Hydrochloric Acid → (R)-methyl 2-chloro-5-iodo-6-(tetrahydrofuran-3-yloxy)pyrimidine-4-carboxylate

Temperature

0 °C

To a solution of (R)-(−)-3-hydroxy-tetrahydrofuran (0.214 g, 2.42 mmol) in anhydrous THF (10 mL) at 0° C. was added NaH (60% in mineral oil, 103 mg, 2.58 mmol). The mixture was stirred at 0° C. for 30 min, then methyl 2,6-dichloro-5-iodopyrimidine-4-carboxylate (0.539 g, 1.62 mmol) was added to the mixture at −10° C. The reaction mixture was stirred at the same temperature for 30 min, and then allow warm to r.t. for 4 h. The reaction was then diluted with EtOAc and acidified with 2 N HCl. The aqueous layer was extracted with EtOAc. The organic layer was dried (Na2SO4) and concentrated in vacuo. The residue was dissolved in ether (8 mL) and MeOH (2 mL), and then trimethylsilyldiazomethane (2 M, 2 mL, 4 mmol) was added at 0° C. The reaction was stirred at r.t. for 1 h, and then quenched by 2 N HCl and concentrated in vacuo. The residue was purified by ISCO chromatography (24 g silica gel, 1-10% EtOAc in hexanes in 40 min) to give the title compound (0.140 g, 26%) as a colorless oil. 1H NMR (CDCl3, 500 MHz) δ 5.69-5.66 (m, 1H), 4.10 (dd, 1H), 4.05-3.92 (m, 6H), 2.38-2.30 (m, 1H), 2.24-2.18 (m, 1H).

1. stirringThe reaction mixture was stirred at the same temperature for 30 min
2. temperatureallow warm to r.t. for 4 h
3. extractionThe aqueous layer was extracted with EtOAc
4. dry with materialThe organic layer was dried (Na2SO4)
5. concentrationconcentrated in vacuo
6. dissolutionThe residue was dissolved in ether (8 mL)
7. stirringThe reaction was stirred at r.t. for 1 h
8. customquenched by 2 N HCl
9. concentrationconcentrated in vacuo
10. customThe residue was purified by ISCO chromatography (24 g silica gel, 1-10% EtOAc in hexanes in 40 min)

ORD record

ord-a2088aecb536486b8c66ebe3d4ab1a92

Source dataset

uspto-grants-2012_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08334292B1