Boron trifluoride etherate → (S)-1-tert-butyl 2-methyl 2,4,4-trimethylpyrrolidine-1,2-dicarboxylate

Temperatur

-78 °C

To a stirred solution of (S)-1-tert-butyl 2-methyl 2,4,4-trimethyl-5-oxopyrrolidine-1,2-dicarboxylate 106C (13.96 g, 48.9 mmol) in THF (100 mL) was added Super-hydride (lithium triethylboro-hydride) (58.7 mL, 58.7 mmol) at −78° C. under nitrogen atmosphere. The reaction mixture was stirred at −78° C. for 2 h and quenched with saturated NaHCO3 at −78° C. The reaction mixture was warmed to 0° C. and hydrogen peroxide (15 ml) was added drop-wise at 0° C. The mixture was stirred at 0° C. for 30 min and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over Na2SO4. After concentration, the crude product was used for the next step without purification. To a stirred solution of the crude product obtained above in CH2Cl2, was added half of triethylsilane (17.19 mL., 108 mmol) and half of BF3.OEt2 (13.64 mL., 108 mmol) at −78° C. under nitrogen atmosphere. The reaction mixture was stirred at −78° C. for 1 h, then the remaining triethylsilane (17.19 mL., 108 mmol) and BF3.OEt2 (13.64 mL, 108 mmol) were added. The reaction mixture was stirred at −78° C. for 2 h and quenched with saturated NaHCO3 solution. The reaction mixture was extracted with CH2Cl2. The combined organic layers were washed with water and brine, dried over Na2SO4. The crude product was purified by Biotage (0-30% EtOAc/Hexane, 1.5 L) to give (S)-1-tert-butyl 2-methyl 2,4,4-trimethylpyrrolidine-1,2-dicarboxylate 106D (10 g, 75%) as an oil.

1. customquenched with saturated NaHCO3 at −78° C
2. temperatureThe reaction mixture was warmed to 0° C.
3. additionhydrogen peroxide (15 ml) was added drop-wise at 0° C
4. stirringThe mixture was stirred at 0° C. for 30 min
5. extractionextracted with ethyl acetate
6. washThe combined organic layers were washed with water and brine
7. dry with materialdried over Na2SO4
8. concentrationAfter concentration
9. customthe crude product was used for the next step without purification
10. customTo a stirred solution of the crude product obtained above in CH2Cl2
11. stirringThe reaction mixture was stirred at −78° C. for 1 h
12. stirringThe reaction mixture was stirred at −78° C. for 2 h
13. customquenched with saturated NaHCO3 solution
14. extractionThe reaction mixture was extracted with CH2Cl2
15. washThe combined organic layers were washed with water and brine
16. dry with materialdried over Na2SO4
17. customThe crude product was purified by Biotage (0-30% EtOAc/Hexane, 1.5 L)

ORD-Eintrag

ord-eb1228fdcb0c4a14803298450dbac595

Quelldatensatz

uspto-grants-2013_04

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US08415340B2