1,1'-Carbonyldiimidazole → 1-[5-(1-fluoromethyl-cyclopropyl)-2-p-tolyl-2H-pyrazol-3-yl]-3-{1-[1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yloxy]-isoquinolin-4-yl}-urea

HRID 729630Notes

Reaction equation

HRID 729630 reaction equation
[F:1][CH2:2][C:3]1([C:6]2[CH:7]=[C:8]([NH2:18])[N:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[N:10]=2)[CH2:5][CH2:4]1.[C:19](N1C=CN=C1)(N1C=CN=C1)=[O:20].[NH2:31][C:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]([O:42][CH:43]2[CH2:48][CH2:47][N:46]([C:49]([C:51]3([CH3:54])[CH2:53][CH2:52]3)=[O:50])[CH2:45][CH2:44]2)=[N:34][CH:33]=1>C(Cl)Cl>[F:1][CH2:2][C:3]1([C:6]2[CH:7]=[C:8]([NH:18][C:19]([NH:31][C:32]3[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[C:35]([O:42][CH:43]4[CH2:48][CH2:47][N:46]([C:49]([C:51]5([CH3:54])[CH2:53][CH2:52]5)=[O:50])[CH2:45][CH2:44]4)=[N:34][CH:33]=3)=[O:20])[N:9]([C:11]3[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=3)[N:10]=2)[CH2:4][CH2:5]1

Participants

5

Reactant 3

HCID 682631,1'-CarbonyldiimidazoleHCID 57832814[4-(4-Amino-isoquinolin-1-yloxy)-piperidin-1-yl]-(1-methyl-cyclopropyl)-methanoneHCID 685381145-(1-fluoromethyl-cyclopropyl)-2-p-tolyl-2H-pyrazol-3-ylamine

Product 1

HCID 578328051-[5-(1-fluoromethyl-cyclopropyl)-2-p-tolyl-2H-pyrazol-3-yl]-3-{1-[1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yloxy]-isoquinolin-4-yl}-ureaYield 5%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent3×

Conditions

Temperature
40 °C

Procedure

Add 5-(1-fluoromethyl-cyclopropyl)-2-p-tolyl-2H-pyrazol-3-ylamine (160.00 mg; 652.26 μmoles) dissolved in 1 L of DCM slowly to a solution of 1,1′-carbonyldiimidazole (158.65 mg, 978.39 μmoles) in DCM. Stir mixture at 40° C. for 7 hours. Then add a solution of [4-(4-Amino-isoquinolin-1-yloxy)-piperidin-1-yl]-(1-methyl-cyclopropyl)-methanone (Preparation 23, 212.25 mg, 652.26 μmoles, 1.00 equiv) in 1 mL of DCM. Stir mixture overnight. Evaporate solvent under N2. Purify first by HLB cartridge (6 g) using NH4CO3/MeOH (100:0 to 0:100) and then finally by HPLC (Kromasil C18 column (100×21.2 mm, 5 □m (Hi-Chrom). The mobile phase is water (solvent A) and acetonitrile (solvent B), both containing 0.05% trifluoroacetic acid (TFA). Gradient mode: 2 min at 40% of B, from 40 to 60% of B in 6 min. Finally, 2 min at 95% of B. Flow rate: 25 mL/min) affording 1-[5-(1-fluoromethyl-cyclopropyl)-2-p-tolyl-2H-pyrazol-3-yl]-3-{1-[1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yloxy]-isoquinolin-4-yl}-urea as a solid (19 mg, 5% yield). ES+ (m/z):597[M+1].

Workup

  1. stirringStir mixture overnight
  2. customPurify first by HLB cartridge (6 g)
  3. waitGradient mode: 2 min at 40% of B, from 40 to 60% of B in 6 min
  4. custom2 min

Sources & evidence

ORD record
ord-88e8d88a13b84ef486be9e4147dabd2b
Source dataset
uspto-grants-2009_09
Patent number
US07582638B2

Reaction notes

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