Sodium bis(trimethylsilyl)amide → HCID 131734618, compound

Participants

Reaction Conditions

Reaction Steps

To a 1 L flask was added 2-bromo-5-(2,5-dimethyl-1H-pyrrol-1-yl)pyrazine (23 g, 67 mmol), (1R,3S,4S)-ethyl 4-((tert-butyldimethylsilyl)oxy)-3-fluorocyclohexanecarboxylate (28 g, 83 mmol), {[P(t-Bu)3]PdBr}2 (800 mg, 1 mmol) followed by toluene (250 mL). The reaction mixture was degassed three times by purging with nitrogen and then cooled to −35±5° C. To the reaction mixture was added NaHMDS (47 mL, 2 M in THF, 94 mmol), dropwise. The temperature was raised to room temeperature over a one hour period and stirred for a further 30 minutes. The reaction mixture was quenched with 8% aqueous ammonium chloride (200 mL), the phases separated, and the aqueous layer extracted with heptane (300 mL). The combined organic layer was washed with 10% brine (400 mL), concentrated under reduced pressure(45±5° C., 50˜100 mbar) to give 48 g of (1RS,3S,4S)-ethyl 4-((tert-butyldimethylsilyl)oxy)-1-(5-(2,5-dimethyl-1H-pyrrol-1-yl)pyrazin-2-yl)-3-fluorocyclohexanecarboxylate as a mixture of 1R and 1S diastereomers. This material was used for next step without further purification. HPLC retention time=8.274 min HPLC method d: Instrument: Agilent Technologies 1200 series. Column: Waters Xbridge C18, 150*3.0 mm, 3 um. Column temperature: 35° C. Flow rate: 0.70 mL/min. Detection: 210 nm/DAD. Mobile phase composition: A: 0.1% H3PO4 in water; B: acetonitrile. Gradient: 0 min: 90% A, 10% B; 5 min: 100% B; 11 min 100% B. LC-MS method: [M+H]+=476.2706, 1H NMR (400 MHz, DMSO-d6): 8.47 (s. 1H), 8.43 (s, 1H), 5.85 (s, 2H), 4.39˜4.52 (m, 1H), 4.14 (dd, J=12 Hz, J=8 Hz, 2H), 3.59˜3.66 (m, 1H), 2.28˜2.94 (m, 1H), 2.06 (s, 6H), 1.84˜1.97 (m, 3H), 1.46˜1.52 (m, 3H), 1.14˜1.17 (t, J=12 Hz, J=8 Hz, 2H), 0.81 (s, 9H), 0.01 (d, J=4 Hz, 6H).

Provenance & Evidence