Triethylamine → 7-(2,2-Dimethyl-1,3-dioxolan-4-yl)-9b-morpholino-3-(5-phenyl-4-(trifluoromethyl)-isoxazol-3-yl)-3a,4,5,9b-tetrahydroisoxazolo[5,4-f]quinoline

HRID 1506413Notes

Reaction equation

HRID 1506413 reaction equation
[CH3:1][C:2]1([CH3:23])[O:6][CH:5]([C:7]2[CH:16]=[CH:15][C:14]3[C:13]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[CH:12][CH2:11][CH2:10][C:9]=3[N:8]=2)[CH2:4][O:3]1.[OH:24]/[N:25]=[C:26](\Cl)/[C:27]1[C:31]([C:32]([F:35])([F:34])[F:33])=[C:30]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[O:29][N:28]=1.C(N(CC)CC)C>ClCCl>[CH3:1][C:2]1([CH3:23])[O:6][CH:5]([C:7]2[CH:16]=[CH:15][C:14]3[C:13]4([N:17]5[CH2:22][CH2:21][O:20][CH2:19][CH2:18]5)[O:24][N:25]=[C:26]([C:27]5[C:31]([C:32]([F:35])([F:33])[F:34])=[C:30]([C:36]6[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=6)[O:29][N:28]=5)[CH:12]4[CH2:11][CH2:10][C:9]=3[N:8]=2)[CH2:4][O:3]1

Participants

5

Reactant 3

HCID 8471TriethylamineHCID 671700704-(2-(2,2-Dimethyl-1,3-dioxolan-4-yl)-7,8-dihydroquinolin-5-yl)morpholineHCID 136374584(3Z)-N-hydroxy-5-phenyl-4-(trifluoromethyl)-1,2-oxazole-3-carboximidoyl chloride2×

Product 1

HCID 671705577-(2,2-Dimethyl-1,3-dioxolan-4-yl)-9b-morpholino-3-(5-phenyl-4-(trifluoromethyl)-isoxazol-3-yl)-3a,4,5,9b-tetrahydroisoxazolo[5,4-f]quinoline

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Conditions

Temperature
0 °C

Procedure

To a solution of 4-(2-(2,2-dimethyl-1,3-dioxolan-4-yl)-7,8-dihydroquinolin-5-yl)morpholine (Preparation 15F, 0.194 g, 0.613 mmol) in dichloromethane (2 mL) was added a solution of (Z)—N-hydroxy-5-phenyl-4-(trifluoromethyl)isoxazole-3-carbimidoyl chloride (Intermediate 13, 0.210 g, 0.613 mmol) in dichloromethane (1 mL). The reaction mixture was cooled to 0° C., and triethylamine (0.093 mL, 0.674 mmol) was added dropwise over 2 min. The ice-bath was removed, and the resulting cloudy solution was stirred at room temperature for 30 min. The reaction mixture was diluted with dichloromethane (30 mL), washed with water (15 mL), dried over anhydrous sodium sulfate, and concentrated to give the morpholino-intermediate, 7-(2,2-dimethyl-1,3-dioxolan-4-yl)-9b-morpholino-3-(5-phenyl-4-(trifluoromethyl)-isoxazol-3-yl)-3a,4,5,9b-tetrahydroisoxazolo[5,4-f]quinoline, as an orange oil. To the oil was added dichloroethane (3 mL) and TFA (0.071 mL, 0.920 mmol), and the reaction mixture was heated at 80° C. for 60 min. The reaction mixture was stirred overnight at room temperature. Additional TFA (0.071 mL, 0.920 mmol) was added, and the reaction mixture was heated at 80° C. for 6 h. The reaction mixture was diluted with dichloromethane (30 mL), washed with a saturated aqueous solution of sodium bicarbonate (15 mL), and dried over anhydrous sodium sulfate. Concentration under reduced pressure followed by trituration with methanol with sonication afforded 44 mg of a 3:7 mixture of 1-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydroisoxazolo[5,4-f]quinolin-7-yl)ethane-1,2-diol and 7-(oxiran-2-yl)-3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydroisoxazolo[5,4-f]quinoline as a light brown solid.

Workup

  1. customThe ice-bath was removed
  2. additionThe reaction mixture was diluted with dichloromethane (30 mL)
  3. washwashed with water (15 mL)
  4. dry with materialdried over anhydrous sodium sulfate
  5. concentrationconcentrated

Sources & evidence

ORD record
ord-7863a567add041ce98f097cebc481bd5
Source dataset
uspto-grants-2015_12
Patent number
US09216972B2

Reaction notes

Loading…