Application
2-Amino-4-methoxy-5-(3-morpholinopropoxy)benzonitrile can be used as an intermediate for gefitinib in the pharmaceutical research and development process.
Synthesis
General procedure for the synthesis of 2-amino-4-methoxy-5-(3-morpholinopropoxy)-2-nitrobenzonitrile from 4-methoxy-5-(3-morpholinopropoxy)-2-nitrobenzonitrile: Sodium dithionite (89%, 81.4 kg) was added to a stirred slurry of 4-methoxy-5-(3-morpholinopropoxy)-2-nitrobenzonitrile (48.8 kg) in water (867 L) , and the resulting mixture was heated to 50 °C. The reaction was completed after about 2 hours. The temperature of the reaction mixture was raised to about 70 °C and a concentrated aqueous hydrochloric acid solution (36%, 270 kg) was slowly added over a period of 3 hours. The resulting mixture was cooled to 20-25 °C while stirring was continued and sodium hydroxide solution (47%, 303.7 kg) was added. The reaction mixture was extracted with dichloromethane (twice, 1082 kg and 541 kg), the organic extracts were combined and washed with deionized water (510 L). Evaporation of the organic phase gave 2-amino-4-methoxy-5-(3-morpholinopropoxy)benzonitrile (46.3 kg, 99% yield); melting point 87.5 °C; NMR hydrogen spectrum (DMSO-d6) δ: 1.79 (m, 2H), 2.36 (t, 4H), 2.36 (t, 2H), 3.56 (t, 4H), 3.73 (s, 3H), and 3.86 (t, 2H), 5.66 (br s, 2H), 6.4 (s, 1H), 6.89 (s, 1H); MS: M+H+ 292.
References
[1] Patent: WO2005/23783, 2005, A1. Location in patent: Page/Page column 18
[2] Patent: WO2004/24703, 2004, A1. Location in patent: Page 10
[3] Organic Process Research and Development, 2007, vol. 11, # 5, p. 813 - 816
[4] Patent: CN105503749, 2016, A. Location in patent: Paragraph 0053; 0054; 0055
[5] Patent: CN107586279, 2018, A. Location in patent: Paragraph 0008; 0018
