Isatoic Anhydride → 1-[3-(2-chloro-4-methoxyphenoxy)propyloxymethyl]-4-hydroxy-2(1H)-quinolinone

Temperature

80 °C

A solution of 2-chloro-4-methoxyphenol (15.5 gm) in DMF (20 ml) was added to a suspension of 60% sodium hydride (4 gm) in DMF (10 ml). To the resulting solution there was added a solution of 3-chloropropyl benzoate (15.5 gm) in DMF (20 ml). The solution was heated at 80° C. for 20 hrs, then diluted with ethyl acetate, then washed with water then dried and then evaporated. The crude product was dissolved in a 1:1 mixture of methanol/THF (40 ml) to which 10% sodium hydroxide (50 ml) was added. The mixture was refluxed for 3 hrs, then diluted with ethyl acetate, then washed with water and then evaporated. The crude product was purified by chromatography on silica gel using 40% ethyl acetate in hexane as the eluting solvent. The product was then dissolved in dichloroethane (40 ml) containing paraformaldehyde (2.25 gm). The solution was cooled in an ice bath and a stream of HCl gas was bubbled through the solution for 3.5 hrs. The solution was then dried over magnesium sulfate and the solvent was then removed under reduced pressure. Following the procedure set forth in Steps (2) to (4) of Preparation A, the resulting 3-(2-chloro-4-methoxyphenoxy) propyloxymethyl chloride was reacted with isatoic anhydride to give 1-[3-(2-chloro-4-methoxyphenoxy)-propyloxymethyl]-4-hydroxy-2(1H)-quinolinone. That the expected product was obtained was confirmed by the spectral data: MS: m/e 389 (M·+); NMR (DMSO): δ1.9 (t, 2H, CH2), 3.65 (t, 2H, CH2O), 3.70 (s, 3H, OCH3), 3.90 (t, 2H, CH2O), 5.65 (s, 2H, NCH2O), 5.84 (s, 1H, =CH).

1. washwashed with water
2. customthen dried
3. customevaporated
4. dissolutionThe crude product was dissolved in a 1:1 mixture of methanol/THF (40 ml) to which 10% sodium hydroxide (50 ml)
5. additionwas added
6. temperatureThe mixture was refluxed for 3 hrs
7. additiondiluted with ethyl acetate
8. washwashed with water
9. customevaporated
10. customThe crude product was purified by chromatography on silica gel using 40% ethyl acetate in hexane as the eluting solvent
11. dissolutionThe product was then dissolved in dichloroethane (40 ml)
12. additioncontaining paraformaldehyde (2.25 gm)
13. temperatureThe solution was cooled in an ice bath
14. customa stream of HCl gas was bubbled through the solution for 3.5 hrs
15. dry with materialThe solution was then dried over magnesium sulfate
16. customthe solvent was then removed under reduced pressure
17. customset forth in Steps (2) to (4) of Preparation A

ORD record

ord-a6c9947472a04633b985d04eae67cc7a

Source dataset

uspto-grants-1995_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US05378694