Formic Acid → HCID 60171875, compound

HRID 2401152Notes

Reaction equation

HRID 2401152 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:24]=[N:25][C:26]([N:29]3[CH:33]=[CH:32][CH:31]=[N:30]3)=[CH:27][CH:28]=2)=[CH:19][CH:18]=1.[OH-].[Na+]>O.C1COCC1>[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]=[N:25][C:26]([N:29]3[CH:33]=[CH:32][CH:31]=[N:30]3)=[CH:27][CH:28]=2)=[CH:21][CH:22]=1

Participants

7

Reactant 4

HCID 284Formic AcidHCID 14798Sodium HydroxideHCID 516920Potassium bisulfateHCID 89558412HCID 89558412, compound

Product 1

HCID 60171875HCID 60171875, compound

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
60 °C

Procedure

A mixture of formic acid (6 mL, 156 mmol), saturated aqueous KHSO4 (0.66 mL, 2.58 mmol), and (3R,3aR,6R,6aR)-6-[6-chloro-5-[4-(6-pyrazol-1-yl-3-pyridyl)phenyl]-1-(2-trimethylsilylethoxymethyl)imidazo[4,5-b]pyridin-2-yl]oxy-2,3,3a,5,6,6a-hexahydro-furo[3,2-b]furan-3-ol (1.67 g, 2.58 mmol) 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 (6.24 g, 156 mmol) in water (5 mL). THF (10 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 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+0.05% TFA gradient 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: 517.22 (M+H)+ (Rt 1.16/2 min); 1H NMR δ (ppm) (CD3OD): 8.80 (d, J=2.5 Hz, 1H), 8.67 (d, J=2.0 Hz, 1H), 8.30 (dd, J=2.8 Hz, 8.5 Hz, 1H), 8.06 (d, J=9.0 Hz, 1H), 7.81-7.83 (m, 6H), 6.84 (t, J=2.3 Hz, 1H), 5.56 (qt, J=55 Hz, 1H), 4.99 (t, J=5.3 Hz, 1H), 4.49 (t, J=5.0 Hz, 1H), 4.28-4.32 (m, 1H), 4.19 (dd, J=6.0 Hz, 10 Hz, 1H), 4.13 (dd, J=4.8 Hz, 10.3 Hz, 1H), 3.92 (dd, J=7.0 Hz, J=8.0 Hz, 1H), 3.62 (t, J=8.5 Hz, 1H).

Workup

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

Sources & evidence

ORD record
ord-e5548aa07022485c875e193e6a46a9c9
Source dataset
uspto-grants-2014_08
Patent number
US08796258B2

Reaction notes

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