Hydrogen Peroxide → dibenzyl 3,3-difluoro-1-((2-methoxy-4-(2-oxo-3-(4-(trifluoromethoxy)phenylthio)pyrazin-1(2H)-yl)phenoxy)methyl)cyclobutyl phosphate

HRID 562593Notes

Reaction equation

HRID 562593 reaction equation
C(N(C(C)C)[P:5]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(C)C.[F:25][C:26]1([F:60])[CH2:29][C:28]([CH2:31][O:32][C:33]2[CH:38]=[CH:37][C:36]([N:39]3[CH:44]=[CH:43][N:42]=[C:41]([S:45][C:46]4[CH:51]=[CH:50][C:49]([O:52][C:53]([F:56])([F:55])[F:54])=[CH:48][CH:47]=4)[C:40]3=[O:57])=[CH:35][C:34]=2[O:58][CH3:59])([OH:30])[CH2:27]1.N1C=NC=N1.[OH:66]O>ClCCCl.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>[P:5]([O:30][C:28]1([CH2:31][O:32][C:33]2[CH:38]=[CH:37][C:36]([N:39]3[CH:44]=[CH:43][N:42]=[C:41]([S:45][C:46]4[CH:47]=[CH:48][C:49]([O:52][C:53]([F:55])([F:54])[F:56])=[CH:50][CH:51]=4)[C:40]3=[O:57])=[CH:35][C:34]=2[O:58][CH3:59])[CH2:29][C:26]([F:25])([F:60])[CH2:27]1)([O:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:66]

Participants

8

Reactant 4

HCID 784Hydrogen PeroxideHCID 92571H-1,2,4-TriazoleHCID 196621Bis(benzyloxy)(diisopropylamino)phosphineHCID 57540520HCID 57540520, compound

Product 1

HCID 57540648dibenzyl 3,3-difluoro-1-((2-methoxy-4-(2-oxo-3-(4-(trifluoromethoxy)phenylthio)pyrazin-1(2H)-yl)phenoxy)methyl)cyclobutyl phosphateYield 77%

Reagents, catalysts & solvents 3

HCID 111,2-DichloroethaneSolventHCID 962WaterSolventHCID 24477Sodium ThiosulfateSolvent

Procedure

To a mixture of dibenzyl diisopropylphosphoramidite (135 mg, 0.390 mmol), 1-(4-((3,3-difluoro-1-hydroxycyclobutyl)methoxy)-3-methoxyphenyl)-3-(4-(trifluoromethoxy)phenylthio)pyrazin-2(1H)-one (Example 75) (69 mg, 0.130 mmol) and 1H-1,2,4-triazole (27.0 mg, 0.390 mmol) in DCE (20 mL) was stirred at reflux for 6 hours. The mixture was cooled to RT. 30% hydrogen peroxide in water (10 ml) was slowly added and the mixture was stirred at RT for 30 min. The mixture was diluted with a solution of aqueous 10% sodium thiosulfate (40 ml) and was extracted with DCM (50 ml). The DCM layer was dried over sodium sulfate and concentrated. The crude product was purified by ISCO silica gel Column (40 g) and the product was eluted with hexane to 100% ethyl acetate in 10 min. Yield dibenzyl 3,3-difluoro-1-((2-methoxy-4-(2-oxo-3-(4-(trifluoromethoxy)phenylthio)pyrazin-1(2H)-yl)phenoxy)methyl)cyclobutyl phosphate (79 mg, 0.100 mmol, 77% yield) as off-white solid. 1H NMR (400 MHz, chloroform-d) δ ppm 7.57-7.66 (2H, m), 7.27-7.39 (12H, m), 7.13 (1H, d, J=4.53 Hz), 6.81-7.00 (4H, m), 4.97-5.14 (4H, m), 4.29 (2H, s), 3.75 (3H, s), 2.93-3.20 (4H, m).

Workup

  1. temperatureat reflux for 6 hours
  2. stirringthe mixture was stirred at RT for 30 min
  3. extractionwas extracted with DCM (50 ml)
  4. dry with materialThe DCM layer was dried over sodium sulfate
  5. concentrationconcentrated
  6. customThe crude product was purified by ISCO silica gel Column (40 g)
  7. washthe product was eluted with hexane to 100% ethyl acetate in 10 min

Sources & evidence

ORD record
ord-74c62050b61e48cbbfe280586091e320
Source dataset
uspto-grants-2011_11
Patent number
US08067420B2

Reaction notes

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