Other

Hoffmann-la Roche Inc.

Genentech, Inc.

Novartis Ag

Mochida Pharmaceutical Co., Ltd.

Yonghui Ge

Tao Jiang

Jie Li

Francis Gosselin

Tsutomu Satoh

Haiming Zhang

Truc Ngoc Nguyen

Pierre-Yves Michellys

Stephan Bachmann

Baogen Wu

Thomas H Marsilje, Iii

Bei Chen

Xuefeng Zhu

Wei Pei

Stefan Koenig

Fenglai Sun

Hideharu Uchida

Chunbo Sha

Michael Dalziel

Chen Yi Huang

Andreas Stumpf

Jinguang Lin

Jian Luo

Chuan Chen

Xiaofei Cai

Jiajie Ye

Yuki Nakagawa

Jie Zhang

Xiaomin Gu

Yanliang Chen

Zhaobo Gao

Yuncheng Li

Eduardo V Mercado-marin

Daniel Zell

Diane E Carrera

Raphael Bigler

Laure Elizabeth Simone Finet

Regis Jean Georges Mondiere

Bin Zhao

Baoquan Sun

Chen Huang

A manufacturing process to a bis-mesylate salt 1b of the pan-RAF inhibitor 4-amino-n-(1-((3-chloro-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide. The process features a number of efficient key reactions, including a robust and scalable Pd-catalyzed carbonylation reaction to generate thienopyrimidine 2 and a highly chemoselective Pt/V/C-catalyzed nitro group reduction to access penultimate intermediate 7. The final amide coupling of 7 and 2 was accomplished by a mild and safe protocol employing N,N,N',N′-tetramethylchloroformamidinium hexafluorophosphate (TCFH) as the coupling reagent, to produce a 1:1 adduct of the freebase and THF. The adduct afforded compound 1b with excellent yield, purity, and form stability on a multikilogram production scale after reaction with MsOH and recrystallization. The methods are able to produce a compound having upwards of 95% purity.

Synthesis of a bis-mesylate salt of 4-amino-N-(1-((3-chloro-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide and intermediates thereto

The invention provides novel pyrimidine derivatives and pharmaceutical compositions thereof, and methods for using such compounds. For example, the pyrimidine derivatives of the invention may be used to treat, ameliorate or prevent a condition which responds to inhibition of anaplastic lymphoma kinase (ALK) activity, c-ros oncogene (ROS), insulin-like growth factor (IGF-1R), and/or insulin receptor (InsR) or a combination thereof. 

Compounds and compositions as protein kinase inhibitors

Growing community of inventors

Suzhou, China

Yonghui Ge