反应详情

(S)-4-((3-Methoxypyridin-2-yl)methyl)-7-cyano-1,2,3,4-tetrahydrocyclopenta[b]indol-2-ylcarbamic acid isopropyl ester (4.59 g, 11.4 mmol) and pyridine hydrochloride (21.0 g, 182 mmol) are mixed with a magnetic stirrer in a 75 mL sealed vessel that is immersed in a preheated oil bath (170° C.). The solids melt within approximately 30 sec and are stirred for 60 min. The mixture is cooled to room temperature, transferred to another flask, and dissolved in tetrahydrofuran (100 mL) and water (100 mL). Potassium carbonate (40 g) is added slowly in portions and after stirring for 5 min a 1 M solution of isopropyl chloroformate in toluene (34.0 mL, 34.0 mmol) is added at room temperature. A portion of the solvent is removed under reduced pressure and the residue is diluted with dichloromethane and ethyl acetate. The brown insoluble residue is filtered off and the phases are separated. The organic phase is washed with 10% potassium carbonate once, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain a brown foam. The foam is dissolved in methanol (20 mL), 2 M sodium hydroxide (10 mL) is added and the reaction is stirred at room temperature for 1 hour. The solvent is removed under reduced pressure. The residue is dissolved in 0.5 M HCl/EtOAc/CHCl3 and the bilayer is filtered. It is then acidified to pH 7-8 with 5% potassium carbonate. The phases are separated and the organic phase is washed with 5% potassium carbonate once, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain an orange foam. The foam is purified by silica flash chromatography eluting with 10 to 40% ethyl acetate/chloroform to obtain a red solid (3.33 g). The solid is dissolved in 0.5 M sodium hydroxide (30 mL). The aqueous layer is washed with dichloromethane twice and the organic layers are discarded. The aqueous layer is adjusted to pH 4-5 with 5 M hydrochloric acid. An off-white/yellow solid crashes out of solution. The pH is adjusted to 8-9 with potassium carbonate, the yellow solid is collected by filtration and air dried for one hour. It is then suspended in a minimum amount of acetonitrile, filtered, and rinsed with a minimum amount of acetonitrile. The mother liquor is concentrated and the procedure is repeated two times to afford a white powder, which is dried under high vacuum overnight to obtain the title compound as a white solid (1.45 g, 33%). LC-ES/MS m/z 391.2 [M+H]+, TR=3.32 min.

1. customsealed vessel that
2. customis immersed in a preheated oil bath
3. custom(170° C.)
4. customtransferred to another flask
5. additionis added at room temperature
6. customA portion of the solvent is removed under reduced pressure
7. additionthe residue is diluted with dichloromethane and ethyl acetate
8. filtrationThe brown insoluble residue is filtered off
9. customthe phases are separated
10. washThe organic phase is washed with 10% potassium carbonate once
11. dry with materialdried over anhydrous sodium sulfate
12. filtrationfiltered
13. concentrationconcentrated in vacuo
14. customto obtain a brown foam
15. stirringthe reaction is stirred at room temperature for 1 hour
16. customThe solvent is removed under reduced pressure
17. dissolutionThe residue is dissolved in 0.5 M HCl/EtOAc/CHCl3
18. filtrationthe bilayer is filtered
19. customThe phases are separated
20. washthe organic phase is washed with 5% potassium carbonate once
21. dry with materialdried over anhydrous sodium sulfate
22. filtrationfiltered
23. concentrationconcentrated in vacuo
24. customto obtain an orange foam
25. customThe foam is purified by silica flash chromatography
26. washeluting with 10 to 40% ethyl acetate/chloroform