The Total Synthesis of Two New Type of Antidepressant Drugs-DPI-289 and API-121
|School||Kunming University of Science and Technology|
|Keywords||DPI-289 API-121 antidepressantdrugs chiral-synthesis|
Animal model test showed that DPI-221, analogue of DPI-289 and API-121, had high affinity withδ-opioid receptor,which can be used for the treatment of depression, with smaller dose, faster onset time and no resistance. DPI-289 and API-121 may have the similar biological effect.In this paper development, mechanism and classification of antidepressant drugs was summaried. Refer to route of professor Kwen-Jen Chang, target compound was prepared as the following steps:Used 4-formyl benzoicacid as originate compound, two 4-formylbenzamide analogue (4-formyl-N,N-diethylbenzamide and 4-formyl-4’-methylpiperidylbenzamide) were prepared. With (2R,5S)-2,5-dimethylpiperazine as raw material, high purity (2R,5S)-2,5-dimethyl-4-(3-fluorobenzyl) piperazine was prepared by salification、mono-substitution reaction、and isomer separatation by L-tartaric acid. Used 3-bromophenol as raw material, protected phenolic hydroxyl with tert-butyl chloro dimethyl silane, tert-butyl chlorodimethylsilane was prepared and by simple modification,3-tert-butyldimethylsilyl oxyphenyl magnesium bromide was systhesised.Mixed 4-formylbenzamide (2R,5S)-2,5-dimethyl-4-(3-fluorobenzyl) piperazine with benzotriazole, heated to dehydration, then reacted with 3-tert-butyldimethylsilyl-oxyphenyl magnesium bromide,after remove of the protect group, target compound, DPI-289 and API-121, was systhesised.In the systhesis route, preparation of (2R,5S)-2,5-dimethyl-4-(3-fluorobenzyl) piperazine was innovative to some extent; By the steric hindrance effort of the two methyl in piperazidine, asymmetric synthesis and chiral-synthesis of two target compound was achieved. In signal factor experiment, effort of temperature,reaction time and ratio of materials on yield was studied.To summarize,high purity DPI-289 and API-121 was synthesized. Some intermediates and the target compound was confirmed by1HNMR or MS.