Methanol → 5-(3,5-dimethylisoxazol-4-yl)-N'-hydroxy-1-(4-hydroxyphenyl)-3-methyl-1H-pyrazole-4-carboximidamide

HRID 242178Notes

Reaction equation

HRID 242178 reaction equation
Cl.[NH2:2][OH:3].C([O-])(O)=O.[Na+].CO.[CH3:11][C:12]1[C:16]([C:17]2[N:21]([C:22]3[CH:27]=[CH:26][C:25]([O:28]C)=[CH:24][CH:23]=3)[N:20]=[C:19]([CH3:30])[C:18]=2[C:31]#[N:32])=[C:15]([CH3:33])[O:14][N:13]=1>O.[Cl-].[Na+].O.CCOC(C)=O>[NH2:13][OH:14].[CH3:11][C:12]1[C:16]([CH:17]2[N:21]([C:22]3[CH:23]=[CH:24][C:25]([OH:28])=[CH:26][CH:27]=3)[N:20]=[C:19]([CH3:30])[CH:18]2[C:31](=[N:2][OH:3])[NH2:32])=[C:15]([CH3:33])[O:14][N:13]=1.[CH3:11][C:12]1[C:16]([C:17]2[N:21]([C:22]3[CH:23]=[CH:24][C:25]([OH:28])=[CH:26][CH:27]=3)[N:20]=[C:19]([CH3:30])[C:18]=2[C:31](=[N:2][OH:3])[NH2:32])=[C:15]([CH3:33])[O:14][N:13]=1

Participants

10

Reactant 4

HCID 887MethanolHCID 443297Hydroxyamine hydrochlorideHCID 516892Sodium BicarbonateHCID 671200255-(3,5-dimethylisoxazol-4-yl)-1-(4-methoxyphenyl)-3-methyl-1H-pyrazole-4-carbonitrile

Product 3

HCID 787HydroxylamineHCID 759521745-(3,5-dimethylisoxazol-4-yl)-N'-hydroxy-1-(4-hydroxyphenyl)-3-methyl-1H-pyrazole-4-carboximidamideYield 62.5%HCID 866689725-(3,5-dimethylisoxazol-4-yl)-N'-hydroxy-1-(4-hydroxyphenyl)-3-methyl-4H-pyrazole-4-carboximidamide

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 8857Ethyl AcetateSolventHCID 57417360Sodium chloride; waterSolvent

Conditions

Temperature
130 °C

Procedure

A hydroxylamine solution was prepared. Hydroxylamine-HCl (26 mg, 0.37 mmol) and NaHCO3 (32 mg, 0.37 mmol) dissolved in water (0.2 mL), methanol (0.4 mL) was stirred 2 min until gas ceased to evolve, the mixture was filtered and degassed (N2). This was added to the 5-(3,5-dimethylisoxazol-4-yl)-1-(4-methoxyphenyl)-3-methyl-1H-pyrazole-4-carbonitrile (11 mg, 0.037 mmol) and stirred at 130° C. for 30 min in the microwave. EtOAc and brine were added and the phases were separated. Purification using preparative HPLC gave E1 5-(3,5-dimethylisoxazol-4-yl)-N′-hydroxy-1-(4-hydroxyphenyl)-3-methyl-1H-pyrazole-4-carboximidamide (2.52 mg, 7.71 μmol, 21%) ES/MS m/z: 328.19 (M+H), 326.22 (M−H); 1H NMR (acetone-d6, 500 MHz): 7.10 m 2H; 6.84 m 2H, 2.36 s 3H, 2.10 s 3H, 1.89 s 3H. Starting material 5-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-3-methyl-1H-pyrazole-4-carbonitrile was recovered (0.99 mg, 3.36 μmol) as well as E2 5-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-3-methyl-1H-pyrazole-4-carboxamide (3.22 mg, 0.01 mmol) ES/MS m/z: 313.17 (M+H), 311.22 (M−H); 1H NMR (acetone-d6, 500 MHz): 7.10 m 2H, 6.85 m 2H, 2.47 s 3H, 2.12 s 3H, 1.95 s 3H. Identification of Example 6 by 1H-NMR showed that the oxime product was a single isomer, but did not confirm whether the (E) or (Z) oxime isomer had been obtained.

Workup

  1. filtrationthe mixture was filtered
  2. customdegassed (N2)
  3. customthe phases were separated
  4. customPurification

Sources & evidence

ORD record
ord-01aecca03e9545e0b2298dc065d2018b
Source dataset
uspto-grants-2014_02
Patent number
US08653112B2

Reaction notes

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