Phosphoric Acid → 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

HRID 85696Notes

Reaction equation

HRID 85696 reaction equation
[NH2:1][C@:2]12[CH2:38][CH2:37][C@@H:36]([C:39]([CH3:41])=[CH2:40])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:35])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]([F:34])[CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.[I-].[K+].P(=O)(O)(O)O.[K].FC(F)(F)S(O[CH2:56][CH2:57][CH2:58][N:59]1[CH2:63][CH2:62][CH2:61][C:60]1=[O:64])(=O)=O>C(#N)C>[F:34][C:26]1[CH:25]=[C:24]([C:11]2[C:12]([CH3:22])([CH3:23])[C@H:13]3[C@:8]([CH3:35])([CH2:9][CH:10]=2)[C@@H:7]2[C@:16]([CH3:21])([C@@:17]4([CH3:20])[C@H:4]([CH2:5][CH2:6]2)[C@H:3]2[C@H:36]([C:39]([CH3:41])=[CH2:40])[CH2:37][CH2:38][C@:2]2([NH:1][CH2:56][CH2:57][CH2:58][N:59]2[CH2:63][CH2:62][CH2:61][C:60]2=[O:64])[CH2:19][CH2:18]4)[CH2:15][CH2:14]3)[CH:33]=[CH:32][C:27]=1[C:28]([O:30][CH3:31])=[O:29]

Participants

7

Reactant 5

HCID 1004Phosphoric AcidHCID 4875Potassium IodideHCID 5462222PotassiumHCID 68358156methyl 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-fluorobenzoateHCID 86676625HCID 86676625, compound

Product 1

HCID 68358157methyl 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)benzoateYield 26.2%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Conditions

Temperature
120 °C

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).

Workup

  1. customprepared above) (1.0 mL, 0.384 mmol)
  2. additionwas added
  3. customThe mixture was flushed with N2
  4. customthe vial was sealed
  5. temperatureAfter 15.5 h of heating
  6. temperaturethe mixture was cooled to rt
  7. additionAn additional 0.5 mL of the above crude solution containing the triflate
  8. additionwas added
  9. temperaturethe mixture was again heated to 120° C
  10. temperatureAfter heating the mixture for an additional 70.25 h
  11. temperaturethe mixture was cooled to rt
  12. customwas purified by flash chromatography
  13. additionThe fractions containing the expected product
  14. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-a810fab2c15540c895e981d05f908f90
Source dataset
uspto-grants-2014_09
Patent number
US08846647B2

Reaction notes

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