Methyl iodide → Ethyl 2-(diphenylmethyleneamino)-2-methyl-4-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)butanoate

HRID 1506504Notes

Reaction equation

HRID 1506504 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[C:37]([C:38]([F:41])([F:40])[F:39])=[C:36]([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)[O:35][N:34]=4)=[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.[Cl-].[NH4+]>C1COCC1.O>[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[C:37]([C:38]([F:41])([F:40])[F:39])=[C:36]([C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=5)[O:35][N:34]=4)=[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

7

Reactant 4

HCID 6328Methyl iodide2×HCID 25517Ammonium ChlorideHCID 2733832Lithium HexamethyldisilazideHCID 86669931Ethyl 2-(diphenylmethyleneamino)-4-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)butanoate

Product 1

HCID 86669932Ethyl 2-(diphenylmethyleneamino)-2-methyl-4-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)butanoateYield 52.5%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

To a clear solution of ethyl 2-(diphenylmethyleneamino)-4-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)butanoate (Preparation 91A, 560 mg, 0.829 mmol) in anhydrous THF (20 mL) was added 1 M THF solution of lithium bis(trimethylsilyl)amide (4 mL, 4.00 mmol) dropwise at 0° C. under nitrogen. The mixture was stirred at the same temperature for 60 min. before half the amount of the required iodomethane (0.25 mL, 4.00 mmol) was added. The mixture was stirred at 0° C. for 20 min. before the rest of the iodomethane was added. The mixture was stirred at 0° C. for an additional 50 min. and saturated aqueous ammonium chloride solution (5 mL) and water (2 mL) were added. The mixture was extracted with ethyl acetate (10 mL and then 2×5 mL). The combined ethyl acetate extracts were dried (sodium sulfate) and concentrated under reduced pressure. Flash chromatography purification (24 g silica gel column, 5→50% ethyl acetate in hexanes) afforded ethyl 2-(diphenylmethyleneamino)-2-methyl-4-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)butanoate (300 mg, 0.435 mmol, 52.5% yield) as a glassy solid. The compound had an LC/MS M+1=690.4.

Workup

  1. additionwas added
  2. additionwas added
  3. extractionThe mixture was extracted with ethyl acetate (10 mL
  4. dry with materialThe combined ethyl acetate extracts were dried (sodium sulfate)
  5. concentrationconcentrated under reduced pressure
  6. customFlash chromatography purification (24 g silica gel column, 5→50% ethyl acetate in hexanes)

Sources & evidence

ORD record
ord-ebca98ac80374d1497c43c2a6128e7e4
Source dataset
uspto-grants-2015_12
Patent number
US09216972B2

Reaction notes

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