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

HRID 872379Notes

Reaction equation

HRID 872379 reaction equation
ClC(N(C)C)=C.[CH3:7][O:8][C@@H:9]([CH3:13])[C:10]([OH:12])=O.[NH2:14][C:15]1[CH:20]=[C:19]([CH2:21][O:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]([NH:33][C:34]([NH:36][C:37]3[N:41]([C:42]4[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=4)[N:40]=[C:39]([C:49]([CH3:52])([CH3:51])[CH3:50])[CH:38]=3)=[O:35])=[CH:25][CH:24]=2)[CH:18]=[CH:17][N:16]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.N.CO>[C:49]([C:39]1[CH:38]=[C:37]([NH:36][C:34](=[O:35])[NH:33][C:26]2[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:23]([O:22][CH2:21][C:19]3[CH:18]=[CH:17][N:16]=[C:15]([NH:14][C:10](=[O:12])[C@@H:9]([O:8][CH3:7])[CH3:13])[CH:20]=3)=[CH:24][CH:25]=2)[N:41]([C:42]2[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=2)[N:40]=1)([CH3:52])([CH3:51])[CH3:50]

Participants

8

Reactant 4

HCID 81531DiisopropylethylamineHCID 57025662-methoxypropanoic acid, (S)-HCID 190103761-chloro-N,N-dimethylethenamineHCID 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 45256895(S)-N-(4-((4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)methyl)pyridin-2-yl)-2-methoxypropanamideYield 30%

Reagents, catalysts & solvents 3

HCID 222AmmoniaSolventHCID 887MethanolSolventHCID 6344DichloromethaneSolvent2×

Procedure

1-Chloro-N,N-dimethylethenamine (50 μL, 0.48 mmol) was added to a stirring solution of (S)-2-methoxypropionic acid (50 mg, 0.48 mmol) in DCM (1.0 mL) and the resulting yellow solution was stirred at RT for 1 hr. The solution was added dropwise to a stirring 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 (167 μl, 0.96 mmol) in DCM (1.0 mL). Stirring was continued overnight. The reaction mixture was stirred in 1% NH3 in MeOH (20 mL), evaporated in vacuo, pre-adsorbed on silica and purified by column chromatography (12 g, 10-50% EtOAc in iso-hexane, gradient elution) to give (S)—N-(4-((4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)methyl)pyridin-2-yl)-2-methoxypropanamide (Example 4) as a colourless solid (18 mg, 30%): m/z 607 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.27 (9H, d), 1.31 (3H, s), 2.38 (3H, s), 3.30 (3H, s), 4.02 (1H, q), 5.39 (2H, s), 6.37 (1H, s), 7.00 (1H, d), 7.29 (1H, dd), 7.35 (2H, m), 7.45 (2H, m), 7.56-7.64 (3H, m), 7.93 (1H, m), 8.30-8.37 (3H, m), 8.58 (1H, s), 8.79 (1H, s), 10.06 (1H, s).

Workup

  1. stirringStirring
  2. waitwas continued overnight
  3. customevaporated in vacuo, pre-adsorbed on silica
  4. custompurified by column chromatography (12 g, 10-50% EtOAc in iso-hexane, gradient elution)

Sources & evidence

ORD record
ord-490ee1960d2b43afb16767f52fdda13e
Source dataset
uspto-grants-2015_03
Patent number
US08975285B2

Reaction notes

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