Reaction #172878

Reaction equation

methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-2-fluorobenzoate

3-(2-oxopyrrolidin-1-yl)propyl trifluoromethanesulfonate

potassium iodide

phosphoric acid

potassium

→

methyl 2-fluoro-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(3-(2-oxopyrrolidin-1-yl)propylamino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate

Yield 26.2%

Solvents

—

crude solution

acetonitrile

Conditions

Workup

1. 1
   Otherprepared above) (1.0 mL, 0.384 mmol)
2. 2
   workup.ADDITIONwas added
3. 3
   OtherThe mixture was flushed with N2
4. 4
   Otherthe vial was sealed
5. 5
   TemperatureAfter 15.5 h of heating
6. 6
   Temperaturethe mixture was cooled to rt
7. 7
   workup.ADDITIONAn additional 0.5 mL of the above crude solution containing the triflate
8. 8
   workup.ADDITIONwas added
9. 9
   Temperaturethe mixture was again heated to 120° C
10. 10
    TemperatureAfter heating the mixture for an additional 70.25 h
11. 11
    Temperaturethe mixture was cooled to rt
12. 12
    Otherwas purified by flash chromatography
13. 13
    workup.ADDITIONThe fractions containing the expected product
14. 14
    Concentrationconcentrated under reduced pressure

Procedure

To a sealable flask containing methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-2-fluorobenzoate (50 mg, 0.089 mmol) was added potassium iodide (39.9 mg, 0.240 mmol) and phosphoric acid, potassium salt (83 mg, 0.392 mmol). The mixture was diluted with acetonitrile (1 mL) and 3-(2-oxopyrrolidin-1-yl)propyl trifluoromethanesulfonate (the crude solution prepared above) (1.0 mL, 0.384 mmol) was added. The mixture was flushed with N2, then the vial was sealed and heated to 120° C. After 15.5 h of heating, the mixture was cooled to rt. An additional 0.5 mL of the above crude solution containing the triflate was added and the mixture was again heated to 120° C. After heating the mixture for an additional 70.25 h, the mixture was cooled to rt. The mixture was adsorbed to silica gel and was purified by flash chromatography using a 0-5% MeOH in DCM gradient and a Thomson 12 g silica gel column. The fractions containing the expected product were combined and concentrated under reduced pressure to give methyl 2-fluoro-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(3-(2-oxopyrrolidin-1-yl)propylamino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (16 mg, 0.023 mmol, 26.2% yield) as a yellow film. LCMS: m/e 687.5 (M+H)+, 2.04 min (method 2).

Source