Formic Acid → (4'-(6-chloro-2-(((3R,5 S,6R)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1'-biphenyl]-4-yl)((R)-3-hydroxypyrrolidin-1-yl)methanone

HRID 1050263Notes

Reaction equation

HRID 1050263 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]2[N:38](COCC[Si](C)(C)C)[C:37]([O:47][C@H:48]3[CH2:57][O:56][C@H:55]4[C@@H:50]([O:51]C(C5C=CC=CC=5)[O:53][CH2:54]4)[CH2:49]3)=[N:36][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([N:22]3[CH2:26][CH2:25][C@@H:24]([O:27]COCC[Si](C)(C)C)[CH2:23]3)=[O:21])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.C(O)=O.S([O-])(O)(=O)=O.[K+].[OH-].[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]2[NH:38][C:37]([O:47][C@@H:48]3[CH2:49][C@H:50]([OH:51])[C@@H:55]([CH2:54][OH:53])[O:56][CH2:57]3)=[N:36][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[O:21])=[CH:18][CH:19]=2)=[CH:10][CH:9]=1

Participants

5

Reactant 4

HCID 284Formic AcidHCID 14798Sodium HydroxideHCID 516920Potassium bisulfateHCID 90044253(4'-(6-chloro-2-(((4aR,7R,8aS)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1'-biphenyl]-4-yl)((R)-3-((2-(trimethylsilyl)ethoxy)methoxy)pyrrolidin-1-yl)methanone

Product 1

HCID 73332561(4'-(6-chloro-2-(((3R,5 S,6R)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1'-biphenyl]-4-yl)((R)-3-hydroxypyrrolidin-1-yl)methanone

Procedure

To a solution of (4′-(6-chloro-2-(((4aR,7R,8aS)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)((R)-3-((2-(trimethylsilyl)ethoxy)methoxy)pyrrolidin-1-yl)methanone (181 mg, 0.198 mmol) in formic acid (1 ml, 26.1 mmol) at 0° C., was added saturated potassium hydrogen sulfate (0.2 ml, 0.198 mmol). The resulting mixture was stirred at room temperature for 48 h. The reaction mixture was then cooled down to 0° C. and basified to pH 11 with 2.5N NaOH. The mixture was stirred at room temperature for 30 minutes, then the layers were separated. The aqueous layer was extracted with EtOAc; and the combined organic layers was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The purification of the resulting residue by HPLC eluting with 10-100% MeCN:H2O 0.1% formic acid afforded the title compound LC-MS: calculated for C29H29ClN4O6 564.18 observed m/e: 565.09 (M+H)+ (Rt: 1.72/4 min).

Workup

  1. stirringThe mixture was stirred at room temperature for 30 minutes
  2. customthe layers were separated
  3. extractionThe aqueous layer was extracted with EtOAc
  4. washand the combined organic layers was washed with brine
  5. dry with materialdried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customThe purification of the resulting residue by HPLC
  9. washeluting with 10-100% MeCN

Sources & evidence

ORD record
ord-5a833a7d228d4bff8bb1fa6236bbfe64
Source dataset
uspto-grants-2016_07
Patent number
US09382243B2

Reaction notes

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