Tetrahydrofuran → (3R,3aR,6R,6aR)-6-[[6-chloro-5-(4-pyrrolidin-1-ylphenyl)-1H-imidazo[4,5-b]pyridin-2-yl]oxy]-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol

HRID 929241Notes

Reaction equation

HRID 929241 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]2[NH:21][C:20]([O:22][C@@H:23]3[CH2:27][O:26][C@@H:25]4[C@H:28]([O:31][Si](C(C)(C)C)(C)C)[CH2:29][O:30][C@H:24]34)=[N:19][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>>[Cl:1][C:2]1[CH:3]=[C:4]2[NH:21][C:20]([O:22][C@H:23]3[C@H:24]4[O:30][CH2:29][C@@H:28]([OH:31])[C@H:25]4[O:26][CH2:27]3)=[N:19][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1

Participants

4

Reactant 3

HCID 8028TetrahydrofuranHCID 2724141Tetrabutylammonium FluorideHCID 123775948HCID 123775948, compound

Product 1

HCID 90067170(3R,3aR,6R,6aR)-6-[[6-chloro-5-(4-pyrrolidin-1-ylphenyl)-1H-imidazo[4,5-b]pyridin-2-yl]oxy]-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol

Procedure

[(3R,3aR,6R,6aS)-3-[[6-chloro-5-(4-pyrrolidin-1-ylphenyl)-1H-imidazo[4,5-b]pyridin-2-yl]oxy]-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy-tert-butyl-dimethyl-silane (31.8 mg, 0.057 mmol) and tetrabutylammonium fluoride 1.0 M in THF (0.6 ml, 0.600 mmol) were combined in a vial. The reaction mixture was a light amber solution that was stirred at room temperature. After 3.5 hours, the reaction mixture was partitioned between EtOAc (40 ml) and water (40 ml). The aqueous layer was extracted with EtOAc (2×20 ml) and a few milliliters of brine. The organic layers were combined, washed with brine (1×20 ml), dried over MgSO4, filtered, and evaporated under reduced pressure to give a pale yellow residue. The residue (loaded in DMSO/MeOH) was purified by preparative HPLC reverse phase (C-18), using a 30×150 mm Sunfire™ column and eluting (20 ml/min) with a 17 minute 20%-80% acetonitrile/water+0.05% TFA gradient followed by a 2 minute 80% acetonitrile/water+0.05% TFA flush. The product fractions were combined, frozen, and lyophilized to give the title compound as a yellow solid. LC-MS: calculated for C22H23ClN4O4 442.14 observed m/e: 443.19 (M+H)+ (Rt 1.09/2 min); 1H NMR δ (ppm) (500 MHz CD3OD): 8.01 (s, 1H), 7.54-7.56 (m, 2H), 6.72-6.74 (m, 2H), 5.59 (q, J=5.4 Hz, 1H), 4.97 (t, J=5.3 Hz, 1H), 4.48 (t, J=5.0 Hz, 1H), 4.27-4.31 (m, 1H), 4.13-4.19 (m, 2H), 3.88-3.91 (m, 1H), 3.60 (dd, J=9.1, 7.6 Hz, 1H), 3.37-3.40 (m, 4H), 2.08-2.10 (m, 4H).

Workup

  1. customthe reaction mixture was partitioned between EtOAc (40 ml) and water (40 ml)
  2. extractionThe aqueous layer was extracted with EtOAc (2×20 ml) and a few milliliters of brine
  3. washwashed with brine (1×20 ml)
  4. dry with materialdried over MgSO4
  5. filtrationfiltered
  6. customevaporated under reduced pressure
  7. customto give a pale yellow residue
  8. customThe residue (loaded in DMSO/MeOH) was purified by preparative HPLC reverse phase (C-18)
  9. washeluting (20 ml/min) with a 17 minute 20%-80% acetonitrile/water+0.05% TFA
  10. waitgradient followed by a 2 minute
  11. custom80% acetonitrile/water+0.05% TFA flush
  12. temperaturefrozen

Sources & evidence

ORD record
ord-cd319aec4cf04af58e97812527fd4753
Source dataset
uspto-grants-2016_03
Patent number
US09290517B2

Reaction notes

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