Sodium Bicarbonate → Disodium;[3,3-difluoro-1-[[2-methoxy-4-[2-oxo-3-[4-(trifluoromethoxy)phenyl]sulfanylpyrazin-1-yl]phenoxy]methyl]cyclobutyl] phosphate

HRID 906235Notes

Reaction equation

HRID 906235 reaction equation
[P:1]([O:19][C:20]1([CH2:26][O:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH:39]=[CH:38][N:37]=[C:36]([S:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][C:48]([F:51])([F:50])[F:49])=[CH:43][CH:42]=4)[C:35]3=[O:52])=[CH:30][C:29]=2[O:53][CH3:54])[CH2:23][C:22]([F:25])([F:24])[CH2:21]1)([O:11]CC1C=CC=CC=1)([O:3]CC1C=CC=CC=1)=[O:2].C(=O)(O)[O-].[Na+:59]>C(O)(C(F)(F)F)=O.C(#N)C.O>[P:1]([O-:11])([O-:3])([O:19][C:20]1([CH2:26][O:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH:39]=[CH:38][N:37]=[C:36]([S:40][C:41]4[CH:42]=[CH:43][C:44]([O:47][C:48]([F:51])([F:50])[F:49])=[CH:45][CH:46]=4)[C:35]3=[O:52])=[CH:30][C:29]=2[O:53][CH3:54])[CH2:23][C:22]([F:25])([F:24])[CH2:21]1)=[O:2].[Na+:59].[Na+:59]

Participants

6

Reactant 2

HCID 516892Sodium BicarbonateHCID 57540648dibenzyl 3,3-difluoro-1-((2-methoxy-4-(2-oxo-3-(4-(trifluoromethoxy)phenylthio)pyrazin-1(2H)-yl)phenoxy)methyl)cyclobutyl phosphate

Product 1

HCID 57540655Disodium;[3,3-difluoro-1-[[2-methoxy-4-[2-oxo-3-[4-(trifluoromethoxy)phenyl]sulfanylpyrazin-1-yl]phenoxy]methyl]cyclobutyl] phosphateYield 103.3%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6342AcetonitrileSolventHCID 6422Trifluoroacetic acidSolvent

Procedure

To a solution of 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) in TFA (2 mL) was stirred at RT for 3.5 hours. The mixture was concentrated. The crude product was purified by prep-HPLC (Phenomenex, Luna 5 micron 25×250 mm, flow rate=30 ml/min., gradient=20% A to 100% B in 10 min., A=90% H2O/10% MeOH/0.1% TFA, B=10% H2O/90% MeOH/0.1% TFA). Yield 46 mg, 0.075 mmol as yellow gum. The yellow gum in ACN (2 ml) was added 0.5 N aqueous sodium bicarbonate (302 μl, 0.151 mmol), the mixture was diluted with water (5 ml). The solution was then lyophilized. Yield sodium 3,3-difluoro-1-((2-methoxy-4-(2-oxo-3-(4-(trifluoromethoxy)phenylthio)pyrazin-1(2H)-yl)phenoxy)methyl)cyclobutyl phosphate (51.08 mg, 0.078 mmol, 78% yield) as off-white powder. MS (M+H=611). 1H NMR (400 MHz, MeOD) δ ppm 7.54-7.63 (2H, m), 7.19-7.33 (3 H, m), 7.02-7.17 (3H, m), 6.91 (1H, dd, J=8.44, 2.39 Hz), 4.28 (2H, s), 3.80 (3H, s), 3.13-3.32 (2H, m), 2.75-2.90 (2H, m).

Workup

  1. concentrationThe mixture was concentrated
  2. customThe crude product was purified by prep-HPLC (Phenomenex, Luna 5 micron 25×250 mm, flow rate=30 ml/min., gradient=20% A to 100% B in 10 min.

Sources & evidence

ORD record
ord-e4f90b23a52d4b4daa1de1b343d85976
Source dataset
uspto-grants-2011_09
Patent number
US08012984B2

Reaction notes

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