1,1'-Carbonyldiimidazole → HCID 178517362, Verbindung

(R)-tert-Butyl 3-cyclohexyl-1-(3,5-dibromopyrazin-2-ylamino)-1-oxopropan-2-ylcarbamate. (R)-2-(tert-Butoxycarbonylamino)-3-cyclohexylpropanoic acid (1.00 g, 3.69 mmol), 1,1′-carbonyldiimidazole (896 mg, 5.53 mmol), dichloromethane (3 mL), and DMF (1 mL) were combined in a scintillation vial and stirred 3.75 h at room temperature under nitrogen. 3,5-Dibromopyrazin-2-amine (1.86 g, 7.37 mmol) was added and the resulting mixture sealed and heated 21 h at 40° C., then 22.5 h at 50° C. Diisopropylethylamine (1.3 mL, 7.37 mmol) was added and the resulting mixture sealed and heated at 45° C. with stirring overnight. The dichloromethane was removed on a rotary evaporator. The resulting mixture was diluted with ethyl acetate and water and shaken in a separatory funnel. The resulting suspension was filtered through Celite and the filter cake washed thoroughly with ethyl acetate. Brine was added to the filtrate and the resulting two layers separated in a separatory funnel. The organics were washed with water, then brine, and concentrated on a rotary evaporator. The residue was dissolved in methanol, filtered, and purified using reverse-phase preparatory HPLC (20-100% acetonitrile+0.1% TFA in H2O+0.1% TFA, over 30 min). Vials containing product were combined and neutralized with saturated aqueous sodium bicarbonate. Acetonitrile was removed on a rotary evaporator and the resulting aqueous mixture extracted with ethyl acetate. The organics were washed with brine, dried over magnesium sulfate, filtered, concentrated on a rotary evaporator, and dried under vacuum to give the desired product (616 mg, 33%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.54 (s, 1H), 8.77 (s, 1H), 7.14 (d, J=8.20, 1H), 4.26 (q, J=7.81, 1H), 1.77 (d, J=12.49, 1H), 1.58-1.72 (m, 5H), 1.51-1.57 (m, 2H), 1.38 (s, 9H), 1.07-1.25 (m, 3H), 0.80-0.98 (m, 2H); MS (ESI) m/z 507 [M+1]+.

1. customthe resulting mixture sealed
2. temperatureheated 21 h at 40° C.
3. custom22.5 h
4. customat 50° C
5. customthe resulting mixture sealed
6. temperatureheated at 45° C.
7. stirringwith stirring overnight
8. customThe dichloromethane was removed on a rotary evaporator
9. additionThe resulting mixture was diluted with ethyl acetate and water
10. stirringshaken in a separatory funnel
11. filtrationThe resulting suspension was filtered through Celite
12. washthe filter cake washed thoroughly with ethyl acetate
13. additionBrine was added to the filtrate
14. customthe resulting two layers separated in a separatory funnel
15. washThe organics were washed with water
16. concentrationbrine, and concentrated on a rotary evaporator
17. dissolutionThe residue was dissolved in methanol
18. filtrationfiltered
19. custompurified
20. customreverse-phase preparatory HPLC (20-100% acetonitrile+0.1% TFA in H2O+0.1% TFA, over 30 min)
21. additionVials containing product
22. customAcetonitrile was removed on a rotary evaporator
23. extractionthe resulting aqueous mixture extracted with ethyl acetate
24. washThe organics were washed with brine
25. dry with materialdried over magnesium sulfate
26. filtrationfiltered
27. concentrationconcentrated on a rotary evaporator
28. customdried under vacuum

ORD-Eintrag

ord-36fc2024d94c40db9a1749917882e45c

Quelldatensatz

uspto-grants-2011_07

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US07981893B2