Sodium borohydride → N-(2-ethyl-7-(2-methyl-4-nitro-pyrazol-3-yl)oxepan-4-yl)-2-methyl-propane-2-sulfinamide

To a solution of 2-ethyl-7-(2-methyl-4-nitro-pyrazol-3-yl)oxepan-4-one (120 mg, 0.45 mmol) in THF (3 mL) was added (R)-2-methylpropane-2-sulfinamide (70 mg, 0.58 mmol) followed by titanium(IV) ethoxide (0.30 mL, 1.12 mmol). The reaction mixture was heated at reflux for 4 hr then allowed to cool to room temperature. The crude solution was added dropwise to a solution of sodium borohydride (69 mg, 1.80 mmol) in THF (3 mL) at −60° C. The reaction mixture was warmed to 0° C., quenched with MeOH (3 mL) and brine (50 mL), and stirred at room temperature for 18 hr. The mixture was filtered through Celite® washing with EtOAc (200 mL). The aqueous layer was extracted with EtOAc (3×50 mL) and the combined organic layers were washed with brine (150 mL), separated, dried over MgSO4 and concentrated under reduced pressure. Purification via silica gel column chromatography (0-10% MeOH/DCM) gave N-(2-ethyl-7-(2-methyl-4-nitro-pyrazol-3-yl)oxepan-4-yl)-2-methyl-propane-2-sulfinamide as a mixture of diastereomers (ratio 5:2) as a colourless solid (118 mg, 71% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.03 and 8.02 (2s, 1H), 5.60-5.51 (m, 1H), 4.08 and 4.06 (2s, 3H), 3.83-3.66 (m, 2H), 3.62-3.50 (m, 1H), 3.22 and 3.15 (d, J=6.2 and 4.0 Hz, 1H), 2.11-1.96 (m, 4H), 1.76 (s, 1H), 1.63-1.54 (m, 2H), 1.28-1.15 (m, 9H), 0.91 (td, J=7.4, 2.4 Hz, 3H).

1. temperatureThe reaction mixture was heated
2. temperatureat reflux for 4 hr
3. temperatureThe reaction mixture was warmed to 0° C.
4. customquenched with MeOH (3 mL) and brine (50 mL)
5. filtrationThe mixture was filtered through Celite®
6. washwashing with EtOAc (200 mL)
7. extractionThe aqueous layer was extracted with EtOAc (3×50 mL)
8. washthe combined organic layers were washed with brine (150 mL)
9. customseparated
10. dry with materialdried over MgSO4
11. concentrationconcentrated under reduced pressure
12. customPurification via silica gel column chromatography (0-10% MeOH/DCM)

ORD record

ord-f954f041c51a410cac00ea1a3515fc4a

Source dataset

uspto-grants-2016_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09328106B2