Ammonia → (R)-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 1916780Notes

Reaction equation

HRID 1916780 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.N>C(Cl)Cl.CO.CCCC(C)C.CCOC(C)=O>[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

10

Reactant 5

HCID 222AmmoniaHCID 81531DiisopropylethylamineHCID 2733584(2R)-2-methoxypropanoic acidHCID 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 45256896(R)-N-(4-((4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)methyl)pyridin-2-yl)-2-methoxypropanamideYield 45.9%

Reagents, catalysts & solvents 4

HCID 887MethanolSolventHCID 6344DichloromethaneSolvent2×HCID 78922-MethylpentaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

1-Chloro-N,N-dimethylethenamine (38 μL, 0.36 mmol) was added to a stirred solution of (R)-2-methoxypropionic acid (37 mg, 0.36 mmol) in DCM (1.0 mL) and the resulting solution was stirred at RT for 1 hr. The solution was 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) (75 mg, 0.14 mmol) and DIPEA (75 μL, 0.43 mmol) in DCM (2.0 mL) at 0° C. Stirring was continued for a further 48 hr. The mixture was poured in to 1% NH3 in MeOH (20 mL) and stirred for 1 hr, and evaporated in vacuo to give a yellow residue. Column chromatography (12 g, 20-50% EtOAc in iso-hexane) gave (R)—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 5) as a light pink solid (39 mg, 43%): m/z 607 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.27 (9H, d), 1.30 (3H, s), 2.39 (3H, s), 3.31 (3H, s), 4.02 (1H, q), 5.39 (2H, s), 6.35 (1H, s), 7.02 (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), 10.09 (1H, s).

Workup

  1. stirringStirring
  2. waitwas continued for a further 48 hr
  3. stirringstirred for 1 hr
  4. customevaporated in vacuo
  5. customto give a yellow residue

Sources & evidence

ORD record
ord-862f2a90f3134457ace42ab9f3a90d5c
Source dataset
uspto-grants-2013_12
Patent number
US08618140B2

Reaction notes

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