Phenol → HCID 21913933, compound

Temperature

4 °C

A solution of phenol (94 g, 998.9 mmol) in diglyme (200 mL) was added slowly over 45 minutes to a solution of sodium hydride (38.06 g, 951.5 mmol, 60% in mineral oil) in diglyme (100 mL) cooled to 4° C. with an ice bath. Hydrogen gas evolved, and the temperature increased to a maximum of 34° C., but was immediately reduced by slowing the rate of phenol addition. After addition was complete, the reaction mixture was stirred for 1 hour. About 200 mL of the resulting clear solution was removed and set aside. The ice bath was removed, and 1-[(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]ethan-2-ol (55.2 g, 224.69 mmol) dissolved in diglyme (400 mL) was added to the clear reaction solution under nitrogen. The flask from which the starting material was transferred was rinsed with diglyme (2×100 mL), and the rinsings were added to the resulting reaction mixture. This reaction mixture was heated to 110° C. for 4 hours under a flow of nitrogen, and then the resulting reaction mixture was concentrated under reduced pressure. The resulting oil was cooled to about 5° C. for 2 days, triturated with hexane, and passed through a silica gel column using 8/2 hexane/ethyl acetate, then 7/3 hexane/ethyl acetate, and ending with 6/4 hexane ethyl acetate over 3 days. A first 10.5 g fraction of impure product and a second 3.9 g fraction of pure product were isolated. The first fraction (9.6510 g) was dissolved in ethyl acetate/hexane and the product allowed to crystallize. The crystals were filtered off and dried to provide 9.6510 g of product, which was combined with the previous 3.9 g of pure product and carried on to the next step.

1. temperaturethe temperature increased to a maximum of 34° C.
2. additionAfter addition
3. customAbout 200 mL of the resulting clear solution was removed
4. customThe ice bath was removed
5. additionwas added to the clear reaction solution under nitrogen
6. washThe flask from which the starting material was transferred was rinsed with diglyme (2×100 mL)
7. additionthe rinsings were added to the resulting reaction mixture
8. temperatureThis reaction mixture was heated to 110° C. for 4 hours under a flow of nitrogen
9. customthe resulting reaction mixture
10. concentrationwas concentrated under reduced pressure
11. temperatureThe resulting oil was cooled to about 5° C. for 2 days
12. customtriturated with hexane
13. wait7/3 hexane/ethyl acetate, and ending with 6/4 hexane ethyl acetate over 3 days
14. customA first 10.5 g fraction of impure product and a second 3.9 g fraction of pure product were isolated
15. customto crystallize
16. filtrationThe crystals were filtered off
17. customdried

ORD record

ord-91a860af6eb74317b4f3878c3d73cfe1

Source dataset

uspto-grants-2004_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06797718B2