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 1502360Notes

Reaction equation

HRID 1502360 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-7d21b334e6a640f7a285a11ee59e0759
Source dataset
uspto-grants-2015_12
Patent number
US09206175B2

Reaction notes

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