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

HRID 1500706Notes

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-b81fdf025a974b6abf6dc2c4e3b40f2a
Source dataset: uspto-grants-2015_12
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09206174B2

Reaction notes

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