Sodium hydride → 1-(4-(S),5-(S)-Bis-benzyloxy-6-(R)-benzyloxymethyl-3-(R)-hydroxy-tetrahydro-pyran-2-(R)-yl)-3-(S)-(5-chloro-2-methoxy-phenyl)-3-fluoro-6-trifluoromethyl-1,3-dihydro-indol-2-one

HRID 895805Notes

Reaction equation

HRID 895805 reaction equation
[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([C@@:8]2([F:22])[C:16]3[C:11](=[CH:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=3)[NH:10][C:9]2=[O:21])[CH:7]=1.[H-].[Na+].[CH2:27]([O:34][C@H:35]1[C@H:40]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C@@H:39]([CH2:49][O:50][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[O:38][C@@H:37]2[O:58][C@H:36]12)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH2:27]([O:34][C@@H:35]1[C@@H:40]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C@@H:39]([CH2:49][O:50][CH2:51][C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=2)[O:38][C@@H:37]([N:10]2[C:11]3[C:16](=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=3)[C@@:8]([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:23][CH3:24])([F:22])[C:9]2=[O:21])[C@@H:36]1[OH:58])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1

Participants

6

Reactant 4

HCID 24758Sodium hydrideHCID 214350Bms 204352HCID 516892Sodium BicarbonateHCID 100943411,2-Anhydro-3,4,6-tri-O-benzyl-alpha-D-glucopyranose

Product 1

HCID 208124891-(4-(S),5-(S)-Bis-benzyloxy-6-(R)-benzyloxymethyl-3-(R)-hydroxy-tetrahydro-pyran-2-(R)-yl)-3-(S)-(5-chloro-2-methoxy-phenyl)-3-fluoro-6-trifluoromethyl-1,3-dihydro-indol-2-one

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

To a round bottom flask containing (S)-3-(5-chloro-2-methoxy-phenyl)-3-fluoro-6-trifluoromethyl-1,3-dihydro-indol-2-one ((S)-II) (0.200 g, 0.55 mmol) was added anhydrous tetrahydrofuran (3 mL) and 95% sodium hydride (0.018 g, 0.7 mmol). The yellow solution was allowed to stir at room temperature for 30 minutes. 1,2-Anhydro-3,4,6-tri-O-benzyl-α-D-glucopyranose (prepared by the method of Halcomb and Danishefsky J. Am. Chem. Soc. 1989, 111, 6661) (0.480 g, 1.1 mmol) was then dissolved in anhydrous tetrahydrofuran (2.5 mL) and added dropwise to the reaction mixture over 15 minutes. The reaction was allowed to stir at reflux overnight. Once complete, the reaction was cooled and then poured into saturated sodium bicarbonate. The solution was extracted with ethyl acetate (3×). The organic layer was washed with brine and then dried over anhydrous sodium sulfate. The crude mixture was purified via flash chromatography (silica gel, 30% ethyl acetate in hexanes). The title product was obtained as a yellow oil (0.287 g, 65%). 1H NMR (CDCl3, 400 MHz): δ 7.79 (dd, 1H, J=1.8 Hz, 0.68 Hz), 7.45 (s, 1H), 7.39-7.20 (m, 18H), 6.69 (dd, 1H, J=7.6 Hz, 1.1 Hz), 5.43 (d, 1H, J=9.5 Hz), 4.93 (m, 3H), 4.67 (m, 1H), 4.55 (dd, 2H, J=12.3 Hz, 5.7 Hz), 4.3 (ddd, 1H, J=4.9 Hz, 4.2 Hz), 3.87 (d, 1H, J=9.3 Hz), 3.79-3.70 (m, 4H), 3.42 (s, 3H), 2.54 (d, 1H, J=4.3 Hz).

Workup

  1. additionadded dropwise to the reaction mixture over 15 minutes
  2. stirringto stir
  3. temperatureat reflux overnight
  4. temperatureOnce complete, the reaction was cooled
  5. extractionThe solution was extracted with ethyl acetate (3×)
  6. washThe organic layer was washed with brine
  7. dry with materialdried over anhydrous sodium sulfate
  8. customThe crude mixture was purified via flash chromatography (silica gel, 30% ethyl acetate in hexanes)

Sources & evidence

ORD record
ord-f2a42148bc984bb2bd64cd99f508a14e
Source dataset
uspto-grants-2005_07
Patent number
US06916937B2

Reaction notes

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