Diisopropylethylamine → N-(4-((4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)methyl)pyridin-2-yl)-2-(4-(2-methoxyethyl)piperazin-1-yl)acetamide

HRID 872386Notes

Reaction equation

HRID 872386 reaction equation
[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:36])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:35])[CH2:33]Cl)[CH:26]=3)=[CH:15][CH:14]=2)[N:7]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:53][O:54][CH2:55][CH2:56][N:57]1[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]1>C(Cl)Cl.CN(C=O)C>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:36])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:35])[CH2:33][N:60]4[CH2:61][CH2:62][N:57]([CH2:56][CH2:55][O:54][CH3:53])[CH2:58][CH2:59]4)[CH:26]=3)=[CH:15][CH:14]=2)[N:7]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]

Participants

6

Reactant 3

HCID 81531DiisopropylethylamineHCID 27346381-(2-Methoxyethyl)piperazine2×HCID 58416746HCID 58416746, compound2×

Product 1

HCID 45254196N-(4-((4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)methyl)pyridin-2-yl)-2-(4-(2-methoxyethyl)piperazin-1-yl)acetamideYield 79.8%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Procedure

To a solution of N-(4-((4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)methyl)pyridin-2-yl)-2-chloroacetamide (Intermediate B) (50 mg, 0.08 mmol) in DCM (1.0 mL), DMF (0.1 mL) and DIPEA (22 μl, 0.13 mmol) was added N-methoxyethyl piperazine (12.5 μl, 0.08 mmol). The reaction mixture was stirred at RT for 3 hr. LC-MS indicated 20% conversion to product. The reaction mixture was heated to 40° C. and stirred for 12 hr. LC-MS indicated 78% conversion to product. A further portion of N-methoxyethyl piperazine (12.5 μl, 0.08 mmol) was added and the reaction mixture continued to stir at 40° C. for 5 hr. LC-MS indicated 89% conversion to product. The crude reaction mixture was purified by column chromatography (12 g, 0-10% MeOH in DCM, gradient elution) to afford N-(4-((4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)methyl)pyridin-2-yl)-2-(4-(2-methoxyethyl) piperazin-1-yl) acetamide (Example 10) as a light orange solid (45 mg, 73%): m/z 705 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO) δ: 1.27 (9H, s), 2.39 (3H, s), 2.46-2.48 (3H, m, obscured by DMSO), 2.57-2.50 (4H, m), 3.17 (2H, s), 3.23 (3H, s), 3.42 (2H, t), 5.39 (2H, s), 6.35 (1H, s), 7.01 (1H, d), 7.29 (1H, d), 7.35 (2H, d), 7.43 (2H, d), 7.65-7.55 (3H, m), 7.93 (1H, d), 8.36-8.30 (3H, m), 8.58 (1H, s), 8.79 (1H, s), 9.92 (1H, s).

Workup

  1. temperatureThe reaction mixture was heated to 40° C.
  2. stirringstirred for 12 hr
  3. stirringto stir at 40° C. for 5 hr
  4. customThe crude reaction mixture
  5. customwas purified by column chromatography (12 g, 0-10% MeOH in DCM, gradient elution)

Sources & evidence

ORD record
ord-cd047472445f409babd294c33c65cb60
Source dataset
uspto-grants-2015_03
Patent number
US08975285B2

Reaction notes

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