反应详情

温度

140 °C

A mixture of 4-(2-amino-2-methylpropyl)phenol acetic acid salt (45.06 g, 200 mmol), powdered K2CO3 (69.1 g, 500 mmol), 6-chloronicotinamide (31.32 g, 200 mmol), DMAC (622 mL) and iso-octane (70 mL) was slowly heated to reflux at 140° C. A water trap filled with iso-octane was used to collect water formed in the reaction, and reflux was maintained for 5.5 h. The mixture was allowed to cool to room temperature, and the solids were filtered and washed with EtOAc. The filtrate was concentrated in vacuo to 88.6 g of solid which was dissolved in EtOAc (500 mL). To this solution was added water (800 mL), 1N HCl (200 mL) and MeOH (50 mL). The pH of this mixture was adjusted to 7.2 with con. HCl, and the aqueous layer was separated and washed with methyl t-butyl ether (500 mL). The product was crystallized by addition of 10N NaOH (20 mL) which raised the pH to 11. This pH was maintained by addition of 10N NaOH as needed during the course of the crystallization (90 min). The product was filtered, washed with water and dried in vacuo at 45° C. to 53.11 g (93%) of white solid which was >98% pure by HPLC analysis: 1H NMR (300 MHz, DMSO-d6) NMR was consistent with the desired product.

1. temperaturewas slowly heated
2. customto collect water
3. customformed in the reaction
4. temperaturereflux
5. temperaturewas maintained for 5.5 h
6. temperatureto cool to room temperature
7. filtrationthe solids were filtered
8. washwashed with EtOAc
9. concentrationThe filtrate was concentrated in vacuo to 88.6 g of solid which
10. dissolutionwas dissolved in EtOAc (500 mL)
11. additionTo this solution was added water (800 mL), 1N HCl (200 mL) and MeOH (50 mL)
12. customHCl, and the aqueous layer was separated
13. washwashed with methyl t-butyl ether (500 mL)
14. customThe product was crystallized by addition of 10N NaOH (20 mL) which
15. temperatureraised the pH to 11
16. temperatureThis pH was maintained by addition of 10N NaOH
17. customas needed during the course of the crystallization (90 min)
18. filtrationThe product was filtered
19. washwashed with water
20. dry with materialdried in vacuo at 45° C. to 53.11 g (93%) of white solid which