Hydrochloric Acid → tert-butyl (5-(2-(4-(N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-2,5-difluorophenoxy)-5-chlorophenyl)benzo[d]isoxazol-3-yl)carbamate

HRID 2203439Notes

Reaction equation

HRID 2203439 reaction equation
[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][C:26]2[CH:31]=[C:30]([F:32])[C:29]([S:33](=[O:52])(=[O:51])[N:34](CC3C=CC(OC)=CC=3OC)[C:35]3[S:39][N:38]=[CH:37][N:36]=3)=[CH:28][C:27]=2[F:53])=[C:6]([C:8]2[CH:9]=[CH:10][C:11]3[O:15][N:14]=[C:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:12]=3[CH:24]=2)[CH:7]=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+].Cl>ClCCl>[S:39]1[C:35]([NH:34][S:33]([C:29]2[C:30]([F:32])=[CH:31][C:26]([O:25][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][C:6]=3[C:8]3[CH:9]=[CH:10][C:11]4[O:15][N:14]=[C:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:22])[CH3:20])[C:12]=4[CH:24]=3)=[C:27]([F:53])[CH:28]=2)(=[O:51])=[O:52])=[N:36][CH:37]=[N:38]1

Participants

6

Reactant 4

HCID 313Hydrochloric AcidHCID 6422Trifluoroacetic acidHCID 516892Sodium BicarbonateHCID 71558770tert-butyl (5-(5-chloro-2-(4-(N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-2,5-difluorophenoxy)phenyl)benzo[d]isoxazol-3-yl)carbamate

Product 1

HCID 71558918tert-butyl (5-(2-(4-(N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-2,5-difluorophenoxy)-5-chlorophenyl)benzo[d]isoxazol-3-yl)carbamateYield 59%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Conditions

Temperature
0 °C

Procedure

To a solution of tert-butyl (5-(5-chloro-2-(4-(N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-2,5-difluorophenoxy)phenyl)benzo[d]isoxazol-3-yl)carbamate (0.150 g, 0.19 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.1 mL) at 0° C. The reaction mixture was stirred for 20 minutes at 0° C. and saturated aqueous sodium bicarbonate (5 mL) was added. The mixture was allowed to warm to ambient temperature, diluted with dichloromethane (50 mL), and acidified to pH 5 with 1 N hydrochloric acid. The organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography, eluting with a 0-100% ethyl acetate in hexanes, followed by a 0-10% gradient of methanol in ethyl acetate, to afford tert-butyl (5-(2-(4-(N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-2,5-difluorophenoxy)-5-chlorophenyl)benzo[d]isoxazol-3-yl)carbamate in 59% yield (0.071 g) as a colorless solid: 1H NMR (300 MHz, DMSO-d6) δ10.52 (s, 1H), 8.27 (s, 1H), 8.24 (d, J=1.5 Hz, 1H), 7.77 (dd, J=8.8, 1.6 Hz, 1H), 7.69 (d, J=8.7 Hz, 1H), 7.67 (dd, J=6.8, 3.3 Hz, 1H), 7.63 (d, J=2.5 Hz, 1H), 7.48 (dd, J=8.8, 2.6 Hz, 1H), 7.22 (d, J=8.9 Hz, 1H), 7.22-7.16 (m, 1H), 1.44 (s, 9H), (NH not observed); MS (ES+) m/z 657.6 (M+23), 659.5 (M+23).

Workup

  1. temperatureto warm to ambient temperature
  2. washThe organic phase was washed with brine (10 mL)
  3. dry with materialdried over anhydrous sodium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. customThe residue was purified by column chromatography
  7. washeluting with a 0-100% ethyl acetate in hexanes

Sources & evidence

ORD record
ord-7fbb54ab1c254d238f2af8a797b66c21
Source dataset
uspto-grants-2016_06
Patent number
US09365578B2

Reaction notes

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