Tert-butyl 5-(3-(cyclopropanecarboxamido)isoquinolin-7-yl)-4-methylpyridin-2-ylcarbamate → N-(7-(6-amino-4-methylpyridin-3-yl)isoquinolin-3-yl)cyclopropanecarboxamide

HRID 468843Notes

Reaction equation

HRID 468843 reaction equation
[CH:1]1([C:4]([NH:6][C:7]2[N:8]=[CH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[C:12]([C:17]2[C:18]([CH3:31])=[CH:19][C:20]([NH:23]C(=O)OC(C)(C)C)=[N:21][CH:22]=2)[CH:11]=3)=[O:5])[CH2:3][CH2:2]1>ClCCl.FC(F)(F)C(O)=O>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:12]2[CH:11]=[C:10]3[C:15]([CH:16]=[C:7]([NH:6][C:4]([CH:1]4[CH2:2][CH2:3]4)=[O:5])[N:8]=[CH:9]3)=[CH:14][CH:13]=2)=[C:18]([CH3:31])[CH:19]=1

Participants

4

Reactant 1

HCID 67977233Tert-butyl 5-(3-(cyclopropanecarboxamido)isoquinolin-7-yl)-4-methylpyridin-2-ylcarbamate

Product 1

HCID 67974334N-(7-(6-amino-4-methylpyridin-3-yl)isoquinolin-3-yl)cyclopropanecarboxamideYield 12%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 6422Trifluoroacetic acidSolvent

Procedure

A solution of the crude tert-butyl 5-(3-(cyclopropanecarboxamido)isoquinolin-7-yl)-4-methylpyridin-2-ylcarbamate in dichloromethane (4 mL) and trifluoroacetic acid (4 mL) was stirred for 60 mins at ambient temperature and concentrated in vacuo. The residue was treated with saturated aqueous sodium bicarbonate and brine and extracted twice with dichloromethane, and the combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica, ISCO, 0.5-20% methanol in dichloromethane) and subsequently repurified by reverse phase HPLC (gradient of acetonitrile in water with 0.1% formic acid) to afford the title compound as a white amorphous solid (7.0 mg, 12% over 2 steps). 1H NMR (400 MHz, DMSO) δ 10.86 (s, 1H), 9.14 (s, 1H), 8.46 (s, 1H), 7.94 (s, 1H), 7.86 (d, J=8.8 Hz, 1H), 7.84, (s, 1H), 7.66 (dd, J=8.8, 1.4 Hz, 1H), 6.40 (s, 1H), 5.91 (s, 2H), 2.17 (s, 3H), 2.12-2.03 (m, 1H), 0.90-0.79 (m, 4H). LCMS (Method E): RT=3.241 min, M+H+=319.1.

Workup

  1. concentrationconcentrated in vacuo
  2. additionThe residue was treated with saturated aqueous sodium bicarbonate and brine
  3. extractionextracted twice with dichloromethane
  4. washthe combined organic phases were washed with brine
  5. dry with materialdried over magnesium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customThe residue was purified by flash chromatography (silica, ISCO, 0.5-20% methanol in dichloromethane)
  9. customsubsequently repurified by reverse phase HPLC (gradient of acetonitrile in water with 0.1% formic acid)

Sources & evidence

ORD record
ord-ce23c20d63364df586f7609bf26fcbf7
Source dataset
uspto-grants-2014_01
Patent number
US08623889B2

Reaction notes

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