Intermediate compound of antitumor drug neratinib and its preparation method and use
The technology of a compound and a compound of general formula is applied in the application field of preparing neratinib, which can solve problems such as low yield, adverse effects on health, and environmental pollution
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Embodiment 1
[0116] Example 1 Preparation of 3-crotonamido-4-ethoxybenzoic acid methyl ester
[0117]
[0118] Add methyl 3-amino-4-ethoxybenzoate (1.6g, 8mmol) (commercially purchased), THF (5mL), water (0.1mL), potassium carbonate (3.1g, 22mmol), ice Add crotonyl chloride (0.86g, 8mmol) under stirring in the bath, and after stirring for half an hour, the reaction solution is concentrated to dryness. After cooling in an ice-water bath, adjust the pH to 4-5 with dilute hydrochloric acid, and a white solid product precipitates out. Half an hour later, it was filtered and slurried with ethyl acetate to obtain 1.85 g of the title compound as a white powder, with a yield of 86%. 1 HNMR (400MHz, CDCl 3 ): δ1.52(t, 3H), 1.96(d, 3H), 3.90(s, 3H), 4.20(q, 2H), 6.02(d, 1H), 6.91(d, 1H), 7.03(m, 1H), 7.74(s, 1H), 7.80(dd, 1H), 9.12(s, 1H).
Embodiment 2
[0119] Example 2 Preparation of 2-nitro-5-crotonamido-4-ethoxybenzoic acid methyl ester
[0120]
[0121] The compound of Example 1 (1.8g, 7mmol) and dichloromethane (15mL) were sequentially added into the one-necked flask, and fuming nitric acid (1.2g, 20mmol) was added with stirring in an ice bath. After the addition was complete, the reaction was continued for 5 hours. The reaction solution was poured into ice water, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and beaten with ethyl acetate to obtain 1.32 g of the light yellow title compound with a yield of 65%. 1 HNMR (300MHz, CDCl 3 ): δ1.54(t, 3H), 1.96(d, 3H), 3.90(s, 3H), 4.24(q, 2H), 6.02(d, 1H), 7.04(m, 1H), 7.46(s, 1H), 7.87(s, 1H), 8.84(s, 1H).
Embodiment 3
[0122] Example 3 Preparation of 2-amino-5-crotonamido-4-ethoxybenzoic acid methyl ester
[0123]
[0124] Add embodiment 2 compound (1.28g, 4mmol) successively in one-necked bottle, CH 3 COOH (10 mL), zinc powder (0.81 g, 12 mmol) was added in batches under stirring in an ice bath, and after the addition was complete, the reaction was continued for another 2 hours. The reaction solution was filtered, concentrated to remove most of the acetic acid, and saturated aqueous sodium bicarbonate (10 mL) was added. Each was extracted three times with dichloromethane (10 mL), dried, concentrated, and the solid was slurried with ethyl acetate to obtain 0.9 g of the off-white title compound with a yield of 78%. 1 HNMR (300MHz, CDCl 3 ): δ1.46(t, 3H), 1.91(d, 3H), 3.83(s, 3H), 4.08(q, 2H), 5.94(dd, 1H), 6.10(s, 1H), 6.95(m, 1H), 7.40(s, 1H), 8.87(s, 1H).
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