Sodium Hydroxide → 1-Cyclopropyl-3-(2-fluoro-4-iodo-phenylamino)-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid (2-vinyloxy-ethoxy)-amide

HRID 2264971Notes

Reaction equation

CO[C:3]([C:5]1[N:13]([CH:14]2[CH2:16][CH2:15]2)[C:12]2[CH:11]=[CH:10][N:9]=[CH:8][C:7]=2[C:6]=1[NH:17][C:18]1[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:19]=1[F:25])=[O:4].[OH-].[Na+].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH:49]([O:51][CH2:52][CH2:53][O:54][NH2:55])=[CH2:50].CCN(C(C)C)C(C)C>C1COCC1.CO>[CH:49]([O:51][CH2:52][CH2:53][O:54][NH:55][C:3]([C:5]1[N:13]([CH:14]2[CH2:16][CH2:15]2)[C:12]2[CH:11]=[CH:10][N:9]=[CH:8][C:7]=2[C:6]=1[NH:17][C:18]1[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:19]=1[F:25])=[O:4])=[CH2:50]

Participants

Conditions

Temperature: 65 °C

Procedure

To a stirred solution of 1-cyclopropyl-3-(2-fluoro-4-iodo-phenylamino)-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid methyl ester (150.0 mg, 0.33 mmol) in anhydrous THF (3.5 mL) and anhydrous methanol (1.0 mL) under N2 was added freshly prepared 1N aqueous sodium hydroxide (0.66 ml, 2.0 eq). The reaction mixture was stirred at 65° C. for 1 h. The resultant reaction mixture was evaporated in vacuo and azeotroped with toluene (3×5 ml) to give a yellow solid. The yellow solid was redissolved in anhydrous THF (6.6 ml). EDCI (127.0 mg, 0.66 mmol, 2.0 eq) and HOBT (89.7 mg, 0.66 mmol, 2.0 eq) were added. The reaction mixture was stirred at room temperature. After 5 minutes O-(2-vinyloxy-ethyl)-hydroxylamine (68.5 mg, 0.66 mmol, 2.0 eq) and DIPEA (0.12 mL, 0.66 mmol, 2.0 eq) were added, and the reaction mixture was stirred at ambient temperature under N2 for 16 h. The reaction mixture was absorbed onto silica and purified by flash column chromatography (silica, ISCO, 45 mL/min, 0 to 20% EtOH in DCM) to give the desired product as a pale yellow solid (57.5 mg, 33.1%). 1H-NMR (400 MHz, CD3OD) δ ppm 8.72 (s, 1H), 8.24 (d, J=6.0 Hz, 1H), 7.54-7.32 (m, 2H), 7.21 (ddd, J=8.5, 1.1 Hz, 1H), 6.61-6.39 (m, 1H), 3.86-3.70 (m, 2H), 3.62 (t, J=6.0 Hz, 2H), 3.35-3.24 (m, 1H), 3.34-3.32 (m, 1H), 3.14-3.00 (m, 2H), 1.42-1.27 (m, 2H), 0.94-0.78 (m, 2H); LC-MS (method D): [M+H]+=523.2, RT=2.21 min.

Workup

customThe resultant reaction mixture
customwas evaporated in vacuo
customazeotroped with toluene (3×5 ml)
customto give a yellow solid
stirringThe reaction mixture was stirred at room temperature
stirringthe reaction mixture was stirred at ambient temperature under N2 for 16 h
customThe reaction mixture was absorbed onto silica
custompurified by flash column chromatography (silica, ISCO, 45 mL/min, 0 to 20% EtOH in DCM)

Sources & evidence

ORD record: ord-5ccb26224b3441e8ae87a1e2a131474f
Source dataset: uspto-grants-2010_12
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US07855216B2

Reaction notes

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