1-(4-(6-(4-Methoxybenzylamino)pyrimidin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea → tert-Butyl 4-(2-(4-(2-fluoro-4-(3-(2-(4-fluorophenyl)acetyl)ureido)phenoxy)pyridin-3-yl)ethynyl)cyclohex-3-enylcarbamate

HRID 1670255Notes

Reaction equation

HRID 1670255 reaction equation
[NH2:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:13]#[C:14][C:15]2[CH2:20][CH2:19][CH:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:17][CH:16]=2)=[C:4]([F:31])[CH:3]=1.[F:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][C:40]([N:42]=[C:43]=[O:44])=[O:41])=[CH:35][CH:34]=1.COC1C=CC(CNC2N=CN=C(OC3C=CC(NC(NC(=O)CC4C=CC(F)=CC=4)=O)=CC=3F)C=2)=CC=1>C(Cl)Cl>[F:31][C:4]1[CH:3]=[C:2]([NH:1][C:43]([NH:42][C:40](=[O:41])[CH2:39][C:36]2[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=2)=[O:44])[CH:30]=[CH:29][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[C:13]#[C:14][C:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])[CH2:17][CH:16]=1

Participants

5

Reactant 3

HCID 115698931-(4-(6-(4-Methoxybenzylamino)pyrimidin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea2×HCID 231530882-(4-Fluorophenyl)acetyl isocyanateHCID 59853058tert-Butyl 4-(2-(4-(4-amino-2-fluorophenoxy)pyridin-3-yl)ethynyl)cyclohex-3-enylcarbamate

Product 1

HCID 59852858tert-Butyl 4-(2-(4-(2-fluoro-4-(3-(2-(4-fluorophenyl)acetyl)ureido)phenoxy)pyridin-3-yl)ethynyl)cyclohex-3-enylcarbamateYield 69%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

A solution of tert-butyl 4-(2-(4-(4-amino-2-fluorophenoxy)pyridin-3-yl)ethynyl)cyclohex-3-enylcarbamate (50 mg, 0.12 mmol) in dry CH2Cl2 (2 mL) was treated with a 0.3 M solution of 2-(4-fluorophenyl)acetyl isocyanate in toluene (Compound D of Example 11, 0.8 mL, 0.24 mmol) and the mixture stirred at rt for 1 h. The solvents were evaporated under vacuum and the residue purified by flash chromatography on silica gel eluting with 10-60% EtOAc/hexanes to give the title compound (50 mg, 69%) as a white solid. 1H NMR (DMSO-d6) δ 11.03 (s, 1H), 10.57 (s, 1H), 8.57 (s, 1H), 8.36 (d, 1H, J=5.7 Hz), 7.78 (dd, 1H, J=1.8, 13.1 Hz), 7.41-7.29 (m, 3H), 7.16 (dd, 3H, J=8.6, 8.6 Hz), 6.85 (d, 1H, J=8.3 Hz), 6.70 (d, 1H, J=5.7 Hz), 6.13-6.08 (m, 1H), 3.73 (s, 2H), 3.51-3.41 (m, 1H), 2.38-2.27 (m, 1H), 2.27-2.20 (m, 2H), 1.82-1.72 (m, 1H), 1.54-1.28 (m, 2H), 1.37 (s, 9H); ESI MS): m/z 603.24 (M+H)+.

Workup

  1. customThe solvents were evaporated under vacuum
  2. customthe residue purified by flash chromatography on silica gel eluting with 10-60% EtOAc/hexanes

Sources & evidence

ORD record
ord-399c39caa3a64aa7a3215a7dc0bfe4ce
Source dataset
uspto-grants-2011_08
Patent number
US07989477B2

Reaction notes

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