Isopropanol → (4aR,6R,8aS)-2-(Benzoylamino)-8a-(2,4-difluorophenyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazine-6-carboxylic acid

HRID 590598Notes

Reaction equation

HRID 590598 reaction equation
[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:18][O:17][C@@H:16]([CH2:19][OH:20])[CH2:15][C@H:14]1[CH2:13][S:12][C:11]([NH:21][C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[N:10]2.O.C[N+]1([O-])CC[O:35]CC1.CC(O)C>C(#N)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[C:22]([NH:21][C:11]1[S:12][CH2:13][C@@H:14]2[CH2:15][C@H:16]([C:19]([OH:35])=[O:20])[O:17][CH2:18][C@:9]2([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[N:10]=1)(=[O:29])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1

Participants

6

Reactant 3

HCID 3776IsopropanolHCID 2724197N-Methylmorpholine N-oxide monohydrateHCID 86729527N-[(4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-(hydroxymethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide

Product 1

HCID 89889273(4aR,6R,8aS)-2-(Benzoylamino)-8a-(2,4-difluorophenyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazine-6-carboxylic acid

Reagents, catalysts & solvents 2

HCID 178419074HCID 178419074, compoundCatalystHCID 6342AcetonitrileSolvent

Procedure

Tetrapropylammonium perruthenate (1.09 g, 3.10 mmol) was added to a mixture of N-[(4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-(hydroxymethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (P1) (13.0 g, 31.1 mmol) and 4-methylmorpholine N-oxide monohydrate (25.2 g, 186 mmol) in acetonitrile (207 mL), and the reaction mixture was stirred for 90 minutes at room temperature. After addition of 2-propanol (100 mL), it was stirred for an additional 2 hours and then concentrated in vacuo. The residue was partitioned between ethyl acetate and 0.5 M aqueous sodium hydroxide solution. The organic layer was extracted twice with 0.5 M aqueous sodium hydroxide solution, and the combined aqueous layers were acidified to a pH of approximately 1 with 2 M aqueous hydrochloric acid, then extracted three times with ethyl acetate. The combined ethyl acetate layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure; the residue was dissolved in dichloromethane, washed with water and with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification via chromatography on silica gel (Gradient: 0% to 20% methanol in dichloromethane) provided the product as a reddish solid. Yield: 12.36 g, 28.58 mmol, 92%. LCMS m/z 433.2 [M+H+]. 1H NMR (400 MHz, CD3OD) δ 8.09-8.13 (m, 2H), 7.52-7.57 (m, 1H), 7.43-7.51 (m, 3H), 7.03-7.11 (m, 2H), 4.35 (dd, J=11.2, 3.4 Hz, 1H), 4.19 (dd, J=12.0, 1.4 Hz, 1H), 3.97 (d, J=12.1 Hz, 1H), 3.20-3.27 (m, 1H), 2.96 (dd, half of ABX pattern, J=13.1, 4.0 Hz, 1H), 2.78 (dd, half of ABX pattern, J=13.2, 2.8 Hz, 1H), 2.03-2.15 (m, 2H).

Workup

  1. stirringwas stirred for an additional 2 hours
  2. concentrationconcentrated in vacuo
  3. customThe residue was partitioned between ethyl acetate and 0.5 M aqueous sodium hydroxide solution
  4. extractionThe organic layer was extracted twice with 0.5 M aqueous sodium hydroxide solution
  5. extractionextracted three times with ethyl acetate
  6. dry with materialThe combined ethyl acetate layers were dried over sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated under reduced pressure
  9. dissolutionthe residue was dissolved in dichloromethane
  10. washwashed with water and with saturated aqueous sodium chloride solution
  11. dry with materialdried over sodium sulfate
  12. filtrationfiltered
  13. concentrationconcentrated in vacuo
  14. customPurification via chromatography on silica gel (Gradient: 0% to 20% methanol in dichloromethane)

Sources & evidence

ORD record
ord-31cc66cdf78b46079a2b95f5bdf6feb8
Source dataset
uspto-grants-2016_01
Patent number
US09233981B1

Reaction notes

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