Phosphorus oxychloride → Methyl 6-fluoroimidazo[1,5-a]pyridine-3-carboxylate

HRID 245851Notes

Reaction equation

P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][C:8](=[O:20])[C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=1)=O>C1(C)C=CC=CC=1>[CH3:6][O:7][C:8]([C:9]1[N:14]2[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]2=[CH:12][N:11]=1)=[O:20]

Participants

Conditions

Temperature: 105 °C

Procedure

In a round-bottomed flask, N-(5-fluoro-pyridin-2-ylmethyl)-oxalamic acid methyl ester (crude from Step 1) was dissolved in toluene (8 ml) and phosphorus oxychloride (1.5 ml, 16.1 mmol) was added. The reaction mixture was stirred at 105° C. in an oil bath overnight then cooled to 0° C. and carefully quenched with ice. Aqueous 25% ammonium hydroxide was added until pH=˜9. The mixture was diluted with water and extracted with dichloromethane (3×). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was absorbed on silica gel and chromatographed with EtOAc/hexanes (gradient 0-50% EtOAc) to give 230 mg (31%, 2 steps) of 6-fluoro-imidazo[1,5-a]pyridine-3-carboxylic acid methyl ester as a light brown solid. 1H NMR (CDCl3, 300 MHz): δ (ppm) 9.33 (dd, J=5.1, 1.3 Hz, 1H), 7.75 (s, 1H), 7.69 (dd, J=9.8, 5.3 Hz, 1H), 7.09 (ddd, J=9.7, 7.5, 2.1 Hz, 1H), 4.06 (s, 3H).

Workup

temperaturethen cooled to 0° C.
customcarefully quenched with ice
additionAqueous 25% ammonium hydroxide was added until pH=˜9
additionThe mixture was diluted with water
extractionextracted with dichloromethane (3×)
dry with materialdried over sodium sulfate
filtrationfiltered
concentrationconcentrated
customThe residue was absorbed on silica gel
customchromatographed with EtOAc/hexanes (gradient 0-50% EtOAc)

Sources & evidence

ORD record: ord-2fdcfbcc870e4d129cb09caa65843c69
Source dataset: uspto-grants-2014_02
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08658646B2

Reaction notes

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