4-Isothiocyanato-2-(trifluoromethyl)benzonitrile → N-Desmethylenzalutamide

HRID 570769Notes

Reaction equation

HRID 570769 reaction equation
[C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([CH3:17])([CH3:16])[C:12]([O:14]C)=O)=[CH:6][C:5]=1[F:18])(=[O:3])[NH2:2].[F:19][C:20]([F:33])([F:32])[C:21]1[CH:28]=[C:27]([N:29]=[C:30]=[S:31])[CH:26]=[CH:25][C:22]=1[C:23]#[N:24]>CS(C)=O.O>[C:23]([C:22]1[CH:25]=[CH:26][C:27]([N:29]2[C:12](=[O:14])[C:11]([CH3:17])([CH3:16])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([C:1]([NH2:2])=[O:3])=[C:5]([F:18])[CH:6]=3)[C:30]2=[S:31])=[CH:28][C:21]=1[C:20]([F:19])([F:32])[F:33])#[N:24]

Participants

5

Reactant 2

HCID 116155404-Isothiocyanato-2-(trifluoromethyl)benzonitrileHCID 66617687Alanine, N-[4-(aminocarbonyl)-3-fluorophenyl]-2-methyl-, methyl ester

Product 1

HCID 70678916N-Desmethylenzalutamide

Reagents, catalysts & solvents 2

HCID 679Dimethyl SulfoxideSolventHCID 962WaterSolvent

Procedure

A solution of methyl 2-(4-carbamoyl-3-fluorophenylamino)-2-methylpropanoate and 2-(trifluoromethyl)-4-isothiocyanatobenzonitrile (1.5 equivalents) in dry DMSO (5 mL per mmol) was heated to 80-82° C. for 12 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with 40% Acetone-Hexanes. MS (m/z): 451 (M+1). HPLC: Column, YMC ODS A, 4.6×150 mm, 5 μm, Mobile Phase A: 10 mM Ammonium acetate, Mobile Phase B: Acetonitrile, Gradient, 10% B up to 2 min, 10% to 90% B in 3 min, hold for 3 min, 90% to 10% B in 5 min, Retention time, 2.782 min, HPLC Purity, 99.4%, Flow Rate, 1 mL/min. 1H NMR (CDCl3, Freebase): δ (ppm) 8.3 (t, 1H), 8.0 (d, 1H) 7.98 (s, 1H), 7.8 (d, 1H), 7.27 (d, 1H), 7.2 (d, 1H), 6.65 (d, 1H), 6.0 (s, 1H), 1.62 (s, 6H).

Workup

  1. extractionextracted with ethyl acetate
  2. concentrationThe combined organic layer was concentrated under reduced pressure
  3. customthe residue was purified by silica gel chromatography
  4. washeluting with 40% Acetone-Hexanes
  5. wait10% to 90% B in 3 min
  6. waithold for 3 min
  7. wait90% to 10% B in 5 min
  8. customRetention time, 2.782 min, HPLC Purity, 99.4%, Flow Rate, 1 mL/min

Sources & evidence

ORD record
ord-66cb35ff3ac144c3ac94492fd411bb1f
Source dataset
uspto-grants-2015_05
Patent number
US09023879B2

Reaction notes

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