Methanol → 3,5-Dichloro-2-methoxy-4-(3-isopropyl-4-hydroxyphenoxy)-6-hydroxycarbonylmethylaminopyridine

To a solution of 3,5-dichloro-2-fluoro-4-(3-isopropyl-4-methoxyphenoxy)-6-methoxycarbonylmethylamino-pyridine (161 mg) in methanol (3.0 mL) was added a solution of sodium methoxide in methanol (0.5 M, 1.0 mL). The resulting mixture was stirred at ambient temperature for 18 hours, followed by stirring at 80° C. for 5 hours. Cooled reaction mixture was then diluted with 1 N HCl (50 mL) and extracted with ethyl acetate (50 mL×2). The combined organic layers were dried (Na2SO4) and concentrated. The dried crude product was dissolved in CH2Cl2 (3.0 mL) and treated with a solution of BBr3 in CH2Cl2 (1 mL, 1.0 M) at ambient temperature. The resulting mixture was stirred for 1 hour, poured to stirring water (50 mL), extracted with CH2C2 (20 mL×3) from water, dried (Na2SO4) and concentrated to dryness under reduced pressure. The residue was dissolved in THF:MeOH:H2)=3:1:1 (3 mL), treated with LiOH in one portion (50 mg) and stirred at ambient temperature for 1 hour. The reaction mixture was diluted with a 1.0 M solution of HCl (50 mL), extracted with ethyl acetate (50 mL×3), dried (Na2SO4) and concentrated under reduced pressure. Purification by HPLC afforded the title compound as a white solid (30 mg).

1. stirringby stirring at 80° C. for 5 hours
2. temperatureCooled
3. customreaction mixture
4. extractionextracted with ethyl acetate (50 mL×2)
5. dry with materialThe combined organic layers were dried (Na2SO4)
6. concentrationconcentrated
7. customThe dried crude product
8. dissolutionwas dissolved in CH2Cl2 (3.0 mL)
9. additiontreated with a solution of BBr3 in CH2Cl2 (1 mL, 1.0 M) at ambient temperature
10. stirringThe resulting mixture was stirred for 1 hour
11. additionpoured
12. stirringto stirring water (50 mL)
13. extractionextracted with CH2C2 (20 mL×3) from water
14. dry with materialdried (Na2SO4)
15. concentrationconcentrated to dryness under reduced pressure
16. dissolutionThe residue was dissolved in THF
17. additionMeOH:H2)=3:1:1 (3 mL), treated with LiOH in one portion (50 mg)
18. stirringstirred at ambient temperature for 1 hour
19. additionThe reaction mixture was diluted with a 1.0 M solution of HCl (50 mL)
20. extractionextracted with ethyl acetate (50 mL×3)
21. dry with materialdried (Na2SO4)
22. concentrationconcentrated under reduced pressure
23. customPurification by HPLC

ORD record

ord-858c531ddba84908a119d1f171b91027

Source dataset

uspto-grants-2004_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06747048B2