Ethyl 2,4-dichloronicotinate → 2,4-Dichloropyridine-3-methanol

The required (2,4-dichloro-pyridin-3-yl)-methanol was prepared as follows: To a solution of 2,4-dichloropyridine (3.00 mL; 27.8 mmol) in THF (25 mL) was added dropwise a solution of LDA (15.3 mL; 2.00 mol/l in THF/heptane/ethylbenzene; 30.6 mmol), at −78° C. The resulting mixture was stirred at −78° C. for 1 h. Subsequently, a solution of ethyl chloroformate (3.2 mL; 33.33 mmol) in THF (5 mL), was added dropwise, at −78° C. and the mixture was stirred for another 1 h at the same temperature. To the resulting mixture was added 5% aqueous NaHCO3-solution, dropwise, at −78° C. The mixture was allowed to warm to RT and extracted with EtOAc. The organic layer was dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Et2O:hexanes 1:3) to afford 2,4-dichloro-nicotinic acid ethyl ester (2.45 g). To a solution of 2,4-dichloro-nicotinic acid ethyl ester (2.35 g; 10.68 mmol) in THF (50 mL) was added dropwise diisobutylaluminum hydride (32.0 mL; 1.00 mol/l in THF, 32.0 mmol), at 4° C. After 15 minutes the ice-bath was removed and the reaction mixture was stirred at RT overnight. Subsequently, the resulting mixture was concentrated in vacuo and partitioned between 5% aqueous NaHCO3 and EtOAc. The layers were separated and the organic layer was dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography (Et2O:hexanes 1:1) to afford (2,4-dichloro-pyridin-3-yl)-methanol (0.40 g).

1. customat 4° C
2. customAfter 15 minutes the ice-bath was removed
3. concentrationSubsequently, the resulting mixture was concentrated in vacuo
4. custompartitioned between 5% aqueous NaHCO3 and EtOAc
5. customThe layers were separated
6. dry with materialthe organic layer was dried (Na2SO4)
7. concentrationconcentrated in vacuo
8. customThe residue was purified by column chromatography (Et2O:hexanes 1:1)

ORD-Eintrag

ord-db798a06f4cb42a8831c1b6e9d1394ed

Quelldatensatz

uspto-grants-2015_06

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US09045441B2