A kind of synthetic method of metafenil

A synthesis method and compound technology, which are applied in the field of synthesis of anticancer active substance metafinil, can solve problems such as being unsuitable for industrial production, and achieve the effects of mild conditions, increased yield, and reduced solvent usage

Active Publication Date: 2018-07-10
GUANGZHOU NANXIN PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the second step reaction, compound 3 and 4-chloro-3-trifluoromethylphenyl isocyanate were heated and reacted in ethyl acetate, and the product was purified by silica gel column, and the yield was about 18%, which was obviously low. Suitable for industrial production

Method used

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  • A kind of synthetic method of metafenil
  • A kind of synthetic method of metafenil
  • A kind of synthetic method of metafenil

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] Example 1 Synthesis of 2-carbamoyl-4-((3-fluoro-4-amino)phenoxy)pyridine (compound 4)

[0019] In a dry reaction flask, put CuI (9.5g, 49.9mmoL), Cs 2 CO 3 (490.0g, 1504.0mmoL), Me 4 Phen (24.0 g, 101.6 mmoL), compound 2 (247.2 g, 1000 mmoL), toluene (500 mL). mixture under argon atmosphere at 80 - 85 0 C oil bath reaction 24h. Cool to room temperature, add ethyl acetate (1500 mL), filter the reaction solution through a silica gel column, wash the filter cake with 500 mL of ethyl acetate, combine the filtrates, and evaporate the filtrate solvent under reduced pressure. The concentrated residue was crystallized in an appropriate amount of ethyl acetate-petroleum ether to obtain 173.1 g of a white solid. The yield is 70%. 1 H NMR (400MHz, DMSO- d 6 ): δ5.21 (s, 2 H), 6.77 (dd, 1 H), 6.85 (t, 1 H), 7.01 (dd, 1 H), 7.10 (dd, 1 H), 7.34 (d, 1 H ), 7.68 (br s, 1 H), 8.10 (br s, 1 H), 8.45 (d, 1 H); MS (ESI) m / z: 248.1 (M + H + ).

Embodiment 2

[0020] Example 2 Synthesis of 4-{4-[3-(4-chloro-3-trifluoromethylphenyl)urea]-3-fluorophenoxy}pyridine-2-carboxamide (Compound 1)

[0021] Put 4-chloro-3-trifluoromethylphenylisocyanate (26.6g, 120mmoL), DMF (50mL), and N,N-diisopropylethylamine (2.6g, 20mmoL) into a reaction flask. A solution of 2-carbamoyl-4-((3-fluoro-4-amino)phenoxy)pyridine (24.7 g, 100 mmoL) in dichloromethane (350 mL) was slowly added dropwise to the reaction flask. The reaction solution was stirred at room temperature for 24 h until the reaction was complete. The solvent was evaporated. The residue was recrystallized from ethyl acetate to obtain 28.1 g of white solid (compound 1), yield 60%. 1 H NMR (400MHz, DMSO- d 6 ): δ7.18 (d, 1H), 7.20(m, 1H), 7.32(m, 1H), 7.40(d, 1H), 7.61(d,2H), 7.72(s, 1H), 8.18(m, 3H), 8.52(d, 1H), 8.73(s, 1H), 9.51(s, 1H); MS(ESI)m / z: 469.1(M+H) + .

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Abstract

The invention relates to a synthesis method of an anti-cancer active compound-metafenib. The chemical name of metafenib is 4-4{4-[3-(4-chloro-3-trifluoromethylphenyl)urea]-3-flrophenoxy}pyridine-2-methnamide (the compound 1). Metafenib is prepared by taking 4-chloropyridine-2-carboxamide as a raw material through the two synthesis steps of a metal catalytic coupling reaction and an isocyanate addition reaction. Compared with existing methods reported in literatures, the method is effective and practical and can be enlarged for massive production, and the total yield of the product is obviously increased.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a method for synthesizing VEGFR and RAF-targeted anticancer active substance metafenib. Background technique [0002] Vascular endothelial growth factor (VEGF) is one of the most important cell growth factors in the process of tumor angiogenesis. Tumor blood vessels are highly sensitive to VEGF, and the VEGF mRNA concentration in many tumor cells is significantly higher than that in normal cells, including lung cancer. Metafenil, the chemical name is 4-{4-[3-(4-chloro-3-trifluoromethylphenyl)urea]-3-fluorophenoxy}pyridine-2-carboxamide, the structure is as follows (Compound 1) shows that it is an effective VEGF and RAF kinase inhibitor, so it is a potentially effective anticancer active substance (see CDE Review Weekly 2015.7.19-2015.7.25). At the same time, according to the report of the Miyagi Cancer Research Center in Japan, in the preclinical anticancer activity study, metafini...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D213/81
CPCC07D213/81
Inventor 林寨伟胡盼张世喜
Owner GUANGZHOU NANXIN PHARMA
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