Diisopropylamine → HCID 86658257, compound

Temperature

-65 °C

A solution of N,N-Diisopropylamine (13.98 mL, 98 mmol) in THF (55 mL) was cooled to −78° C. n-butyllithium (1.6M in hexanes, 61.3 mL, 98 mmol) was added portionwise via syringe, maintaining an internal temperature lower than −65° C. The reaction mixture warmed to −60° C. and aged for 45 min. and then cooled back to −78° C. A solution of N-[3-methyl-5-(1,3-thiazol-5-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (INTERMEDIATE 4, 2.113 g, 6.28 mmol) in THF (55 mL) was transferred via cannula (using positive pressure) to the freshly made LDA over the course of 30 min, maintaining the internal temperature below −70° C. The reaction mixture was aged at −78° C. for 35 min, warmed to −50° C. and aged for another 15 min., then cooled to −70° C. A solution of methyl 2,2-dimethyl-4-oxocyclohexanecarboxylate (9.04 g, 49.1 mmol) in THF (50 mL) was transferred via cannula (using positive pressure) to the flask containing the lithium salt, over the course of 45 min, maintaining the internal temperature below −65° C. The reaction was aged at −65° C. for 20 min. The cold bath was removed and the reaction allowed to warm to rt. The solution was cooled to 0° C. and quenched using ethanol (1 mL) and water (1 mL). The mixture was diluted with EtOAc (1 L) and washed with saturated ammonium chloride (3 times, total volume of wash 1.5 L). The organic layer was concentrated under reduced pressure and purified by column chromatography on silica (0-30% EtOAc:Hexanes) to afford the title compound (149 mg, 0.8%) as a yellow solid. MS ESI: [M+H]+ m/z 489. 1H NMR (600 MHz, CDCl3) δ 8.66 (d, J=4.8, 1H), 7.89 (d, J=7.0, 2H), 7.39 (s, 1H), 7.29-7.22 (m, 1H), 7.11-7.01 (m, 2H), 2.40 (m, 1H) 2.39 (s, 3H), 2.29 (m, 2H), 2.15 (m, 2H), 2.05-1.90 (m, 2H), 1.24 (s, 3H), 1.15 (s, 3H). rhSYK activity=++

1. additionwas added portionwise via syringe
2. temperatureThe reaction mixture warmed to −60° C. and aged for 45 min.
3. temperaturecooled back to −78° C
4. temperaturemaintaining the internal temperature below −70° C
5. temperaturewarmed to −50° C.
6. waitaged for another 15 min.
7. temperaturecooled to −70° C
8. temperatureover the course of 45 min, maintaining the internal temperature below −65° C
9. waitThe reaction was aged at −65° C. for 20 min
10. customThe cold bath was removed
11. temperatureto warm to rt
12. temperatureThe solution was cooled to 0° C.
13. customquenched
14. additionThe mixture was diluted with EtOAc (1 L)
15. washwashed with saturated ammonium chloride (3 times, total volume of wash 1.5 L)
16. concentrationThe organic layer was concentrated under reduced pressure
17. custompurified by column chromatography on silica (0-30% EtOAc:Hexanes)

ORD record

ord-b4ec6e609c5d416eba49fe2c9c06353e

Source dataset

uspto-grants-2014_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08759366B2