Patent GB-685696-A (GB)
Title: Process for the manufacture of anti-histaminic compounds
IPC: C07D213/38
Filed: 1949-10-13
Abstract: Pyridylpropylamines of the formula Py-CHAr-CH2-CH2-R, wherein Ar stands for phenyl or an alkyl-, alkoxy-, dialkylamino-, chloro-, or bromo-phenyl, or for 2-thienyl, Py stands for 2-pyridyl and R stands for a dialkylamino-, piperidino-, pyrrolidino-, or morpholino-group are prepared by reacting a ketone Ar-CO-CH2-CH2-R with an organometallic 2-pyridyl compound, e.g. 2-pyridyllithium or 2-pyridyl magnesium halide) to give a carbinol Py-CAr(OH)-CH2-CH2-R, followed by replacement of the hydroxyl group by a hydrogen atom.  The alkyl and alkoxy groups have less than 6 carbon atoms.  The carbinol may be dehydrated to give a compound of formula Py-C(Ar)=CH-CH2-R, followed by hydrogenation. Alternatively, the carbinol is reacted to give Py-C(Ar) (Cl)-CH2-CH2-R, or with phosphorus tribromide or hydrogen bromide to give the corresponding bromine compound, followed by removal of hydrogen bromide, e.g. by heating with dimethylamine, to give the unsaturated amine, and reducing the latter.  Or the carbinol may be converted with thionyl chloride to the chloride, which on reduction with zinc dust and acetic acid gives the substituted propane.  The starting compounds are made by the Mannich reaction from formaldehyde and the appropriate amine, e.g. dialkylamines, piperidine, pyrrolidine or morpholine and acetophenone or its substitution products.  The products may be converted to salts with, e.g. hydrochloric, hydrobromic, sulphuric, phosphoric, salicylic, tartaric, maleic, succinic, citric or lactic acids.  In examples: (1) 2-pyridyllithium and b  - dimethylaminopropiophenone are reacted to give phenyl-(21-pyridyl1) b -dimethylaminoethylcarbinol. The latter is converted to the bromide with phosphorus tribromide or hydrogen bromide and the product on heating quinoline or dimethyl aniline gives 1 - phenyl - 1 - (21 - pyridyl) - 3 - dimethyl - aminopropene-1 and the latter is hydrogenated to 1-phenyl-1-(21-pyridyl)-3-dimethylaminopropane.  The substituted carbinol may alternatively be converted to the substituted propane by reaction with thionyl chloride, and reduction of the product with zinc dust and acetic acid.  By similar reactions are prepared (2) 1-(p-methoxyphenyl) - 1 - (21 - pyridyl) - 3 - dimethylaminopropane; (3) 1-(p-chlorophenyl)-1-(21 - pyridyl) - 3 - dimethylaminopropane; (4) 1-(phenyl)-1-(21-pyridyl)-3-diethylaminopropane; (5) 1 - phenyl - 1 - (21 - pyridyl) - 3 - N - piperidinopropane; (6) 1-phenyl-1-(21-pyridyl)-3-pyrrolidyl - propane; (7) 1 - (p - chlorophenyl)-1 - (21 - pyridyl) - 3 - pyrrolidyl - propane.  Also mentioned are 1 - (211 - pyridyl) - 3 - dimethylaminopropanes substituted at the 1-position by a (21-thienyl)-, (p-methylphenyl)-, (4-dimethyl - aminophenyl) -, (2,3 - dimethoxyphenyl)-, or (p-isopropylphenyl)-radical.  Specifications 307,304, [Class 2 (iii)], and 646,198 are referred to.  As open to inspection under Sect. 91, the Specification comprises also the preparation by the above methods of 1-(21-thiazyl-1-(211-pyridyl) - 3 - dimethylaminopropane and of other compounds of the general formula Py-CH(R2)-CH2)n-R1, where Py is a pyridine ring generally which may be substituted by halogen, alkoxy, or alkyl groups, n is an integer from 2 to 4, R1 is dialkylamino, piperidino, pyrrolidino or morpholino, and R2 is an aryl, aralkyl, or heterocyclic group which may have alkyl, alkoxy, dialkylamino, chloro- or bromo-substituents, or is an alkyl or cycloalkyl group or their chloro or bromo substituents. This subject-matter does not appear in the Specification as accepted.