Water → tert-Butyl(4((2-((3-ethynyl-5-((2-(2-(2-methoxyethoxy)ethoxy)ethyl)carbamoyl)phenyl)-amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)carbamate

HRID 1423261Notes

Reaction equation

HRID 1423261 reaction equation
[NH2:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([C:21]#[CH:22])[CH:20]=1)[C:5]([NH:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])=[O:6].[C:23]([O:27][C:28](=[O:48])[NH:29][C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]([O:40][C:41]2[CH:46]=[CH:45][N:44]=[C:43](Cl)[N:42]=2)=[CH:32][CH:31]=1)([CH3:26])([CH3:25])[CH3:24].CC1C=CC(S(O)(=O)=O)=CC=1.O.ClC1N=CC=CN=1>C1COCC1>[C:23]([O:27][C:28](=[O:48])[NH:29][C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]([O:40][C:41]2[CH:46]=[CH:45][N:44]=[C:43]([NH:1][C:2]3[CH:3]=[C:4]([C:5](=[O:6])[NH:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])[CH:18]=[C:19]([C:21]#[CH:22])[CH:20]=3)[N:42]=2)=[CH:32][CH:31]=1)([CH3:26])([CH3:24])[CH3:25]

Participants

7

Reactant 5

HCID 962WaterHCID 6101p-Toluenesulfonic acidHCID 744042-Chloropyrimidine2×HCID 86660490tert-Butyl 4-(2-chloropyrimidin-4-yloxy)naphthalen-1-ylcarbamateHCID 904331363-Amino-5-ethynyl N (2 (2 (2 methoxyethoxy)ethoxy)ethyl)benzamide4×

Product 1

HCID 131732230tert-Butyl(4((2-((3-ethynyl-5-((2-(2-(2-methoxyethoxy)ethoxy)ethyl)carbamoyl)phenyl)-amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)carbamate

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

Under N2 was charged the product from step (iv) above (301.2 g, 250.0 g active, 0.816 mol), tert-butyl(4-((2-chloropyrimidin-4-yl)oxy)naphthalen-1-yl)carbamate (see, for example, Ito, K. et al., WO 2010/067130, 17 Jun. 2010; 252.8 g, 0.680 mol), pTSA.H2O (24.7 g, 0.130 mol) and THF (7600 mL). The dark red solution was heated to reflux for 6 h then cooled to room temperature, after which HPLC analysis indicated 0.25% the product of step (iv), 22.24% the product of step (vi), 8.98% chloropyrimidine starting material and 64.08% the product of step (v). Further product from step (iv) above (27.1 g, 22.5 g active, 73.4 mmol) was charged and the reaction was heated back to reflux and stirred overnight, with HPLC analysis subsequently revealing 0.20% the product of step (iv), 30.23% the product of step (vi), 4.50% starting chloropyrimidine and 58.61% the product of step (v).

Workup

  1. temperatureThe dark red solution was heated
  2. temperatureto reflux for 6 h
  3. temperaturethe reaction was heated back
  4. temperatureto reflux

Sources & evidence

ORD record
ord-6b772b4eef53400cb84380b99b8e7dd4
Source dataset
uspto-grants-2015_01
Patent number
US08927563B2

Reaction notes

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