Reaction #62326

Reaction equation

2-(2-bromoethoxy)-tetrahydropyran

ammonium chloride

3-[(E)-2-(4-fluorophenyl)-vinyl]-4-hydroxy-1H-indazole-1,5-dicarboxylic acid 1-tert-butyl ester 5-ethyl ester

2-(2-bromoethoxy)-tetrahydropyran

cesium carbonate

2-(2-bromoethoxy)-tetrahydropyran

cesium carbonate

→

title compound

Yield 56.5%

3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-[2-(tetrahydropyran-2-yloxy)-ethoxy]-1H-indazole-1,5-dicarboxylic acid 1-tert-butyl Ester 5-ethyl ester

Yield 56.5%

Solvents

N,N-dimethylformamide

Conditions

Workup

1. 1
   workup.STIRRINGstirred at 50° C. for 17 hours
2. 2
   workup.STIRRINGstirred for 3 hours at room temperature and for 2 hours at 50° C.
3. 3
   workup.STIRRINGfurther stirred at 50° C. for 4 hours
4. 4
   Extractionextracted twice with ethyl acetate
5. 5
   Washthe resultant organic layer was washed once with saturated brine
6. 6
   Dryingdried over magnesium sulfate
7. 7
   OtherThe solvent was evaporated
8. 8
   Otherthe crude product was purified
9. 9
   Otherseparated by silica gel column chromatography

Procedure

To a solution of 200 mg of 3-[(E)-2-(4-fluorophenyl)-vinyl]-4-hydroxy-1H-indazole-1,5-dicarboxylic acid 1-tert-butyl ester 5-ethyl ester in 13 mL of N,N-dimethylformamide were added 196.5 mg of 2-(2-bromoethoxy)-tetrahydropyran and 306.3 mg of cesium carbonate, stirred for 1 hour and 30 minutes at room temperature, stirred at 50° C. for 17 hours, added with 196.5 mg of 2-(2-bromoethoxy)-tetrahydropyran and 306.3 mg of cesium carbonate, stirred for 3 hours at room temperature and for 2 hours at 50° C., added with 554 mg of 2-(2-bromoethoxy)-tetrahydropyran, and further stirred at 50° C. for 4 hours. Then, the reaction solution was added saturated aqueous ammonium chloride, extracted twice with ethyl acetate, and the resultant organic layer was washed once with saturated brine and dried over magnesium sulfate. The solvent was evaporated, and the crude product was purified and separated by silica gel column chromatography, to afford 147 mg of the title compound as a colorless oil.

Source