Reaction #155608

Reaction equation

sodium bicarbonate

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

trimethyl orthoformate

→

product

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

Solvents

dichloromethane

dichloromethane

Conditions

Workup

1. 1
   Otherexceed 3° C
2. 2
   OtherThe organic layer was separated
3. 3
   Otherresulting aqueous layer
4. 4
   Extractionwas extracted with further dichloromethane (200 mL)
5. 5
   WashThe combined organics were washed with brine (200 mL)
6. 6
   Dryingdried over sodium sulfate
7. 7
   Filtrationfiltered
8. 8
   Concentrationconcentrated

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).

Source