新型非甾体类孕酮受体调节剂的合成与表征

Synthesis and Characterization of Novel Nonsteroidal Progestrone Receptor Modulator

以2-氨基-5-溴苯乙酮为起始原料,经格氏加成,N,N-羰基二咪唑闭环,Suzuki偶联,氰基取代,硼氢化氧化和高温脱除叔丁氧羰基6步反应合成得到一种新的化合物5-(1-H-2,4-二氢-4-甲基-4-(3-羟基)-2-氧苯并[d][1,3]噁嗪-6-基)-1-H-吡咯-2-氰基,进而甲基化得到5-(1-H-2,4-二氢-4-甲基-4-(3-羟基)-2-氧苯并[d][1,3]噁嗪-6-基)-1-甲基-吡咯-2-氰基。采用核磁氢谱、红外、质谱测试技术,对各中间体及目标物的结构分别进行表征。分析了新合成的化合物吡咯环上N-甲基化反应的机理,结果表明,N,N-二甲基甲酰胺和固体无机碱碳酸钾的组合可以选择性地对吡咯环上的N进行甲基化。

5- （4- （3-Hydroxy） -4-methyl-2-oxo-2,4-dihydro-1 H-benzo [ d ] [ 1,3 ] oxazin-6-yl） -1H-pyrrole-2-carbonitrile was prepared by six reaction steps of Grignard reagent addition, N,N-carbonyldiimidazole ring closure, Suzuki coupling, cyan replacement, borohydride oxidation and the high temperature removal t-BOC respectively from the raw material 2-amino-5-bromine acetophenone. It was further methylated to obtain 5-（4-（3-Hydroxy）- 4-methyl-2-oxo-2, 4-dihydro-lH-benzo[d] [ 1, 3]oxazin-6-yl）-1-methyl-pyrrole-2-Carbonitrile. The compounds and intermediates were characterized by IR, MS and 1 H NMR techniques, respectively. The reaction mechanism of the new synthetic compound pyrrole ring N- methylation was analyed, and the results show that the combination of N, N - dimethyl formamide and solid inorganic base potash can be selective in pyrrole ring N for methylation.