Patent GB-815926-A (GB)
Title: 4-phenyl isonipecotate derivatives and their preparation
Filed: 1956-06-06
Abstract: The invention comprises compounds of the formula <FORM:0815926/IV (b)/1> (wherein R is hydroxy, chloro, iodo, bromo, nitro, amino, alkylamino, acylamino or alkoxy and R1 is an alkyl group of at most 5 carbon atoms) and their acid-addition salts, except the compounds wherein R is amino or acylamino and R1 is ethyl, these being described and claimed in Specification 793,010.  The invention also comprises the preparation of these compounds by reacting a compound of the formula <FORM:0815926/IV (b)/2> (wherein R3 is hydroxy, chloro, iodo, bromo, nitro, amino, alkylamino or alkoxy and X is halogen) with an alkyl 4-phenyl isonipecotate, advantageously in the form of its acid-addition salt, the acylamino compounds being prepared by subsequent acylation of the amino compounds.  The reaction is conveniently conducted by heating the reactants in an inert solvent, preferably a lower alcohol, and advantageously in the presence of an alkali metal bicarbonate.  In examples: (1) methyl 1-(4-aminophenylethyl)-4-phenyl isonipecotate (isolated as the dihydrochloride) is prepared from the ethyl ester by trans-esterification with methanol in presence of KOH; (2) ethyl 4-phenyl-isonipecotate carbonate and beta-(p-hydroxyphenyl)-ethyl chloride give ethyl 1-(4-hydroxy - phenylethyl) - 4 - phenyl isonipecotate, the hydrochloride of which is also prepared; (3) to (6) the corresponding 4-methoxy-, 4-nitro-, 4-chloro- and 4-methylamino-compounds are prepared by similar methods. Reference is also made to other starting materials in which the group R3 has the additional values of ethoxy, propoxy, iodo and bromo and to other salt-forming mineral acids.  Reference is also made to acylation of the products wherein R is an amino group with acylating agents such as acid halides and anhydrides, these preferably being derived from an alkyl, alicyclic, aryl or aralkyl carboxylic acid containing at most 9 carbon atoms such as formic, acetic, propionic, butyric, valeric, hexanoic, heptanoic, octanoic, cyclopentanecarboxylic, cyclopentylpropionic, benzoic, toluic or oxalic acid.  The reaction is ordinarily carried out in an inert solvent, e.g. glacial acetic acid when a lower alkanoic anhydride is used.  Reference is made to propyl 1-(4-acetylaminophenylethyl)-4-phenyl isonipecotate and methyl 1 - (4 - cyclopentanecarboxylaminophenylethyl)-4-phenyl isonipecotate as typical products of this process.  Starting materials.-b -Phenylethyl bromide on nitration with fuming nitric acid in acetic acid/acetic anhydride yields b -(p-nitrophenyl)-ethyl bromide, this on reduction with stannous chloride in HCl yields a mixture of b -(p-aminophenyl)-ethyl bromide hydrochloride and b -(p-aminophenyl)-ethyl chloride hydrochloride and this mixture is converted into either (1) b -(p-chlorophenyl)ethyl chloride by diazotization and reaction with cuprous chloride in HCl; or (2) b  - (p - N - methylaminophenyl) - ethyl chloride hydrochloride by reductive formylation with formaldehyde and PtO2 in alcoholic HCl under pressure; or (c) to b -(p-hydroxyphenyl)-ethyl chloride by heating with aqueous sulphuric acid and sodium nitrite. b -(p-Methoxyphenyl)-ethyl chloride is prepared by methylation of the hydroxy compound with dimethyl sulphate in caustic soda.