tert-Butyl 4-(2-chloropyrimidin-4-yloxy)naphthalen-1-ylcarbamate → 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 1423254Notes

Reaction equation

HRID 1423254 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]>CN(C=O)C>[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

4

Reactant 2

HCID 86660490tert-Butyl 4-(2-chloropyrimidin-4-yloxy)naphthalen-1-ylcarbamateHCID 904331363-Amino-5-ethynyl N (2 (2 (2 methoxyethoxy)ethoxy)ethyl)benzamide

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 6228DimethylformamideSolvent

Conditions

Temperature
60 °C

Procedure

To a stirred solution of the product from step (iv) above (1 g, 3.13 mmol) and 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; 777 mg, 2.090 mmol) in DMF (60 mL) was added pTSA monohydrate (200 mg, 1.051 mmol). The resulting solution was stirred at 60° C. for 72 h. The reaction was cooled to rt, then partitioned between EtOAc (150 mL) and sat. aq. NaHCO3 (100 mL). The aqueous layer was further extracted with EtOAc (2×150 mL), then the combined organic extracts were washed with water (3×200 mL) and brine (200 mL), before being dried (MgSO4), filtered and concentrated to afford an orange oil (1.17 g). The crude product was purified by chromatography on silica gel (80 g column, 0-5% MeOH in EtOAc) to afford the sub-title compound (552 mg) as a light brown foam.

Workup

  1. temperatureThe reaction was cooled to rt
  2. custompartitioned between EtOAc (150 mL) and sat. aq. NaHCO3 (100 mL)
  3. extractionThe aqueous layer was further extracted with EtOAc (2×150 mL)
  4. washthe combined organic extracts were washed with water (3×200 mL) and brine (200 mL)
  5. dry with materialbefore being dried (MgSO4)
  6. filtrationfiltered
  7. concentrationconcentrated

Sources & evidence

ORD record
ord-e0ea011dd2a5482ca8517b0a8c6f31a3
Source dataset
uspto-grants-2015_01
Patent number
US08927563B2

Reaction notes

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