反应详情

Crude 1-[[3-chloro-4-(methoxycarbonyl)benzoyl]oxy]-2,5-pyrrolidinedione (Example 5; ˜35 g, ˜0.1 mol) was charged to a 1L RB flask equipped with a magnetic stirrer, ice cooling bath, and a argon inlet tube, using dimethylformamide (350 mL) to complete the transfer. The mixture was cooled to about 10° C., then with stirring in an argon atmosphere, (3-hydroxyphenyl)methylamine hydrochloride salt (18.35 g, 0.115 mol) and triethylamine (35 mL, 0.25 mol) were added in rapid succession. A precipitate began to form immediately. After the reaction was stirred at ambient temperature overnight, the volatiles were removed under reduced pressure (<0.5 mm). The oily residue was taken up in ethyl acetate (600 mL) and washed in turn with 0.5N hydrochloric acid (400 mL), brine (300 mL), saturated sodium bicarbonate solution (2×300 mL) and brine (300 mL). Each aqueous layer was back-extracted in turn with ethyl acetate (2×300 mL), then the combined organic extracts were dried (MgSO4), and evaporated to give crude 2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoic acid methyl ester (˜32g) as an off white solid. In a 2 L RB flask equipped with a magnetic stirrer, a slurry of crude 2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoic acid methyl ester (˜32 g, ˜0.10 mol) in deionized water (300 mL) was treated with 1 N sodium hydroxide solution (300 mL, 0.3 mol). Most of the solids quickly dissolved, and the solution was stirred at room temperature overnight. The mixture was filtered through Celite to remove undissolved solids (residual DCU) and the filter cake was washed with deionized water (2×30 mL). The combined filtrates were transferred to a separatory funnel and extracted with diethyl ether (2×300 mL). Each ether extract was back-washed in turn with brine (50 mL). The combined aqueous phases were stirred as they were acidified by the addition of 6 N hydrochloric acid (55 mL, 0.33 mol). The resulting mixture was stirred overnight at room temperature, then the precipitated solids were collected by filtration and the filter cake was washed with deionized water (2×60 mL). The slightly off-white solid was dried in vacuo over P2O5 then was dissolved in warm ethyl acetate (400 mL), and the solution was treated with charcoal (4 g) and filtered through a bed of Celite. The filter cake was washed with ethyl acetate (2×40 mL). The combined filtrates were concentrated to about 250 mL then sufficient hexane was added to the hot stirred solution to produce a permanent cloud point. The mixture was cooled to room temperature, then was stored at −20° C. overnight. The solids were collected by filtration and were washed with hexane (2×50 mL) to give 2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoic acid, mp 167-169° C. (27.1 g, 88.6% from 2-chloro-1,4-benzenedicarboxylic acid, 1-methyl ester).

1. customIn a 2 L RB flask equipped with a magnetic stirrer
2. dissolutionMost of the solids quickly dissolved
3. filtrationThe mixture was filtered through Celite
4. customto remove undissolved solids (residual DCU)
5. washthe filter cake was washed with deionized water (2×30 mL)
6. customThe combined filtrates were transferred to a separatory funnel
7. extractionextracted with diethyl ether (2×300 mL)
8. extractionEach ether extract
9. washwas back-washed in turn with brine (50 mL)
10. stirringThe combined aqueous phases were stirred as they
11. stirringThe resulting mixture was stirred overnight at room temperature
12. filtrationthe precipitated solids were collected by filtration
13. washthe filter cake was washed with deionized water (2×60 mL)
14. dry with materialThe slightly off-white solid was dried in vacuo over P2O5
15. dissolutionthen was dissolved in warm ethyl acetate (400 mL)
16. additionthe solution was treated with charcoal (4 g)
17. filtrationfiltered through a bed of Celite
18. washThe filter cake was washed with ethyl acetate (2×40 mL)
19. concentrationThe combined filtrates were concentrated to about 250 mL
20. additionsufficient hexane was added to the hot stirred solution
21. customto produce a permanent cloud point
22. temperatureThe mixture was cooled to room temperature
23. waitwas stored at −20° C. overnight
24. filtrationThe solids were collected by filtration
25. washwere washed with hexane (2×50 mL)