Formic Acid → HCID 86684742, compound

HRID 2401150Notes

Reaction equation

HRID 2401150 reaction equation
[OH:1][C@@H:2]1[CH2:6][O:5][C@@H:4]2[C@H:7]([O:10][C:11]3[NH:12][C:13]4[C:14]([N:42]=3)=[N:15][C:16]([C:28]3[CH:33]=[CH:32][C:31]([C:34]5[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[CH:36][CH:35]=5)=[CH:30][CH:29]=3)=[C:17]([Cl:27])[C:18]=4COCC[Si](C)(C)C)[CH2:8][O:9][C@H:3]12.C(O)=O.OS([O-])(=O)=O.[K+].[OH-].[Na+]>C1COCC1>[OH:1][C@@H:2]1[CH2:6][O:5][C@@H:4]2[C@H:7]([O:10][C:11]3[NH:12][C:13]4[C:14]([N:42]=3)=[N:15][C:16]([C:28]3[CH:29]=[CH:30][C:31]([C:34]5[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[CH:36][CH:35]=5)=[CH:32][CH:33]=3)=[C:17]([Cl:27])[CH:18]=4)[CH2:8][O:9][C@H:3]12

Participants

6

Reactant 4

HCID 284Formic AcidHCID 14798Sodium HydroxideHCID 516920Potassium bisulfateHCID 86684743HCID 86684743, compound

Product 1

HCID 86684742HCID 86684742, compound

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
40 °C

Procedure

A mixture of 4-[4-[2-[[(3R,3aR,6R,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-6-chloro-(2-trimethylsilylethoxymethyl)imidazo[4,5-b]pyridin-5-yl]phenyl]benzonitrile (49.4 mg, 0.082 mmol), formic acid (1.0 mL, 26.1 mmol), and saturated aqueous KHSO4 (0.06 mL) was heated to 40° C. with stirring. After 6.5 hours, the reaction mixture was cooled to room temperature and placed in the refrigerator overnight, and then cooled to 0° C. in an ice bath. The pH was adjusted to pH 14 through the addition of 5 N NaOH (5.2 mL, 26 mmol). THF (2 mL) was added to the reaction mixture, which was removed from the ice bath and allowed to warm to room temperature. After stirring for 45 minutes at room temperature, the pH was adjusted to 7 through the addition of 2 N HCl. The reaction mixture was partitioned between EtOAc (30 mL) and water (30 mL). The aqueous layer was extracted with EtOAc (2×20 mL). The organic layers were combined, washed with brine (1×20 mL), dried over Na2SO4, filtered, and evaporated under reduced pressure to give a pale yellow solid. Purification by HPLC reverse phase (C-18), using a 30×150 mm Sunfire™ column and eluting with a 20%-100% acetonitrile/water+0.05% TFA gradient followed by a 100% acetonitrile+0.05% TFA flush afforded the title compound as a white solid following lyophilization from ethanol and benzene. LC-MS: calculated for: C25H19ClN4O4 474.11 observed m/e: 475.12 (M+H)+ (Rt 1.15/2 min).

Workup

  1. temperaturethe reaction mixture was cooled to room temperature
  2. customplaced in the refrigerator overnight
  3. temperaturecooled to 0° C. in an ice bath
  4. customwas removed from the ice bath
  5. temperatureto warm to room temperature
  6. stirringAfter stirring for 45 minutes at room temperature
  7. additionthe pH was adjusted to 7 through the addition of 2 N HCl
  8. customThe reaction mixture was partitioned between EtOAc (30 mL) and water (30 mL)
  9. extractionThe aqueous layer was extracted with EtOAc (2×20 mL)
  10. washwashed with brine (1×20 mL)
  11. dry with materialdried over Na2SO4
  12. filtrationfiltered
  13. customevaporated under reduced pressure
  14. customto give a pale yellow solid
  15. customPurification by HPLC reverse phase (C-18)
  16. washeluting with a 20%-100% acetonitrile/water+0.05% TFA
  17. customflush

Sources & evidence

ORD record
ord-bdb960a0c9814bfe9eb9ca6587e1c0be
Source dataset
uspto-grants-2014_08
Patent number
US08796258B2

Reaction notes

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