Sodium hydride → benzyl 3-((4-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-6-((4-methoxybenzyl)oxy)pyrimidin-2-yl)oxy)-(trans)-4-fluoropiperidine-1-carboxylate

HRID 1529439Notes

Reaction equation

HRID 1529439 reaction equation
[F:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][C@H:3]1[OH:18].[H-].[Na+].[Br:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[N:27]([CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][O:32]1)[N:26]=[C:25]2[C:37]1[CH:42]=[C:41]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=2)[N:40]=[C:39](S(C)(=O)=O)[N:38]=1>C1COCC1>[Br:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[N:27]([CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][O:32]1)[N:26]=[C:25]2[C:37]1[CH:42]=[C:41]([O:43][CH2:44][C:45]2[CH:46]=[CH:47][C:48]([O:51][CH3:52])=[CH:49][CH:50]=2)[N:40]=[C:39]([O:18][C@H:3]2[C@H:2]([F:1])[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[O:9])[CH2:4]2)[N:38]=1

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 67958238Benzyl (3R,4R)-4-fluoro-3-hydroxypiperidine-1-carboxylateHCID 679596205-bromo-3-(6-((4-methoxybenzyl)oxy)-2-(methylsulfonyl)pyrimidin-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

Product 1

HCID 67959946benzyl 3-((4-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-6-((4-methoxybenzyl)oxy)pyrimidin-2-yl)oxy)-(trans)-4-fluoropiperidine-1-carboxylateYield 77%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

To a solution of benzyl trans-4-fluoro-3-hydroxypiperidine-1-carboxylate (racemic) (0.486 g, 1.92 mmol) in dry THF (10 mL) at 0° C. was added NaH (0.126 g, 5.24 mmol) and the reaction was stirred at RT for 30 min. A solution of 5-bromo-3-(6-((4-methoxybenzyl)oxy)-2-(methylsulfonyl)pyrimidin-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (1 g, 1.74 mmol) in dry THF (5 mL) was added drop wise to the above mixture and the reaction was stirred for 2 h. The reaction was quenched with ice cold water (10 mL) and extracted with EtOAc (2×20 mL) and the combined organic layers were dried, filtered and concentrated. The residue was purified with silica gel chromatography (eluting with 35% EtOAc in petroleum ether) to give benzyl 3-((4-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-6-((4-methoxybenzyl)oxy)pyrimidin-2-yl)oxy)-(trans)-4-fluoropiperidine-1-carboxylate (racemic) (1 g, 77%) as a off white solid. MS (ESI, pos. ion) m/z: 745.7 (M+1).

Workup

  1. stirringthe reaction was stirred for 2 h
  2. customThe reaction was quenched with ice cold water (10 mL)
  3. extractionextracted with EtOAc (2×20 mL)
  4. customthe combined organic layers were dried
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe residue was purified with silica gel chromatography (eluting with 35% EtOAc in petroleum ether)

Sources & evidence

ORD record
ord-d4f55651484c464ab10668c212616af0
Source dataset
uspto-grants-2015_07
Patent number
US09090593B2

Reaction notes

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