反应详情

温度

45 °C

1(S)-(4-(Methoxymethoxy)piperidin-1-yl-carbonyl)-2-phenylethanol (European Patent Application No. EP364804, published Apr. 25, 1991) (43.13 g, 147.2 mmol) in 200 mL dry THF was added dropwise to the suspension of sodium hydride (60% dispersion in oil, 12.36 g, 309.1 mmol) in 136 mL dry THF and 22.7 mL DMF at 45° C. oil bath temperature under N2 atmosphere. The addition took approximately 1 h. The mixture was allowed to stir at 45° C. for additional 3 h. The gray suspension turned white after stiring for an hour and became very viscous. An additional 36 mL of dry THF was added to facilitate stirring. A solution of (R)-2-bromohexanoic acid (31.57 g, 161.9 mmol) in 180 mL THF was added dropwise to the thick, white suspension at 45° C. The addition took approximately 1.75 h. The suspension was removed from the oil bath 45 min after addition was completed and quenched immediately with careful addition of 120 mL of pH 7 phosphate buffer (0.3 M). The solution was then concentrated under reduced pressure at 35° C. and the resulting liquid extracted with 3×100 mL of diethyl ether to remove the unreacted alcohol. The aqueous phase was mixed with 300 mL of CH2Cl2 and acidified to pH 2 with 200 mL of 1 M sodium hydrogen sulfate. The layers were shaken and separated, then the aqueous phase was extracted with 2×300 mL of CH2Cl2. The combined organic phase was dried (MgSO4), filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 1.5% HOAc-5% iPrOH-35% THF-hexane) to obtain 36.35 g (88.32 mmol, 60%) of the desired compound as a low-melting solid: Rf 0.30 (EtOAc-hexane 5:2); 1H NMR (CDCl3) δ 0.8 (d, 3 H), 0.95 (m, 5 H), 1.2-1.9 (m, 22 H), 3.0 (q, 2 H), 3.2 (m, 4 H), 3.55 (m, 2 H), 3.65 (m, 2 H), 3.8 (t, 1 H),4.4 (q, 1 H), 7.3 (m, 5 H).

1. additionThe addition
2. waitafter stiring for an hour
3. stirringto facilitate stirring
4. additionThe addition
5. waittook approximately 1.75 h
6. customThe suspension was removed from the oil bath 45 min
7. additionafter addition
8. customquenched immediately with careful addition of 120 mL of pH 7 phosphate buffer (0.3 M)
9. concentrationThe solution was then concentrated under reduced pressure at 35° C.
10. extractionthe resulting liquid extracted with 3×100 mL of diethyl ether
11. customto remove the unreacted alcohol
12. additionThe aqueous phase was mixed with 300 mL of CH2Cl2
13. stirringThe layers were shaken
14. customseparated
15. extractionthe aqueous phase was extracted with 2×300 mL of CH2Cl2
16. dry with materialThe combined organic phase was dried (MgSO4)
17. filtrationfiltered
18. concentrationconcentrated under reduced pressure
19. customThe crude product was purified by column chromatography (silica gel, 1.5% HOAc-5% iPrOH-35% THF-hexane)