4-羟基-5(4′-氯苯基)双环[4,4,0]-1-氮杂癸烷的合成

以 4′ 氯哌醋甲酯为原料,研究了作为潜在的治疗可卡因滥用症的药物———4 羟基- 5- (4′- 氯苯基 )双环 [4,4, 0]- 1 氮杂癸烷的合成。4′- 氯哌醋甲酯首先用乙酸酐在室温下进行乙酰基化,然后在 -70℃下经二异丙基胺锂(LDA)作用关环得中间产物(±)- threo -2, 4 -二氧代- 5- (4′- 氯苯基)双环[4, 4, 0] -1 氮杂癸烷,产率 60%。中间体先用硼氢化钠在甲醇中室温下选择性地将酮羰基还原,粗产物经V(石油醚)∶V(乙酸乙酯) =1∶1重结晶后,在四氢呋喃中于回流温度下用乙硼烷 四氢呋喃络合物进一步还原酰胺基,得到(±) threo 4α 羟基- 5 -(4′- 氯苯基 )双环[4, 4, 0]- 1 氮杂癸烷,两步产率为 67%。所得α位羟基产物经过Swern氧化,然后在四氢呋喃中在 -78℃下用三(仲丁基)硼氢化钾选择性还原,立体专一性地得到 (±) threo- 4β 羟基- 5 (4′- 氯苯基 )双环 [4, 4, 0]- 1 氮杂癸烷,氧化 还原反应总产率为 70%。

Synthesis of 4-Hydroxy-5-(4′-chlorophenyl)bicyclo[4,4,0]-1-azadecane

Hydroxy-5-(4′-chlorophenyl)bicyclo[4,4,0]-1-azadecane,a potential treatment agent for cocaine abuse,was synthesized with 4′-chloro-methylphenidate as starting material.4′-Chloro-methylphenidate was acetylized by acetic anhydride at room temperature,then cyclized by lithium diisopropylamide(LDA) at -70 ℃ to give the intermediate,2,4-dioxo-5-(4′-chlorophenyl)-bicyclo[4,4,0]-1-azadecane in 60% yield.Its carbonyl group was reduced selectively by sodium borohydride in methanol at room temperature.The crude product was recrystallized in mixed solvent〔 V(petroleum ehter)∶V(ethyl acetate)=1∶1〕,then reduced further by B_2H_6-THF under reflux in THF to give (±)-threo-4α-hydroxy-5-(4′-chlorophenyl) bicyclo[4,4,0]-1-azadecane in 67% yield.The obtained α-hydroxy product was oxidized through Swern oxidation,then reduced stereospecifically by potassium tri-sec-butylborohydride in THF at -78 ℃ to give (±)-threo-4β-hydroxy-5-(4′-chlorophenyl) bicyclo[4,4,0]-1-azadecane.The overall yield of the oxidation-reduction steps was 70%.