Reacción #332611

Ecuación de reacción

LDA

Intermediate 45

(2R,6S)-4-(2-((tert-butyldiphenylsilyloxy)methyl)-4-chloro-5-fluoropyridin-3-yl)-2,6-dimethylmorpholine

N-methoxy-N-methylpicolinamide

(2R,6S)-4-(2-((tert-butyldiphenylsilyloxy)methyl)-4-chloro-5-fluoropyridin-3-yl)-2,6-dimethylmorpholine

Diisopropylamine

n-butyllithium

hexane

→

title compound

Rendimiento 67.4%

(6-((tert-butyldiphenylsilyloxy)methyl)-4-chloro-5-((2R,6S)-2,6-dimethylmorpholino)-3-fluoropyridin-2-yl)(pyridin-2-yl)methanone

Rendimiento 67.4%

Disolventes

THF

THF

THF

Condiciones de reacción

Tratamiento posterior

1. 1
   Temperaturathen cooled again to −78° C
2. 2
   Otroat −78° C.
3. 3
   Otroat −78° C
4. 4
   TemperaturaAllowed the solution to warm to −50° C.
5. 5
   Otroquenched with saturated ammonium chloride solution
6. 6
   ExtracciónExtracted mixture with ethyl acetate
7. 7
   Lavadowashed
8. 8
   Otroresulting organics with brine
9. 9
   FiltraciónDried organics over sodium sulfate, filtered
10. 10
    Otroevacuated filtrate under vacuum
11. 11
    Otroto give crude yellow oil
12. 12
    OtroThe crude oil was purified on silica using 10-30% acetone in n-hexane as eluant

Procedimiento

Diisopropylamine (0.925 mL, 6.55 mmol) was added dropwise to a stirring solution of 2.5M n-butyllithium in hexane (2.495 mL, 6.24 mmol) in THF (10 mL) at −78° C. Allowed solution to warm to 0° C. for 10 minutes then cooled again to −78° C. Cannulated the prepared LDA at −78° C. into (2R,6S)-4-(2-((tert-butyldiphenylsilyloxy)methyl)-4-chloro-5-fluoropyridin-3-yl)-2,6-dimethylmorpholine (Intermediate 45, 1.6 g, 3.12 mmol) in THF (10 mL) at −78° C. Allowed the dark solution to stir for 20 minutes and then cannulated into a stirring solution of N-methoxy-N-methylpicolinamide (1.05 g, 6.24 mmol) in THF (10 mL) at −78° C. Allowed the solution to warm to −50° C. and then quenched with saturated ammonium chloride solution. Extracted mixture with ethyl acetate and washed resulting organics with brine. Dried organics over sodium sulfate, filtered, and evacuated filtrate under vacuum to give crude yellow oil. The crude oil was purified on silica using 10-30% acetone in n-hexane as eluant to give 1.3 g (67%) of the title compound as oil.

Fuente