DE730119C - Process for the preparation of tetrahydroisoquinoline compounds - Google Patents

Description

Process for the production of tetrahydroisoquinoline compounds The subject of patent 707 705 is a process for the production of papaverine-like tetrahydroisoquinoline compounds which are substituted on the nitrogen by an aralkyl. The patent relates to analog 726 oo8 tetrahydroisoquinoline compounds, which are substituted by an aralkylene radical on the nitrogen. Both the aralkyl and the aral'lcylene-substituted tetrahydroisoquinoline compounds can be added to the isoquinoline nucleus and / or the benzene nucleus and / or on the aliphatic chain of the aralkyl or aralkylene substituents by further groups, e.g. B. alkyl, alkylene, aryl, aralkyl, aralkylene, alkoxy, alkylenedioxy or hydroxyl groups @ or various such groups; be a substitute. According to these patents, these compounds are prepared by adding the desired aralkyl or aralkylene radical to the nitrogen atom of a tetrahydroisoquinoline in a manner known per se or by allowing a suitable derivative of an aralkyl or aralkylene alcohol to act on isoquinolines or dihydroisoquinolines and the quaternary salts formed in this way are hydrogenated to the corresponding tetrahydroisoquinoline compounds.

It has now been found, surprisingly, that tetrahydroisoquinolines, which are substituted on the nitrogen by an aralkyl or aralkylene radical and preferably at least two in one of the two benzene nuclei in Acylated, in particular acetylated, hydroxyl groups in the o-position to one another contain analgesic effects. The connections can furthermore Substituents, e.g. B. All; yl or alkylene groups, in various places of the molecule and / or in the benzene nucleus free of Acvloxvgruppen Alkoxv- and / or Alkvlendioxvgruppen be substituted.

The preparation of the new compounds takes place in a manner known per se and described in patents 707705 and 726 oos, for. B. by adding the desired aralkyl or aralkylene radical to the nitrogen atom of an appropriately substituted tetraliydroisoquinoline. This accumulation can, for. B. be done by allowing "Cetraliydroisocliinoline derivatives of an aralkylene or aralkylene alcohol, for example halides, benzene or oluenesulfonic acid esters, to act.

The production of the new compounds succeeds inter alia. also by represent a correspondingly substituted tetrahydroisoquinoline with an aralkyl or aralkylene aldehyde or ketone according to Leuckart-Wallach. Finally can to prepare the new compounds by one on the nitrogen atom Isoquinolines or Dilivdroisoquinolines represent the desired aralkyl or aralkylene radical by the action of one of the above-described aralkyl or aralkylene alcohols derived compounds and hydrogenated the resulting quaternary salts. Depending on the desired end product, the hydrogenation can be carried out in such a way that that only the double bonds of the pyride: inringes or also the double bonds of the aralkylene substituent are hydrogenated. The hydrogenation can be carried out e.g. B. catalytic or, if you want to reduce partially, with 1-lethal, if appropriate in the presence be carried out by acids.

In all of these reactions, one of the compounds to be reacted on the Ilenzolkeru must carry at least two acylated, in particular acetylated, hydroxyl groups which are preferably in the ortho-position to one another. The compounds to be reacted can furthermore be substituted by alkyl or alkylene radicals at any point and in the benzene nucleus free of acyloxy groups by alkoxy and / or alkylenedioxy groups. Examples i. Preparation of 1. 3-Dinietliyl-2- (j-plienylallyl) - 6,; - diacetoxy - 1, 2, 3, q.-tetrahydroisoquinoline. 7.1 g bromohydrate of -1, 3-dimethyl-6, 7-diacetoxv-1, 2, 3, 4-tetrahydroisoquinoline with a temperature of 24.o to 24o ° are dissolved in water, treated with potassium carbonate and the free base with Ether shaken out. To the well-dried ethereal solution, 1.9 g of freshly prepared ^ / - Plienylallvlbroini (1 are added and the whole thing is refluxed for 5 hours. Then the ether is evaporated and the residue is heated to 100 ° for 30 minutes. It is taken up in ether again The bromohydrate of the starting base is sucked off and the desired base is precipitated from the ethereal solution by means of ethereal hydrobromic acid. The amorphous precipitated bromohydrate is dissolved in water, the solution is made alkaline with potassium carbonate while cooling with ice, the base is etched out and the ether residue is distilled in a good high vacuum 1.8 g of the base mentioned in the title distill over a first run of unchanged starting material at 170 to 180 ° C. bath temperature below 0.04 mm as a colorless, non-crystallizing resin.

That by precipitating the ethereal solution: with the calculated amount of ethereal Hydrochloric acid obtained hydrochloric acid crystallizes from acetone and melts at 166 bis 17o ° after previous sintering from 162 °.

2. Preparation of 1, 3-dimethyl-2 - (^ - plienylpropyl) -6, 7-diacetoxy-1, 2,3, d.-tetrahydroisoquinoline.

2.2 g of 1, 3-.diinethyl-6, 7-diacetoxy-1, 2, 3, .ftetrahydroisoquinoline (prepared by acetylating the bromohydrate of 1, 3-dimethyl-6, 7-dioxy-1, 2, 3, 4 - tetrahvdroisoquinoline with acetic anhydride in glacial acetic acid or by catalytic hydrogenation of the bromohydrate of i, 3-dimethyl-6, 7-, diacetoxy-3, 4-dihydroisoquinoline in glacial acetic acid, dissolving the bromohydrate from a temperature of 24o to 242 ° iii water, making it alkaline and Ethers; are heated to 60 ° for 6 hours with careful exclusion of moisture with i, og γ-phenylpropyl iodide. After cooling, the iodine hydrate of the starting base is precipitated with ether and the base which is formed is distilled in a high vacuum of ether o, oi mm, in which it passes after an initial run of unchanged starting material at igo to 200 ° band temperature. It is dissolved in ether, filtered and the 1,3-dimethyl-2- (y-phenylpropyl) - precipitated with hydrogen chloride in ether. 6, 7-diacetoxy-1, 2, 3, 4-tetrahydroisoquinoline chlorohydrate, which after recrystallization melts from ivIethanol with the addition of absolute ether at 154 to 156 °. 3. Preparation of i-methyl-2- (y-phenylpropyl) -6, 7-diacetoxy-i, 2, 3, 4-tetrahydroisoquinoline.

2.6g of i-methyl-6, 7-diacetoxy-3, 4-dihydroisoquinoline (prepared by acetylating i-methyl-6, 7-dioxy-3, 4-dihydroisoquinoline bromohydrate with acetic anhydride at 100 °, dissolving in water, precipitating with ice-cold saturated potassium carbonate solution and ether) are heated with 3.5 g; i-phenylpropyliodi.d for 1/2 hour at 70 °. It is triturated with ether, the resulting i-methyl-2- (y-phenylpropyl) -6, 7-diaaetoxy-3, 4-dihydroisoquinolinium iodide is recrystallized from absolutely no alcohol and the quaternary salt, which melts at 194 to 1g6 °, is then reduced by boiling for two hours with zinc dust in vinegar. The excess zinc dust is sucked off hot, precipitated with ether, taken up in methanol and poured into ice-cold dilute ammonia. The precipitated base is extracted with ether, the ether washed with ice-cold dilute sodium hydroxide solution and water, dried and evaporated. The residue, the i-methyl-2- (γ-phenylpropyl) -6, 7-diacetoxy-i, 2, 3, 4-tetrahydroisoquinoline, distilled over in a high vacuum of 0.07 mm at a bath temperature of 180 to 185 °. q .. Preparation of -i-methyl-2- (y-phenylallyl) -6, 7-dipropionyloxy-i, 2, 3, 4-tetrahydroisoquinoline. 0.6 g of i-methyl-6, 7-dipropionyloxy-3, 4-dihydroisoquinoline are heated to 60 ° with 0.8 g; r-phenylallylbromide for 10 minutes. It is triturated with ether, filtered off with suction, the resulting i-methyl = 2- (@, - phenylallyl) -6, 7-dipropionyloxy-3, 4-dihydroisoquinolinium chloride is dissolved in ten times the amount of propionic acid and reduced to 100 by heating with ig zinc dust for three hours °. It is worked up as in Example 3 and the resulting i-methyl-2- (y-phenylallyl) -6, 7-dipropionyloxy-1,2, 3, 4-tetrahydroisoquinoline is distilled in a high vacuum, in which it is below 0.07 mm 195 to 2oo ° bath temperature passes. 5. Preparation of 1-methyl-2 - (; / - plieinylpropyl) -6, 7-dipropionyloxy-1,2,3,4-tetrahydroisoquinoline.

ig according to example q. The iM.ethy1-2 - (- @ - phenvlal lyl) - (i,; -dipropionyloxv-3, q.-d ilivdroisoquinoliniuml) romide is shaken in 10 cc propionic acid with a palladium-barium sulfate catalyst under hydrogen, with a little more than the for 2 moles. The calculated amount is absorbed. The solution is filtered off from the catalyst, evaporated in vacuo, and the residue is dissolved in water. falls the resulting , se with soda, ether out and distill that I A i # mdene i-methyl-2 - (@ # - phenylpropyl) - 6 = dipropionyloxy-i, a, 3. 4 - tetrahydroiso- quinoline in a high vacuum, in which it passes over bath temperature after a preliminary run at igo to zoo. 6. Preparation of 2- [x-Iletliyl-ß- (3 ', -.'- di- acetoxyphenyl) - ethyl] - i, 2, 3, q.- tetrahydro- isoquinoline, ig 2- [2-Metl'YI-J # - (3 '"1! -diaceto-xyphenyl) - i iith Yl] -isoquinolinium bromide (shown by the action of homophthalaldehyde to x-methyl-p '- [3, .4-diacetoxyphenyl] -ethyl- amine bromide rate from melting point i So to 152 °) are in 5 ccm glacial acetic acid with -ig zinc- dust 2 hours on the reflux condenser to the that heated. The then colorless one is filtered off Solution hot from the excess zinc dust, the filtrate falls with ether, dissolves the precipitate in a little methanol and pours into excess ice-cold dilute ammonia. The precipitating base is extracted with ether, the ether washed with ice-cold dilute sodium hydroxide solution with water, dried and evaporated and the residue, the 2- [x-llieth @ -I-pJ- (3 ', -'-diacetoxyphenyl) ethyl ] - i, 2, 3. .1-tetrahydroisoquinoline, distilled in a high vacuum. It goes under o, oi mm at i8o to ih; Bath temperature above.

Claims (2)

PATE N CLAIMS: i. Process for the preparation of tetrahydroisoquinolines which are substituted on the nitrogen by an aralkyl or aralkylene radical and which contain in one of the two benzene nuclei at least two acylated, in particular acetylated, hydroxyl groups preferably in the ortho-position to one another, characterized in that known ``. '' iron attaches the desired aralkylene or aralkylene radical to the nitrogen atom of an appropriately substituted tetrahydroisoquinoline or allows a suitable derivative of an aralk1-l- or aralkylene alcohol to act on an appropriately substituted isoquinoline or dihydroisoquinoline and hydrogenates the quaternary salt formed in this way to the corresponding tetrahydroisoquinoline. 2. The method according to claim i, characterized in that compounds are reacted in the core or in the aliphatic chain through alkylene or alkylene radicals and optionally also in the benzene nucleus free of acyloxy groups by alkoxy and ie, between. or Alk_vlendioxvreste are substituted.