Trimethyl orthoformate → N-[(4aR,6R,8aS)-8a-(5-bromo-2-fluorophenyl)-6-(1,1,3,3-tetramethoxypropan-2-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide

HRID 1496769Notes

Reaction equation

HRID 1496769 reaction equation
[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:31])=[C:6]([C@:8]23[CH2:17][O:16][C@@H:15](/[CH:18]=[CH:19]/[O:20][CH3:21])[CH2:14][C@H:13]2[CH2:12][S:11][C:10]([NH:22][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:9]3)[CH:7]=1.[CH:32](OC)([O:35][CH3:36])[O:33][CH3:34].[C:39](=O)(O)[O-:40].[Na+]>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:31])=[C:6]([C@:8]23[CH2:17][O:16][C@@H:15]([CH:18]([CH:32]([O:35][CH3:36])[O:33][CH3:34])[CH:19]([O:40][CH3:39])[O:20][CH3:21])[CH2:14][C@H:13]2[CH2:12][S:11][C:10]([NH:22][C:23](=[O:30])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[N:9]3)[CH:7]=1

Participants

5

Reactant 3

HCID 9005Trimethyl orthoformateHCID 516892Sodium BicarbonateHCID 86762662N-{(4aR,6R,8aS)-8a-(5-bromo-2-fluorophenyl)-6-[(E)-2-methoxyethenyl]-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl}benzamide

Product 1

HCID 86762663N-[(4aR,6R,8aS)-8a-(5-bromo-2-fluorophenyl)-6-(1,1,3,3-tetramethoxypropan-2-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

To a solution of N-{(4aR,6R,8aS)-8a-(5-bromo-2-fluorophenyl)-6-[(E)-2-methoxyethenyl]-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl}benzamide (C43) (0.54 g, 1.1 mmol) in dichloromethane (2 mL) at 0° C., was added trimethyl orthoformate (0.239 mL, 2.19 mmol) followed by drop-wise addition of boron trifluoride-diethyl etherate (0.136 mL, 1.08 mmol), without letting the reaction temperature exceed 3° C. The resulting solution was allowed to stir at the same temperature for 1.5 hours. The reaction mixture was diluted with dichloromethane (200 mL) and a saturated aqueous solution of sodium bicarbonate (200 mL). The organic layer was separated and resulting aqueous layer was extracted with further dichloromethane (200 mL). The combined organics were washed with brine (200 mL), dried over sodium sulfate, filtered and concentrated to give the product (0.65 g) as a white solid, which was taken directly to the following step. 1H NMR (400 MHz, CD3OD) characteristic peaks: δ 8.23 (br d, J=7.0 Hz, 2H), 7.41-7.52 (m, 5H), 6.99 (dd, J=1.7, 9.0 Hz, 1H), 4.52 (dd, J=17.7, 4.2 Hz, 1H), 4.13 (d, J=12.5 Hz, 1H), 4.04 (d, J=8.4 Hz, 1H), 3.79 (d, J=11.9 Hz, 1H), 3.13-3.19 (m, 1H), 2.98 (dd, J=13.1, 2.7 Hz, 1H), 2.64 (dd, J=13.1, 1.3 Hz, 1H).

Workup

  1. customexceed 3° C
  2. customThe organic layer was separated
  3. customresulting aqueous layer
  4. extractionwas extracted with further dichloromethane (200 mL)
  5. washThe combined organics were washed with brine (200 mL)
  6. dry with materialdried over sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated

Sources & evidence

ORD record
ord-98714e8c024e4840b09e3785978dd7e2
Source dataset
uspto-grants-2015_12
Patent number
US09198917B2

Reaction notes

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