Hydrazine → rac-5-[(1R,2R)-2-fluorocyclopropyl]-1H-pyrazol-3-amine

To a solution of MeCN (7.28 mL, 139 mmol) in anhydrous THF (130 mL) at −78° C. under N2 was added n-butyllithium (2.4 mol/L) in hexanes (58 mL, 139 mmol) dropwise. The mixture was stirred at −78° C. for 30 min then cis-ethyl-2-fluorocyclo-propanecarboxylate (1.5 g; 87.0 mmol) was added dropwise with stirring while maintaining the temperature at −78° C. The resulting solution was stirred at 25° C. for 2 h, quenched by the addition of 50% satd. aq. NH4Cl solution and extracted with EtOAc (3×50 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated under vacuum to afford 7.7 g of crude cis-3-(2-fluorocyclopropyl)-3-oxopropanenitrile as a red oil. Crude cis-3-(2-fluoro-cyclopropyl)-3-oxopropanenitrile was dissolved in EtOH (130 mL) and hydrazine (8.45 mL, 261 mmol) was added. The reaction mixture was heated at reflux for 16 h then concentrated in vacuo. The resultant orange solid was triturated with DCM (ca. 50 mL). The precipitate was filtered, rinsed with DCM, and dried in vacuo to obtain 7.48 g (60.9%) of cis-5-(2-fluorocyclopropyl)-1H-pyrazol-3-amine as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ 11.18 (br s, 1H), 5.16 (s, 1H), 4.81 (ddd, J=66.3, 9.5, 5.2 Hz, 1H), 4.46 (br s, 2H), 1.99-1.81 (m, 1H), 1.23-1.02 (m, 2H).

1. temperatureThe reaction mixture was heated
2. temperatureat reflux for 16 h
3. concentrationthen concentrated in vacuo
4. customThe resultant orange solid was triturated with DCM (ca. 50 mL)
5. filtrationThe precipitate was filtered
6. washrinsed with DCM
7. customdried in vacuo

ORDレコード

ord-4514a42fa4324a82a5d5a661e1d63f43

出典データセット

uspto-grants-2014_08

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US08815877B2