反应详情

温度

5 °C

A suspension of (1 S,4R)-4-((2-Amino-6-chloro-5-((4chlorophenyl)azo)-4-pyrimidinyl)amino)-2-cyclopentene-1-methanol hydrate (1.96 g, 5 mmol) in tetrahydrofuran (15 mL) was treated with acetic acid/water (1:1, 5 mL), then with zinc dust (1.63g, 25 mmol) in portions so as to keep the pot temperature below 35° C. The deep yellow color faded after 10 min, and after an additional 50 min the solution was filtered to remove precipitated zinc salts. The filter cake was rinsed with tetrahydrofuran and the filtrate was refiltered to remove additional zinc salts, then concentrated in vacuo with addition of toluene to facilitate removal of water and acetic acid. The residue was rinsed with toluene/hexane to separate some of the 4-chloroaniline byproduct, taken up in triethyl orthoformate (40 mL), cooled on an ice bath (5° C.), and treated dropwise with concentrated hydrochloric acid (1.9 mL). The mixture was stirred at 5° C. for 5 h (tan suspension soon formed), slowly warmed to room temperature, and stirred for an additional 18 h, then cooled on an ice bath and filtered. The filter cake was rinsed with ether (save filtrate), and this solid was taken up in water (30 mL), filtered, and the solids washed with water. The aqueous filtrate was basified with sodium carbonate to pH-9, then extracted with 5% isopropanol-hloroform (3×25 mL) The combined extracts were dried (Na2SO4) and concentrated in vacuo to a residual tan foam (0.85 g). The organic filtrate from above was concentrated in vacuo and the residue taken up in 1N hydrochloric acid (30 mL), stirred for 1h, filtered, and the filtrate adjusted to pH-6 with 5 N sodium hydroxide (6 mL, then basified with sodium carbonate. This aqueous suspension was extracted with 5% isopropanol-chloroform (3×25 mL), and the combined organic extracts were dried (Na2SO4) and concentrated in vacuo to a tan foam (0.55 g ). The two batches were combined, dissolved in warm chloroform, and loaded onto a silica gel column, which was eluted with 7% methanol-chloroform to afford pure fractions containing the subject compounds. These were concentrated in vacuo and the residual foam crystallized from ethyl acetate(2 crops) to afford 0.86 g (65%) of the title compound as a pale tan solid; mp 160°-162° C. 1H-NMR (DMSO-d6)δ: 8.04(s,1H); 6.91(s,2H); 6.15(m,1H); 5.90 (m,1H); 5.45 (m,1H); 4.73 (t, 1H,J =5 Hz); 3.45 (t,2H,J=5 Hz); 2.80-2.95(m, 1H); 2.55-2.70(m,1H); 1.60-1.70(m,1H). Ms(Cl): m/z 170 (m-C5ring, 100); 230 (m-Cl, 50); 266 (m+H+, 100). [α]20589 -104°, [α]20436 -267°(c=0.29, methanol).

1. customthe pot temperature below 35° C
2. filtrationafter an additional 50 min the solution was filtered
3. customto remove
4. customprecipitated zinc salts
5. washThe filter cake was rinsed with tetrahydrofuran
6. customto remove additional zinc salts
7. concentrationconcentrated in vacuo with addition of toluene
8. customremoval of water and acetic acid
9. washThe residue was rinsed with toluene/hexane
10. customto separate some of the 4-chloroaniline byproduct
11. additiontreated dropwise with concentrated hydrochloric acid (1.9 mL)
12. customsoon formed),
13. temperatureslowly warmed to room temperature
14. stirringstirred for an additional 18 h
15. temperaturecooled on an ice bath
16. filtrationfiltered
17. washThe filter cake was rinsed with ether (save filtrate)
18. filtrationfiltered
19. washthe solids washed with water
20. extractionextracted with 5% isopropanol-hloroform (3×25 mL) The combined extracts
21. dry with materialwere dried (Na2SO4)
22. concentrationconcentrated in vacuo to a residual tan foam (0.85 g)
23. concentrationThe organic filtrate from above was concentrated in vacuo
24. stirringstirred for 1h
25. filtrationfiltered
26. extractionThis aqueous suspension was extracted with 5% isopropanol-chloroform (3×25 mL)
27. dry with materialthe combined organic extracts were dried (Na2SO4)
28. concentrationconcentrated in vacuo to a tan foam (0.55 g )
29. dissolutiondissolved in warm chloroform
30. washwas eluted with 7% methanol-chloroform
31. customto afford pure fractions
32. additioncontaining the subject compounds
33. concentrationThese were concentrated in vacuo
34. customthe residual foam crystallized from ethyl acetate(2 crops)