Acetic Acid → 2-[(1-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}-3-hydroxypyrrolidin-3-yl)methyl]nicotinic acid

Temperature

-45 °C

To a solution of 2,2,6,6-tetramethyl-piperidine (0.123 g, 0.000872 mol) in tetrahydrofuran (3.00 mL, 0.0370 mol) at −75° C. was added 2.50 M of n-butyllithium in hexane (0.500 mL). After stirring for 15 min., a suspension of 2-methylnicotinic acid (120.5 mg, 0.0008787 mol) in THF (5.0 mL) was added at −55° C. The mixture was stirred at −55° C. for 1 h. 1-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}pyrrolidin-3-one (100.0 mg, 0.0003792 mol, prepared in steps 1 and 2 of example 288) was added to the above mixture and the reaction temperature was maintained at −50 to −40° C. The mixture was stirred at −40° C. for 30 minutes, then slowly warmed up to 0° C. To the mixture was added acetic acid (0.50 mL, 0.0088 mol) at 0° C. and the reaction mixture was stirred overnight while gradually warming to rt. The reaction mixture was carefully neutralized with NaHCO3 and the resulting mixture was extracted with AcOEt (4×30 mL). The combined organic layer was washed with brine (30 mL), dried over MgSO4, and concentrated. The residue was purified by Combiflash with ethyl acetate/heaxane to give the desired product. LC/MS (M+H+) 401.7.

1. additionwas added at −55° C
2. stirringThe mixture was stirred at −55° C. for 1 h
3. stirringThe mixture was stirred at −40° C. for 30 minutes
4. temperatureslowly warmed up to 0° C
5. stirringthe reaction mixture was stirred overnight
6. temperaturewhile gradually warming to rt
7. extractionthe resulting mixture was extracted with AcOEt (4×30 mL)
8. washThe combined organic layer was washed with brine (30 mL)
9. dry with materialdried over MgSO4
10. concentrationconcentrated
11. customThe residue was purified by Combiflash with ethyl acetate/heaxane

ORD record

ord-822c981760db4ef086a4dfc219438b59

Source dataset

uspto-grants-2007_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07304081B2