Sodium methanethiolate → N-(4-((4-(3-(3-tert-Butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)methyl)pyridin-2-yl)-2-(methylthio)acetamide

HRID 2067044Notes

Reaction equation

HRID 2067044 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].[CH3:44][S-:45].[Na+]>CO>[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][S:45][CH3:44])[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

4

Reactant 2

HCID 4378561Sodium methanethiolateHCID 58416746HCID 58416746, compound2×

Product 1

HCID 45257074N-(4-((4-(3-(3-tert-Butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)methyl)pyridin-2-yl)-2-(methylthio)acetamideYield 27.1%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

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) (100 mg, 0.17 mmol) was added portionwise to a stirred mixture of sodium thiomethoxide (35 mg, 0.50 mmol) in MeOH (5.0 mL) and the resulting mixture was stirred for 1 hr at RT. The mixture was evaporated in vacuo and partitioned between brine (20 mL) and DCM (30 mL). The organic layer was concentrated in vacuo, the residue pre-adsorbed on silica and purified by column chromatography (12 g, 10-100% EtOAc in iso-hexane, gradient elution). Product fractions were evaporated in vacuo to give N-(4-((4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)methyl)pyridin-2-yl)-2-(methylthio) acetamide (Example 6) as a light yellow solid (28 mg, 26%): m/z 610 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.27 (9H, s), 2.16 (3H, s), 2.39 (3H, s), 3.53 (2H, s), 5.37 (2H, s), 6.35 (1H, s), 7.01 (1H, d), 7.26 (1H, dd), 7.35 (2H, m), 7.44 (2H, m), 7.55-7.64 (3H, m), 7.92 (1H, m), 8.30-8.35 (3H, m), 8.58 (1H, s), 8.78 (1H, s), 10.60 (1H, s).

Workup

  1. customThe mixture was evaporated in vacuo
  2. custompartitioned between brine (20 mL) and DCM (30 mL)
  3. concentrationThe organic layer was concentrated in vacuo
  4. customthe residue pre-adsorbed on silica and purified by column chromatography (12 g, 10-100% EtOAc in iso-hexane, gradient elution)
  5. customProduct fractions were evaporated in vacuo

Sources & evidence

ORD record
ord-0fc4bd8003174cbc9a6d0b9d7def11e4
Source dataset
uspto-grants-2012_10
Patent number
US08293748B2

Reaction notes

Loading…