p-Toluenesulfonic acid monohydrate → Benzimidazole

HRID 1056937Notes

Reaction equation

[NH2:1][C:2]1[C:3](OC2C=CC(F)=CC=2F)=[C:4](C2C3C=CN(S(C4C=CC(C)=CC=4)(=O)=O)C=3C(=O)N(C)C=2)[CH:5]=[CH:6][C:7]=1[NH2:8].[CH:39]([O-])([O-])OCC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1>[N:1]1[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=2[NH:8][CH:39]=1

Participants

Conditions

Temperature: 50 °C

Procedure

A solution of 4-[3,4-diamino-2-(2,4-difluorophenoxyl)phenyl]-6-methyl-1-[(4-methylphenyl)sulfonyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (31.0 mg, 0.058 mmol) in tetrahydrofuran (0.50 mL) was treated with ethyl orthoformate (28.8 μL, 0.173 mmol) followed by p-toluenesulfonic acid monohydrate (1.1 mg, 5.8 μmol) and stirred at 50° C. for 1 h. The reaction mixture was concentrated to give the intermediate benzimidazole which was used immediately without further purification. The intermediate benzimidazole was dissolved in ethanol (1.0 mL), treated with 1.0 M sodium hydroxide in water (300 μL, 0.90 mmol), and heated at 60° C. overnight. The reaction mixture was purified via preparative LCMS (XBridge C18 column, eluting with a gradient of methanol/water containing 0.1% trifluoroacetic acid, at flow rate of 60 mL/min) to give the desired product (6 mg, 26%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 12.01 (s, 1H), 8.72 (br s, 1H), 7.65 (d, J=8.4 Hz, 1H), 7.44 (d, J=8.3 Hz, 1H), 7.32-7.15 (m, 3H), 6.80-6.65 (m, 1H), 6.63-6.48 (m, 1H), 6.20-6.03 (m, 1H), 3.48 (s, 3H); LCMS calculated for C21H15F2N4O2 (M+H)+: m/z=393.1. found: 393.1.

Workup

concentrationThe reaction mixture was concentrated

Sources & evidence

ORD record: ord-7be095f9fec545eda2a0b8c59964208b
Source dataset: uspto-grants-2016_07
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09399640B2

Reaction notes

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