Patent GB-754372-A (GB)
Title: Pyridine and piperidine derivatives
IPC: C07D211/14
Filed: 1954-05-07
Abstract: The invention comprises bases of the formula <FORM:0754372/IV(a)/1> wherein X is hydrogen, halogen, a lower alkyl or an amino group, R1 is hydrogen, a lower alkyl, a lower alkenyl, a monocyclic aralkyl, a cycloalkyl, a cycloalkenyl or a monocyclic aryl group, and R2 is a lower alkyl, a lower alkenyl, a monocyclic aralkyl, a cycloalkyl or a cycloalkenyl group and R3 is pyridyl, piperidyl or N-alkylpiperidyl. The term "lower" means a group containing 12 or less carbon atoms. Such compounds where R3 is pyridyl are obtained by reacting an appropriate benzyl pyridine with one or two mols. of the corresponding halides to replace the a -hydrogen atoms by R1 and/or R2 in liquid ammonia in the presence of a basic condensing agent such as an alkali metal amide or alkoxide, lithium alkyls or aryls, Grignard reagents and triphenylmethyl sodium.  Alternatively the corresponding benzoyl-pyridine is reacted with R2Mg halide or LiR2, and in the product <FORM:0754372/IV(a)/2> the hydroxy group is replaced by hydrogen by treatment with hydrogen iodide and phosphorus, or by treatment with a halogenating agent and hydrogenation of the a -halogen compound in the presence of Raney nickel, or by dehydration followed by reduction of resulting olefinic compound, and the product may then be further alkylated.  As a further alternative the nitrile group of the appropriate a -cyano compound can be replaced by hydrogen by heating with sodamide or (where the pyridyl group is attached through its 2- or 4-position) with aqueous sulphuric acid.  In a further method a cycloalkenyl halide and an a - or g -picoline are reacted in liquid ammonia in the presence of an alkali metal amide, and the cycloalkenylmethyl-pyridine obtained is aromatized by heating with a palladium catalyst at 200 DEG  to 250 DEG  C.  The piperidyl compounds are obtained by hydrogenating corresponding pyridyl compounds as bases, acid addition salts or quaternary compounds in the presence of platinum oxide.  In Example (1), 1-phenyl-1-(4-pyridyl) propane is prepared by reacting 4-benzylpyridine with ethyl bromide in liquid ammonia in the presence of sodamide.  Similarly prepared are (2) 1-phenyl-1-(4-pyridyl) pentane; (3) 1-phenyl-1-(4-pyridyl)-nonane; (4) 1 - phenyl - 1 - (4 - pyridyl) - iso - butane; (5) 1 - phenyl - 1 - (4 - pyridyl) - isopentane; (6) 4 - phenyl - 4 - (4 - pyridyl) - butene - 1; (7) 3-phenyl - 3 - (4 - pyridyl) - pentane (from the product of Example (1)); (8) cyclohexylphenyl-4-pyridyl methane; (9) 1-p-chlorophenyl-1-(4-pyridyl)-propane; (16) 1-phenyl-1-(3-pyridyl)-ethane.  In further Examples, (10) 1-phenyl-1-(4-pyridyl)-propane is nitrated at 0 DEG  to 5 DEG  C. and the product reduced with stannous chloride to 1 - p - aminophenyl - 1 - (4 - pyridyl) - propane; (11) 1-phenyl-1-(2-pyridyl)-propane is prepared by treatment of a -phenyl-a -(2-pyridyl)-butyronitrile with 80 per cent sulphuric acid at 140 DEG  C.; (12) 1-phenyl-1-(3-pyridyl)-propane is prepared by treatment of 1-phenyl-1-(3-pyridyl)-propanol-1 with 47 per cent hydriodic acid; (13) 1-phenyl-1-(4-pyridyl)-propanol-1 heated with 40 per cent sulphuric acid gives 1-phenyl-1-(4-pyridyl)-propene, which on hydrogenation gives the same product as in Example (1); (14) and (15) the hydrogen sulphate and the hydrobromide of the free base of (1) are prepared by reaction in acetone; (17) p-methyl-2-benzyl-pyridine and n-amyl bromide are reacted in the presence of butyllithium to give 1-p-methylphenyl-1-(2-pyridyl)-n-hexane; (18) 1-phenyl-1-(4-pyridyl)-ethane is obtained similarly; (19) n-propyl magnesium bromide and 2-benzoylpyridine are reacted and the carbinol obtained on hydrolysis is heated with 47 per cent hydriodic acid to give 1-phenyl-1-(2-pyridyl)-butane; (20) 1-phenyl-1-(4-pyridyl)-heptane is obtained similarly; (21) 1-phenyl-1-(4-pyridyl)-propane is heated with p-toluenesulphonate and the product is hydrogenated to 1-phenyl-1-(N-methyl-4-piperidyl)-propane; (22) cyclohexylphenyl-4-pyridylmethane is hydrogenated to cyclohexylphenyl-4-piperidylmethane which is methylated with formic acid and formaldehyde to a -cyclohexyl-N-methyl-4-benzyl-piperidine.