4-[2-(Dimethylamino)ethoxy]benzylamine

Uses

4-[2-(Dimethylamino)ethoxy]benzylamine is an impurity of Itopride (HCl: I931500), a gastroprokinetic benzamide derivative that is used to treat patients with dyspepsia.

Definition

ChEBI: 4-[2-(Dimethylamino)ethoxy]benzylamine is an aromatic amine.

Synthesis

General procedure for the synthesis of 4-[2-(dimethylamino)ethoxy]benzylamine from 4-(2-(dimethylamino)ethoxy)benzenecarboxaldehyde: 27 kg of 80% acetic acid was added to the reactor, followed by 5.3 kg of hydroxylamine hydrochloride. The mixture was cooled to 0-5 °C. A solution of acetic acid containing 13.5 kg of 100% 4-(2-dimethylaminoethoxy)benzaldehyde was added to the above cooled mixture. The reaction mixture was kept at 0-5°C for at least 2 hours. Upon completion of the reaction, 10.8 kg of powdered zinc was added in batches and the temperature was controlled not to exceed 50°C. The mixture was stirred at 45-50°C for at least 5 hours and then heated to 65-70°C and kept for at least 2 hours. Upon completion of the reaction, the reaction mixture was distilled to give a thick but stirrable residue. To the residue was added 20.3 kg of deionized water and the mixture was cooled to 20-30 °C. 54 kg of 30% ammonia was added slowly and dropwise to ensure that the pH of the reaction mixture was above 9.5. After stirring for at least 10 minutes at 20-30 °C, the reaction mixture was extracted with 40.5 kg of dichloromethane at 20-25 °C. The reaction mixture was then extracted with aqueous phase of 30% ammonia. The organic phase was separated and the aqueous phase was then subjected to a second extraction with 27 kg of dichloromethane, stirring for at least 5 minutes before combining the organic phases. The solvent was removed by distillation to give an oily residue. To the residue was added 54 kg of sec-butanol and 20.3 kg of N,N-dimethylformamide to give a solution containing 11.5 kg of 4-(2-dimethylaminoethoxy)benzylamine in 84.7% yield.

References

[1] Patent: WO2006/51079, 2006, A1. Location in patent: Page/Page column 5-6
[2] Patent: US2879293, 1957,
[3] Organic Process Research and Development, 2013, vol. 17, # 7, p. 981 - 984
[4] Patent: KR101819771, 2018, B1. Location in patent: Paragraph 0023; 0045-0052