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

HRID 2168286Notes

Reaction equation

HRID 2168286 reaction equation
B(Cl)(Cl)Cl.C([O:12][CH2:13][C@@H:14]1[O:32][CH2:31][C@:17]2([C:33]3[CH:38]=[C:37]([Br:39])[CH:36]=[CH:35][C:34]=3[F:40])[N:18]=[C:19]([NH:22][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[S:20][CH2:21][C@@H:16]2[CH2:15]1)C1C=CC=CC=1>ClCCl>[Br:39][C:37]1[CH:36]=[CH:35][C:34]([F:40])=[C:33]([C@:17]23[CH2:31][O:32][C@@H:14]([CH2:13][OH:12])[CH2:15][C@H:16]2[CH2:21][S:20][C:19]([NH:22][C:23](=[O:30])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[N:18]3)[CH:38]=1

Participants

4

Reactant 2

HCID 25135Boron TrichlorideHCID 86762651N-[(4aR,6R,8aS)-6-[(benzyloxy)methyl]-8a-(5-bromo-2-fluorophenyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide

Product 1

HCID 86762652N-[(4aR,6R,8aS)-8a-(5-bromo-2-fluorophenyl)-6-(hydroxymethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

Boron trichloride (45.8 mL, 45.8 mmol) was added to a solution of N-[(4aR,6R,8aS)-6-[(benzyloxy)methyl]-8a-(5-bromo-2-fluorophenyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C32) (8.70 g, 15.3 mmol) in dichloromethane (76 mL) at 0° C., while maintaining the internal temperature below 5° C. The heterogeneous mixture was allowed to stir for 10 minutes at 0° C. and then at room temperature for 16 hours. The reaction mixture was then quenched by drop-wise addition of methanol (100 mL). The methanol solution was refluxed for 15 minutes and then concentrated under reduced pressure. The residue was re-dissolved in dichloromethane (100 mL) and washed sequentially with 1 N sodium hydroxide (2×100 mL) and with brine (100 mL), dried over sodium sulfate and filtered. Purification via silica gel chromatography (Gradient: 30% to 100% ethyl acetate in heptane) afforded the product as an off-white solid. Yield: 4.98 g, 68%. LCMS m/z 410 [M+H+]. 1H NMR (400 MHz, CD3OD) δ 8.13 (d, J=6.8 Hz, 1H), 7.59-7.45 (m, 4H), 7.16 (dd, J=12.1, 8.6 Hz, 1H), 4.15-4.11 (m, 1H), 3.91 (d, J=11.9 Hz, 1H), 3.79-3.73 (m, 1H), 3.59 (d, J=5.1 Hz, 1H), 3.21 (br s, 1H), 2.96 (dd, J=13.0, 4.0 Hz, 1H), 2.76 (dd, J=13.2, 2.8 Hz, 1H), 1.81-1.90 (m, 1H), 1.72-1.68 (m, 1H).

Workup

  1. temperaturewhile maintaining the internal temperature below 5° C
  2. waitat room temperature for 16 hours
  3. customThe reaction mixture was then quenched by drop-wise addition of methanol (100 mL)
  4. temperatureThe methanol solution was refluxed for 15 minutes
  5. concentrationconcentrated under reduced pressure
  6. dissolutionThe residue was re-dissolved in dichloromethane (100 mL)
  7. washwashed sequentially with 1 N sodium hydroxide (2×100 mL) and with brine (100 mL)
  8. dry with materialdried over sodium sulfate
  9. filtrationfiltered
  10. customPurification via silica gel chromatography (Gradient: 30% to 100% ethyl acetate in heptane)

Sources & evidence

ORD record
ord-340b8fa9430d474d8eb22d49b91a8b53
Source dataset
uspto-grants-2015_06
Patent number
US09045498B2

Reaction notes

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