Cesium carbonate → (3R,4R)-tert-butyl 4-(6-((3-ethyl-4-(imidazo[1,2-a]pyridine-3-carboxamido)-1H-indazol-1-yl)methyl)pyridin-2-yloxy)-3-fluoropiperidine-1-carboxylate

HRID 79305

Reaction equation

HRID 79305 reaction equation
[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[N:26]=2)[N:4]=1)[CH3:2].[F:32][C@H:33]1[C@@H:38](OS(C)(=O)=O)[CH2:37][CH2:36][N:35]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:34]1.CS(OC1CCN(C(OC(C)(C)C)=O)CC1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CC(N(C)C)=O>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:24][C:25]2[N:26]=[C:27]([O:31][C@@H:38]3[CH2:37][CH2:36][N:35]([C:44]([O:46][C:47]([CH3:49])([CH3:48])[CH3:50])=[O:45])[CH2:34][C@H:33]3[F:32])[CH:28]=[CH:29][CH:30]=2)[N:4]=1)[CH3:2]

Participants

6

Reactant 4

HCID 10796Cesium carbonateHCID 41848691-(tert-Butoxycarbonyl)-4-(methanesulfonyloxy)piperidineHCID 52324470Tert-butyl cis-3-fluoro-4-(methylsulfonyloxy)piperidine-1-carboxylateHCID 178437935HCID 178437935, compound

Product 1

HCID 67261845(3R,4R)-tert-butyl 4-(6-((3-ethyl-4-(imidazo[1,2-a]pyridine-3-carboxamido)-1H-indazol-1-yl)methyl)pyridin-2-yloxy)-3-fluoropiperidine-1-carboxylate

Reagents, catalysts & solvents 1

HCID 31374DimethylacetamideSolvent

Conditions

Temperature
90 °C

Procedure

To N-(3-ethyl-1-((6-hydroxypyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (25 mg, 0.061 mmol; prepared according to Example 17, Step A) in DMA (2 mL) was added a mixture (approximately 9:1) of (3R,4S)-tert-butyl 3-fluoro-4-(methylsulfonyloxy)piperidine-1-carboxylate (prepared as described in WO 2008/124323) and tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate (27 mg). Cs2CO3 (39 mg, 0.12 mmol) was added, the reaction vial was sealed, and the mixture was heated to 90° C. and stirred for 6 hours. DMA was removed under reduce pressure. The residue was diluted with EtOAc (20 mL), washed with saturated NaHCO3 aqueous solution and brine, and concentrated. Silica gel chromatography (DCM/MeOH 10:0.5) gave the desired product (12 mg). (The non-fluorinated product, which was also isolated, was utilized in Example 19, Step A).

Workup

  1. customthe reaction vial was sealed
  2. customDMA was removed
  3. additionThe residue was diluted with EtOAc (20 mL)
  4. washwashed with saturated NaHCO3 aqueous solution and brine
  5. concentrationconcentrated

Sources & evidence

ORD record
ord-b5df516809ac4fe3baef5e8ecb3e0628
Source dataset
uspto-grants-2014_09
Patent number
US08841455B2

Linked notes

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