Methyl chloroformate → HCID 90093357, compound

Temperature

120 °C

A solution of ethyl 2-(3-bromo-4-iodo-1-methyl-1H-pyrazol-5-yl)-2-oxoacetate (11f) (750 mg, 1.94 mmol), potassium carbonate (536 mg, 3.88 mmol), and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman (494 mg, 1.90 mmol) in a mixture of dioxane (16 mL) and water (4 mL) was degassed for 5 minutes. Palladium tetrakis(triphenylphosphine) (157 mg, 0.14 mmol) was added and the reaction mixture was heated at 120° C. overnight. After concentrating in vacuo, the residue was dissolved in 1N sodium hydroxide (15 mL). The aqueous layer was washed with diethyl ether (20 mL), acidified with 1M hydrochloric acid until pH 3 and extracted with diethyl ether (2×15 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude was dissolved in dichloromethane (7 mL), cooled to 0° C., and under a nitrogen atmosphere, triethylamine (0.41 mL, 2.91 mmol) and methyl chloroformate (0.22 mL, 2.91 mmol) were added. The reaction mixture was stirred at 0° C. for 30 minutes, and allowed to reach room temperature. Dichloromethane (10 mL) was added, and the mixture was successively washed with 1N hydrochloric acid (10 mL), a saturated solution of sodium hydrogenocarbonate (10 mL), and brine (10 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 90/10) to provide methyl 2-[3-bromo-4-(3,4-dihydro-2H-1-benzopyran-6-yl)-1-methyl-1H-pyrazol-5-yl]-2-oxoacetate (11g) (531 mg, 1.40 mmol, 72%) as a yellow solid.

1. customwas degassed for 5 minutes
2. concentrationAfter concentrating in vacuo
3. dissolutionthe residue was dissolved in 1N sodium hydroxide (15 mL)
4. washThe aqueous layer was washed with diethyl ether (20 mL)
5. extractionextracted with diethyl ether (2×15 mL)
6. dry with materialThe organic layer was dried over sodium sulfate
7. concentrationconcentrated in vacuo
8. dissolutionThe crude was dissolved in dichloromethane (7 mL)
9. temperaturecooled to 0° C.
10. customto reach room temperature
11. washthe mixture was successively washed with 1N hydrochloric acid (10 mL)
12. dry with materialThe organic layer was dried over sodium sulfate
13. concentrationconcentrated in vacuo
14. customThe residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 90/10)

ORD record

ord-a077a96601c94d5cbb3f1de81005c389

Source dataset

uspto-grants-2016_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09260395B2