BenzeneMethanol, -[[[2-(4-nitrophenyl)ethyl]aMino]Methyl]-, (R)-

Uses

(R)-2-((4-nitrophenethyl)amino)-1-phenylethanol is an intermediate used to prepare (aminothiazolyl)acetanilide derivatives via coupling reactions for treatment of diabetes.

Synthesis

To a stirred solution of (R)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl]-2-phenylacetamide (100 g, prepared according to Example 1a) in tetrahydrofuran (400 mL) was added sodium borohydride (44.07 g) in batches at 28 °C (±2). After addition, the reaction system was cooled down to 2°C (±2). To this cooled solution a solution of tetrahydrofuran (600 mL) with iodine (169.03 g) was slowly added dropwise. The temperature was then raised to reflux and the reaction mixture was stirred continuously for 10 hours. Upon completion of the reaction, the mixture was cooled to 5°C (±2), methanol (50 mL) was added and stirring was continued for 30 minutes. The reaction solution was concentrated. Under keeping the temperature below 10°C, 35% aqueous hydrochloric acid solution (20.83 mL) was slowly added and stirred for 30 minutes. The reaction mixture was warmed to 28°C (±2), water was added and subsequently heated at 68°C (±2) for 1 hour. Tetrahydrofuran and methanol were removed by distillation under reduced pressure. The mixture was cooled to 30 °C (±2) and diluted with dichloromethane (800 mL) and aqueous ammonia solution (200 mL). An isopropanol solution of 17% hydrochloric acid (100 mL) was slowly added to the organic layer and stirred for 3 hours. The precipitated solid was filtered, washed with dichloromethane (100 mL) and dried in vacuum at 48 °C (±2) to give (R)-2-((4-nitrophenylethyl)amino)-1-phenylethanol hydrochloride. Yield: 94.8 g (90.5%); HPLC purity: 99.09%.

References

[1] Patent: WO2015/44965, 2015, A1. Location in patent: Page/Page column 32; 33
[2] Patent: CN105801438, 2016, A. Location in patent: Paragraph 0016; 0019-0020
[3] Patent: CN105481705, 2016, A. Location in patent: Paragraph 0017; 0018; 0020
[4] Patent: EP1440969, 2004, A1. Location in patent: Page 6
[5] Patent: EP1559427, 2005, A1. Location in patent: Page/Page column 6