, Volume 259 t1954] p. 267).

Papaverine causes a relatively sudden onset and short-term drop in arterial blood pressure, thereby increasing the cerebral blood flow initially changed passively, but increased significantly as the pressure rises again.

With »D 119« the pressure drop is much flatter in the same test the increase takes place slowly with an increase in the pressure amplitude. It occurs an increased blood flow in the white matter of the brain already during the drop in pressure one whose re-fall is shallower than that of papaverine.

The advantages of D119e over papaverine are based on the slower lowering of blood pressure, so that the first pressure-passive reduction in blood flow omitted, and on the increased blood pressure amplitude.

In fact, testing of »D 119 (e in clinical trials has shown that with this connection an increased blood flow in the brain is achieved. Furthermore has "D 119" in combination with 8- (di-n-butylaminomethyl) -theophylline its usefulness Proven in urology as a valuable spasmolytic component (Die Medizinische [1957], p. 324).

Example 1 l- (3 ', 4'-dimethoxybenzyl) -2- (diethylamino-2-ethyl) 6,7-dimethoxy- 1, 2,3,4-tetrahydro-isoquinoline In a solution of 150 g papaverine base in 300 ccm 60 g of diethylamino-, B-ethyl chloride (freshly distilled) are added to hot methanol, and the solution is refluxed for 36 hours. When cold, divorce about 85 g of unchanged papaverine, which is separated from the solution. The filtrate is evaporated to dryness and the residue is boiled with a little isopropanol, whereby 29.5 g 1,1,4,4-tetraethyl piperazinium dichloride (autocondensation product of ß-diethylaminoethyl chloride) remain, which is filtered off. After evaporation, the filtrate becomes of the solvent 111 g of the quaternary salt as a yellow crystal mass of F = 170 to 172.5 "C (from acetone).

The salt obtained is in methanol solution in the presence of Raney nickel hydrogenated at 120 "C. and 110 atm. hydrogen. After the catalyst has been separated off If the solvent is evaporated, the remaining oil is dissolved in 500 ccm of alcohol and hydrogen chloride is passed into the alcoholic solution until it has an acidic reaction. This gives 5 g of crystals from F = 200 to 203 "C (from alcohol) with decomposition, which is the dihydrochloride of the base sought. The yield is 60 ° lo the theory (after deduction of the papaverine received back).

Example 2 1 - (3 ', 4'-Dimethoxybenzyl) -2- (diethylamino-ß-ethyl) -6,7-dimethoxy- 1,2,3,4-tetrahydro-isoquinoline A solution of 280 g of 3,4-dihydropapaverine base and 114 g of diethylamino-ß-ethyl chloride in 500 com methanol is refluxed for 36 hours heated in a nitrogen atmosphere and then in an autoclave for the equivalent of Raney nickel hydrogenated to 100 "C and 100 atü hydrogen, the calculated amount of hydrogen will be recorded in about 15 minutes.

After the catalyst has been separated off, the solvent is evaporated, and an oil remains which is digested with dilute sulfuric acid. the sulfuric acid solution is shaken out with ether and from it by alkalizing deposited the base with sodium hydroxide solution. After taking up the base in benzene and Conversion of the benzene solution into methanol solution is obtained by introducing Hydrogen chloride gas until the acidic reaction, the dihydrochloride of the base sought from F = 203 to 205 ° C (from alcohol-acetone mixture) with decomposition. The yield is 210 g = 60% of theory (taking into account 75 g of tetrahydropapaverine hydrochloride formed next to it).

Example 3 1- (3 ', 4'-Dimethoxybenzyl) -2- (N-methyl-N-3 ", 4" -dimethoxyphenyl-β-ethyl) -amino-β-ethyl-6,7-dimethoxy-1 , 2,3,4-tetrahydro-isoquinoline 142.5 g of 3,4-dihydropapaverine base and 125 g of N- (3,4-dimethoxyphenyl-ß-ethyl) -N-methyl- amino-ß-chloroethane are dissolved in 500 cc of methanol and 48 hours in a nitrogen atmosphere refluxed. The reaction mixture is then placed in an autoclave and hydrogenates it at 100 "and 80 atm. hydrogen in the presence of Raney nickel, whereby the calculated amount of hydrogen is absorbed within 20 minutes. Man separates the solution from the catalyst, evaporates the solvent, takes the oily one Residue in dilute hydrochloric acid, shake out the acidic extract with ether, then makes it alkaline and removes the basic oil which separates out with benzene the end. The part of the oil dissolved in benzene becomes after evaporation of the solvent dissolved in acetone and deposited as hydrochloride by introducing hydrochloric acid gas. The salt obtained (118 g) is used to remove tetrahydropapaverine hydrochloride which has formed at the same time boiled with 11% ethanol and sucked off the undissolved material. Separates from the mother liquor tetrahydropapaverine hydrochloride. The undissolved residue consists of the Dihydrochloride of the desired base and melts with it after being drawn out again hot ethanol at 224 to 225.5 "C.

Claims (1)

PATENT CLAIM: Further development of the process for the preparation of basic substituted derivatives of 1-benzyl-1, 2,3,4-tetrahydro-isoquinoline of the general formula in which R are hydrogen atoms, meth or ethoxy groups, but at least one of the alkoxy groups mentioned is present on each aromatic ring, X is a hydrogen atom or a low molecular weight alkyl group, Rl and R2 are hydrogen atoms or low molecular weight alkyl groups or aralkyl groups optionally substituted by low molecular weight alkoxy groups and Y mean a straight or branched low molecular weight alkylene chain, according to patent application K 20957 IVb / 12p (German Auslegeschrift 1108 223), characterized in that one is a derivative of l-benzylisoquinoline of the general formula or a corresponding 3,4-dihydro compound in a manner known per se with a haloalkylamine of the general formula in which X, Y, R1, R2 and R are as defined above, are reacted and the quaternary ammonium salt obtained is catalytically hydrogenated in a known manner. Printed publications considered: German Patent No. 910 299; U.S. Patent Nos. 2,524,392, 2,683,146. Journal of the Chemical Society, London, 1951, p. 2853, and 1952, P. 144.