Boron trifluoride etherate → HCID 118021648, compound

HRID 2284539Notes

Reaction equation

HRID 2284539 reaction equation
[C:1]([O:4][CH2:5][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([O:20][C:21](=[O:23])[CH3:22])[C@H:8]([N:24]2[C:32]3[C:27](=[C:28]([CH3:33])[CH:29]=[CH:30][CH:31]=3)[C:26]([CH:34]([C:36]3[CH:41]=[CH:40][C:39]([Br:42])=[CH:38][CH:37]=3)[OH:35])=[CH:25]2)[O:7]1)(=[O:3])[CH3:2].C([SiH](CC)CC)C.B(F)(F)F.CCOCC.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.O.ClCCl.C(#N)C>[C:1]([O:4][CH2:5][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([O:20][C:21](=[O:23])[CH3:22])[C@H:8]([N:24]2[C:32]3[C:27](=[C:28]([CH3:33])[CH:29]=[CH:30][CH:31]=3)[C:26]([C:34](=[O:35])[C:36]3[CH:41]=[CH:40][C:39]([Br:42])=[CH:38][CH:37]=3)=[CH:25]2)[O:7]1)(=[O:3])[CH3:2]

Participants

9

Reactant 4

HCID 8000Boron trifluoride etherate2×HCID 12052TriethylsilaneHCID 516892Sodium Bicarbonate2×HCID 118021714HCID 118021714, compound

Product 1

HCID 118021648HCID 118021648, compound

Reagents, catalysts & solvents 4

HCID 962WaterSolventHCID 6342AcetonitrileSolventHCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

To a 20 L temperature controlled reactor charge [(2R,3R,4S,5R,6R)-3,4,5-triacetoxy-6-[3-[(4-bromophenyl)-hydroxy-methyl]-4-methyl-indol-1-yl]tetrahydropyran-2-yl]methyl acetate (1492.5 g; 65% purity; 1.506 moles), then acetonitrile (4.87 L), and then dichloromethane (4.87 L). Cool the mixture to 0° C. Add triethylsilane (3.77 moles; 437.83 g) over 5 minutes. Set the reactor jacket to −5° C. When the reaction mixture temperature is −2° C., start addition of boron trifluoride etherate (3.77 moles; 534.4 g). Note: at the start, this addition results in a significant exotherm (temperature increases to ˜8° C. during the first ˜10 ml of addition). Once the initial exothermic event has taken place, add the remainder of the boron trifluoride etherate at a rate to maintain the temperature between 5° C. and 7° C. When the addition is complete stir the reaction mixture at 5° C. for 50 minutes. Charge a 50 L glass flask equipped with a bottom outlet valve with ice (6 kg), and then water (˜15 C; 3.74 Kg). Add sodium bicarbonate (11.16 moles; 937.55 g) and stir the mixture for 5 minutes. Pump the reaction mixture into the sodium bicarbonate mixture over about 5 minutes. A little effervescence is seen, but no tendency to foam. Add ethyl acetate (17.04 L) and stir the mixture for 10 minutes. Stop the stiffing and allow the mixture to stand for 30 minutes. Separate the layers, wash the organic phase with brine (4.87 L), and concentrate under reduced pressure. Split the mixture into two approximately equal portions and purify each by passage through a 4.5 Kg pad of silica eluting with dichloromethane. Concentrate the appropriate fractions to give the title compound (990 g, about 70% purity (as determined by quantative NMR; 73% yield from [(2R,3R,4S,5R,6R)-3,4,5-triacetoxy-6-[3-(4-bromobenzoyl)-4-methyl-indol-1-yl]tetrahydropyran-2-yl]methyl acetate): mass spectrum (m/z): 630.2/632.2 (M+1).

Workup

  1. customto −5° C
  2. customis −2° C.
  3. additionat the start, this addition
  4. customresults in a significant exotherm (temperature
  5. temperatureincreases to ˜8° C. during the first ˜10 ml of addition)
  6. temperatureto maintain the temperature between 5° C. and 7° C
  7. additionWhen the addition
  8. additionCharge a 50 L glass flask
  9. waitto stand for 30 minutes
  10. customSeparate the layers
  11. washwash the organic phase with brine (4.87 L)
  12. concentrationconcentrate under reduced pressure
  13. customSplit the mixture into two approximately equal portions
  14. custompurify each by passage through a 4.5 Kg pad of silica eluting with dichloromethane
  15. concentrationConcentrate the appropriate fractions

Sources & evidence

ORD record
ord-a0c39b7d9d134747baac3c38b327c3af
Source dataset
uspto-grants-2015_09
Patent number
US09145435B2

Reaction notes

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