Boron trifluoride etherate → HCID 67250697, compound

HRID 1019516Notes

Reaction equation

HRID 1019516 reaction equation
[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@H:11]([N:17]2[C:25](=[O:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[NH:27][C:28]([CH:30]3[CH2:32][CH2:31]3)=[O:29])[CH2:18]2)[CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:7]=[CH:8][C:9]=1[OH:10])[CH3:2].[CH2:33]([O:40][C:41]([CH:43]1[CH:48]([O:49][C:50](=[O:52])[CH3:51])[CH:47]([O:53][C:54](=[O:56])[CH3:55])[CH:46]([O:57][C:58](=[O:60])[CH3:59])[CH:45](OC(=N)C(Cl)(Cl)Cl)[O:44]1)=[O:42])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.B(F)(F)F.CCOCC>ClCCl.CCOC(C)=O>[C:50]([O:49][C@H:48]1[C@H:47]([O:53][C:54](=[O:56])[CH3:55])[C@@H:46]([O:57][C:58](=[O:60])[CH3:59])[C@H:45]([O:10][C:9]2[CH:8]=[CH:7][C:6]([C@H:11]([N:17]3[CH2:18][C:19]4[C:24](=[C:23]([NH:27][C:28]([CH:30]5[CH2:31][CH2:32]5)=[O:29])[CH:22]=[CH:21][CH:20]=4)[C:25]3=[O:26])[CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:5][C:4]=2[O:3][CH2:1][CH3:2])[O:44][C@@H:43]1[C:41]([O:40][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:42])(=[O:52])[CH3:51]

Participants

6

Reactant 3

HCID 8000Boron trifluoride etherateHCID 53242133HCID 53242133, compoundHCID 67253320HCID 67253320, compound

Product 1

HCID 67250697HCID 67250697, compoundYield 56%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

A reaction mixture of (S)—N-(2-(1-(3-ethoxy-4-hydroxyphenyl)-2-(methylsulfonyl)ethyl)-3-oxoisoindolin-4-yl)cyclopropanecarboxamide (0.38 g, 0.83 mmol) and 3,4,5-triacetoxy-6-(2,2,2-trichloro-acetimidoyloxy)-tetrahydro-pyran-2-carboxylic acid benzyl ester (0.46 g, 0.83 mmol) in dichloromethane (40 mL) was chilled to −15° C. to −20° C., treated with BF3.OEt2 (0.10 mL, 0.83 mmol), and stirred for 2 hours at −15° C. to −20° C. After 2 hours, the reaction mixture was then allowed to warm to room temperature and stirred overnight. The reaction mixture was diluted with EtOAc (10 vol) then washed with saturated aqueous NaHCO3 (5 vol), 2% NaCl (5 vol), dried (MgSO4), and concentrated. The crude mixture was eluted through a 120 g ISCO column, 5% to 20% EtOAc/CH2Cl2. After concentration of the fractions, the product was dried under vacuum for 12 hours, which afforded (2S,3S,4S,5R,6S)-2-(benzyloxycarbonyl)-6-(4-((S)-1-(7-(cyclopropanecarboxamido)-1-oxoisoindolin-2-yl)-2-(methylsulfonyl)ethyl)-2-ethoxyphenoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (250 mg, 56% yield) as a light yellow solid: 1H-NMR (DMSO-d6): 10.4 (s, 1H), 8.26-8.23 (d, J=8 Hz, 1H), 7.53-7.48 (t, J=7 Hz, 1H), 7.39-7.31 (m, 5H), 7.20-7.18 (d, J=7 Hz, 1H), 7.13-7.12 (d, J=2 Hz, 1H), 7.09-7.07 (d, J=9 Hz, 1H), 6.95-6.92 (dd, J=1.8 Hz, 1H), 5.9-5.88 (dd, J=4, 10 Hz, 1H), 5.44-5.37 (overlapping d and t, Jd=8 Hz, Jt=10 Hz, 2H), 5.17-5.03 (m, 4H), 4.70-4.63 (m, 2H), 4.38-4.30 (m, 1H), 4.21-4.15 (d, J=18 Hz, 1H), 4.08-3.95 (m, 3H), 3.04 (s, 3H), 2.00 (s, 3H), 1.97 (s, 3H), 1.81-1.76 (m, 4H), 1.32-1.27 (t, J=7 Hz, 3H), 0.89-0.86 (d, J=6 Hz, 4H). HPLC: Waters Nova-Pak C18 column, 150×3.9 mm, 4 μm; Gradient CH3CN/0.1% aq H3PO4 10/90 to 90/10 in 20 min, 1.0 mL/min, tR 14.022 min, 98.5 AP at 240 nm.

Workup

  1. temperaturewas chilled to −15° C. to −20° C.
  2. waitAfter 2 hours
  3. stirringstirred overnight
  4. washthen washed with saturated aqueous NaHCO3 (5 vol), 2% NaCl (5 vol)
  5. dry with materialdried (MgSO4)
  6. concentrationconcentrated
  7. washThe crude mixture was eluted through a 120 g ISCO column, 5% to 20% EtOAc/CH2Cl2
  8. customAfter concentration of the fractions, the product was dried under vacuum for 12 hours

Sources & evidence

ORD record
ord-84276847be0347f1a9d7234ee5f3bcc0
Source dataset
uspto-grants-2014_05
Patent number
US08716252B2

Reaction notes

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