N-(叔丁氧羰基)-2-氮杂双环[2.2.1]庚-5-烯-3-酮的手性拆分

Enantioselective Resolution of N-(tert-Butoxycarbonyl)- 2-azabicyclo[2.2.1]hept-5-en-3-one

(-)-(1R,4S)-N-(叔丁氧羰基)-2-氮杂双环[2.2.1]庚-5-烯-3-酮是抗艾滋病药物阿巴卡韦的重要中间体。今以2-氮杂双环[2.2.1]庚-5-烯-3-酮为原料,先与(Boc)2O反应生成外消旋体(±)-N-(叔丁氧羰基)-2-氮杂双环[2.2.1]庚-5-烯-3-酮,再以固定化脂肪酶作为拆分试剂选择性拆分制得。试验中分别使用了三种酶,三种酶均表现出较好的反应活性和较高的反应收率,其中固定化酶Lipozyme RM IM的反应活性最高,对其催化的酶促反应进行了优化,得到最佳的反应条件:以异丙醚为反应溶剂,酶与底物质量投料比为1.5/2.0,反应温度为30℃,收率46.5%,对映体过量大于99%。结构经1H-NMR确证。该方法成本低,酶的选择性、催化活性和反应收率高。

（-）-（1R,4S）-N-（tert-Butoxycarbonyl）-2-azabicyclo[2.2.1]hept-5-en-3-one is an important intermediate of abacavir which is widely used in AIDS treatment. This chemical was prepared with 2-azabicyclo-[2.2.1]hept-5-en-3-one（2） as the starting material in this study. The starting material（2） was first reacted with（Boc）2O to give the raceme（±）-N-（tert-Butoxycarbonyl）-2-azabicyclo[2.2.1]hept-5-en-3-one（3） via amidation. The key intermediate was prepared via a prominent turnover from the raceme（3） with immobilized lipases, and its structure was identified by 1H-NMR. The optimum conditions of the enzymatic reaction were as follows： Lipozyme RM IM and isopropyl elther were used as the enzyme reaction catalyst, and reaction solvent separatively, the mass ratio of enzyme： substrate 1.5/2.0 and the reaction temperature of 30℃. The yield can reach to 46.5% under these optimal conditions with enantiomeric excess up to 99%. This synthetic process is suitable for large-scale manufacture due to the cheap available material and higher catalytic activity and selectivity of the lipase.