Hydrochloric Acid → (4aR,8aS)-8a-(2,4-difluorophenyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-amine

HRID 1427392Notes

Reaction equation

HRID 1427392 reaction equation
[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([NH:17][C:18]([NH:20]C(=O)OCC2C3C=CC=CC=3C3C2=CC=CC=3)=[S:19])[C@H:14]([CH2:15]O)[CH2:13][CH2:12][O:11][CH2:10]1.Cl>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:10][O:11][CH2:12][CH2:13][C@H:14]1[CH2:15][S:19][C:18]([NH2:20])=[N:17]2

Participants

4

Reactant 2

HCID 313Hydrochloric AcidHCID 866771049H-fluoren-9-ylmethyl {[(3S,4R)-3-(2,4-difluorophenyl)-4-(hydroxymethyl)tetrahydro-2H-pyran-3-yl]carbamothioyl}carbamate

Product 1

HCID 71268850(4aR,8aS)-8a-(2,4-difluorophenyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-amine

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Conditions

Temperature
70 °C

Procedure

A suspension of 9H-fluoren-9-ylmethyl {[(3S,4R)-3-(2,4-difluorophenyl)-4-(hydroxymethyl)tetrahydro-2H-pyran-3-yl]carbamothioyl}carbamate (C12) (1.417 g, 2.701 mmol) in methanol (20 mL) was treated with concentrated hydrochloric acid (12 M, 0.675 mL, 8.10 mmol) and heated at 70° C. for 2 hours. The reaction mixture was concentrated in vacuo, dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in acetonitrile (20 mL) and treated with piperidine (2 mL); this reaction mixture was stirred at room temperature for 18 hours, and then concentrated in vacuo. Purification via silica gel chromatography (Gradient: 0% to 7% methanol in dichloromethane) provided the product as a white solid. Yield: 281 mg, 0.988 mmol, 37%. LCMS m/z 285.0 (M+1). 1H NMR (400 MHz, CD3OD) δ 1.45-1.52 (m, 1H), 1.99-2.12 (m, 1H), 2.67-2.73 (m, 1H), 2.82-2.90 (m, 2H), 3.62-3.70 (m, 1H), 3.63 (br d, J=10.9 Hz, 1H), 3.99-4.05 (m, 2H), 6.92-7.00 (m, 2H), 7.35 (ddd, J=9.5, 8.7, 6.7 Hz, 1H).

Workup

  1. concentrationThe reaction mixture was concentrated in vacuo
  2. dissolutiondissolved in dichloromethane
  3. washwashed with saturated aqueous sodium bicarbonate solution
  4. dry with materialThe organic layer was dried over magnesium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated under reduced pressure
  7. dissolutionThe residue was dissolved in acetonitrile (20 mL)
  8. additiontreated with piperidine (2 mL)
  9. concentrationconcentrated in vacuo
  10. customPurification via silica gel chromatography (Gradient: 0% to 7% methanol in dichloromethane)

Sources & evidence

ORD record
ord-18dd3ee2a1a94c42882ca4ef014e1963
Source dataset
uspto-grants-2015_01
Patent number
US08933221B2

Reaction notes

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