Sodium hydride → 3-[5-Fluoro-3-(tetrahydro-pyran-4-YL)-pyridin-2-yloxy]-cyclobutanecarboxylic acid methyl ester

HRID 1846787Notes

Reaction equation

[OH:1][CH:2]1[CH2:5][CH:4]([C:6]([O:8][CH3:9])=[O:7])[CH2:3]1.[H-].[Na+].F[C:13]1[C:18]([CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[CH:17][C:16]([F:25])=[CH:15][N:14]=1>CN(C=O)C>[CH3:9][O:8][C:6]([CH:4]1[CH2:5][CH:2]([O:1][C:13]2[C:18]([CH:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)=[CH:17][C:16]([F:25])=[CH:15][N:14]=2)[CH2:3]1)=[O:7]

Participants

Conditions

Temperature: 60 °C

Procedure

To a solution of methyl 3-hydroxycyclobutanecarboxylate (1.2 g, 9.0 mmol) in DMF (20 mL) was added sodium hydride (60% wt in mineral oil) (1.8 g, 45 mmol) at RT. The mixture was stirred for 1 h and then 2,5-difluoro-3-(tetrahydro-pyran-4-yl)-pyridine (1.8 g, 9.0 mmol) was added. The reaction mixture was heated to 60° C. for 3 h and then quenched with saturated NH4Cl. The solution was diluted with EtOAc and water and extracted with EtOAc (2×10 mL). The organic extracts were combined, washed with brine (10 mL), dried over MgSO4, filtered, and concentrated to get a residue, which was purified by flash column chromatography on silica gel (5% to 30% EtOAc in hexanes) to give the product (3.2 g) as yellow oil.

Workup

customquenched with saturated NH4Cl
additionThe solution was diluted with EtOAc and water
extractionextracted with EtOAc (2×10 mL)
washwashed with brine (10 mL)
dry with materialdried over MgSO4
filtrationfiltered
concentrationconcentrated
customto get a residue, which
customwas purified by flash column chromatography on silica gel (5% to 30% EtOAc in hexanes)

Sources & evidence

ORD record: ord-bd943488edc349adada2d4b197862f21
Source dataset: uspto-grants-2015_02
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08952037B2

Reaction notes

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