Ethanol → HCID 67054931, compound

Participants

Reaction Conditions

Reaction Steps

A solution of 4-{[4-{3-cyano-2-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propyl}-3-(hydroxymethyl)piperazin-1-yl]carbonyl}-3-fluorobenzonitrile (13 mg, 0.020 mmol; Peak 1 from Example 156, Step 5) in methylene chloride (0.87 mL, 14 mmol) was cooled to 0° C., then 2-methoxy-N-(2-methoxyethyl)-N-(trifluoro-λ(4)-sulfanyl)ethanamine (11 μL, 0.060 mmol, Aldrich) was added, followed by ethanol (0.24 μL, 0.0040 mmol). The mixture was stirred at 0° C. for 70 min, then at RT for 20 min, and quenched by the addition of 5% sodium bicarbonate. The mixture was then extracted with EtOAc. The extract was washed with water (2×), brine, dried over sodium sulfate, decanted and concentrated. The yellow solid obtained was then dissolved and stirred for 1 h in a 1:1 mixture of TFA:DCM (1.74 mL). Solvent was removed in vacuo and the residue was stirred in a solution of methanol (0.43 mL) containing aqueous ammonium hydroxide (0.13 mL). After reaction was complete as determined by LCMS, solvent was removed in vacuo. Purification via preparative HPLC-MS (C18, eluting with a gradient of H2O/MeCN containing 0.15% NH4OH) afforded two regioisomeric products, the second peak to elute was the desired piperazine product (2 mg, 19%). 1H NMR (500 MHz, CD3OD, rotamers): δ 8.66 (s, 0.45H), 8.65 (s, 0.55H), 8.62 (s, 0.45H), 8.60 (s, 0.55H), 8.37 (s, 0.45H), 8.37 (s, 0.55H), 7.68-7.58 (m, 2H), 7.55-7.48 (m, 2H), 6.94 (d, 0.45H), 6.93 (d, 0.55H), 4.90-4.43 (m, 3H), 3.81-3.60 (m, 2H), 3.33-3.05 (m, 6H), 2.90-2.50 (m, 3H); 19F NMR (400 MHz, CD3OD): −230.21 (t, 1F), −115.45 (br s, 1F); LCMS (M+H)+: 516.3.

Provenance & Evidence