Methanol → N-(4-((4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido) naphthalen-1-yloxy)methyl)pyridin-2-yl)tetrahydro-2H-pyran-4-carboxamide

HRID 872378Notes

Reaction equation

HRID 872378 reaction equation
[C:1](Cl)(=[O:5])[C:2](Cl)=O.[NH2:7][C:8]1[CH:13]=[C:12]([CH2:14][O:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([NH:26][C:27]([NH:29][C:30]3[N:34]([C:35]4[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=4)[N:33]=[C:32]([C:42]([CH3:45])([CH3:44])[CH3:43])[CH:31]=3)=[O:28])=[CH:18][CH:17]=2)[CH:11]=[CH:10][N:9]=1.CCN([CH:52]([CH3:54])[CH3:53])C(C)C.[CH3:55][OH:56]>CN(C=O)C.C(Cl)Cl.N>[C:42]([C:32]1[CH:31]=[C:30]([NH:29][C:27](=[O:28])[NH:26][C:19]2[C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:16]([O:15][CH2:14][C:12]3[CH:11]=[CH:10][N:9]=[C:8]([NH:7][C:55]([CH:54]4[CH2:2][CH2:1][O:5][CH2:53][CH2:52]4)=[O:56])[CH:13]=3)=[CH:17][CH:18]=2)[N:34]([C:35]2[CH:36]=[CH:37][C:38]([CH3:41])=[CH:39][CH:40]=2)[N:33]=1)([CH3:45])([CH3:44])[CH3:43]

Participants

8

Reactant 4

HCID 887MethanolHCID 65578Oxalyl chlorideHCID 81531DiisopropylethylamineHCID 584167531-(4-((2-Aminopyridin-4-yl)methoxy)naphthalen-1-yl)-3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)urea2×

Product 1

HCID 45256894N-(4-((4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido) naphthalen-1-yloxy)methyl)pyridin-2-yl)tetrahydro-2H-pyran-4-carboxamideYield 28%

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideCatalystHCID 222AmmoniaSolventHCID 6344DichloromethaneSolvent3×

Procedure

DMF (2 drops) was added to a stirred solution of tetrahydropyran-2H-4-carboxylic acid and oxalyl chloride (21 μL, 0.25 mmol) in DCM (1.0 mL) and the resulting solution was stirred at RT for 1 hr. The solution was evaporated in vacuo to give a colourless oil, which was redissolved in DCM (1.0 mL) and added dropwise to a stirred mixture of 1-(4-((2-aminopyridin-4-yl)methoxy)naphthalen-1-yl)-3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)urea (Intermediate A) (50 mg, 0.10 mmol) and DIPEA (84 μL, 0.50 mmol) in DCM (1.0 mL). Stirring was continued for 18 hr. The reaction mixture was stirred in 1% NH3 in MeOH (20 mL) for 30 mins, evaporated in vacuo, pre-adsorbed on silica, and purified by column chromatography (12 g, 0-5% MeOH in DCM, gradient elution) to give N-(4-((4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido) naphthalen-1-yloxy)methyl)pyridin-2-yl)tetrahydro-2H-pyran-4-carboxamide (Example 3) as a light tan solid (18 mg, 28%): m/z 633 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.26 (9H, s), 1.57-1.72 (4H, m), 2.38 (3H, s), 2.75 (1H, m), 3.28-3.33 (2H, m), 3.88 (2H, m), 5.35 (2H, s), 6.34 (1H, s), 6.99 (1H, d), 7.24 (1H, dd), 7.35 (2H, m), 7.43 (2H, m), 7.55-7.64 (3H, m), 7.92 (1H, m), 8.27-8.33 (3H, m), 8.58 (1H, s), 8.78 (1H, s), 10.50 (1H, s).

Workup

  1. customThe solution was evaporated in vacuo
  2. customto give a colourless oil, which
  3. stirringStirring
  4. waitwas continued for 18 hr
  5. customevaporated in vacuo, pre-adsorbed on silica
  6. custompurified by column chromatography (12 g, 0-5% MeOH in DCM, gradient elution)

Sources & evidence

ORD record
ord-a372f89ba6b3428492befcfac9c28a41
Source dataset
uspto-grants-2015_03
Patent number
US08975285B2

Reaction notes

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