Sodium Carbonate → 6-(2-Carbamoyl-4-methylpiperazin-1-yl)-2-(4-(4-(trifluoromethyl)phenoxy) phenyl)pyrimidine-4-carboxamide

온도

100 °C

To a mixture of 6-(2-carbamoyl-4-methylpiperazin-1-yl)-2-chloropyrimidine-4-carboxamide (0.300 g, 1.00 mmol) in dioxane (5 mL) was added 4,4,5,5-tetramethyl-2-(4-(4-(trifluoromethyl)phenoxy)phenyl)-1,3,2-dioxaborolane (0.404 g, 1.11 mmol), 2M aqueous Na2CO3 (1.0 mL, 2.0 mmol) and PdCl2(dppf) (0.046 g, 0.056 mmol). The reaction vessel was flushed with argon, sealed and heated at 100° C. overnight. After cooling, the reaction mixture was evaporated in vacuo and the residue chromatographed over silica gel with 0-20% MeOH in acetone. The product fractions were evaporated in vacuo and the residue triturated with 1:1 acetonitrile/MeOH (5 mL). The solid was filtered, washed with MeOH (1×1 mL), and acetonitrile (1×1 mL). An additional batch of material was obtained by evaporation of the filtrates, trituration of the residue with 1:1 acetonitrile/MeOH (2 mL) and washing the solid with MeOH (1×0.5 mL) then acetonitrile (1×0.5 mL). The combined solids were dried under vacuum at 40° C. to give 6-(2-carbamoyl-4-methylpiperazin-1-yl)-2-(4-(4-(trifluoromethyl)phenoxy)phenyl)pyrimidine-4-carboxamide as a very pale tan powder (0.271 g, 0.541 mmol, 54% yield). 1H NMR (400 MHz, CD3OD): 8.57 (2H, d, J=9.0 Hz), 7.71 (2H, d, J=8.6 Hz), 7.39 (1H, s), 7.21 (2H, d, J=8.6 Hz), 7.16 (2H, d, J=9.0 Hz), 5.68-5.23 (1H, br), 4.49-3.93 (1H, br), 3.65-3.54 (1H, m), 3.51-3.43 (1H, m), 3.00-2.93 (1H, m), 2.40 (1H, dd, J=12.1 Hz, 4.6 Hz), 2.34 (3H, s), 2.21 (1H, dt, J=11.8 Hz, 3.5 Hz). LC/MS: m/z=501.1 [M+H]+.

1. customThe reaction vessel was flushed with argon
2. customsealed
3. temperatureAfter cooling
4. customthe reaction mixture was evaporated in vacuo
5. customthe residue chromatographed over silica gel with 0-20% MeOH in acetone
6. customThe product fractions were evaporated in vacuo
7. customthe residue triturated with 1:1 acetonitrile/MeOH (5 mL)
8. filtrationThe solid was filtered
9. washwashed with MeOH (1×1 mL), and acetonitrile (1×1 mL)
10. customAn additional batch of material was obtained by evaporation of the filtrates, trituration of the residue with 1:1 acetonitrile/MeOH (2 mL)
11. washwashing the solid with MeOH (1×0.5 mL)
12. customThe combined solids were dried under vacuum at 40° C.

ORD 기록

ord-b3ea7a96b89e4f25a09083f2ef5c2247

출처 데이터셋

uspto-grants-2015_10

DOI

10.6084/m9.figshare.5104873.v1

특허 번호

US09163008B2