Thionyl Chloride → 7-(2,6-Difluoro-phenoxy)-4-hydroxy-isoquinoline-3-carboxylic acid ethyl ester

To an ice-water bath cooled solution of 4-(2,6-difluoro-phenoxy)-2-{[(2,4-dimethoxy-benzyl)-ethoxycarbonylmethyl-amino]-methyl}-benzoic acid ethyl ester (1.09 g) in THF (10 mL) was added a solution of potassium tert-pentoxide (1.77 mL, 1.7 M in toluene); the mixture was stirred for 30 min at rt after addition; then the mixture was quenched with 2 M HCl (0.9 mL) diluted with EtOAc and water, EtOAc phase was separated and washed with water, diluted NaCl solution and dried over anhydrous sodium sulphate, filtered off, concentrated to give the desired cyclized intermediate. This intermediate was then dissolved in DCM (20 mL) and treated with thionyl chloride (0.15 mL) overnight. Then the reaction mixture was concentrated; the residue was dissolved in EtOAc, washed with water, diluted NaCl solution, then dried over sodium sulphate, filtered, concentrated and the residue was column purified to give the desired product (449 mg). LC MS ESI: 346 (M+1)+.

1. additionafter addition
2. customthen the mixture was quenched with 2 M HCl (0.9 mL)
3. additiondiluted with EtOAc and water, EtOAc phase
4. customwas separated
5. washwashed with water, diluted NaCl solution
6. dry with materialdried over anhydrous sodium sulphate
7. filtrationfiltered off
8. concentrationconcentrated
9. customto give the
10. concentrationThen the reaction mixture was concentrated
11. dissolutionthe residue was dissolved in EtOAc
12. washwashed with water, diluted NaCl solution
13. dry with materialdried over sodium sulphate
14. filtrationfiltered
15. concentrationconcentrated
16. custompurified

ORD record

ord-14eb9bdc54de4091a741ea16bb9a03d5

Source dataset

uspto-grants-2016_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09409892B2