Preparation method of (5-fluoro-2,3-dihydrobenzofuran-4-yl)methanamine or its salt, and intermediates thereof
AssigneesAscentage Pharma (Suzhou) Co., Ltd., Ascentage Pharma Group Corp Limited
InventorsQingquan Wu, Xiuling Wang, Jiawei Wang, Rubin Zhou
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Abstract
The present invention provides a preparation method of (5-fluoro-2,3-dihydrobenzofuran-4-yl)methylamine or a salt thereof, which uses 4-fluoro-3-methylphenol as the starting material, and is carried out through the steps of bromination, O-alkylation, cyclization, bromination, azidation or ammonolysis, and reduction. The reaction route of the present invention has simple synthesis process, convenient operation, high yield, and is environmentally friendly. The prepared (5-fluoro-2,3-dihydrobenzofuran-4-yl)methylamine can be used as an intermediate in pharmaceuticals and fine chemicals.
Claims11
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.
The method of claim1, wherein the hydrogenation in step 5.2) is carried out by hydrogenating 7-bromo-4-(aminomethyl)-5-fluorobenzofuran under pressure in the presence of a catalyst, and optionally has one or more of the following features:
- the hydrogen pressure is 0.2-3 Mpa;
- the reaction temperature is 40-100° C.;
- the reaction solvent is selected from C1-C4 alcohols, and is more preferably selected from methanol or ethanol;
- the catalyst is selected from at least one of palladium catalyst or Raney nickel;
- the mass ratio of 7-bromo-4-(aminomethyl)-5-fluorobenzofuran to the catalyst is (10-50):
- 1;
- and/or
- the reaction time is 24-48 h.
The method of claim1, wherein the salt of (5-fluoro-2,3-dihydrobenzofuran-4-yl) methylamine is hydrobromide.
An intermediate compound used for the preparation of (5-fluoro-2,3- dihydrobenzofuran-4-yl) methylamine or a salt thereof, which is selected from the group consisting of:
- 1-bromo-2-(2,2-diethoxyethoxy)-5-fluoro-4-toluene, 7-bromo-4-(bromomethyl)-5-fluorobenzofuran, 7-bromo-5-fluoro-4-azidomethyl benzofuran and 7-bromo-4-(aminomethyl)-5-fluorobenzofuran.
Dependencies are inferred from the claim text.