NO123327B - - Google Patents

Description

Process for the preparation of salts of basic ethers of diphenyl-ethynyl-carbinols.

It is known that salts of basic ethers of

diphenylcarbinols with the ordinary lbrmel

where the phenyl residues may be substituted and R denotes an alkyl residue and especially products having the formula

IN

has an antihistamine effect and therefore i.a. a. finds application in the treatment of allergic disease states. It was now found that introduction of an ethynyl group (CH=C-) at the "-carbon atom corresponding to the general formula

where R a and R 2 denote alkyl residues with 1-3 C atoms and the phenyl nuclei may be substituted with halogen and/or methyl, results in a significant strengthening of the anticholinergic effect. This was first observed in an isolated guinea pig intestine, but has in principle been shown to occur to the same extent in experiments with live animals. In addition, these compounds also exhibit a strong nicotinolytic activity component, which cannot be detected in the compounds of formula I and II. The present invention preferably relates to the production of products of the general formula

where X denotes hydrogen or a halogen atom and R and R denote alkyl residues with carbon atoms.

The products of formulas III and IV are likewise used in the form of their salts.

With the development of this specific anticholinergic activity component, these compounds gain importance beyond the framework as antihistamines for special clinical indications, for which atropine is usually used. It then emerged from experiments with animals that there are evidence that the known disadvantages of antropine (systemic effects) are avoided by the new compounds.

The table below relates to investigations with «-ethynyl-substituted benzhydroethers on an isolated guinea pig intestine. In the table, the increase in the anticholinergic effect is visualized as activity indices. The activity index characterizes the multiple of the activity (DE50 values) of diphenylhydramine (= 1). As can be seen, the ethynylation in the «-position of the base molecule in compounds III and IV causes an increase up to half of the antropine effect (33.0%). The compounds listed in the table below correspond to those with the general formula

where the substituents Xlf X2, Rx and R2 are indicated in the table. The production of the new compounds of the general formula III can take place by transferring benzophenone or a derivative of benzophenone substituted by a halogen and/or methyl nucleus with acetylene and an alkali metal in liquid ammonia to the corresponding ethynyl carbinol, after which this is condensed with tertiary halogenated bases of the general formula

where Rj and R2 denote alkyl residues with 1-3 carbon atoms, in the presence of alkaline substances, especially sodium amide, so that the basic ethers are obtained, after which these are transferred in the usual way to salts, e.g. with hydrogen halides to hydrogen halogen acid salts or with alkyl halides or alkyl ethers to quaternary ammonium salts.

According to the equation A below, e.g. p-chlorobenzophenone (a) condensed with sodium acetylene in liquid ammonia to obtain ethynyl carbinol (b), after which this is reacted in the next step according to equation B with a basic alkyl halide in the presence of sodium amide, so that the corresponding basic ether having the general formula (c).

The thus obtained bases (c) are then converted in the usual way into the water-soluble hydrochloric acid salts by means of hydrogen halogen, e.g. hydrogen chloride, or they are converted to quaternary ammonium salts by reaction with alkyl halides or alkyl esters.

Example 1:

The production of 4-chloro-«-ethynyl-benzhydrol can be carried out in the following way: 1 liter of ammonia is placed in a 2 liter flask with three tubulations equipped with a stirrer, gas introduction tube and dropping funnel. The flask is cooled with a mixture of carbonic acid and 1 acetone. Acetylene is introduced into the ammonia, the Acetylene is washed with a hydrochloric acid sublimate solution and nitric acid calcium bichromate solution and dried with calcium chloride and phosphorus pentoxide. During the introduction, slowly introduce 25.3 g (1.1 mol) of sodium in such a way that the solution does not turn blue. After the introduction of sodium, acetylene is introduced for another hour and then a solution of 216.5 g (1 mol) of 4-chlorobenzophenone in 800 ml of ether (dried over sodium) is added. After the introduction, the cooling is removed, the ammonia is allowed to evaporate during the night and the remainder is introduced into a mixture of ice and sulfuric acid. The mixture was shaken out with ether, the ether distilled from and the residue fractionated in vacuo.

Kp0.3 150—156° m.p. 50-52° (from naphtha) Yield 200 g = 82%.

The transfer of 4-chloro-u-ethynyl-benzhydrol to /?-dimethylamino-ethyl-(4-chloro-«-ethynyl-benzhy-dryl)-ether can be carried out in the following way: In a 1 liter flask with three turbulations out- controlled with a stirrer and reflux condenser, dissolve 121.3 g (0.5 mol) of 4-chloro-ethynyl-benzhydrol in 300 ml of toluene and add 19.5 g (0.5 mol) of sodium amide. After 15 minutes, 54 g (0.5 mol) of 6-dimethylaminoethyl chloride are added and the mixture is heated to boiling for two hours. After cooling, shake out first three times with water and then with diluted hydrochloric acid. The hydrochloric acid extract is triturated twice with ether to remove unchanged carbinol, then made alkaline and deethered. The ether extract is dried with sodium sulphate, the ether is distilled off and the residue is fractionated in vacuum.

Kp0)2 150—155°. Sm.p. 52—55° (from petroleum ether)

Yield 86 g = 54%.

The hydrochloride is prepared from the aforementioned base and hydrogen chloride-containing ether in ether.

Melting point 150-152° (from acetic acid).

N-dimethyl-N-ethyl-N-[[?(4-chloro-«-ethynyl-benzhydroxy)-ethyl]-ammonium iodide is prepared as follows: 15.7 g (1/20 mol) base, 8 g (1/20 mol) ethyl iodide and 50 ml of acetic acid are heated to boiling for one hour. After cooling, precipitate with ether, suction off and wash with ether.

Sm.p. 134—138° (from acetone and ether). Yield approx. 70%.

N-trimethyl-N-[/5-(4-chloro-«-ethynyl-benzhydryl-oxy)-ethyl]-ammonium methosulfate is prepared from 15.7 g (1/20 mol) base, 6.3 g (1/20 mol) of dimethyl sulphate and 50 ml of acetic acid.

Sm.p. 154—157° (crude material). Yield approx. 60%.

Example 2: /?-diethylamino-ethyl-(4-chloro-«-ethynyl-benzhydryl)-ether can be prepared from 121.3 g (0.5 mol) 4-chloro-«-ethynyl-benz-hydrol, 300 cm <3 >toluene, 19.5 g (0.5 mol) sodium amide and 68 g [0.5 mol) diethylaminoethyl chloride in the same way as in example 1. K<p.>0>15 157—160° n^ <3> 1.5520 Yield 108 g 63%.

The hydrochloride is obtained from the aforementioned base and

hydrochloric ether in ether.

Sm.p. 111—113° (from acetic acid). N-triethyl-N-[/3'-(4-chloro-«-ethynyl-benzhydryl-oxy)-ethyl]-ammonium iodide is prepared from 17.1 g (1/20 mol) of the aforementioned base, 8 g ( 1/20 mol) ethyl iodide and 50 cm<3> acetic ester. The mixture is heated for 4 hours until boiling.

Sm.p. 152—155°. (from acetone and ether) Yield

about. 75%.

N-methyl-N-diethyl-N-[[¥-(4-chloro-«-ethynyl-benz-hydryl-oxy)-ethyl]-ammonium methosulphate is prepared from 17.1 g (1/20 mol) of base, 6.3 g (1/20 mol) dimethyl sulfate and 50 cm<3> acetic ester. The mixture is heated to boiling for one hour. This substance was not obtained in solid form.

Example 3: /?-pyrrolidino-ethyl-(4-chloro-«-ethynyl-benz-hydryl)-ether is obtained from 121.3 g (0.5 mol) of 4-chloro-«-ethynyl-benzhydrol, 300 cm< 3> toluene and 19.5 g (0.5 mol) sodium amide and 67 g (0.5 mol) pyrrolidinoethyl chloride.

Kp0)75 175-184°. Yield 42 g = 24%. The hydrochloride is obtained from the aforementioned base

and hydrochloric ether in ether.

Sm.p. 113—116° (from acetone and ether).

Example 4:

From 215 g (1 mol) 4,4'-dichloro-benzophenone, 25.3 g (1.1 mol) sodium, 1 liter of ammonia and acetylene, 4,4'- dichloro-«-ethynyl-benzhydrol, which has Kp015 = 157-159° C. The yield amounts to 187 g = 67% of the theoretical.

138.5 g (0.5 mol) of 4,4'-dichloro-«-ethynyl-benzhydrol, 19.5 g (0.5 mol), sodium amide and 54 g of dimethylaminoethyl chloride are dissolved in 300 ml of toluene, analogously to in example 1, converted to /?-dimethyl-amino-ethyl-(4,4'-dichloro-«-ethynyl-benzhydryl)-ether. This product has Kp0.6 = 179-183° C.

The yield is 73 g = 41% of the theoretical.

The base's hydrochloride is obtained from the above-mentioned base and hydrogen chloride-containing ether.

Sm.p. 173-177° C (from acetone).

Claims (1)

1. Process for the preparation of anti-cholinergic active salts of basic ethers with the general formula where Rj and R2 denote alkyl residues with 1-3 O atoms and the phenyl nuclei may be substituted with halogen and/or methyl, characterized by transferring benzophenone or a derivative of benzophenone substituted with a halogen and/or methyl nucleus with acetylene and an alkali metal in liquid ammonia to the corresponding to ethynyl- carbinol, this condenses with tertiary halogenated bases of the general formula where Rj and R2 denote alkyl residues with 1-3 C atoms, in the presence of alkaline substances, especially sodium amide, to the basic ethers and then transfer the latter in the usual way to salts, for example with hydrohalogens to hydrohalogen acid salts or with alkyl halides or alkyl esters to quaternary ammonium salts.