反応 #679552

反応方程式

HCl

HOBt

LiOH.H2O

EDCl

tert-butyl 3-(4-((4-(2-(1-(methoxycarbonyl)cyclopropyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)azetidine-1-carboxylate

tert-Butyl 3-(4-((4-(2-(1-(methoxycarbonyl)cyclopropyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)azetidine-1-carboxylate

LiOH.H2O

ammonium carbonate

HCl

DIPEA

→

title compound A9

収率 53.0%

tert-Butyl 3-(4-((4-(2-(1-carbamoylcyclopropyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)azetidine-1-carboxylate

収率 53.0%

溶媒

EtOAc

THF

MeOH

H2O

反応条件

後処理

1. 1
   その他the layers were separated
2. 2
   抽出the aqueous phase was extracted with EtOAc (2×50 mL)
3. 3
   洗浄washed with brine
4. 4
   乾燥dried (MgSO4)
5. 5
   その他then evaporated to dryness
6. 6
   workup.DISSOLUTIONThe residue was dissolved in THF (12 mL)
7. 7
   workup.WAIT40° C. for a further 24 hours
8. 8
   その他The volatiles were removed in vacuo and EtOAc (20 mL) and saturated NaHCO3 (20 mL)
9. 9
   workup.ADDITIONwere added
10. 10
    その他The layers were separated
11. 11
    抽出the aqueous phase extracted with EtOAc (2×20 mL)
12. 12
    洗浄washed with brine
13. 13
    乾燥dried (MgSO4)
14. 14
    その他then evaporated to dryness
15. 15
    その他The residue was purified by silica gel column chromatography (Biotage Isolera, 24 g SiO2 cartridge, 10-50% EtOAc in petroleum benzine 40-60° C.)

実験手順

A solution of tert-butyl 3-(4-((4-(2-(1-(methoxycarbonyl)cyclopropyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)azetidine-1-carboxylate (A8) (347 mg, 0.582 mmol) and LiOH.H2O (293 mg, 6.98 mmol) in THF (7.0 mL), MeOH (7.0 mL) and H2O (2.0 mL) was stirred at room temperature for 3 days. LiOH.H2O (147 mg, 3.49 mmol) was added and the resulting mixture was heated at 35° C. for 16 hours. EtOAc (50 mL) and aqueous HCl (2 M, 50 mL) were added cautiously, then the layers were separated and the aqueous phase was extracted with EtOAc (2×50 mL). The organic layers were combined, washed with brine, dried (MgSO4) then evaporated to dryness. The residue was dissolved in THF (12 mL) and DMF (2.0 mL), to which HOBt (157 mg, 1.16 mmol), EDCl.HCl (223 mg, 1.16 mmol) and DIPEA (0.507 mL, 2.91 mmol) were added under an atmosphere of nitrogen. After 10 minutes ammonium carbonate (280 mg, 2.91 mmol) was added in one portion and the resulting mixture was stirred at room temperature for 16 hours, then 40° C. for a further 24 hours. The volatiles were removed in vacuo and EtOAc (20 mL) and saturated NaHCO3 (20 mL) were added. The layers were separated then the aqueous phase extracted with EtOAc (2×20 mL). The organic extracts were combined, washed with brine, dried (MgSO4) then evaporated to dryness. The residue was purified by silica gel column chromatography (Biotage Isolera, 24 g SiO2 cartridge, 10-50% EtOAc in petroleum benzine 40-60° C.) to give the title compound A9 as a white solid (179 mg, 53%); 1H NMR (400 MHz, d6-DMSO) δ 10.22 (s, 1H), 8.69 (s, 1H), 7.73 (d, J=8.6 Hz, 2H), 7.37-7.27 (m, 5H), 7.26-7.19 (m, 1H), 6.98 (s, 1H), 5.99 (s, 1H), 4.23 (t, J=7.7 Hz, 2H), 3.88-3.70 (m, 3H), 3.21-3.14 (m, 2H), 3.14-3.07 (m, 2H), 1.44 (d, J=3.5 Hz, 2H), 1.40 (s, 9H), 0.97 (s, 2H). LCMS-A: rt 6.168 min; m/z 582 [M+H]+.

出典