2-(2-Methoxyethoxy)acetyl chloride → N-(4-(2-(4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)ethyl)pyridin-3-yl)-2-(2-methoxyethoxy)acetamide

HRID 872407Notes

Reaction equation

HRID 872407 reaction equation
[NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][O:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([NH:21][C:22]([NH:24][C:25]2[N:29]([C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)[N:28]=[C:27]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:26]=2)=[O:23])=[CH:13][CH:12]=1.[CH3:41][O:42][CH2:43][CH2:44][O:45][CH2:46][C:47](Cl)=[O:48]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:37]([C:27]1[CH:26]=[C:25]([NH:24][C:22](=[O:23])[NH:21][C:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:11]([O:10][CH2:9][CH2:8][C:7]3[CH:6]=[CH:5][N:4]=[CH:3][C:2]=3[NH:1][C:47](=[O:48])[CH2:46][O:45][CH2:44][CH2:43][O:42][CH3:41])=[CH:12][CH:13]=2)[N:29]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)[N:28]=1)([CH3:40])([CH3:39])[CH3:38]

Participants

5

Reactant 2

HCID 70103382-(2-Methoxyethoxy)acetyl chlorideHCID 584167481-(4-(2-(3-aminopyridin-4-yl)ethoxy)naphthalen-1-yl)-3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)urea2×

Product 1

HCID 45254764N-(4-(2-(4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)ethyl)pyridin-3-yl)-2-(2-methoxyethoxy)acetamideYield 57.2%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6344DichloromethaneSolvent

Procedure

To 1-(4-(2-(3-aminopyridin-4-yl)ethoxy)naphthalen-1-yl)-3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)urea (Intermediate E) (50 mg, 0.094 mmol) and DMAP (5.71 mg, 0.047 mmol) in DCM (3.0 mL) was added 2-(2-methoxyethoxy)acetyl chloride (30 μl, 0.281 mmol) at 0° C. and the reaction mixture stirred at RT for 1.5 hr. The solvent was removed in vacuo and the residue subjected to SCX capture and release eluting with 1% NH3 in MeOH solution. The residue was purified by column chromatography (4.0 g) gradient elution with 0-8% MeOH in DCM and the product fractions concentrated in vacuo to give N-(4-(2-(4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)ethyl)pyridin-3-yl)-2-(2-methoxyethoxy)acetamide (Example 22) as a light purple solid (35 mg, 56%): m/z 651 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.25 (9H, s), 2.40 (3H, s), 3.26 (5H, m), 3.50 (2H, m), 3.70 (2H, m), 4.15 (2H, s), 4.40 (2H, t), 6.35 (1H, s), 6.98 (1H, d), 7.35 (2H, m), 7.42 (2H, m), 7.50 (3H, m), 7.62 (1H, d), 7.87 (1H, d), 8.07 (1H, dd), 8.36 (1H, d), 8.56 (1H. br s), 8.60 (1H, s), 8.76 (1H, br s), 9.55 (1H, br s.).

Workup

  1. customThe solvent was removed in vacuo
  2. washeluting with 1% NH3 in MeOH solution
  3. customThe residue was purified by column chromatography (4.0 g) gradient elution with 0-8% MeOH in DCM
  4. concentrationthe product fractions concentrated in vacuo

Sources & evidence

ORD record
ord-e784251b46284b14984ed6920cd621e0
Source dataset
uspto-grants-2015_03
Patent number
US08975285B2

Reaction notes

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