ChemicalBook CAS DataBase List Chidamide

Chidamide synthesis

1synthesis methods

Product Name:Chidamide
CAS Number:743420-02-2
Molecular formula:C22H19FN4O2
Molecular Weight:390.41

The scalable synthetic approach to chidamide very closely follows the discovery route. The sequence began with the condensation of commercial nicotinaldehyde (52) and malonic acid (53) in a mixture of pyridine and piperidine. Next, activation of acid 54 with N,N0-carbonyldiimidazole (CDI) and subsequent reaction with 4-aminomethyl benzoic acid (55) under basic conditions afforded amide 56 in 82% yield. Finally, activation of 56 with CDI prior to treatment with 4-fluorobenzene- 1,2-diamine (57) and subsequent treatment with TFA and THF yielded chidamide (VIII) in 38% overall yield from 52. However, no publication reported that mono-N-Boc-protected bis-aniline was used to approach Chidamide.

367-31-7 Synthesis

367-31-7
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(E)-4-((3-(pyridin-3-yl)acrylaMido)Methyl)benzoic acid

219964-34-8
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743420-02-2
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Yield:743420-02-2 57%

Reaction Conditions:

Stage #1:4-[N-(pyridin-3-ylacryloyl)aminomethyl]benzoic acid with 1,1'-carbonyldiimidazole in tetrahydrofuran at 45; for 1 h;
Stage #2:4-fluoro-1,2-phenylenediamine with trifluoroacetic acid in tetrahydrofuran at 20; for 24 h;

Steps:

2 Example 2
To a suspension of 0.29 g (1.78 mmol) of N, N’-carbonyldiimidazole in tetrahydrofuran (15 ml) is added 0.50 g (1.78mmol)) of 4-[N-Pyridin-3-ylacryloyl)aminomethyl]benzoic acid, followed by stirring at 45°C for 1 hour. After cooling, thereaction mixture is added to a separately prepared furan tetrahydrofuran (10 ml) solution including 0.28 g (2.22 mmol)of 4-fluoro-1,2-phenylenediamine and 0.20 g (1.78 mmol) of trifluoroacetic acid at room temperature. After reaction atroom temperature for 24 hours, the deposited white solid is collected by filtration, washed with tetrahydrofunan, andthen dried to give the title compound (0.40 g, 57%). 1H NMR (300 MHz, DMSO-d6): δppm: 4.49 (2H, d), 4.84 (2H, br.s),6.60 (1H, t), 6.80 (2H, m), 6.96 (1H, t), 7.18 (1H, d), 7.42 (2H, d), 7.52 (1H, d), 7.95 (2H, d), 8.02 (1H, d), 8.56 (1H, d),8.72 (1H, br. t), 8.78 (1H, s), 9.60 (1H, br.s). 1R (KBr) cm-1: 3310, 1655, 1631, 1524, 1305, 750. HRMS calcd forC22H19N4O2F: 390.4170. Found: 390.4172. MA calcd for C22H19O2F: C, 67.68%; H, 4.40%; N, 14.35. Found: C, 67,52%; H, 4.38%; N, 14.42%.

References:

Shenzhen Chipscreen Biosciences Ltd.;Lu, Xian-Ping;Li, Zhibin;Xie, Aihua;Li, Boyu;Ning, Zhiqiang;Shan, Song;Deng, Tuo;Hu, Weiming;Shi, Leming EP2860174, 2017, B1 Location in patent:Paragraph 0040; 0041

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