Sodium hydride → HCID 10857231, compound

A solution of (2S)-2-[(tert-butoxy)carbonylamino]-N-methoxy-N-methylpropanamide (13.05 g, 56.18 mmol) in ethyl ether (560 mL) was chilled with an ice water bath and then 95% lithium aluminum hydride (2.80 g, 70.23 mmol) was added. The reaction was stirred at room temperature for 20 minutes and then a solution of aqueous potassium hydrogen sulfate (300 mL, 0.33M) was added. The resulting mixture was extracted three times with ethyl ether. The combined organic layers were washed three times with 1N hydrogen chloride, three times with saturated aqueous sodium hydrogen carbonate, and once with brine. The solution was then dried over anhydrous sodium sulfate, filtered, and the solvent evaporated. The resulting solid was dissolved in anhydrous tetrahydrofuran (430 mL) then added to a cold solution of trimethyl phosphonoacetate (27.3 mL, 168.5 mmol) and sodium hydride (112 mmol) in anhydrous tetrahydrofuran (130 mL) that had been previously stirred at room temperature for 30 minutes. The reaction was stirred for 5 minutes in a ice water bath, at room temperature for 20 minutes, and then water (500 mL) was added. The reaction mixture was diluted with brine and ethyl acetate, stirred, and the layers separated. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent evaporated. The resulting residue was purified by chromatography on a normal phase silica gel column with 0-30% ethyl acetate in hexanes. Fractions containing clean product were combined and the solvent evaporated to give the title compound (8.85 g, 69%): ES-MS (m/z) 230.4 [M+1]+.

1. extractionThe resulting mixture was extracted three times with ethyl ether
2. washThe combined organic layers were washed three times with 1N hydrogen chloride, three times with saturated aqueous sodium hydrogen carbonate
3. dry with materialThe solution was then dried over anhydrous sodium sulfate
4. filtrationfiltered
5. customthe solvent evaporated
6. dissolutionThe resulting solid was dissolved in anhydrous tetrahydrofuran (430 mL)
7. stirringhad been previously stirred at room temperature for 30 minutes
8. stirringThe reaction was stirred for 5 minutes in a ice water bath, at room temperature for 20 minutes
9. stirringstirred
10. customthe layers separated
11. dry with materialThe organic layer was dried over anhydrous sodium sulfate
12. filtrationfiltered
13. customthe solvent evaporated
14. customThe resulting residue was purified by chromatography on a normal phase silica gel column with 0-30% ethyl acetate in hexanes
15. additionFractions containing clean product
16. customthe solvent evaporated

ORD record

ord-93f84dfef53e4d968ff39d3c8711d839

Source dataset

uspto-grants-2013_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08440661B2