Sodium Carbonate → (S)-methyl 2-(4-(4-fluorophenoxy)phenyl)-6-((1-methoxy-1-oxopropan-2-yl)amino)pyrimidine-4-carboxylate

Temperatur

100 °C

To a mixture of the (S)-methyl 2-chloro-6-((1-methoxy-1-oxopropan-2-yl)amino)pyrimidine-4-carboxylate (4.826 g, 17.63 mmol) in dioxane (100 mL) was added 2-(4-(4-fluorophenoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (6.651 g, 21.17 mmol), 2M aqueous Na2CO3 (17.6 mL, 35.2 mmol) and PdCl2(dppf) (0.727 g, 0.89 mmol). The flask was flushed with argon, sealed, and heated on a 100° C. oil bath for 30 minutes. The flask ruptured. As much of the reaction mixture as possible was partitioned between methanol and hexanes. The hexanes were removed and the methanol layer was washed a second time. The methanol fraction was evaporated in vacuo and chromatographed over silica gel with 20-60% EtOAc in hexanes. The product fractions were isolated and evaporated in vacuo and chromatographed a second time over silica gel with 10-50% EtOAc in hexanes. The product fractions were evaporated in vacuo and the resulting solid triturated with 2 mL MeOH, filtered, rinsed once with 1 mL MeOH, and dried under vacuum at 40° C. to give (S)-methyl 2-(4-(4-fluorophenoxy)phenyl)-6-((1-methoxy-1-oxopropan-2-yl)amino)pyrimidine-4-carboxylate as a yellow powder (0.140 g, 0.329 mmol, 2% yield). 1H NMR (400 MHz, DMSO-d6): 8.34-8.25 (3H, m), 7.31-7.24 (2H, m), 7.19-7.14 (2H, m), 7.10 (1H, s), 7.06 (2H, d, J=8.8 Hz), 4.60-4.52 (1H, m), 3.89 (3H, s), 3.64 (3H, s), 1.45 (3H, d, J=7.2 Hz). LC/MS: m/z=426.1 [M+H]+.

1. customThe flask was flushed with argon
2. customsealed
3. customAs much of the reaction mixture as possible was partitioned between methanol and hexanes
4. customThe hexanes were removed
5. washthe methanol layer was washed a second time
6. customThe methanol fraction was evaporated in vacuo
7. customchromatographed over silica gel with 20-60% EtOAc in hexanes
8. customThe product fractions were isolated
9. customevaporated in vacuo
10. customchromatographed a second time over silica gel with 10-50% EtOAc in hexanes
11. customThe product fractions were evaporated in vacuo
12. customthe resulting solid triturated with 2 mL MeOH
13. filtrationfiltered
14. washrinsed once with 1 mL MeOH
15. customdried under vacuum at 40° C.

ORD-Eintrag

ord-c4313b55411748fba55fd91b73d92a91

Quelldatensatz

uspto-grants-2015_10

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US09163008B2