Ethanol → Brilanestrant

HRID 1254467Notes

Reaction equation

HRID 1254467 reaction equation
Cl.[Cl:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1/[C:10](/[CH2:34][CH3:35])=[C:11](\[C:21]1[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29]([O:31]CC)=[O:30])=[CH:23][CH:22]=1)/[C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][N:16]=[CH:15]2.C(O)C.[Li+].[OH-]>O>[Cl:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1/[C:10](/[CH2:34][CH3:35])=[C:11](\[C:21]1[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30])=[CH:23][CH:22]=1)/[C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][N:16]=[CH:15]2

Participants

5

Reactant 3

HCID 702EthanolHCID 3939Lithium HydroxideHCID 86663370HCID 86663370, compound2×

Product 1

HCID 56941241BrilanestrantYield 71.5%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Procedure

A round-bottom flask equipped with a magnetic stir bar was charged with (E)-ethyl 3-(4-((E)-2-(2-chloro-4-fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylate hydrochloride (198.5 g, 388 mmol; Compound 110) and ethyl alcohol (517 mL). A solution of LiOH (27.9 g, 1164 mmol) in water (388 mL) was added, and the mixture was stirred at room temperature overnight. The ethyl alcohol was removed by rotary evaporation, and the remaining solution was cooled to 0° C. and acidified with 2M aqueous HCl to pH 3. Dichloromethane (500 mL) was added, the mixture was stirred, and then the layers were separated. The organic layer was washed with water, washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was passed through a silica column (800 g, 5% MeOH in DCM) and concentrated. The product was then dissolved in DCM (400 mL), and acetonitrile (500 mL) was added. Approximately 200 mL of DCM was removed by rotary evaporation (solids began to precipitate). Acetonitrile (550 mL) was added followed by water (25 mL). The mixture was stirred at room temperature for 2 h. The solvent was decanted, and then acetonitrile:DCM (10:1; 550 mL) was added. The mixture stirred at room temperature for 1.5 h, the solvent was again decanted, and then acetonitrile:DCM (10:1; 550 mL) was added. The mixture was again stirred at room temperature for 1.5 h and then filtered. The solids were resuspended in acetonitrile:DCM (10:1; 550 mL), stirred at room temperature for 1.5 h, filtered, and washed to give the title compound (123.9 g) as an off-white powder. 1H NMR (DMSO-d6): δ 13.12 (s, 1H), 12.34 (br, 1H), 8.11 (d, 1H), 7.69 (s, 1H), 7.56 (d, 1H), 7.44-7.33 (m, 5H), 7.21-7.10 (m, 2H), 6.96 (d, 2H), 6.38 (d, 1H), 2.34 (q, 2H), 0.90 (t, 3H); LCMS: 447 (M+H)+.

Workup

  1. customA round-bottom flask equipped with a magnetic stir bar
  2. customThe ethyl alcohol was removed by rotary evaporation
  3. temperaturethe remaining solution was cooled to 0° C.
  4. additionDichloromethane (500 mL) was added
  5. stirringthe mixture was stirred
  6. customthe layers were separated
  7. washThe organic layer was washed with water
  8. washwashed with brine
  9. dry with materialdried over sodium sulfate
  10. filtrationfiltered
  11. concentrationconcentrated
  12. concentrationconcentrated
  13. dissolutionThe product was then dissolved in DCM (400 mL)
  14. additionacetonitrile (500 mL) was added
  15. customApproximately 200 mL of DCM was removed by rotary evaporation (solids began to precipitate)
  16. additionAcetonitrile (550 mL) was added
  17. stirringThe mixture was stirred at room temperature for 2 h
  18. customThe solvent was decanted
  19. additionacetonitrile:DCM (10:1; 550 mL) was added
  20. stirringThe mixture stirred at room temperature for 1.5 h
  21. customthe solvent was again decanted
  22. additionacetonitrile:DCM (10:1; 550 mL) was added
  23. stirringThe mixture was again stirred at room temperature for 1.5 h
  24. filtrationfiltered
  25. stirringstirred at room temperature for 1.5 h
  26. filtrationfiltered
  27. washwashed

Sources & evidence

ORD record
ord-510383f847da495694a0a440f200e5e8
Source dataset
uspto-grants-2013_06
Patent number
US08455534B2

Reaction notes

Loading…