Synthesis Of Quinoline Derivatives And Drugs Intermediates Based On Phenylacetonitrile

Phenylacetonitrile compounds have been found widely used in medicine, pesticides, dyes, optical materials and quinoline derivatives, due to its molecule containing cyano group, benzene ring, α-H and other important building blocks, which the cyano group could easily convert into the amino group, the amide group, the carboxyl group, the aldehyde group and the aldehyde oxime, the benzene ring could introduce a veriety of many functional groups through substitution reaction, α-H could occur condensation reaction. Four compounds of phenylacetonitrile derivatives(2) were synthesized via benzylchloride and sodium cyanide in this thesis, and the investigation effects of reaction conditions on the synthesis of 4-cyanobenzylcyanide and optimal the procedure were focused on. Furthermore, the side reaction and byproduct I {4-[2-cyano-(4-cyanophenyl) ethyl] benzonitrile} and rarely reported byproduct II [1,2,3-tris(4-cyanophenyl)-2-cyanopropane], were also researched. The crystal structures of 4-cyanobenzylcyanide and byproducts were analyzed by single crystal diffraction.Four compounds of 3-phenyl-2,1-benzisoxazole derivatives(3) were synthesized using phenylacetonitrile and p-substituted nitrobenzene as raw materials, and subsequently were reduced to the corresponding o-aminobenzophenone derivatives(4) by Fe/HC l system, catalytic hydrogenation and catalytic transfer hydrogenation. The synthetic procedure of 2-amino-5-chlorobenzophenone was optimized as follows: the total reaction time were shorted 5.5 h and 6 h, the total yields increased by 9.4% and 7.8% respectively. The effect of different substituted nitrobenzene on the yield of 3-phenyl-2,1-benzisoxazole derivatives were also studied. The crystal structure of 5-chloro-3-phenyl-2,1-benzisoxazole(3a) was determined by single crystal diffraction, and three aromatic rings almost on a plane was confirmed.Twenty compounds of multi-substituted quinoline derivatives(6) were prepared via Friedlander synthesis of ten compounds of ketones(5) with 2-amino-5-chlorobenzophenone(4a) or 2-amino-5-bromobenzophenone(4b) in the solvent of acetic acid under the catalysis of concentrated sulfuric acid. The effects of different kinds of ketone on the yields of quinoline were also studied, and the results showed that the aromatic ketones reacted with(4a) or(4b) to afford a far higher yield than other ketones, while those ketones bearing electron-withdrawing groups were much higher than electron-donating groups in the yield of quinoline synthesis. Reactions of dimedone with equimolar or 2 molar 2-amino-5-chlorobenzophenone were studied to obtain 7-chloro-3,3-dimethyl-9-phenyl-3,4-dihydroacridin-1(2H)-one(6d) and 2,10-dichloro-13,13-dimethyl-12,14-diphenyl-6,13-dihydroquinolino[3,2-b] acridine.The structures of 6-chloro-2-methyl-4-phenylquinoline(6a), 7-chloro-9-phenyl-1,2,3,4-tetrahydroacridine(6c),6d,6-chloro-2-(4-nitrophenyl)-4-phe nylquinoline(6h) and 6-bromo-2-isobutyl-4-phenylquinoline(6l) were analyzed with X-ray and showed that the dihedral angle between quinoline ring and benzene ring is from 50.8o to 74.1 o.1-[cyano-(4-methoxy-phenyl)- methyl]cyclohexanol(7) was prepared from 4-methoxybenzylcyanide and cyclohexanone under the catalysis of TEBA and Na OH, and then was reduced to 1-[2-amino-(4- methoxy-phenyl)-ethyl]cyclohexanol(8), finally methylation of(8) under the effect of formic acid, formaldehyde and concentrated hydrochloric acid was undertaken to obtain venlafaxine hydrochloride(9) with the total yield of 65.7%.