Patent GB-713517-A (GB)
Title: Piperidinium compounds
Filed: 1952-12-01
Abstract: The invention comprises salts having neuro-muscular-blocking activity, whose actions have the general formula <FORM:0713517/IV (b)/1> where " lower " indicates from 1 to 4 carbon atoms, n is an integer of from 2 to 8, C1-3 is an alkylene radical of from 1 to 3 carbon atoms and R is an electron-acceptor group such as a nitro, cyano or carbamyl group, or an alkanoyl, carbalkoxy or alkylsulphonyl group in which the alkyl component is methyl or ethyl.  The salts may be prepared by quaternizing the appropriate 1, n-bis-[11-lower alkyl-piperidyl-(41)]-alkanes with a phenyl-alkyl halide containing one of the above nuclear substituents.  The salts thus obtained can be converted into other salts, e.g. by forming the hydroxide, and reacting this with an acid.  Alternatively, the 1,n-bis-[11-substituted phenyl alkyl-piperidyl-(41)]-alkanes may be quaternized with lower alkyl halides.  In examples, 1(c) describes the production of 1,2-bis-[11-methyl-11-(411-nitro - benzyl) - piperidinium - (41)] - ethane dibromide from 1,2-bis-[11-methyl-piperidyl-(41)]-ethane and p-nitro-benzyl bromide; the dichloride is similarly prepared and the dinitrate is prepared by hydrolysing the dibromide with silver oxide in water and acidifying with nitric acid.  The 311-nitro-benzyl derivative is prepared using m-nitro-benzyl bromide.  The 411-cyano-, 411-carbamyl-, 411-carbethoxy-, 411-acetyl- and 411-methylsulphonyl-benzyl derivatives are prepared in an analogous manner to the 411-nitro compound.  The 411-nitrophenylpropyl derivative is prepared using instead 1 - bromo - 3 - (41 - nitrophenyl) - propane.  Examples (2) and (3): 1,2-bis-[11-propyl-11 - (411 - nitro - benzyl) - piperidinium - (41)]-ethane dibromide and the 11-butyl compound respectively.  In examples (4), (5), (6) and (7), the 1,3-bis-substituted propane, 1,4-bis-substituted butane, 1,6-bis-substituted hexane and 1,7-bis-substituted heptane dibromides.  Example (8), 1,3-bis-[11-(411-nitro-phenylethyl) -piperidyl-(41)]-propane, prepared from 1,3-bis-piperidyl-(41)]-propane and p-nitro-phenyl-ethyl bromide, is quaternized with methyl bromide to yield 1,3 - bis - [11 - methyl - 11 - (411 - nitrophenyl - ethyl) - piperidinium - (41)] - propane dibromide. Example (9), 1,2-bis-[11-(411-nitrophenylethyl) - piperidyl - (41)] - ethane, prepared from 1,2-bis-[piperidyl-(41)]-ethane and p-nitro-phenylethyl bromide, is quaternized with methyl or ethyl bromide.  Examples (11) and (12), the 1,5-substituted pentane and 1,8-substituted octane salts are prepared as in examples (1) to (7).  The 1, n - bis - [11 - alkyl - piperidyl - (41)]-alkanes used as starting materials can be prepared by catalytic hydrogenation of the corresponding 1, n - bis - [11 - alkyl - pyridinium-(41)]-alkane dihalides which are obtainable by quaternizing the corresponding 1, n-bis-[pyridyl-(41)]-alkanes with an alkyl halide.  1,3 - bis - [pyridyl - (41)] - propane is prepared by refluxing 4-vinyl pyridine and 4-methyl pyridine in benzene in the presence of potassium and hydroquinone.  1,4 - bis -[pyridyl - (41)] - butane is prepared by heating 1-methoxy-3-[pyridyl-(41)]-propane with HBr to give 1-bromo-3-[pyridyl-(41)]-propane hydrobromide which is treated with K2CO3 to give the free base which is reacted with a -picoline potassium.  1,6 - bis -[pyridyl - (41)] - hexane is prepared from potassium amide, g -picoline and 1,4-dibromo-butane; and the pyridyl-heptane, -pentane and -octane are similarly prepared. p-Methylsulphonyl-benzyl chloride.-p-Methylmercapto-benzoic acid is reduced with lithium aluminium hydride to give p-methylmercaptobenzyl alcohol.  This is reacted with thionyl chloride to give p-methyl mercapto benzyl chloride which is oxidized by hydrogen peroxide.