反应详情

Charge to a flask under an inert atmosphere a 2 M THF solution of lithium borohydride (1140 mL, 2280 mmol) and apply ice bath cooling. Meanwhile in a separate vessel dissolve 3-(4-{[2-(4-chloro-phenyl)-4-methoxycarbonylmethyl-thiazole-5-carbonyl]-amino}-2-methoxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (2058 g, 3500 mmol) in THF (12.35 L). Agitate until complete dissolution is obtained. Transfer this solution to an addition funnel and begin the slow stream addition to the reducing agent. Once the addition is complete, remove the ice bath and stir for 30-90 min. Quench the reaction by adding acetone (407 g, 7008 mmol). Stir at ambient temperature for 30 min and add ethyl acetate (8230 mL) with water (8230 mL). Separate the layers and wash the upper organic layer a second time with water (8230 mL) followed by 5% brine (8230 mL). Distill off the solvent until <5% solvent composition is THF, by adding EtOAc as needed. Reduce the volume of the slurry to 6200 mL and add heptane (2050 mL). Allow the slurry to slowly cool back to room temperature, filter the precipitate, wash with 1:1 heptane/ethyl acetate and dry to constant weight in a vacuum oven at 40° C. to obtain the title compound (88%). ES/MS m/z (35Cl) 560 [M+1]+.

1. temperaturecooling
2. customis obtained
3. customTransfer this solution to an addition funnel and begin
4. additionthe slow stream addition to the reducing agent
5. additionOnce the addition
6. customremove the ice bath
7. stirringstir for 30-90 min
8. customQuench
9. customthe reaction
10. stirringStir at ambient temperature for 30 min
11. customSeparate the layers
12. washwash the upper organic layer a second time with water (8230 mL)
13. distillationDistill off the solvent until <5% solvent composition
14. additionby adding EtOAc
15. additionadd heptane (2050 mL)
16. filtrationfilter the precipitate
17. washwash with 1:1 heptane/ethyl acetate
18. customdry to constant weight in a vacuum oven at 40° C.