27143-07-3

Light yellow to dark yellow solid

Acetic acid, 2-chloro-2-[2-(4-methoxyphenyl)hydrazinylidene], ethyl ester is an ester derivative and can be used as an intermediate in the synthesis of apixaban.

Step-1:Water (600 ml) was added to p-anisidine (100 g) at room temperature and the resulting mixture was cooled to 10°C, followed by the addition of concentrated hydrochloric acid (133.5 g). The resulting mixture was cooled to —5°C to 0°C, followed by portion-wise addition of 40 % aqueous sodium nitrite solution over 45 minutes to 1 hour. The resulting mass was stirred for 1 hour 30 minutes at —5°C to0°C, followed by slow addition of 11 % sulfamic acid solution over 1 hour to 1 hour 30 minutes to produce a reaction mass (first part).Step-2:Sodium acetate (146 g) was added to water (300 ml) at room temperature and then stirred for 10 minutes to 15 minutes, followed by the addition of ethyl 2-chloroacetoacetate (160.4g) and acetone (300 ml) at room temperature to form a reaction mixture. The resulting mixture was cooled to 0°C. The resulting mixture was added to the reaction mass (first part) obtained in step-i at —5°C to 0°C and then stirred for 1 hour at the same temperature. Acetone (200 ml) was added to the resulting mass and stirred for 30 minutes at —5°C to 0°C. The resulting mass was settled for 5 hours at —5°C to 0°Cand then filtered the solid. Methanol (150 ml) was added to the resulting solid at room temperature and then stirred for 2 hours at the same temperature. Ethyl 2-chloro-2-(2-(4-methoxyphenyl) hydrazone)acetate was obtained through further purity.

[1] Patent: CN104513239, 2017, B. Location in patent: Paragraph 0197; 0238; 0243; 0244
[2] European Journal of Medicinal Chemistry, 2016, vol. 123, p. 431 - 446
[3] Patent: CN107400131, 2017, A. Location in patent: Paragraph 0026; 0031; 0042-0044
[4] Patent: CN105384739, 2016, A. Location in patent: Paragraph 0391; 0392; 0393
[5] Patent: CN104395312, 2016, B. Location in patent: Paragraph 0396; 0451-0455; 0501; 0502-0506