Ammonia → N-(4-(4-(3-(3-tert-Butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)pyridin-2-yl)-2-(methylsulfonyl)acetamide

HRID 2069075Notes

Reaction equation

HRID 2069075 reaction equation
[CH3:1][S:2]([CH2:5][C:6]([OH:8])=O)(=[O:4])=[O:3].ClC(N(C)C)=C(C)C.[NH2:17][C:18]1[CH:23]=[C:22]([O:24][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]([NH:35][C:36]([NH:38][C:39]3[N:43]([C:44]4[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][CH:45]=4)[N:42]=[C:41]([C:51]([CH3:54])([CH3:53])[CH3:52])[CH:40]=3)=[O:37])=[CH:27][CH:26]=2)[CH:21]=[CH:20][N:19]=1.CCN(C(C)C)C(C)C.N>C(Cl)Cl.CO>[C:51]([C:41]1[CH:40]=[C:39]([NH:38][C:36](=[O:37])[NH:35][C:28]2[C:29]3[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:25]([O:24][C:22]3[CH:21]=[CH:20][N:19]=[C:18]([NH:17][C:6](=[O:8])[CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH:23]=3)=[CH:26][CH:27]=2)[N:43]([C:44]2[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][CH:45]=2)[N:42]=1)([CH3:54])([CH3:53])[CH3:52]

Participants

8

Reactant 5

HCID 222AmmoniaHCID 81531DiisopropylethylamineHCID 6407921-Chloro-N,N-2-trimethylpropenylamineHCID 37328412-Methanesulfonylacetic acidHCID 585325691-(4-(2-aminopyridin-4-yloxy)naphthalen-1-yl)-3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)urea

Product 1

HCID 46836045N-(4-(4-(3-(3-tert-Butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)pyridin-2-yl)-2-(methylsulfonyl)acetamideYield 28%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6344DichloromethaneSolvent2×

Procedure

To a suspension of methanesulfonylacetic acid (40 mg, 0.29 mmol) in DCM (2.0 mL) under nitrogen was added 1-chloro-N,N,2-trimethylpropenylamine (48 μL, 0.37 mmol), and the mixture was stirred at RT for 2 hr. The resulting mixture was added to a solution of (Intermediate Q) (37 mg, 0.07 mmol) and DIPEA (51 μL, 0.29 mmol) in DCM (2.0 mL) and stirring continued at RT for 3 hr. The reaction mixture was stirred with 1% NH3 in MeOH (3.0 mL) for 45 min and then evaporated in vacuo. The residue was subjected to SCX capture and release and was then purified by flash column chromatography (SiO2, 12 g, 0-70% [5% MeOH in EtOAc] in isohexane, gradient elution) to afford the title compound (Example 51) as a white powder (13 mg, 28%): m/z 627 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.29 (9H, s), 2.39 (3H, s), 3.10 (3H, s), 4.36 (2H, s), 6.40 (1H, s), 6.71 (1H, dd), 7.33-7.38 (3H, overlapping m), 7.47 (2H, m), 7.56 (1H, m), 7.65 (1H, m), 7.69 (1H, m), 7.85 (1H, d), 7.96 (1H, d), 8.11 (1H, d), 8.22 (1H, d), 8.91 (1H, br s), 9.23 (1H, br s), 10.96 (1H, br s).

Workup

  1. stirringstirring
  2. waitcontinued at RT for 3 hr
  3. customevaporated in vacuo
  4. customwas then purified by flash column chromatography (SiO2, 12 g, 0-70% [5% MeOH in EtOAc] in isohexane, gradient elution)

Sources & evidence

ORD record
ord-72f78c7b52374dda903f5dbe927f82f4
Source dataset
uspto-grants-2012_10
Patent number
US08299073B2

Reaction notes

Loading…