Acetohydroxamic Acid → 1-(3-amino-1,2-benzisoxazol-5-yl)-6-[4-(2-oxo-1-piperidinyl)phenyl]-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridine-7-one

HRID 1391925Notes

Reaction equation

HRID 1391925 reaction equation
C([NH:4][OH:5])(=O)C.C([O-])([O-])=O.[K+].[K+].F[C:13]1[CH:20]=[CH:19][C:18]([N:21]2[C:25]3[C:26](=[O:43])[N:27]([C:30]4[CH:35]=[CH:34][C:33]([N:36]5[CH2:41][CH2:40][CH2:39][CH2:38][C:37]5=[O:42])=[CH:32][CH:31]=4)[CH2:28][CH2:29][C:24]=3[C:23]([C:44]([F:47])([F:46])[F:45])=[N:22]2)=[CH:17][C:14]=1[C:15]#[N:16].C(O)(C(F)(F)F)=O>CN(C=O)C.O>[NH2:16][C:15]1[C:14]2[CH:17]=[C:18]([N:21]3[C:25]4[C:26](=[O:43])[N:27]([C:30]5[CH:35]=[CH:34][C:33]([N:36]6[CH2:41][CH2:40][CH2:39][CH2:38][C:37]6=[O:42])=[CH:32][CH:31]=5)[CH2:28][CH2:29][C:24]=4[C:23]([C:44]([F:46])([F:45])[F:47])=[N:22]3)[CH:19]=[CH:20][C:13]=2[O:5][N:4]=1

Participants

7

Reactant 4

HCID 1990Acetohydroxamic AcidHCID 6422Trifluoroacetic acidHCID 11430Potassium CarbonateHCID 222500932-fluoro-5-[7-oxo-6-[4-(2-oxo-1-piperidinyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-1-yl]benzonitrile

Product 1

HCID 101858661-(3-amino-1,2-benzisoxazol-5-yl)-6-[4-(2-oxo-1-piperidinyl)phenyl]-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridine-7-oneYield 81.6%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent2×

Procedure

Acetohydroxamic acid (54 mg, 0.72 mmol) and K2CO3 (0.2 g, 1.45 mmol) were added to 8 mL of DMF and 4 mL of H2O. The mixture was stirred at rt for 15 min, followed by addition of a solution of 2-fluoro-5-[7-oxo-6-[4-(2-oxo-1-piperidinyl)phenyl]-3-(trifluoromethyl)-4,5,6,7,-tetrahydro-1H-pyrazolo[3,4-c]pyridin-1-yl]benzonitrile (0.12 g, 0.24 mmol) in DMF(2 mL). The mixture was stirred at rt overnight. The mixture was then partitioned between ethylacetate (40 mL) and water (20 mL), washed with H20 (20 mL×3) and brine (20 mL), dried over Na2SO4, filtered, and concentrated. HPLC (C18 RP., 0.5% TFA, H2O/MeCN gradient) purification gave 100 mg (67% yield) of the title compound as its TFA salt. LRMS (ESI−): 623.4 (M+TFA−H)−. 1H NMR (CDCl3) δ 7.80 (s, 1H), 7.72 (d, 1H), 7.44 (d, 1H), 7.34-7.24 (m, 4H), 4.16 (t, 2H), 3.98 (br, 2H), 3.61 (br, 2H), 3.20 (t, 2H), 2.60 (br, 2H), 1.98-1.89 (m, 4H).

Workup

  1. stirringThe mixture was stirred at rt overnight
  2. customThe mixture was then partitioned between ethylacetate (40 mL) and water (20 mL)
  3. washwashed with H20 (20 mL×3) and brine (20 mL)
  4. dry with materialdried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customHPLC (C18 RP., 0.5% TFA, H2O/MeCN gradient) purification

Sources & evidence

ORD record
ord-39daa9fa7ed94adcb6d91a176b8fb01e
Source dataset
uspto-grants-2008_03
Patent number
US07338963B2

Reaction notes

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