(-)-5-氮杂螺[2,4]庚烷-7-醇的合成

Synthesis of(-)-5-Azaspiro[2,4]heptane-7-ol

AL8326是一种新型多靶点小分子酪氨酸激酶抑制剂,目前正处于临床研究中,手性化合物(-)AL8326能发挥更好的治疗效果。以10-(苯基甲基)-5,8-二氧杂-10-氮杂[2.0.4.3]十一烷为起始原料,采用(-)-α-苯乙胺作为化学拆分剂制备了手性化合物(-)AL8326的重要关键中间体,即目标化合物,GC纯度大于99%,总产率达16.8%,其化学结构经MS、^(1)HNMR和^(13)CNMR确证。探讨了还原反应中硼氢化钠的用量对中间体5-苄基-5-氮杂螺[2.4]庚烷-7-醇产率的影响,当n(硼氢化钠)∶n(5-苄基-5-氮杂螺[2.4]庚烷-7-酮)=0.75∶1时,还原反应产率最高,达到90.9%。考察了脱苄反应中甲酸铵及钯碳的用量对目标化合物产率的影响,当n(甲酸铵)∶n((-)-5-苄基-5-氮杂螺[2.4]庚烷-7-醇)=2.0∶1、钯碳用量为(-)-5-苄基-5-氮杂螺[2.4]庚烷-7-醇的0.4倍时,脱苄反应产率最佳,可达到85.0%。实验结果表明此方法操作简单、反应条件温和、适用工业生产。

AL8326 is a novel,high efficient multi-target small molecule tyrosine kinase inhibitor in clinical research at present,and the chiral compound(-)AL8326 can give better therapeutic effect.By using 10-(phenylmethyl)-5,8-dioxa-10-aza[2.0.4.3]undecane as starting material,title compound,an important key intermediate of(-)AL8326 was synthesized by using(-)-α-phenethylamine as the resolution agent.The GC purity was more than 99%,and the total yield was 16.8%.The structure was confirmed by MS,^(1)HNMR,^(13)CNMR.The effect of the amount of NaBH4 on the yield of intermediate 5-benzyl-5-azaspiro[2.4]heptane-7-ol was discussed,when n(sodium borohydride)∶n(5-benzyl-5-azaspiro[2.4]heptane-7-one)=0.75∶1,the yield of 5-benzyl-5-azaspiro[2.4]heptane-7-ol by reduction reaction was up to 90.9%.The amount of ammonium formate and palladium carbon in debenzylation was discussed,when n(ammonium formate)∶n((-)-5-benzyl-5-azaspiro[2.4]heptane-7ol)=2.0∶1 and the amount of palladium carbon was 0.4 times that of(-)-5-benzyl-5-azaspiro[2.4]heptane-7-ol,the yield of target compound by the final debenzylation could reached 85.0%.The experimental results showed that the method was simple,mild and suitable for industrial production.