异恶唑啉的对映体特异性合成。一种RGD模拟血小板糖蛋白IIb/IIIa拮抗剂。

The Enantiospecific Synthesis of an Isoxazoline. A RGD Mimic Platelet GPIIb/IIIa Antagonist.

作者信息

Zhang Lh Lin-hua, Chung J. C., Costello T. D., Valvis I., Ma P., Kauffman S., Ward R.

机构信息

Chemical Process R&D, The DuPont Merck Pharmaceutical Company, Deepwater, New Jersey 08023-0999.

出版信息

J Org Chem. 1997 Apr 18;62(8):2466-2470. doi: 10.1021/jo9612537.

DOI:10.1021/jo9612537

PMID:11671583

Abstract

A convergent, large-scale, chiral synthesis of isoxazoline 1 has been achieved in 37% overall yield and >99.6% optical purity, starting from L-asparagine and 4-cyanobenzaldehyde. Hofmann reaction of N(alpha)-n-Boc-L-asparagine with iodosobenzene diacetate provides optically pure N(alpha)-n-Boc-L-alpha,beta-diaminopropionic acid (8) in 75% yield. A process of lipase resolution-base catalyzed epimerization gives the single enantiomer 5. Reaction of acid 5 with amine 9 in the presence of thionyl chloride forms the framework of 1. A Pinner reaction of intermediate 4 in methyl acetate or anisole, followed by an amidination with ammonium acetate, gives optically pure product 1.

摘要

以L-天冬酰胺和4-氰基苯甲醛为起始原料，实现了异恶唑啉1的汇聚式、大规模手性合成，总收率为37%，光学纯度>99.6%。N(α)-叔丁氧羰基-L-天冬酰胺与二醋酸碘苯的霍夫曼反应以75%的收率提供了光学纯的N(α)-叔丁氧羰基-L-α,β-二氨基丙酸(8)。脂肪酶拆分-碱催化差向异构化过程得到单一对映体5。在亚硫酰氯存在下，酸5与胺9反应形成1的骨架。中间体4在醋酸甲酯或苯甲醚中进行平纳反应，然后用醋酸铵进行脒化反应，得到光学纯产物1。