Patent GB-756713-A (GB)
Title: Substituted piperidines and process of making them
IPC: C07D211/02
Filed: 1954-07-02
Abstract: The invention comprises 2-diphenylmethylpiperidines of the formula <FORM:0756713/IV(a)/1> where R is hydrogen and R1 and R2 may be one or more halogen atoms or alkyl or alkoxy groups of up to 3 carbon atoms and R1 may also be hydrogen, or R is an aliphatic hydrocarbon residue of up to 3 carbon atoms and R1 and R2 may each be hydrogen or halogen atoms or alkyl or alkoxy groups of up to 3 carbon atoms, and acid addition salts of these compounds.  The compounds are made by hydrogenating an appropriately substituted 2-diphenylmethylpyridine or a 2-diphenylmethyl-pyridinium compound which is N-substituted by a lower aliphatic hydrocarbon radical.  A secondary piperidine of the formula I may be converted into a tertiary piperidine by introducing an aliphatic hydrocarbon radical R by known methods. The hydrogenation of the pyridine or pyridinium compound is suitably carried out by reaction with hydrogen in the presence of a catalyst such as platinum, nickel or copper chromite.  The free base may be converted into its salts with acids such as hydrohalic, sulphuric, nitric, phosphoric, thiocyanic, acetic, propionic, oxalic, malonic, succinic, malic, methane sulphonic, ethane sulphonic, oxyethane sulphonic, benzene sulphonic or toluene sulphonic acids.  Preferred products comprise compounds of the formula I in which one phenyl radical is substituted by a methyl or methoxy group.  In examples: (1) 2-diphenylmethylpiperidine obtained by catalytic hydrogenation of 2-diphenylmethyl-pyridine is heated with formaldehyde and formic acid to give 2-diphenylmethyl-1-methyl piperidine which is converted into its picrate; (2) 2-diphenylmethylpyridinium methosulphate is hydrogenated in the presence of platinum oxide to give the product of (1); (3) 2-(para-chlorophenyl-phenylmethyl)-pyridine is hydrogenated to give 2-(para - chlorophenyl - phenyl - methyl) - piperidine which is converted into its hydrochloride; (4) 2 - (para:para1 - dichlorodiphenyl - methyl) pyridine is hydrogenated to give 2-(para:para1-dichlorodiphenyl - methyl) piperidine and its hydrochloride; (5) 2-diphenylmethyl-piperidine is reacted with allyl bromide to give 2-diphenylmethyl-1-allyl piperidine which is converted to its picrate; (6) 2 - (para:para1 - dimethoxy-diphenyl-methyl)-piperidine is hydrogenated to give 2 - (para:para1 - dimethoxydiphenyl - methyl) - piperidine; (7) 2 - (para:para1 - dimethyldiphenyl-methyl) pyridine is hydrogenated to 2 - (para:para1 - dimethyldiphenyl-methyl) piperidine which is converted into its hydrochloride; and (8) 2-[phenyl-(meta: para-dimethylphenyl) - methyl] - pyridine is hydrogenated to 2 - [phenyl - (meta: para - dimethylphenyl)-methyl]-piperidine.  Starting materials.  Substituted 2-diphenyl-methyl-pyridines are made by reacting a diphenylacetic acid derivative such as a diphenyl-acetonitrile with a 2-halogen pyridine to give a pyridyl diphenylacetic acid derivative, splitting the functional derivative of the carboxyl group and, if desired, quaternating the resulting pyridine compound.  The preparation of the starting materials of Examples 1, 3, 4, 6, 7 and 8 by this method, is described.ALSO:Pharmaceutical preparations comprise 2-diphenylmethyl-piperidines of the formula:  <FORM:0756713/VI/1> where R represents hydrogen, R1 and R2 are one or more halogen atoms or alkyl or alkoxy groups of up to 3 carbon atoms and R1 may also be hydrogen or R is an aliphatic hydrocarbon radical of up to 3 carbon atoms and R1 and R2 are one or more hydrogen or halogen atoms or alkyl or alkoxy groups of up to 3 carbon atoms and acid addition salts of these compounds (see Group IV(b)) admixed with an organic or inorganic carrier suitable for enteral or parenteral administration. Suitable substances which may be admixed include water, gelatine, lactose, starch, magnesium stearate, talc, vegetable oils, benzyl alcohols, gums and polyalkylene glycols.  Auxiliary substances such as preservatives, stabilizing, wetting or emulsifying agents, salts to control osmolic pressure or buffer substances may be added. The preparations may be used as tablets, dragees, salves, creams, solutions suspensions or emulsions.  Specified 2-diphenylmethyl-piperidines include 2-diphenylmethyl-1-methyl-piperidine, 2-(p-chlorophenyl - phenyl - methyl) - piperidine, 2 - (p - chlorophenyl - phenyl -methyl) - piperidine, 2 - (p : p1 - dichlorodi - phenyl - methyl) - piperidine, 2 - diphenyl - methyl - 1 - allyl - piperidine, 2 - (p : p1 - dimeth - oxydiphenyl methyl) - piperidine, 2 - p : p1 - dimethyldiphenyl - methyl) - piperidine and 2 - (phenyl - (m : p - dimethylphenyl) - methyl) - piperidine.  In examples (1) tablets are made comprising 2 - (p : p1 - dichlorodiphenylmethyl)-piperidine, talcum, lactose, gelatine, wheat starch, arrowroot and magnesium stearate and (2) a liquid preparation is made comprising 2 - (p : p1 - dichlorodiphenylmethyl) - piperidine, sodium chloride, secondary sodium phosphate and primary sodium phosphate in water.