反应详情

温度

-78 °C

A solution of 4-fluoro-4-[4-[[(phenylmethoxy)carbonyl]amino]-2-fluorophenyl]-1-piperidinecarboxylic acid phenylmethyl ester (EXAMPLE 74, Step 2, 2.03 g, contaminated with the elimination side product) in dry tetrahydrofuran (21 mL) at −78° C. under N2 is treated with n-butyllithium (2.80 mL, 1.6M in hexanes) dropwise over 5 mins. The resulting mixture is stirred at −78° C. for 1.25 hrs and is then treated with (R)-(−)-glycidyl butyrate (0.63 mL) dropwise. The resulting solution is stirred at −78° C. for 1 hr, warmed to ambient temperature and stirred for an additional 20 hrs, after which the reaction is quenched with saturated aqueous ammonium chloride (10 mL), diluted with water (10 mL), and the layers are separated. The organic phase is washed with saline (10 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the crude product which is chromatographed on silica gel (230-400 mesh, 250 g), eluting with methanol/methylene chloride (3/97). Pooling and concentration of those fractions with an Rf=0.51 by TLC (methanol/chloroform, 10/90) and repurification by silica gel chromatography (230-400 mesh, 100 g, methanol/methylene chloride (4/96) eluent) gives the title compound (contaminated with the elimination side product from the starting material). An analytical sample is prepared by radial chromatography (2000 m silica gel rotor, ethyl acetate/hexane (60/40) eluent), NMR (400 MHz, CDCl3) 7.45, 7.34, 7.18, 5.16, 4.74, 4.17, 3.97, 3.72, 3.22, 2.25 and 1.90δ and HRMS calculated for C23H24F2N2O5: 446.1653. Found: 446.1660.

1. customat −78° C.
2. stirringThe resulting solution is stirred at −78° C. for 1 hr
3. temperaturewarmed to ambient temperature
4. stirringstirred for an additional 20 hrs
5. customafter which the reaction is quenched with saturated aqueous ammonium chloride (10 mL)
6. additiondiluted with water (10 mL)
7. customthe layers are separated
8. washThe organic phase is washed with saline (10 mL)
9. dry with materialdried over anhydrous magnesium sulfate
10. concentrationconcentrated under reduced pressure
11. customto give the crude product which
12. customis chromatographed on silica gel (230-400 mesh, 250 g)
13. washeluting with methanol/methylene chloride (3/97)
14. customPooling and concentration of those fractions with an Rf=0.51 by TLC (methanol/chloroform, 10/90) and repurification by silica gel chromatography (230-400 mesh, 100 g, methanol/methylene chloride (4/96) eluent)