Hydrogen Peroxide → (R)-3-(3-benzyloxymethyl-2-methoxy-pyridin-4-yl)-3-hydroxy-pentanoic acid

Temperature

-78 °C

4.733 g (4R,5S)-3-acetyl-4,5-diphenyl-oxazolidin-2-one (16.82 mmol, 1.2 eq) as obtainable from Example 8, were dissolved in 19 mL THF at 65° C. The solution was subsequently cooled to −78° C. and 17.00 mL lithium bis(trimethylsilyl)amide solution in TBF (1.0 M, 16.82 mmol, 1.2 eq) were slowly added (addition time: 10 min). During the addition, the color changed from colorless to bright yellow. After 2 h at −78° C., the clear solution was cooled to −95° C. A solution of 4.000 g 1-(3-benzyloxymethyl-2-methoxy-pyridin-4-yl)-propan-1-one (14.02 mmol) as obtainable from Example 7, in 16 mL THF was slowly added (syringe pump, addition time: 30 min) and the solution was kept for additional 30 min at −95° C. and then for 45 min at −78° C. Subsequently, 87.6 mL aqueous LiOH solution (0.8 M, 70.1 mmol, 5.0 eq) and 7.01 mL aqueous H2O2 solution (10.0 M, 70.1 mmol, 5.0 eq) were added and stirring of the resulting suspension was continued at 0° C. for 30 min and at room temperature for 1 h. The precipitated auxiliary was collected by filtration and the solid was washed with 15 mL water. The filtrate was poured on 200 mL aqueous NaOH solution (2 M). A second portion of precipitated auxiliary was collected by filtration and the solid was washed with 3 mL water. The filtrate was then extracted 3 times with 200 mL, in total with 600 mL TBME in order to remove unreacted 1-(3-benzyloxymethyl-2-methoxy-pyridin-4-yl)-propan-1-one, unprecipitated auxiliary and several impurities. The aqueous phase was then acidified with aqueous HCl until pH 3. The resulting white suspension was extracted twice with 200 mL, in total 400 mL dichloromethane. The combined dichloromethane extracts were washed with 80 mL saturated aqueous NH4Cl and 16 mL brine and were subsequently dried over 20 g sodium sulfate (30 min) and filtered. The solid was washed with 40 mL dichloromethane. After removal of solvent in a rotary evaporator (40° C., 5 mbar), the title compound was obtained as a light yellow oil (3.61 g, 75% by weight, er 87.2:12.8).

1. addition(addition time: 10 min)
2. additionDuring the addition
3. temperaturethe clear solution was cooled to −95° C
4. addition(syringe pump, addition time: 30 min)
5. waitthe solution was kept for additional 30 min at −95° C.
6. waitfor 45 min at −78° C
7. waitwas continued at 0° C. for 30 min and at room temperature for 1 h
8. filtrationThe precipitated auxiliary was collected by filtration
9. washthe solid was washed with 15 mL water
10. additionThe filtrate was poured on 200 mL aqueous NaOH solution (2 M)
11. filtrationA second portion of precipitated auxiliary was collected by filtration
12. washthe solid was washed with 3 mL water
13. extractionThe filtrate was then extracted 3 times with 200 mL
14. customin total with 600 mL TBME in order to remove unreacted 1-(3-benzyloxymethyl-2-methoxy-pyridin-4-yl)-propan-1-one
15. extractionThe resulting white suspension was extracted twice with 200 mL, in total 400 mL dichloromethane
16. washThe combined dichloromethane extracts were washed with 80 mL saturated aqueous NH4Cl and 16 mL brine
17. dry with materialwere subsequently dried over 20 g sodium sulfate (30 min)
18. filtrationfiltered
19. washThe solid was washed with 40 mL dichloromethane
20. customAfter removal of solvent
21. customin a rotary evaporator (40° C., 5 mbar)

ORD record

ord-9b7e3d265ad44c52a4444e880cecd78b

Source dataset

uspto-grants-2010_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07705155B2