Hydrazine hydrate (1:1) → HCID 66991310, compound

Participants

Reaction Conditions

Reaction Steps

To a suspension of racemic (3S,5R)-1-[6-(4-cyano-3-fluorophenyl)-2-(methylamino)-4-pyrimidinyl]-5-methyl-N-(phenylmethyl)-3-pyrrolidinecarboxamide (360 mg total, 0.81 mmol) in EtOH (50 mL) at room temperature was added hydrazine monohydrate (2 mL) in one portion. The suspension was heated in an oil bath to 100° C. for 20 hours. LCMS showed there was still 40% starting material remaining. To the mixture was added 2 mL of hydrazine monohydrate, followed by heating to 100° C. for another 24 h. LCMS showed conversion complete. The mixture was cooled to room temperature, and filtered through celite. The filtrate was concentrated in vacuo, and the resulting residue was taken up in 8 mL of water to form a suspension, which was briefly sonicated. The mixture was filtered. The solids collected were combined with another run starting with 190 mg of racemic (3S,5R)-1-[6-(4-cyano-3-fluorophenyl)-2-(methylamino)-4-pyrimidinyl]-5-methyl-N-(phenylmethyl)-3-pyrrolidinecarboxamide. The combined crude products were purified by silica gel column chromatography using gradient elution of 1% A in CHCl3 to 75% A in CHCl3. A was a mixture of 800/80/3200 CH3OH/NH4OH/CHCl3. Trituration of the purified material in a mixture of CHCl3 (2 mL) and hexane (8 mL), followed by drying under vacuum at 65° C. for 14 hours afforded the title compound (228 mg) as a beige powder. LC-MS (ES) m/z=457 [M+H]+. 1H NMR (400 MHz, CD3OD): δ 1.42 (d, J=6.1 Hz, 3H), 2.00-2.06 (m, 1H), 2.52-2.58 (m, 1H), 2.99 (s, 3H), 3.00-3.10 (m, 1H), 3.68-3.73 (m, 1H), 3.95-4.10 (bs, 1H), 4.21-4.33 (bs, 1H), 4.39-4.47 (m, 2H), 6.23 (s, 1H), 7.25-7.37 (m, 5H), 7.52 (dd, J=8.5, 1.1 Hz, 1H), 7.75 (d, J=8.6 Hz, 1H), 7.85 (s, 1H).

Provenance & Evidence