Study On Synthesis Of Synephrine And Its Analog

Synephrine and its analog 2-diethylamino-1-phenylethanol were synthsized by using phenol and benzene as the staring materials, and they were not reported in China before. 2-chloro-1-(4-hydroxyphenyl) ethanone and 2-bromo-1-(4-hydroxyphenyl)ethanone are the vital intermediates for synthesis of synephrine. 2-chloro-1-(4-hydroxyphenyl) ethanone was prepared by acetylation of the silanized and unsilanized phenol. Because of the unstability of Si-O bond, the acetylation product of trimethyl phenyloxyl silicane and chloroacetyl chloride was a mixture containing 69.3% of phenyl chloroacetate and 11.4% of 2-chloro-1- (4-hydroxyphenyl)ethanone, and it is difficult to get high-purity 2-chloro-1-(4-hydroxyphenyl) ethanone. 2-Chloro-1-(4-hydroxyphenyl)ethanone can be prepared by direct acetylation of phenol with chloroacetyl chloride. The intermediate 2-chloro-1-(4-chloroacetoxyphenyl) ethanone obtained by chloroacetylation of phenol can be purified by recrystallization, and the purity, melting point and recrystallization yield were 98.9%, 105.2-106.5°C and 77.6%, respectively. 2-Chloro-1-(4-hydroxyphenyl)ethanone, a light-yellow needle compound was obtained by hydrolyzing 2-chloro-1-(4-chloroacetoxyphenyl)ethanone with 5% aqueous NaOH solution, acidification, and recrystallization in anhydrous ethanol, and its yield reached 55.6%,melting point was 149.5-151.4°C. 2-chloro-1-(4-hydroxyphenyl)ethanone was determined by GC-MS and 1H-NMR.Phenyl acetate obtained by esterification of phenol with acetylchloride was rearranged in the presence of AlCl3 into ortho- and para-hydroxyacetophenone mixture, and the ortho- and para-position product can be separated furtherly by steam distillation. The suitable synthesis conditions of p-hydroxyacetophenone were determined: molar ratio of phenyl acetate/AlCl3 1:2.5, reaction temperature 140°C, reaction time 1 h, and the yield of p-hydroxyacetophenone reached 52.7%.α-bromo-p-hydroxyacetophenone was obtained by bromination of p-hydroxy acetophenone with CuBr. The suitable bromination conditions were as follows: ethanol as solvebt, CuBr/p-hydroxyacetophenone 2.1/1 (mol/mol), reaction temperature 65-70°C, reaction time 2.5h, and the yield, melting point and purity were 83.7%, 129.0-130.6°C and 99.7% respectively.Synephrine was synthesized by reducing the methylamination product of 2-chloro- 1-(4-hydroxyphenyl)-ethanone or 2-bromo-1-(4-hydroxyphenyl)-ethanone with NaBH4, and the yield of synephrine reached 53.6%, melting point 184.2-186.1°C. Furthermore, the structure of synephrine was characterized by IR and 1H-NMR.Benzene was reacted with chloroacetyl chloride to 2-chloroacetophenone, and it was then aminated with diethylamine to 2-diethylamino-1-phenylethanol with a yield 87.5% and the purity 98.6%. The structure was also examined by IR and GC-MS.Syntheses of synephrine and its alalog were systematically investigated in this paper, and the results will provide good experimental and theory bases for the further research of phenylethanolamine-type compound. Moreover, it is also very significant for phenylethanol amine-type pharmaceutical development.