Water → Cyclopropyl(3-fluoro-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)azetidin-1-yl)methanone

HRID 1961531Notes

Reaction equation

HRID 1961531 reaction equation
[F:1][C:2]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH2:16][C:15]([C:21]4[CH:26]=[C:25]([Cl:27])[C:24]([Cl:28])=[C:23]([Cl:29])[CH:22]=4)([C:17]([F:20])([F:19])[F:18])[O:14][N:13]=3)=[CH:8][CH:7]=2)[CH2:5][NH:4][CH2:3]1.N1C=CC=CC=1.[CH:36]1([C:39](Cl)=[O:40])[CH2:38][CH2:37]1.O>C(Cl)Cl>[CH:36]1([C:39]([N:4]2[CH2:3][C:2]([F:1])([C:6]3[CH:11]=[CH:10][C:9]([C:12]4[CH2:16][C:15]([C:21]5[CH:26]=[C:25]([Cl:27])[C:24]([Cl:28])=[C:23]([Cl:29])[CH:22]=5)([C:17]([F:19])([F:20])[F:18])[O:14][N:13]=4)=[CH:8][CH:7]=3)[CH2:5]2)=[O:40])[CH2:38][CH2:37]1

Participants

6

Reactant 4

HCID 962WaterHCID 1049PyridineHCID 77637Cyclopropanecarbonyl chlorideHCID 781477423-(4-(3-Fluoroazetidin-3-yl)phenyl)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole

Product 1

HCID 56650627Cyclopropyl(3-fluoro-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)azetidin-1-yl)methanoneYield 80.8%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

To a solution of the 3-(4-(3-fluoroazetidin-3-yl)phenyl)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (Preparation 9, 94 mg) in 2 mL CH2Cl2 was added pyridine (0.05 mL) followed by cyclopropane carbonyl chloride (31 mg). The reaction was allowed to stir at room temperature for 1 hour. Water (10 mL) was added. The reaction was diluted with an additional 10 mL of CH2Cl2, stirred for 30 minutes at room temperature then passed through a phase separation tube. The CH2Cl2 layer was collected and condensed. The crude material was adsorbed on silica and chromatographed on a 12 g silica column, eluting with a gradient of 20% EtOAc/hexane to 80% EtOAc/hexane. Fractions containing the desired material were combined and concentrated. Et2O (˜½ mL) was added to the resulting film. Placing the flask on high vac overnight resulted in formation of the product as a white foam (87 mg). 1H NMR (CDCl3) δ ppm 7.76 (d, 2H), 7.67 (s, 2H), 7.58 (d, 2H), 4.8-4.7 (m, 1H), 4.6-4.2 (m, 3H), 4.12 (d, 1H), 3.72 (d, 1H), 1.5-1.4 (m, 1H), 1.08 (m, 2H), 0.86 (m, 2H). LC/MS retention time=3.710 minutes, MS calculated for (C23H17Cl3F4N2O2), 534.03; found 535.0 M+H.

Workup

  1. stirringstirred for 30 minutes at room temperature
  2. customthen passed through a phase separation tube
  3. customThe CH2Cl2 layer was collected
  4. customcondensed
  5. customchromatographed on a 12 g silica column
  6. washeluting with a gradient of 20% EtOAc/hexane to 80% EtOAc/hexane
  7. additionFractions containing the desired material
  8. concentrationconcentrated
  9. additionEt2O (˜½ mL) was added to the resulting film
  10. customon high vac overnight

Sources & evidence

ORD record
ord-96e38bfa7d1742979885af1d623ebdab
Source dataset
uspto-grants-2013_04
Patent number
US08415310B2

Reaction notes

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