반응 #1802504

반응 방정식

NaH

methanesulfonic acid 3-sec-butylcarbamoyl-3-(4-cyano-3-trifluoromethylphenoxy)-2,2-dimethylpropyl ester

→

(3R,S)-(+)-4-(1-sec-Butyl-4,4-dimethyl-2-oxo-pyrrolidin-3-yloxy)-2-trifluoromethylbenzonitrile

용매

methanol

THF

반응 조건

후처리

1. 1
   기타The reaction mixture was quenched
2. 2
   workup.ADDITIONby adding it to 500 mL cold (5-10° C.)
3. 3
   기타The phases were separated
4. 4
   추출the aqueous was extracted with ethyl acetate (“EtOAc”) (2×500 mL)
5. 5
   기타organic was conc'd under vac (40-45° C.) to an orange-yellow oil/gum (83 g)
6. 6
   기타The crude product was purified by extensive silica gel (230-400 mesh) column chromatography (EtOAc/Heptane)
7. 7
   기타followed by crystallization (EtOAc/Heptane)
8. 8
   기타The pure desired diastereomer was isolated as a white granular solid MS+

실험 절차

Solid NaH (60 wt % dispersion in mineral oil, 16.6 g, 416 mmol) was added portion wise over 25 min to a cold (0-5° C.) sol'n of methanesulfonic acid 3-sec-butylcarbamoyl-3-(4-cyano-3-trifluoromethylphenoxy)-2,2-dimethylpropyl ester (104 g, 208 mmol) in 400 mL dry THF under an N2 atmosphere. The reaction mixture was allowed to warm to 20-25° C. and then stirred at this temp. for 90 h. The reaction mixture was quenched by adding it to 500 mL cold (5-10° C.) sat'd aq. NH4Cl. The phases were separated and the aqueous was extracted with ethyl acetate (“EtOAc”) (2×500 mL). The pale yellow organic was conc'd under vac (40-45° C.) to an orange-yellow oil/gum (83 g). The crude product was purified by extensive silica gel (230-400 mesh) column chromatography (EtOAc/Heptane) followed by crystallization (EtOAc/Heptane). The pure desired diastereomer was isolated as a white granular solid MS+: 355. m.p. 101-102° C. Optical rotation [α]58925=+180.10(in methanol) Elemental analysis results: Obsv'd (Theor.): C, 61.03 (61.01); H, 6.02 (5.97); N, 7.88 (7.91); F, 15.98 (16.08). HPLC analysis: Chiral purity: 100%.

출처