Phosphorus oxychloride → 5-(2-Fluoro-4-methylsulfanyl-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid methyl ester

HRID 2063992Notes

Reaction equation

[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][CH:12]=O)=[N:6][C:5]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][C:16]=1[F:23].P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[N:6]([CH:12]=[N:11][CH:10]=2)[C:5]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][C:16]=1[F:23])=[O:24]

Participants

Conditions

Temperature: 95 °C

Procedure

To a suspension of 2-(2-fluoro-4-methylsulfanyl-phenylamino)-6-formylaminomethyl-nicotinic acid methyl ester (309 mg, 0.89 mmol) in toluene (15.6 mL) was added phosphorous oxychloride (91 μl, 0.98 mmol) and the reaction mixture heated to 95° C. and stirred for 1 hour. The cooled reaction mixture was quenched by the addition of water (ca. 2 mL) then concentrated in vacuo. The resultant residue was taken up in ethyl acetate and washed with water followed by a saturated aqueous solution of sodium bicarbonate and brine. The organic phase was isolated, dried (Na2SO4), filtered, concentrated in vacuo, and the residue subjected to flash chromatography (Si-PPC, gradient 0% to 40%, ethyl acetate in hexane) to afford the title compound as a yellow solid (150 mg, 51%). LCMS (method B): RT=3.44 min, [M+H]+=332.

Workup

customThe cooled reaction mixture
customwas quenched by the addition of water (ca. 2 mL)
concentrationthen concentrated in vacuo
washwashed with water
customThe organic phase was isolated
dry with materialdried (Na2SO4)
filtrationfiltered
concentrationconcentrated in vacuo

Sources & evidence

ORD record: ord-f3652c0bf0b444c592f0633ca364a845
Source dataset: uspto-grants-2012_10
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08288408B2

Reaction notes

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