Patent GB-817357-A (GB)
Title: 4-phenylisonipecotate compounds and their preparation
IPC: C07D211/64
Filed: 1956-07-26
Abstract: The invention comprises compounds of the formula <FORM:0817357/IV (b)/1> (wherein R is hydroxy, alkoxy, chloro, bromo, iodo, nitro, amino or acylamino and R1 is a C1-5 alkyl group), their acid-addition salts and their preparation by reacting a compound of the formula <FORM:0817357/IV (b)/2> (wherein R3 is hydroxy, alkoxy, chloro, bromo, iodo, nitro or amino) with the appropriate ester of 4-phenyl isonipecotic acid, with subsequent acylation of the compounds wherein R3 is an amino group to the corresponding acylamino compounds if required.  In the first of these processes the isonipecotate is preferably used in the form of an acid-addition salt, e.g. a carbonate, and the reaction is advantageously performed in the presence of an alkali-metal bicarbonate.  Conveniently, the reactants are heated together in a liquid medium and they are preferably refluxed in a lower alcohol.  Suitable acylating agents for use in the second process are acid halides or, preferably, acid anhydrides, the acyl radical preferably having the formula -CO.R2 wherein R2 is an alkyl, alicyclic, aryl or aralkyl group.  In examples: (1) b  - (m - aminophenyl) - ethyl chloride hydrochloride (prepared by heating b -(p-amino-m-nitrophenyl)-ethyl chloride with sulphuric acid and sodium nitrite in alcohol to give b -(m-nitrophenyl)-ethyl chloride and reducing this with stannous chloride in HCl, and ethyl 4-phenyl isonipecotate carbonate give, on refluxing with sodium bicarbonate in ethanol, ethyl 1-(m-aminophenyethyl)-4-phenyl isonipecotate; (2) the final product of (1) is heated with acetic anhydride and glacial acetic acid to give ethyl 1 - (m - acetylaminophenylethyl) - 4 - phenyl isonipecotate; (3) m-methoxy-phenylacetic acid and thionyl chloride give m-methoxyphenyl acetyl chloride, this on reduction with sodium borohydride yields (m - methoxyphenyl) - ethyl alcohol, this is heated with PBr3, the diluted product extracted with ether, the extract washed with sodium bicarbonate solution and the ether removed to give b -(m-methoxyphenyl)-ethyl bromide and this with ethyl 4-phenyl-isonipecotate carbonate gives 1-(m-methoxy-phenyl ethyl)-4-phenyl isonipecotate; (4) the bicarbonate washings of (3) are acidified to pH3 with sulphuric acid, the acidified solution extracted with ether and the ether removed to yield b  - (m - phosphato - phenyl)-ethyl bromide which on reaction with ethyl 4-phenyl-isonipecotate as in (1) yields ethyl 1-(m-hydroxyphenylethyl)-4-phenyl isonipecotate; (5) b -(m-chlorophenyl)-ethyl chloride and ethyl 4-phenyl-isonipecotate carbonate give ethyl 1 - (m - chlorophenylethyl) - 4 - phenyl isonipecotate; and (6) ethyl 1-(m-nitrophenyl-ethyl)-4-phenyl isonipecotate is similarly prepared.  The preparation of hydrochlorides of the products is described and other salt-forming acids are referred to.  Reference is also made to starting materials wherein R is propoxy, ethoxy, iodo and bromo and to products containing other alkyl radicals R1 and other acylamino groups wherein the acyl radical is for example formyl, propionyl, butyryl, valeryl, hexanoyl, heptanoyl, octanoyl, cyclopentanecarboxyl, cyclopentylpropionyl, benzoyl, toluoyl and oxalyl.