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

HRID 2064011Notes

Reaction equation

[CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])=[N:9][C:8]([CH2:20][NH:21][CH:22]=O)=[CH:7][N:6]=1)=[O:4].P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[N:9]([CH:22]=[N:21][CH:20]=2)[C:10]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=1[F:19])=[O:4]

Participants

Conditions

Temperature: 95 °C

Procedure

To a suspension of 3-(2-fluoro-4-iodo-phenylamino)-5-formylaminomethyl-pyrazine-2-carboxylic acid methyl ester (480 mg, 1.12 mmol) in toluene (18 mL) was added phosphorous oxychloride (0.42 mL, 4.4 mmol, 4.0 eq.), and the reaction mixture was heated at 95° C. for 1 hour. The reaction mixture was cooled to RT and then quenched with a saturated aqueous solution of sodium bicarbonate (2 mL). The resultant residue was dissolved in ethyl acetate and washed with water and brine. The organic phase was isolated, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si-PPC, gradient 0% to 20%, methanol in ethyl acetate) to give a yellow oil. Crystallization from dichloromethane—ether—hexane afforded the desired product as a yellow solid (190 mg, 41.3%). LCMS (method C): RT=2.45 min, [M+H]+=413.

Workup

temperatureThe reaction mixture was cooled to RT
customquenched with a saturated aqueous solution of sodium bicarbonate (2 mL)
dissolutionThe resultant residue was dissolved in ethyl acetate
washwashed with water and brine
customThe organic phase was isolated
dry with materialdried (Na2SO4)
filtrationfiltered
concentrationconcentrated in vacuo
customto give a yellow oil
customCrystallization from dichloromethane—ether—hexane

Sources & evidence

ORD record: ord-413581576c544d0896f6f0949faa2430
Source dataset: uspto-grants-2012_10
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08288408B2

Reaction notes

Loading…