Acetohydroxamic Acid → 5-(2-((S)-2-amino-3-(4-(trifluoromethyl)phenyl)-propylamino)thiazol-5-yl)benzo[d]isoxazol-3-amine

HRID 2109716Notes

Reaction equation

HRID 2109716 reaction equation
[OH:1][NH:2][C:3](=O)[CH3:4].CC(C)([O-])C.[K+].[NH2:12][C@@H:13]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=1)[CH2:14][NH:15][C:16]1[S:17][C:18]([C:21]2[CH:22]=C[C:24](F)=[C:25]([CH:28]=2)C#N)=[CH:19][N:20]=1.C[N:42](C=O)C>CCOC(C)=O>[NH2:12][C@@H:13]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]([F:39])([F:40])[F:38])=[CH:33][CH:32]=1)[CH2:14][NH:15][C:16]1[S:17][C:18]([C:21]2[CH:28]=[CH:25][C:24]3[O:1][N:2]=[C:3]([NH2:42])[C:4]=3[CH:22]=2)=[CH:19][N:20]=1

Participants

6

Reactant 4

HCID 1990Acetohydroxamic AcidHCID 6228Dimethylformamide2×HCID 23665647Potassium tert-butoxideHCID 866137675-(2-((S)-2-amino-3-(4-(trifluoromethyl)phenyl)propylamino)thiazol-5-yl)-2-fluorobenzonitrile

Product 1

HCID 236542585-(2-((S)-2-amino-3-(4-(trifluoromethyl)phenyl)-propylamino)thiazol-5-yl)benzo[d]isoxazol-3-amineYield 20%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Procedure

To a solution of N-hydroxyacetamide (0.02 g, 0.3 mmol) in 1.5 mL of DMF, was added potassium tert-butoxide (1.0 M in THF (0.3 mL, 0.3 mmol)). The mixture was stirred for 30 minutes and then 5-(2-((S)-2-amino-3-(4-(trifluoromethyl)phenyl)-propylamino)thiazol-5-yl)-2-fluorobenzonitrile (0.086 g, 0.2 mmol) was added in 1.5 mL of DMF. The mixture was stirred for 12 hours and was then diluted with 20 mL of EtOAc. The organic layer was washed with 10 mL of brine and was then dried over MgSO4. Filtration and concentration under reduced pressure, followed by HPLC purification (95:5 to 70:30 water:MeCN over 50 minutes) afforded 5-(2-((S)-2-amino-3-(4-(trifluoromethyl)phenyl)-propylamino)thiazol-5-yl)benzo[d]isoxazol-3-amine (0.018 g, 0.04 mmol, 20% yield) as an amorphous solid. 1H NMR (400 MHz DMSO-d6) δ ppm 7.84 (s, 1H), 7.63-7.67 (m, 1H), 7.65 (d, 9.1 Hz, 2H), 7.50 (d, J=8.0 Hz, 2H), 7.40 (d, J=8.7 Hz, 1H), 7.25 (s, 1H), 5.51 (s, 2H), 3.52-3.43 (m, 2H), 3.38-3.32 (m, 1H), 3.03 (dd, J=5.3, 13.7 Hz, 1H), 2.82 (dd, J=7.5, 13.7 Hz, 1H). HRMS (M+H) for C20H18F3N5OS calc. 434.12569, obs. 434.12614.

Workup

  1. stirringThe mixture was stirred for 12 hours
  2. washThe organic layer was washed with 10 mL of brine
  3. dry with materialwas then dried over MgSO4
  4. filtrationFiltration and concentration under reduced pressure
  5. customfollowed by HPLC purification (95:5 to 70:30 water:MeCN over 50 minutes)

Sources & evidence

ORD record
ord-44b26b97e82545029489b67a86d967ec
Source dataset
uspto-grants-2009_04
Patent number
US07514566B2

Reaction notes

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