Phosphorus oxychloride → HCID 71743978, compound

HRID 245848Notes

Reaction equation

P(Cl)(Cl)(Cl)=O.[F:6][C:7]1[C:8]([CH2:14][NH:15][CH:16]=O)=[N:9][CH:10]=[C:11]([F:13])[CH:12]=1>C1(C)C=CC=CC=1>[F:13][C:11]1[CH:12]=[C:7]([F:6])[C:8]2[N:9]([CH:16]=[N:15][CH:14]=2)[CH:10]=1

Participants

Conditions

Temperature: 100 °C

Procedure

In a round-bottomed flask, N-(3,5-difluoro-pyridin-2-ylmethyl)-formamide (crude from Step 2) was dissolved in toluene (14 ml) and phosphorus oxychloride (0.65 ml, 7.0 mmol) was added. The reaction mixture was stirred at 100° C. in an oil bath for 3.5 h 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 0-60% EtOAc) to give 319 mg (45%, 2 steps) of 6,8-difluoro-imidazo[1,5-a]pyridine as a yellow solid. 1H NMR (CDCl3, 300 MHz): δ (ppm) 8.36 (d, J=3.0 Hz, 1H), 7.84 (d, J=3.4 Hz, 1H), 7.65 (s, 1H), 6.39-6.57 (m, 1H).

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 0-60% EtOAc)

Sources & evidence

ORD record: ord-cdd3b90958f943829d297eba0db7fa78
Source dataset: uspto-grants-2014_02
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08658646B2

Reaction notes

Loading…