p-Toluenesulfonic acid → HCID 11488553、化合物

温度

-78 °C

To a solution of 80 mg (0.28 mmol) of 3-(4-chlorophenyl)-2(S)(3-cyanophenyl)-1(S)-methyl-propylamine in 1.5 mL of toluene, 60 mg of 1-phenyl-2(1H-pyrazol-1-yl)ethanone and 5 mg of TsOH were added. Powdered 4A molecular sieves (˜300 mg) were added to the reaction, which was heated to reflux for 5 hr. The mixture was cooled, filtered, and the solid was washed with EtOAc. The filtrate was concentrated and the residue was diluted with 1.5 mL of THF. The solution was cooled in −78° C. bath and 1.4 mL of 1 M LiN(TMS)2 was added. After 5 min 0.1 mL of MeI was added and the reaction was stirred overnight while it warmed to room temperature. The solution was quenched with saturated NH4Cl and extracted with EtOAc. The organic layer was washed with brine, dried and concentrated. The residue was predominantly monomethyl imine. It was dissolved in 1.5 mL of THF cooled in −78° C. bath and treated with 1.5 mL of LiN(TMS)2 and 0.12 mL of MeI. After 10 min, the cold bath was removed, and the mixture was stirred for 5 hr. The reaction was quenched with saturated NH4Cl and extracted with EtOAc. The organic layer was washed with brine, dried, and concentrated. The residue was dissolved in 1.5 mL of THF, 0.1 mL of HOAc, and 32 mg (0.5 mmol) of NaCNBH3 was added. After stirring overnight, the solution was quenched with saturated NaHCO3 and extracted with ETOAc. The organic layer was washed with brine, dried and concentrated. The residue was purified on a prep TLC plate using 50% EtOAc-hexane to isolate the title compound as a mixture of diastereomers. LC-MS: m/e=483 (M+1), 485 (M+3) (3.36 min). Additional two bands containing diastereomers of 3-(1(S)-(4-chlorobenzyl)-2(S)-((1-phenyl-2-(1H-pyrazol-1-yl)propyl)amino)propyl)benzonitrile were also isolated. LC-MS: m/e=469 (M+1), 471 (M+3) (3.24 min) and LC-MS: m/e=469 (M+1), 471 (M+3) (3.94 min).

1. additionwere added to the reaction, which
2. temperaturewas heated
3. temperatureto reflux for 5 hr
4. temperatureThe mixture was cooled
5. filtrationfiltered
6. washthe solid was washed with EtOAc
7. concentrationThe filtrate was concentrated
8. additionthe residue was diluted with 1.5 mL of THF
9. addition1.4 mL of 1 M LiN(TMS)2 was added
10. additionAfter 5 min 0.1 mL of MeI was added
11. temperaturewarmed to room temperature
12. customThe solution was quenched with saturated NH4Cl
13. extractionextracted with EtOAc
14. washThe organic layer was washed with brine
15. customdried
16. concentrationconcentrated
17. dissolutionIt was dissolved in 1.5 mL of THF
18. temperaturecooled in −78° C. bath
19. additiontreated with 1.5 mL of LiN(TMS)2 and 0.12 mL of MeI
20. waitAfter 10 min
21. customthe cold bath was removed
22. stirringthe mixture was stirred for 5 hr
23. customThe reaction was quenched with saturated NH4Cl
24. extractionextracted with EtOAc
25. washThe organic layer was washed with brine
26. customdried
27. concentrationconcentrated
28. dissolutionThe residue was dissolved in 1.5 mL of THF
29. stirringAfter stirring overnight
30. customthe solution was quenched with saturated NaHCO3
31. extractionextracted with ETOAc
32. washThe organic layer was washed with brine
33. customdried
34. concentrationconcentrated
35. customThe residue was purified on a prep TLC plate

ORDレコード

ord-d6240fcb9cca45d99dbdb867fd0942af

出典データセット

uspto-grants-2008_06

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US07390835B2