Tetrahydrofuran → (3R,3aR,6R,6aR)-6-[[6-chloro-5-(4-pyrrol-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 929242Notes

Reaction equation

HRID 929242 reaction equation
[Si]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@H:16]([O:17][C:18]3[NH:19][C:20]4[C:21]([N:39]=3)=[N:22][C:23]([C:27]3[CH:32]=[CH:31][C:30]([N:33]5[CH2:37][CH2:36][C@@H:35](O)[CH2:34]5)=[CH:29][CH:28]=3)=[C:24]([Cl:26])[CH:25]=4)[C@H:12]2[O:11][CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>>[Cl:26][C:24]1[CH:25]=[C:20]2[NH:19][C:18]([O:17][C@H:16]3[C@H:12]4[O:11][CH2:10][C@@H:9]([OH:8])[C@H:13]4[O:14][CH2:15]3)=[N:39][C:21]2=[N:22][C:23]=1[C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH:34]=[CH:35][CH:36]=[CH:37]2)=[CH:29][CH:28]=1

Participants

4

Reactant 3

HCID 8028TetrahydrofuranHCID 2724141Tetrabutylammonium FluorideHCID 90042002(3R)-1-[4-[2-[[(3R,3aR,6R,6aS)-6-[tert-butyl(dimethyl)silyl]oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-yl]oxy]-6-chloro-1H-imidazo[4,5-b]pyridin-5-yl]phenyl]pyrrolidin-3-ol

Product 1

HCID 90067570(3R,3aR,6R,6aR)-6-[[6-chloro-5-(4-pyrrol-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)-1-[4-[2-[[(3R,3aR,6R,6aS)-6-[tert-butyl(dimethyl)silyl]oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-yl]oxy]-6-chloro-1H-imidazo[4,5-b]pyridin-5-yl]phenyl]pyrrolidin-3-ol (229.7 mg, 0.401 mmol) and tetrabutylammonium fluoride 1.0 M in THF (4.2 ml, 4.20 mmol) were combined in a 40 ml vial. The reaction mixture was an amber solution that was stirred at room temperature. After 1.25 hours, the reaction mixture was partitioned between EtOAc (100 ml) and water (50 ml). The aqueous layer was separated, and extracted with EtOAc (2×50 ml). The organic layers were combined, washed with brine (1×30 ml), dried over MgSO4, filtered, and evaporated under reduced pressure to give a yellow residue. This material (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 10%-60% acetonitrile/water+0.05% TFA gradient followed by a 2 minute 60% acetonitrile/water+0.05% TFA flush. The product fractions were combined, frozen, and lyophilized to give the title compound as a light yellow solid. LC-MS: calculated for C22H19ClN4O4 438.11 observed m/e: 439.18 (M+H)+ (Rt 1.14/2 min); 1H NMR δ (ppm) (500 MHz CD3OD): 7.87 (s, 1H), 7.77 (d, J=8.3 Hz, 2H), 7.60 (d, J=8.3 Hz, 2H), 7.28 (d, J=2.5 Hz, 2H), 6.33 (d, J=2.5 Hz, 2H), 5.57 (q, J=5.6 Hz, 1H), 4.98 (t, J=5.3 Hz, 1H), 4.48 (t, J=5.1 Hz, 1H), 4.28-4.32 (m, 1H), 4.18 (dd, J=10.3, 5.8 Hz, 1H), 4.13 (dd, J=10.6, 4.7 Hz, 1H), 3.91 (dd, J=8.3, 6.7 Hz, 1H), 3.61 (dd, J=9.0, 7.6 Hz, 1H).

Workup

  1. customthe reaction mixture was partitioned between EtOAc (100 ml) and water (50 ml)
  2. customThe aqueous layer was separated
  3. extractionextracted with EtOAc (2×50 ml)
  4. washwashed with brine (1×30 ml)
  5. dry with materialdried over MgSO4
  6. filtrationfiltered
  7. customevaporated under reduced pressure
  8. customto give a yellow residue
  9. customThis material (loaded in DMSO/MeOH) was purified by preparative HPLC reverse phase (C-18)
  10. washeluting (20 ml/min) with a 17 minute 10%-60% acetonitrile/water+0.05% TFA
  11. waitgradient followed by a 2 minute
  12. custom60% acetonitrile/water+0.05% TFA flush
  13. temperaturefrozen

Sources & evidence

ORD record
ord-80a5e520bfe84987a585bf6dd5f6e780
Source dataset
uspto-grants-2016_03
Patent number
US09290517B2

Reaction notes

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