2,2,6,6-Tetramethylpiperidine → 2,4-Difluoro-5-[hydroxy(1,3-thiazol-2-yl)methyl]-3-methylbenzoic acid

HRID 577837Notes

Reaction equation

[Li]CCCC.CC1(C)CCCC(C)(C)N1.[F:16][C:17]1[C:25]([CH3:26])=[C:24]([F:27])[CH:23]=[CH:22][C:18]=1[C:19]([OH:21])=[O:20].[S:28]1[CH:32]=[CH:31][N:30]=[C:29]1[CH:33]=[O:34]>C1COCC1>[F:16][C:17]1[C:25]([CH3:26])=[C:24]([F:27])[C:23]([CH:33]([OH:34])[C:29]2[S:28][CH:32]=[CH:31][N:30]=2)=[CH:22][C:18]=1[C:19]([OH:21])=[O:20]

Participants

Conditions

Temperature: -78 °C

Procedure

A solution of 1.9 M n-BuLi (3.8 ml, 7.2 mmol) in hexanes was added at −30° C. to a stirred solution of 2,2,6,6-tetramethylpiperidine (1.2 g, 9.0 mmol) in THF and the mixture was stirred for an hour at the same temperature. After cooling to −78° C., a solution of 2,4-difluoro-3-methylbenzoic acid (Intermediate 46, 0.5 g, 3.0 mmol) in THF was added slowly at and the mixture was stirred for another 2 h at the same temperature. To this mixture, a solution of thiazole-2-carboxaldehyde (0.8 g, 7.2 mmol) in THF was added dropwise over a period of 10 mins and the mixture was brought to the room temperature. The reaction mixture was quenched with 1.5N hydrochloric acid and the organic layer was separated, the aqueous layer was extracted with ethyl acetate (3×10 mL) and the combined organic layer was dried over sodium sulfate. Removal of solvent afforded the title compound as colorless product. Yield: 0.42 g (51%).

Workup

stirringwas stirred for another 2 h at the same temperature
customwas brought to the room temperature
customThe reaction mixture was quenched with 1.5N hydrochloric acid
customthe organic layer was separated
extractionthe aqueous layer was extracted with ethyl acetate (3×10 mL)
dry with materialthe combined organic layer was dried over sodium sulfate
customRemoval of solvent

Sources & evidence

ORD record: ord-e0d276c218324247b3dc8d437024d88c
Source dataset: uspto-grants-2015_05
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09040528B2

Reaction notes

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