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Preparation method of (5-fluoro-2, 3-dihydrobenzofuran-4-yl) methylamine or salt thereof and intermediate of (5-fluoro-2, 3-dihydrobenzofuran-4-yl) methylamine or salt thereof

A technology of fluorobenzofuran and dihydrobenzene, which is applied in the field of the preparation method of methylamine or its salt and its intermediates, can solve the problems of unsuitability for industrial production, high toxic price of raw material reagents, lengthy reaction route, etc., and achieve The post-processing is simple, environment-friendly, and the environment is cheap and easy to obtain.

Active Publication Date: 2021-11-12
ASCENTAGE PHARMA SUZHOU CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Moreover, the post-treatment of the 4-step reaction in the above route requires column chromatography separation and purification
Therefore, this reaction route is relatively lengthy, the raw material reagents are highly toxic and expensive, and the post-treatment requires multiple column chromatography purifications, so it is not suitable for industrial production.

Method used

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  • Preparation method of (5-fluoro-2, 3-dihydrobenzofuran-4-yl) methylamine or salt thereof and intermediate of (5-fluoro-2, 3-dihydrobenzofuran-4-yl) methylamine or salt thereof
  • Preparation method of (5-fluoro-2, 3-dihydrobenzofuran-4-yl) methylamine or salt thereof and intermediate of (5-fluoro-2, 3-dihydrobenzofuran-4-yl) methylamine or salt thereof
  • Preparation method of (5-fluoro-2, 3-dihydrobenzofuran-4-yl) methylamine or salt thereof and intermediate of (5-fluoro-2, 3-dihydrobenzofuran-4-yl) methylamine or salt thereof

Examples

Experimental program
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preparation example Construction

[0085] In one aspect, the present invention provides a method for preparing (5-fluoro-2,3-dihydrobenzofuran-4-yl)methanamine (8) or a salt thereof, which comprises the following reaction steps:

[0086] 1) Using 4-fluoro-3-methylphenol (1) as an initial raw material, brominating it to obtain 2-bromo-4-fluoro-5-methylphenol (2);

[0087] 2) O-alkylation of 2-bromo-4-fluoro-5-methylphenol (2) with 2-bromo-1,1-diethoxyethane (3) to give 1-bromo- 2-(2,2-diethoxyethoxy)-5-fluoro-4-toluene (4);

[0088] 3) Cyclization of 1-bromo-2-(2,2-diethoxyethoxy)-5-fluoro-4-toluene (4) to give 7-bromo-5-fluoro-4-methylbenzene And furan (5);

[0089] 4) bromination of 7-bromo-5-fluoro-4-methylbenzofuran (5) to give 7-bromo-4-(bromomethyl)-5-fluorobenzofuran (6);

[0090] 5) Prepare (5-fluoro-2,3-dihydrobenzofuran-4-yl)methanamine (8) or its salt by using any of the following two-step reactions in 5.1 or 5.2:

[0091] 5.1) Azidation of 7-bromo-4-(bromomethyl)-5-fluorobenzofuran (6) in the pre...

Embodiment 1

[0140] The synthesis of embodiment 1—2-bromo-4-fluoro-5-methylphenol (2)

[0141] A solution of 4-fluoro-3-methylphenol (400 g, 3.17 mol) in 8 L of dichloromethane was cooled to -70 °C, and Br was added dropwise at -60 °C 2 (527g, 3.33mol), the reaction was continued for 2 hours, and no reaction raw material remained by monitoring the reaction. Add 1L saturated Na 2 S 2 o 3 Solution and 3L water, the reaction solution was slowly raised to room temperature, separated, extracted the aqueous phase with dichloromethane (1L*2), combined the organic layer, post-processed, concentrated to obtain 705g product, and obtained 533g product by beating with n-hexane, yield 82%.

[0142] NMR data 1 H NMR (300MHz, CDCl 3 ,ppm), δ7.10(d,1H),6.82(d,1H),2.19(s,3H).

Embodiment 2

[0143] Synthesis of Embodiment 2—1-bromo-2-(2,2-diethoxyethoxy)-5-fluoro-4-toluene (4)

[0144] To a solution of 2-bromo-4-fluoro-3-methylphenol (530 g, 2.59 mol) in 2 L of DMF was added potassium carbonate (713 g, 5.17 mol) and 2-bromo-1,1-diethoxyethane (662 g, 3.36 mol). The mixture was heated to 120° C. and reacted for 16 h, and the reaction was monitored and no reaction raw material remained. The reaction was cooled to room temperature, the mixture was poured into 5L of water, then extracted with methyl tert-butyl ether (4L*3), the combined organic phase was washed with 4L of water and 4L of brine, dried and concentrated to obtain 902g of crude product.

[0145] NMR data 1 H NMR (300MHz, CDCl 3 ,ppm),δ7.16(d,1H),6.70(d,1H),4.82(t,1H),3.96(d,2H),3.79(m,2H),3.54(m,2H),2.18( s,3H), 1.21(t,6H).

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Abstract

The invention provides a preparation method of (5-fluoro-2, 3-dihydrobenzofuran-4-yl) methylamine or a salt thereof. According to the method, 4-fluoro-3-methylphenol ais taken s an initial raw material, and the (5-fluoro-2, 3-dihydrobenzofuran-4-yl) methylamine or the salt thereof is prepared through the steps of bromination, O-alkylation, cyclization, bromination, azidation or ammonolysis, reduction and the like. The reaction route is simple in synthesis process, convenient to operate, high in yield and environmentally friendly, and the prepared (5-fluoro-2, 3-dihydrobenzofuran-4-yl) methylamine can be used as an intermediate of pharmacy and fine chemical engineering.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and particularly relates to a preparation method of (5-fluoro-2,3-dihydrobenzofuran-4-yl)methanamine or a salt thereof and a preparation intermediate thereof. Background technique [0002] (5-Fluoro-2,3-dihydrobenzofuran-4-yl)methanamine is an important class of intermediate compounds that can be used in the synthesis of important pharmaceuticals and agricultural chemicals. At present, the main literature reports adopt the following route to synthesize (5-fluoro-2,3-dihydrobenzofuran-4-yl)methanamine: [0003] [0004] In the above synthetic route, 2-bromo-4-(2,2-diethyl Oxyethoxy)-1-fluorobenzene (A5.1), and then prepared by PPA ring closure reaction to obtain 4-bromo-5-fluorobenzofuran (A5.2a and regioisomer A5.2b), which Then with Zn(CN) 2 , Pd(PPh 3 ) 4 The reaction produces 5-fluorobenzofuran-4-carbonitrile (A5.3), followed by simultaneous hydrogenation reduction and ami...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/79C07C43/313C07C39/27
CPCC07D307/79C07C43/313C07C39/27C07C37/62C07C41/50Y02P20/55C07C43/315
Inventor 吴清泉王秀玲王佳伟周如彬
Owner ASCENTAGE PHARMA SUZHOU CO LTD
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