Patent GB-784334-A (GB)
Title: Benzhydryl ethers of alkamines and thio-alkamines
Filed: 1955-01-20
Abstract: The invention comprises ethers and thioethers of the general formula <FORM:0784334/IV (a)/1> wherein R1 and/or R2 is hydrogen, halogen or methyl, R3 is hydrogen or methyl, R4 is an alkyl group of less than six carbon atoms or a monocyclic aralkyl group, X is O or S, Y is methyl and n is an integer from 1 to 3.  The products are employed in pharmaceutical preparations (see Group VI).  The above ethers and thioethers are prepared by reacting a piperidinol or piperidine thiol of the formula <FORM:0784334/IV (a)/2> with a benzhydryl halide of the formula <FORM:0784334/IV (a)/3> in the presence of a basic condensing agent, R1, R2, R3, R4, X, Y and n in the formul\s having the meanings given above and Hal representing halogen, e.g. chlorine or bromine.  The reaction may also be carried out by merely heating the reactants, preferably in the presence of an inert solvent, e.g. an aliphatic or aromatic hydrocarbon or a high-boiling ether. Acid acceptors which may be employed include pyridine, dialkyl anilines, the basic alcohol or inorganic bases such as sodium or potassium carbonate.  Where the basic alcohol is liquid at the reaction temperature it may be employed as solvent.  Preferably the reaction is carried out under substantially anhydrous conditions.  The reaction may also be carried out in liquid ammonia, using an alkali metal amide as catalyst, e.g. 1,2,6-trimethyl-4-piperidyl p-chlorobenzhydryl ether may be prepared by reacting 1,2,6-trimethyl-4-piperidinol with p-chlorobenzhydryl chloride in liquid ammonia in the presence of sodamide.  Non-toxic addition salts are prepared by reacting the basic ethers or thioethers directly with acid, preferably in the presence of a solvent.  Examples of non-toxic anions include the chloride, bromide, maleate, tartrate and citrate ions.  Anhydrous hydrogen chloride may be passed through an ether solution of 1,2,2,6-tetramethyl-4-piperidinol or the base may be heated with maleic acid in isopropyl acetate.  The quaternary salts may be prepared by reacting the bases with an alkyl halide or sulphate optionally in the presence of an inert solvent. Alternatively the quaternary iodides may be converted to the corresponding bromides and chlorides by heating alcoholic solutions of the iodides with silver halides.  In examples: 1,2,2,6-tetramethyl-4-piperidyl benzhydryl ether is obtained by reacting 1,2,2,6-tetramethyl-4-piperidinol with benzhydryl bromide in xylene in the presence of potassium carbonate (I); the product is converted to the methiodide by reaction with methyl iodide (II); and with maleic acid to obtain the maleate (III); the product of Example II is converted to the corresponding meth-bromide by heating with silver bromide in the presence of methanol (IV); 1,2,2,6 - tetramethyl - 4 - piperidyl p - chlorobenzhydryl ether is obtained by using p-chlorobenzhydryl bromide in a process similar to (I) (V); and the product is converted to the methiodide (VI); 1,2,6-trimethyl-4-piperidyl a ,a -diphenylethyl ether is obtained by reacting 1,2,6-trimethyl-4-piperidinol and 1,1-diphenylethyl bromide as in Example (I) (VII); 1,2,2,6-tetramethyl - 4 - piperidyl p - methylbenzhydryl ether is obtained by substituting p-methyl-benzhydryl bromide in the process of Example (V) (VIII); 1,6-dimethyl-3-piperidyl benzhydryl ether is obtained by reacting 1,6-dimethyl-3-piperidinol with benz-hydryl bromide as in Example I (IX); the product is converted to the methiodide (X); 1,2,6-trimethyl-3-piperidyl benzhydryl ether is obtained by reacting 1,2,6-trimethyl-3-piperidinol with benzhydryl bromide as in Example I (XI); the product is converted to the methiodide (XII); 1,2,6-trimethyl 4-piperidyl benzhydryl thioether is obtained by reacting 1,2,6-trimethyl-4-thiopiperidine with benzhydryl bromide as in Example I (XIII); 1,2,6-trimethyl-4-piperidyl benzhydryl ether (XIV); 1,2,2,6-tetramethyl-4-piperidyl p,p1-dichlorobenzhydryl ether (XV); 1,2,6-trimethyl-3-piperidyl p-p1-dimethyl-benzhydryl ether (XVI); 1-ethyl-2,6-dimethyl-4-piperidyl benzhydryl ether (XVII); and 1-benzyl - 2,6 - dimethyl - 4 - piperidyl benzhydryl ether (XVIII) are obtained in processes similar to Example I; 1,2,6-trimethyl-3-piperidyl m-bromobenzhydryl ether is obtained by refluxing sodamide with m-brombenzhydrol in toluene and adding 1,2,6-trimethyl-3-chlorpiperidine; the same product is obtained from m-bromobenzhydryl bromide and 1,2,6-trimethyl - 3 - piperidinol (XIX); 1,2,6 - trimethyl - 4 - piperidyl p - methyl - p1 - chlorobenzhydryl ether is obtained by removing water by azeotropic distillation from a mixture of potassium hydroxide and toluene and refluxing with 1,2,6-trimethyl-4-chlorpiperidine; alternatively m-methyl-m1-chlorobenzhydryl bromide and 1,2,6-trimethyl-4-piperidinol are reacted (XV); 1,2,6-trimethyl-4-piperidyl a -p-tolyl-a -phenyl ethyl ether is obtained by heating 1,2,6-trimethyl-4-piperidinol in toluene with sodium, reacting the product with a  - p - tolyl - a  - phenylethyl bromide (XXI).  Alkylated piperidinols are obtained by reacting g -pyrones with ammonia and alkyl amines and reducing the product by catalytic hydrogenation.  Thus 1,2,6-trimethyl-4-piperidinol is prepared by reacting 2,6-dimethyl g -pyrone with methylamine and catalytically hydrogenating the product.  1-Benzyl-4-piperidinol may be prepared by using ammonia in place of methylamine and after reduction the 4-hydroxypiperidine is reacted with benzyl chloride. 1,2 - Dimethyl - 5 - hydroxy - piperidine may be obtained by reducing 2-methyl-5-nitropyridine with hydrogen in the presence of platinum oxide and diazotizing and hydrolysing the 2-methyl-5-amino-pyridine to obtain 2-methyl-5-pyridol, quaternizing the product, e.g. with di-methyl sulphate and hydrogenating in the presence of platinum oxide.  Alternatively, 2-methyl-5-pyridol may be reduced using Raney nickel and the hydroxy-piperidine alkylated, e.g. with formaldehyde and formic acid to obtain 1,2 - dimethyl - 5 - piperidinol. Piperidine thiols employed as starting materials may be obtained by the reaction of a piperidinol and phosphorus pentasulphide, e.g. 1,2,6-trimethyl-4-thiopiperidine is obtained from 1,2,6-trimethyl-4-piperidinol.ALSO:Benzhydryl ethers or thioethers of the general formula <FORM:0784334/VI/1> wherein R1 and/or R2 is hydrogen, halogen, or a methyl group, R3 is hydrogen or a methyl group, R4 is an alkyl group having less than six carbon atoms or a monocyclic aralkyl radical, X is O or S, Y is a methyl group and n is an integer from 1-3 and the non-toxic acid addition and quaternary salts thereof (see Group IV (b)) are employed in pharmaceutical preparations such as tablets, capsules and elixirs and may be dissolved or suspended in non-toxic vehicles optionally flavoured to make the medicament palatable.