Sulfuric Acid → Methyl 5-amino-4-fluoro-1H-benzimidazole-6-carboxylate

HRID 571032Notes

Reaction equation

[NH2:1][C:2]1[C:11]([F:12])=[C:10]([NH2:13])[C:9]([NH2:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH:15](OCC)(OCC)OCC.OS(O)(=O)=O>C1COCC1>[CH3:7][O:6][C:4]([C:3]1[C:2]([NH2:1])=[C:11]([F:12])[C:10]2[N:13]=[CH:15][NH:14][C:9]=2[CH:8]=1)=[O:5]

Participants

Conditions

Temperature: 60 °C

Procedure

To a stirred solution of methyl 2,4,5-triamino-3-fluorobenzoate (9) (7.58 g, 38.1 mmol) in THF (152 mL, 20 vol) was added triethyl orthoformate (20.3 g, 22.8 mL, 137.0 mmol), followed by dropwise addition of H2SO4 (9.33 g, 18 M, 94.1 mmol). The mixture was then heated at 60° C. for 6 hours, at which point no starting material was detected by HPLC analysis. The solid product was filtered and rinsed with THF (150 mL, 20 vol), then transferred to a reaction vessel, suspended in water (150 mL) and the resulting mixture was neutralized to about pH 7.5 with 2 N NaOH. After stirring for 30 minutes, the suspension was filtered and the solid product was dried in a vacuum oven at 55° C., overnight to provide 6-amino-7-fluoro-3H-benzoimidazole-5-carboxylic acid methyl ester (12) 7.5 g, 94% yield (100% area by HPLC). 1H NMR (400 Hz, d6 DMSO) δ 3.53 (1H, br s, NH), 3.85, (3H, s, OMe), 6.10 (2H, br s, NH2), 7.90 (1H, s, Ar—H), 7.20 (1H, s, Ar—H). MS APCI (+) m/z 210 (M+1) detected with MS APCI (+).

Workup

filtrationThe solid product was filtered
washrinsed with THF (150 mL, 20 vol)
customtransferred to a reaction vessel
filtrationthe suspension was filtered
customthe solid product was dried in a vacuum oven at 55° C., overnight

Sources & evidence

ORD record: ord-e982a0cb2192494ea0e985ae875cca8a
Source dataset: uspto-grants-2015_05
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09024040B2

Reaction notes

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