Hydrochloric Acid → Darolutamide

HRID 1409405Notes

Reaction equation

HRID 1409405 reaction equation
[BH4-].[Na+].[C:3]([C:6]1[CH:10]=[C:9]([C:11]([NH:13][C@@H:14]([CH3:30])[CH2:15][N:16]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[C:23]([Cl:29])[CH:22]=3)=[N:17]2)=[O:12])[NH:8][N:7]=1)(=[O:5])[CH3:4].Cl.O>CCO.[BH4-].[Na+]>[Cl:29][C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[CH:20][N:16]([CH2:15][C@@H:14]([NH:13][C:11]([C:9]3[CH:10]=[C:6]([CH:3]([OH:5])[CH3:4])[NH:7][N:8]=3)=[O:12])[CH3:30])[N:17]=2)[CH:26]=[CH:25][C:24]=1[C:27]#[N:28]

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 962WaterHCID 4311764Sodium borohydrideHCID 52919826(S)-5-acetyl-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-3-carboxamide

Product 1

HCID 67171867DarolutamideYield 80.9%

Reagents, catalysts & solvents 2

HCID 4311764Sodium borohydrideCatalystHCID 702EthanolSolvent2×

Procedure

Sodium borohydride (0.930 g, 24.57 mmol) and EtOH (105 ml) were placed in to the reaction flask under nitrogen atmosphere. (S)-3-acetyl-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-5-carboxamide (15 g, 37.8 mmol) was added in small portions to keep temperature below 25° C. After 3.5 h sodium borohydride (0.07 g, 1.85 mmol) was added and the mixture was stirred for additional 60 min to complete the reaction. 16 ml of ˜10% HCl in EtOH was added carefully to set pH to 3.5 and the mixture was stirred overnight at RT. Water (30 ml) was added and the stirring was continued for 3 h. The precipitate was filtered, washed with 2×10 ml of cold water:EtOH (1:1) and dried under vacuum to obtain 12.2 g of the title compound. 1H-NMR (400 MHz, DMSO-d6): δ 1.12 (, 3H), 1.39 (d, 3H), 4.24-4.52 (m, 3H), 4.76-4.86 (m, 1H), 5.42 (d, 1H), 6.42 (bs., 1H), 6.94 (d, 1H), 7.82 (d, 1H), 8.00 (bs, 2H), 8.09 (bs, 1H), 8.20 (d, 1H), 13.05 (bs, 1H).

Workup

  1. customtemperature below 25° C
  2. customthe reaction
  3. stirringthe mixture was stirred overnight at RT
  4. waitthe stirring was continued for 3 h
  5. filtrationThe precipitate was filtered
  6. washwashed with 2×10 ml of cold water:EtOH (1:1)
  7. customdried under vacuum

Sources & evidence

ORD record
ord-43a29b18e9974d2fa87defe6b33f5d31
Source dataset
uspto-grants-2014_12
Patent number
US08921378B2

Reaction notes

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