公开(公告)号：US20120289699A1

公开(公告)日：2012-11-15

申请号：US13105964

申请日：2011-05-12

Applicant: Julian Paul Henschke ,  Aiping Xie ,  Xin Yan Huang ,  Yung Fa Chen

Inventor： Julian Paul Henschke ,  Aiping Xie ,  Xin Yan Huang ,  Yung Fa Chen

IPC: C07F5/02 ,  C07F5/04

CPC classification number: C07F5/025 ,  C07F5/02 ,  Y02P20/55

Abstract: The present invention provides a synthetic process for producing bortezomib using a novel intermediate. The present invention also provides a process for purifying bortezomib anhydride, and a new crystalline polymorph of bortezomib anhydride.

Abstract translation: 本发明提供了一种使用新型中间体制备硼替佐米的合成方法。 本发明还提供了一种纯化硼替佐米酐的方法和一种新的硼替佐米酐结晶多晶型物。

公开(公告)号：US08497374B2

公开(公告)日：2013-07-30

申请号：US13105964

申请日：2011-05-12

Applicant: Julian Paul Henschke ,  Aiping Xie ,  Xin Yan Huang ,  Yung Fa Chen

Inventor： Julian Paul Henschke ,  Aiping Xie ,  Xin Yan Huang ,  Yung Fa Chen

IPC: C07D241/02

CPC classification number: C07F5/025 ,  C07F5/02 ,  Y02P20/55

Abstract: A synthetic process for producing bortezomib comprising converting racemic boronic esters, such as the pinacol α-aminoboronic ester, into mixtures of diastereomers [6] by reaction with a suitably protected L-phenylalanine derivative (see Scheme 3), such as N—BOC-L-phenylalanine. The protecting group of the L-phenylalanine moiety is then removed, such as by reacting the diastereomers [6] with an acid, such as hydrochloric acid, to form a mixture of amine salt diastereomers [7] which is then subjected to conditions under which the desired diastereomer (R,S)-[7] is selectively isolated, such as by crystallization, chromatography or stereoselective hydrolysis. The separated desired diastereomer (R,S)-[7] is then converted into bortezomib or bortezomib anhydride.

Abstract translation: 一种用于生产硼替佐米的合成方法，包括通过与适当保护的L-苯丙氨酸衍生物（参见方案3）反应，将外消旋硼酸酯如频哪醇α-氨基硼酸酯转化为非对映体混合物[6]，例如N-BOC- L-苯丙氨酸。 然后除去L-苯丙氨酸部分的保护基团，例如通过使非对映异构体[6]与酸如盐酸反应，形成胺盐非对映异构体的混合物[7]，然后将其进行条件， 选择性分离所需的非对映异构体（R，S） - [7]，例如通过结晶，层析或立体选择性水解。 分离的所需非对映体（R，S） - [7]然后转化成硼替佐米或硼替佐米酐。