Dimethylformamide → ethyl 2-(diphenylmethyleneamino)-2-methyl-4-(3-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)butanoate

HRID 1506401Notes

Reaction equation

HRID 1506401 reaction equation
[C:1]1([C:7](=[N:14][CH:15]([CH2:21][CH2:22][C:23]2[CH:24]=[C:25]3[C:48](=[CH:49][CH:50]=2)[C:29]2=[N:30][O:31][C:32]([C:33]4[CH:34]=[N:35][N:36]([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)[C:37]=4[C:38]([F:41])([F:40])[F:39])=[C:28]2[CH2:27][CH2:26]3)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:51][Si]([N-][Si](C)(C)C)(C)C.[Li+].IC.CN(C=O)C>C1COCC1>[C:1]1([C:7](=[N:14][C:15]([CH3:51])([CH2:21][CH2:22][C:23]2[CH:24]=[C:25]3[C:48](=[CH:49][CH:50]=2)[C:29]2=[N:30][O:31][C:32]([C:33]4[CH:34]=[N:35][N:36]([C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=5)[C:37]=4[C:38]([F:40])([F:41])[F:39])=[C:28]2[CH2:27][CH2:26]3)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1

Participants

6

Reactant 4

HCID 6228DimethylformamideHCID 6328Methyl iodide2×HCID 2733832Lithium Hexamethyldisilazide2×HCID 86669896ethyl 2-(diphenylmethyleneamino)-4-(3-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)butanoate

Product 1

HCID 86669897ethyl 2-(diphenylmethyleneamino)-2-methyl-4-(3-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)butanoateYield 78.4%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

To a stirred clear solution of ethyl 2-(diphenylmethyleneamino)-4-(3-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)butanoate (Preparation 50B, 150 mg, 0.222 mmol) in anhydrous THF (5 mL) was added a 1 M THF solution of lithium bis(trimethylsilyl)amide (333 μL, 0.333 mmol) dropwise at 0° C. under nitrogen. The reaction mixture was stirred at the same temperature for 30 min before iodomethane (50 μL, 0.800 mmol) was added. The reaction mixture was stirred at 0° C. for 30 min and at room temperature for 1 hr. The reaction was not complete. Anhydrous DMF (2 mL) was added, followed by lithium bis(trimethylsilyl)amide (2 mL, 2 mmol) at 0° C. The reaction mixture was stirred at the same temperature for 30 min before iodomethane (0.2 mL) was added. The mixture was stirred at 0° C. for 1 hr and quenched using saturated aqueous ammonium chloride solution (5 mL), ethyl acetate (10 mL), and water (10 mL). The aqueous solution was separated and re-extracted with ethyl acetate (2×5 mL). The combined ethyl acetate extracts were dried over sodium sulfate and concentrated under reduced pressure. Flash chromatography purification using ISCO (4 g silica gel column, 10→100% ethyl acetate in hexanes) afforded ethyl 2-(diphenylmethyleneamino)-2-methyl-4-(3-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)butanoate (120 mg, 0.174 mmol, 78% yield) as a solid. LC/MS M+1=689.5.

Workup

  1. additionwas added
  2. additionwas added
  3. stirringThe mixture was stirred at 0° C. for 1 hr
  4. customquenched
  5. customThe aqueous solution was separated
  6. extractionre-extracted with ethyl acetate (2×5 mL)
  7. dry with materialThe combined ethyl acetate extracts were dried over sodium sulfate
  8. concentrationconcentrated under reduced pressure
  9. customFlash chromatography purification

Sources & evidence

ORD record
ord-435e121a6dd04a9783ba288aa3bef9fd
Source dataset
uspto-grants-2015_12
Patent number
US09216972B2

Reaction notes

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