反应详情

温度

0 °C

A suspension of 5.8 g (12.28 mmol) of (3S,4S)-benzyl 3-((6-bromo-3-carbamoylpyrrolo[1,2-b]pyridazin-4-yl)amino)-4-methylpyrrolidine-1-carboxylate (prepared by coupling Intermediate 2 and enantiopure intermediate 5 as described in Step 1 of Example 52) in acetonitrile (75 mL) was cooled to 0° C. in an ice-water bath. Iodotrimethylsilane (6.99 mL, 49.1 mmol) was then added dropwise and the reaction mixture was stirred while the ice bath was allowed to slowly warm to room temperature. After 90 minutes, the deprotection step is complete. The reaction mixture was recooled to 0° C. and was quenched by slowly adding 35 mL MeOH. After stirring 45 minutes to ensure that the quench was complete, the volatiles were removed in vacuo to afford a solid. After drying for 1 hour under high vacuum, di-t-butyldicarbonate (4.02 g, 18.42 mmol) was weighed into the flask containing the solid. DCM (100 mL) and N,N-Di-iso-propylethylamine (10.69 mL, 61.4 mmol) were then added and the solution was stirred at room temperature. Within 15 minutes the reaction is complete and the product began to precipitate out of solution. The reaction mixture was diluted with 150 mL DCM and the resulting suspension was filtered. The filter cake was washed with 1:1 hexanes:ethyl ether and dried to afford 3.44 gm of title compound as a white solid. The DCM mother liquor was washed 2× with water and 1× brine. After drying over sodium sulfate and concentration, the residue was loaded onto a 120 gm ISCO column for purification by flash chromatography, eluting with 0-10% MeOH in DCM. Concentration of the pure fractions afforded an additional 1.13 gm of the titile compound as a light yellow solid. Concentration gave (3S,4S)-tert-butyl 3-((6-bromo-3-carbamoylpyrrolo[1,2-b]pyridazin-4-yl)amino)-4-methylpyrrolidine-1-carboxylate (4.57 gm; 9.90 mmol; 81% yield). MS (ES+) m/z: 438.0, 440.0 (M+H); LC retention time: 3.103 min (analytical HPLC Method O).

1. temperatureto slowly warm to room temperature
2. customwas recooled to 0° C.
3. customwas quenched
4. additionby slowly adding 35 mL MeOH
5. customthe volatiles were removed in vacuo
6. customto afford a solid
7. additioncontaining the solid
8. stirringthe solution was stirred at room temperature
9. waitWithin 15 minutes the reaction is complete
10. customto precipitate out of solution
11. additionThe reaction mixture was diluted with 150 mL DCM
12. filtrationthe resulting suspension was filtered
13. washThe filter cake was washed with 1:1 hexanes
14. dry with materialethyl ether and dried