Boron trifluoride etherate → Dapagliflozin

HRID 718214Notes

Reaction equation

HRID 718214 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2(OC)[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH3:30])=[CH:24][CH:23]=1.C([SiH](CC)CC)C.B(F)(F)F.CCOCC>ClCCl.C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][CH2:29][CH3:30])=[CH:26][CH:27]=1

Participants

6

Reactant 3

HCID 8000Boron trifluoride etherateHCID 12052TriethylsilaneHCID 24807437Methyl 1-C-{4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl}-alpha-D-glucopyranoside

Product 1

HCID 9887712DapagliflozinYield 93%

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolventHCID 6344DichloromethaneSolvent

Procedure

A solution of (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (7.87 g, crude, ˜17.9 mmol) in dichloromethane (59 mL) and acetonitrile (59 mL) was cooled to −30° C. under argon. Triethylsilane (11.5 mL, 71.6 mmole) was added to the reaction solution followed by addition of boron trifluoride etherate (6.8 mL, 53.7 mmole) so that the temperature didn't exceed −10° C. After the addition was complete the reaction solution was stirred for additional 1.5 h and then quenched with 5% sodium bicarbonate until the pH reached 7.5. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (2×80 mL). The combined organic phases were washed with brine (2×80 mL) and dried over anhydrous sodium sulfate. The sample was concentrated under reduced pressure to provide 6.8 g of the title compound as a pale solid which was used for the next step without purification. Yield: 93%. Purity (LCMS-0013) 2.9 min, 82% (UV); MS ESI (m/z) 409[M+1]+, calc. 408.

Workup

  1. additionAfter the addition
  2. customquenched with 5% sodium bicarbonate until the pH
  3. customThe organic phase was separated
  4. extractionthe aqueous phase was extracted with ethyl acetate (2×80 mL)
  5. washThe combined organic phases were washed with brine (2×80 mL)
  6. dry with materialdried over anhydrous sodium sulfate
  7. concentrationThe sample was concentrated under reduced pressure

Sources & evidence

ORD record
ord-0d9a1845fa0b4c42a33e732fc5052628
Source dataset
uspto-grants-2015_11
Patent number
US09193751B2

Reaction notes

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