Triethylamine → 7-(2,2-dimethyl-1,3-dioxolan-4-yl)-9b-morpholino-3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,9b-dihydro-3aH-chromeno[3,4-d]isoxazole

HRID 1506426Notes

Reaction equation

HRID 1506426 reaction equation
[OH:1][N:2]=[C:3](Cl)[C:4]1[O:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]=1[C:15]([F:18])([F:17])[F:16].[CH3:20][C:21]1([CH3:42])[O:25][CH:24]([C:26]2[CH:35]=[C:34]3[C:29]([C:30]([N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)=[CH:31][CH2:32][O:33]3)=[CH:28][CH:27]=2)[CH2:23][O:22]1.C(N(CC)CC)C>ClCCl>[CH3:20][C:21]1([CH3:42])[O:25][CH:24]([C:26]2[CH:27]=[CH:28][C:29]3[C:30]4([N:36]5[CH2:41][CH2:40][O:39][CH2:38][CH2:37]5)[CH:31]([C:3]([C:4]5[O:8][N:7]=[C:6]([C:9]6[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=6)[C:5]=5[C:15]([F:18])([F:17])[F:16])=[N:2][O:1]4)[CH2:32][O:33][C:34]=3[CH:35]=2)[CH2:23][O:22]1

Participants

5

Reactant 3

HCID 8471TriethylamineHCID 671706084-(7-(2,2-dimethyl-1,3-dioxolan-4-yl)-2H-chromen-4-yl)morpholineHCID 136350289N-hydroxy-3-phenyl-4-(trifluoromethyl)isoxazole-5-carbimidoyl chloride2×

Product 1

HCID 671717007-(2,2-dimethyl-1,3-dioxolan-4-yl)-9b-morpholino-3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,9b-dihydro-3aH-chromeno[3,4-d]isoxazoleYield 12%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

To a solution of the N-hydroxy-3-phenyl-4-(trifluoromethyl)isoxazole-5-carbimidoyl chloride (Intermediate 1-12, 0.340 g, 1.170 mmol) in dichloromethane (3.5 mL) was added 4-(7-(2,2-dimethyl-1,3-dioxolan-4-yl)-2H-chromen-4-yl)morpholine (Preparation 60C, 0.473 M in dichloromethane) (2.47 mL, 1.17 mmol). The reaction mixture was cooled to 0° C., and triethylamine (0.324 mL, 2.34 mmol) was added dropwise over 10 min. The ice-bath was removed, and the resulting cloudy solution was stirred at room temperature for 1.5 h. The reaction mixture was diluted with dichloromethane (50 mL), washed with water (25 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure to afford the crude product as an orange oil. The compound was purified by flash silica gel chromatography using a mixture of ethyl acetate and hexane (5%-12%-20%) to give 7-(2,2-dimethyl-1,3-dioxolan-4-yl)-9b-morpholino-3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,9b-dihydro-3aH-chromeno[3,4-d]isoxazole (0.080 g, 0.140 mmol, 12% yield) as a yellow solid. The product had an HPLC ret. time=3.25 min.−Column: Chromolith SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=572.1.

Workup

  1. customThe ice-bath was removed
  2. additionThe reaction mixture was diluted with dichloromethane (50 mL)
  3. washwashed with water (25 mL)
  4. dry with materialdried over anhydrous sodium sulfate
  5. concentrationconcentrated under reduced pressure
  6. customto afford the crude product as an orange oil
  7. customThe compound was purified by flash silica gel chromatography
  8. additiona mixture of ethyl acetate and hexane (5%-12%-20%)

Sources & evidence

ORD record
ord-cce1ce52de964b85b760496cbf4ebd0c
Source dataset
uspto-grants-2015_12
Patent number
US09216972B2

Reaction notes

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