	US 12,221,427 B2
	Preparation method of (5-fluoro-2,3-dihydrobenzofuran-4-yl)methanamine or its salt, and intermediates thereof
Qingquan Wu, Suzhou (CN); Xiuling Wang, Suzhou (CN); Jiawei Wang, Suzhou (CN); and Rubin Zhou, Suzhou (CN)
Assigned to Ascentage Pharma (Suzhou) Co., Ltd., Suzhou (CN); and Ascentage Pharma Group Corp Limited, Hong Kong (CN)
Appl. No. 17/425,817
Filed by Ascentage Pharma (Suzhou) Co., Ltd., Suzhou (CN); and Ascentage Pharma Group Corp Limited, Hong Kong (CN)
PCT Filed May 10, 2021, PCT No. PCT/CN2021/092728 § 371(c)(1), (2) Date Jul. 26, 2021, PCT Pub. No. WO2021/228034, PCT Pub. Date Nov. 18, 2021.
Claims priority of application No. PCT/CN2020/089677 (WO), filed on May 11, 2020.
Prior Publication US 2022/0298129 A1, Sep. 22, 2022
Int. Cl. C07D 307/79 (2006.01)

CPC C07D 307/79 (2013.01)

11 Claims

1. A method of preparing (5-fluoro-2,3-dihydrobenzofuran-4-yl) methylamine or a salt thereof, which comprises the following reaction steps:

1) Brominating 4-fluoro-3-methylphenol as the starting material to obtain 2-bromo-4-fluoro-5-methylphenol;

2) Performing O-alkylation reaction between 2-bromo-4-fluoro-5-methylphenol and 2-bromo-1, 1-diethoxyethane to obtain 1-bromo-2-(2,2-diethoxyethoxy)-5-fluoro-4-toluene;

3) Cyclizing 1-bromo-2-(2,2-diethoxyethoxy)-5-fluoro-4-toluene to obtain 7-bromo-5-fluoro-4-methylbenzofuran;

4) Brominating 7-bromo-5-fluoro-4-methylbenzofuran to obtain 7-bromo-4-(bromomethyl)-5-fluorobenzofuran; and

5) Preparing (5-fluoro-2,3-dihydrobenzofuran-4-yl) methylamine or a salt thereof using the following two-step reaction in 5.1 or 5.2:

5.1) Aziding 7-bromo-4-(bromomethyl)-5-fluorobenzofuran in the presence of an azide to obtain 7-bromo-5-fluoro-4-azidomethyl-benzofuran, which is then hydrogenated to obtain (5-fluoro-2,3-dihydrobenzofuran-4-yl) methylamine or a salt thereof; or

5.2) Ammonolyzing 7-bromo-4-(bromomethyl)-5-fluorobenzofuran to obtain 7-bromo-4-(aminomethyl)-5-fluorobenzofuran, which is then hydrogenated to obtain (5-fluoro-2,3-dihydrobenzofuran-4-yl) methylamine or a salt thereof.