Enantioselective and Step-Economic Synthesis of the Chiral Amine Fragment in the Tyrosine Kinase Inhibitor Repotrectinib by Direct Asymmetric Reductive Amination under Batch and Flow

Xu, Lei1; Wang, Gang2,3; Rong, Nianxin1; Gu, Yang1; Hu, Le'an4; You, Hengzhi2,3; Yin, Qin1

2023-07-01

10.1021/acs.oprd.3c00152

ORGANIC PROCESS RESEARCH & DEVELOPMENT   影响因子和分区

1083-6160

1520-586X

A one-stepand highly enantioselective synthesis of (R)-2-(1-aminoethyl)-4-fluorophenol((R)-I), a key chiral intermediate towardpreparation of the tyrosine kinaseinhibitor repotrectinib, has been developed. Starting from the easilyavailable substrate 1-(5-fluoro-2-hydroxyphenyl)ethan-1-one (2a), the target product (R)-I was prepared in an optically pure form through a Ru-catalyzed asymmetricreductive amination with NH4OAc as the nitrogen sourceand H-2 as the reducing agent. The reaction can be carriedout on a 20 g scale using a continuous-flow reactor instead of a traditionalbatch reactor. The flow technology enables higher reaction efficiencyand does not require column chromatography for product purification.Compared to the known procedures, this method avoids the use of expensivechiral auxiliaries and protecting group operations, making it a step-economicaland cost-effective alternative strategy for production of repotrectinib.

repotrectinib chiral primary amine asymmetricreductive amination practical synthesis continuousflow

SCI ; EI

英语

其他

National Natural Science Foundation of China[22071097] ; Shenzhen Science and Technology Program["JCYJ20190809142013478","JCYJ20220818100804010","JCYJ20190806142203709","JSGG20191129114029286","JSGG20201103153807021"] ; Guangdong Basic and Applied Basic Research Foundation["2021B1515020062","2021A1515110366"] ; Shenzhen Key Laboratory of Advanced Functional Carbon Materials Research and Comprehensive Application[ZDSYS20220527171407017]

Chemistry

Chemistry, Applied ; Chemistry, Organic

WOS:001024810500001

AMER CHEMICAL SOC

20232914407254

Amines ; Amino acids ; Column chromatography ; Cost effectiveness ; Enantioselectivity ; Enzyme inhibition

Chemistry:801 ; Physical Chemistry:801.4 ; Chemical Plants and Equipment:802.1 ; Organic Compounds:804.1 ; Industrial Economics:911.2

CHEMISTRY

2-s2.0-85164816161

Web of Science

1.Chinese Acad Sci, Shenzhen Inst Adv Technol, Shenzhen 518055, Peoples R China
2.Harbin Inst Technol Shenzhen, Sch Sci, Shenzhen 518055, Peoples R China
3.Harbin Inst Technol Shenzhen, Green Pharmaceut Engn Res Ctr, Shenzhen 518055, Peoples R China
4.Southern Univ Sci & Technol, Dept Chem, Shenzhen 518055, Peoples R China

Xu, Lei,Wang, Gang,Rong, Nianxin,et al. Enantioselective and Step-Economic Synthesis of the Chiral Amine Fragment in the Tyrosine Kinase Inhibitor Repotrectinib by Direct Asymmetric Reductive Amination under Batch and Flow[J]. ORGANIC PROCESS RESEARCH & DEVELOPMENT,2023,28(5):1539-1545.

Xu, Lei.,Wang, Gang.,Rong, Nianxin.,Gu, Yang.,Hu, Le'an.,...&Yin, Qin.(2023).Enantioselective and Step-Economic Synthesis of the Chiral Amine Fragment in the Tyrosine Kinase Inhibitor Repotrectinib by Direct Asymmetric Reductive Amination under Batch and Flow.ORGANIC PROCESS RESEARCH & DEVELOPMENT,28(5),1539-1545.

Xu, Lei,et al."Enantioselective and Step-Economic Synthesis of the Chiral Amine Fragment in the Tyrosine Kinase Inhibitor Repotrectinib by Direct Asymmetric Reductive Amination under Batch and Flow".ORGANIC PROCESS RESEARCH & DEVELOPMENT 28.5(2023):1539-1545.