Formic Acid → (3R,3aR,6R,6aR)-6-[[6-chloro-5-[4-[4-(1,2,4-triazol-1-yl)phenyl]phenyl]-1H-imidazo[4,5-b]pyridin-2-yl]oxy]-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol

HRID 2401153Notes

Reaction equation

HRID 2401153 reaction equation
C(O)=O.OS([O-])(=O)=O.[K+].[Cl:10][C:11]1[CH:12]=[C:13]2[N:36](COCC[Si](C)(C)C)[C:35]([O:45][C@H:46]3[C@H:50]4[O:51][CH2:52][C@@H:53]([OH:54])[C@H:49]4[O:48][CH2:47]3)=[N:34][C:14]2=[N:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH:33]=[N:32][CH:31]=[N:30]3)=[CH:25][CH:24]=2)=[CH:19][CH:18]=1.[OH-].[Na+]>O>[Cl:10][C:11]1[CH:12]=[C:13]2[NH:36][C:35]([O:45][C@H:46]3[C@H:50]4[O:51][CH2:52][C@@H:53]([OH:54])[C@H:49]4[O:48][CH2:47]3)=[N:34][C:14]2=[N:15][C:16]=1[C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:24]=[CH:25][C:26]([N:29]3[CH:33]=[N:32][CH:31]=[N:30]3)=[CH:27][CH:28]=2)=[CH:21][CH:22]=1

Participants

6

Reactant 4

HCID 284Formic AcidHCID 14798Sodium HydroxideHCID 516920Potassium bisulfateHCID 86684744(3R,3aR,6R,6aR)-6-[6-chloro-5-[4-[4-(1,2,4-triazol-1-yl)phenyl]phenyl]-1-(2-trimethylsilylethoxymethyl)imidazo[4,5-b]pyridin-2-yl]oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol

Product 1

HCID 60171877(3R,3aR,6R,6aR)-6-[[6-chloro-5-[4-[4-(1,2,4-triazol-1-yl)phenyl]phenyl]-1H-imidazo[4,5-b]pyridin-2-yl]oxy]-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Conditions

Temperature
60 °C

Procedure

A mixture of formic acid (3 mL, 68.8 mmol), saturated aqueous KHSO4 (0.33 mL, 1.777 mmol), and (3R,3aR,6R,6aR)-6-[6-chloro-5-[4-[4-(1,2,4-triazol-1-yl)phenyl]phenyl]-1-(2-trimethylsilylethoxymethyl)imidazo[4,5-b]pyridin-2-yl]oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol (1.15 g, 1.777 mmol). The reaction mixture was stirred at 60° C. overnight, and then cooled to 0° C. in an ice bath. The pH of the reaction mixture was adjusted to pH>11 through the addition of NaOH (2.75 g, 68.8 mmol) in water (5 mL). THE (5 mL) was added to the reaction mixture, and the reaction was removed from the ice bath and allowed to warm to room temperature. After 30 minutes, the pH of the reaction mixture was adjusted to pH 6 through the addition of concentrated HCl. The biphasic mixture was separated. The organic layer and the resulting white precipitate that had formed were concentrated under reduced pressure, redissolved in DMSO, and filtered before being purified by preparative HPLC Reverse phase (C-18), using a 19×100 mm Sunfire™ column and eluting with a 10%-90% acetonitrile/water gradient+0.05% TFA followed by a 90% acetonitrile/water+0.05% TFA flush. The desired fractions were combined, and evaporated under reduced pressure. The resulting residue was washed with MeOH and lyophilized from acetonitrile and water to afford the title compound as a white solid. LC-MS: calculated for C26H21ClN6O4 516.13 observed m/e: 516.85 (M+H)+ (Rt 1.11/2 min); 1H NMR δ (ppm) (CD3OD): 9.17 (s, 1H), 8.21 (s, 1H), 7.82-7.97 (m, 4H), 7.78-7.80 (m, 5H), 5.56 (qt, J=5.5 Hz, 1H), 4.98 (t, J=5.3 Hz, 1H), 4.49 (t, J=5 Hz, 11H), 4.28-4.32 (m, 1H), 4.19 (dd, J=6.0 Hz, 10.0 Hz, 1H), 4.12 (dd, J=5.0 Hz, 10.0 Hz, 1H), 3.92 (dd, J=7.0 Hz, 8.0 Hz, 1H), 3.62 (t, J=8.8 Hz, 1H).

Workup

  1. temperaturecooled to 0° C. in an ice bath
  2. additionTHE (5 mL) was added to the reaction mixture
  3. customthe reaction was removed from the ice bath
  4. temperatureto warm to room temperature
  5. waitAfter 30 minutes
  6. additionthe pH of the reaction mixture was adjusted to pH 6 through the addition of concentrated HCl
  7. customThe biphasic mixture was separated
  8. customThe organic layer and the resulting white precipitate that had formed
  9. concentrationwere concentrated under reduced pressure
  10. dissolutionredissolved in DMSO
  11. filtrationfiltered
  12. custombefore being purified by preparative HPLC Reverse phase (C-18)
  13. washeluting with a 10%-90% acetonitrile/water gradient+0.05% TFA
  14. customflush
  15. customevaporated under reduced pressure
  16. washThe resulting residue was washed with MeOH

Sources & evidence

ORD record
ord-480163f3c7e1456bae1dd2249c645aa8
Source dataset
uspto-grants-2014_08
Patent number
US08796258B2

Reaction notes

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