Hydrochloric Acid → [(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl] 2-benzyloxy-3-formyl-benzoate

A solution of methyl 2-(benzyloxy)-3-formylbenzoate (598 mg, 2.21 mmol) in THF (4 mL) and MeOH (2 mL) and a solution of 4 N NaOH (1.10 mL, 4.43 mmol) was added at 0° C., and the reaction mixture stirred for 30 minutes. 2N HCl was then added at 0° C. to adjust the pH to −2. After concentration in vacuo, the residue was azeotroped with toluene to dryness. The crude solid was dissolved in DMF (4.4 mL). To half of this solution (2.2 mL, 1.1 mmol) was added (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (553 mg, 1.32 mmol), 4-(dimethylamino)-pyridine (67 mg, 0.55 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (422 mg, 2.2 mmol), and the resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with DCM (100 mL), the organic phase washed with sat. NaHCO3 (2×50 mL). The phases were separated over a hydrophobic fit and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-100% EtOAc in isohexane to give the title compound as a white solid (784 mg, 54% over two steps).

1. concentrationAfter concentration in vacuo
2. customthe residue was azeotroped with toluene to dryness
3. dissolutionThe crude solid was dissolved in DMF (4.4 mL)
4. stirringthe resulting mixture was stirred at room temperature for 4 hours
5. washthe organic phase washed with sat. NaHCO3 (2×50 mL)
6. customThe phases were separated over a hydrophobic fit
7. concentrationconcentrated in vacuo
8. customThe residue was purified via silica gel chromatography
9. washeluting with 0-100% EtOAc in isohexane

ORD record

ord-b02423058f4d4a158311c24d42ab94f2

Source dataset

uspto-grants-2015_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09199980B2