Iodine → 6-Chloro-4-iodo-2-(ethoxymethoxy)-3-hydroxymethylpyridine

Temperature

-10 °C

To a solution of 2.5M n-butyllithium (2.2 mL, 5 mmol) in 20 mL of THF at -10° C. was added 0.94 g 2-chloro-6-(ethoxymethoxy)pyridine (5 mmol) dropwise over 2 min. The reaction mixture was stirred for 10 min. at -10° C., then cooled to -23° C. and 0.72% N-formyl-N,N',N'-trimethytethylenediamine) was added. After stirring at -23° C. for 30 min., n-butyllithium (2.5M, 3 mL, 7.5 mmol) was added dropwise and the dark reaction mixture was stirred at -23° C. for 4 hr. The mixture was transferred via a double-tipped meedle to a solution of 1.9 g of iodine (7.5 mmol) in 10 mL of DME and 10 mL of THF at -78° C. After stirring at -78° C. for 30 min., the cooling bath was removed. 0.3 g of solid sodium borohydride (8 mmol) was added to the red mixture. 10 mL of water was added dropwise with vigorous stirring. After 30 min., the mixture was extracted with three 20-mL portions of EtOAc. The combined organic layers were washed with 20 mL of 10 percent sodium thiosulfate solution, water and brine. After drying over sodium carbonate, the solvents were removed under reduced pressure to yield the 1.3 g of crude product, which was purified by radial PLC (10% EtOAc/hexane) to give 0.7 g (40%) of pure product as a white solid, mp 43°-44° C. 1H NMR (300 MHz, CDCl3) δ7.43 (s, 1H), 5.62 (s, 2H), 4.79 (s, 2H), 3.78 (q, 2H, J=7.1 Hz), 2.24 (brd, 1H), 1.26 (t, 3H, J=7.1 Hz). 13C NMR (75 MHz, CDCl3) δ158.9, 147.8, 127.3, 124.7, 113.5, 92.0, 66.0, 63.2, 15.0. Analysis Calculated for C9H11ClNO3 : C, 31.47; H, 3.23; N, 4.08. Found: C, 31.68; H, 3.28; N, 4.13.

1. temperaturecooled to -23° C.
2. addition0.72% N-formyl-N,N',N'-trimethytethylenediamine) was added
3. stirringAfter stirring at -23° C. for 30 min.
4. customthe dark reaction mixture
5. stirringwas stirred at -23° C. for 4 hr
6. stirringAfter stirring at -78° C. for 30 min.
7. customthe cooling bath was removed
8. waitAfter 30 min.
9. extractionthe mixture was extracted with three 20-mL portions of EtOAc
10. washThe combined organic layers were washed with 20 mL of 10 percent sodium thiosulfate solution, water and brine
11. dry with materialAfter drying over sodium carbonate
12. customthe solvents were removed under reduced pressure
13. customto yield the 1.3 g of crude product, which
14. customwas purified by radial PLC (10% EtOAc/hexane)

ORD record

ord-e950ffaa5e3544309f72c89ac898f0ae

Source dataset

uspto-grants-1996_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US05486615