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0 °C

A mixture of the compound of Example 13A (34 g, 92 wt %, 77 mmol) and NaHCO3 (3.3 g, 39 mmol) in 300 mL dichloromethane and 60 mL methanol was cooled to ←70° C. and treated with ozone (7-8 psi, 90 volts, 4 slpm) until a persistent blue color was observed. After purging with nitrogen to remove the color, the reaction was warmed to ˜0° C., then filtered through paper and concentrated. After chasing with 2×100 mL benzene, 300 mL of dichloromethane and 60 mL of pyridine were added and the reaction was cooled to <5° C. p-Nitrobenzoyl chloride (22.2 g, 120 mmol) was added and stirred for 1 hour, then the bath was removed and the reaction stirred at ambient temperature overnight. The resulting suspension was concentrated in vacuo to a thick slurry, and then diluted with ethyl acetate, and the solids were removed by filtration. The filtrate was washed with 250 mL of saturated aqueous sodium bicarbonate, then with 100 mL each of 2 N HCl, 1 N HCl, and 2 N HCl, and with 200 mL each of 1 N HCl, saturated aqueous sodium bicarbonate, and brine. The organic layer was dried over MgSO4, filtered and concentrated to yield the crude ester. A sample of this product (20.6 g, 32 mmol) was dissolved in 115 mL methanol; 15 mL water was added, followed by 11.0 g of K2CO3. After 2 hours, the reaction was quenched with 6.5 mL of acetic acid, and then concentrated in vacuo. The residue was treated with 100 mL water, and then extracted sequentially with 150 mL and 100 mL of ethyl acetate. The combined organic layers were washed with 100 mL each of saturated aqueous sodium bicarbonate, then 10% aqueous NaCl, then 20% aqueous NaCl. The ethyl acetate layer was dried over MgSO4, filtered and concentrated. Chromatography (Isco CombiFlash® system, Analogix RS 300 300 g column, 1:9 ethyl acetate: dichloromethane for 5 minutes, then to 12:88 over 35 minutes, then hold for 10 minutes) provided the title compound (10.3 g, 91 wt %, 76%).

1. temperaturewas cooled
2. customto ←70° C.
3. customAfter purging with nitrogen
4. customto remove the color
5. filtrationfiltered through paper
6. concentrationconcentrated
7. additionwere added
8. additionwas added
9. customthe bath was removed
10. stirringthe reaction stirred at ambient temperature overnight
11. concentrationThe resulting suspension was concentrated in vacuo to a thick slurry
12. additiondiluted with ethyl acetate
13. customthe solids were removed by filtration
14. washThe filtrate was washed with 250 mL of saturated aqueous sodium bicarbonate
15. dry with materialThe organic layer was dried over MgSO4
16. filtrationfiltered
17. concentrationconcentrated
18. customto yield the crude ester
19. waitAfter 2 hours
20. customthe reaction was quenched with 6.5 mL of acetic acid
21. concentrationconcentrated in vacuo
22. additionThe residue was treated with 100 mL water
23. extractionextracted sequentially with 150 mL and 100 mL of ethyl acetate
24. washThe combined organic layers were washed with 100 mL each of saturated aqueous sodium bicarbonate
25. dry with materialThe ethyl acetate layer was dried over MgSO4
26. filtrationfiltered
27. concentrationconcentrated
28. waitChromatography (Isco CombiFlash® system, Analogix RS 300 300 g column, 1:9 ethyl acetate: dichloromethane for 5 minutes
29. waitto 12:88 over 35 minutes
30. waithold for 10 minutes