反应详情

温度

67 °C

The compound from step 4b above (3.047 kg, 18.3 mol) was dissolved in 14 L of THF and placed under N2. At room temperature, borane-THF complex (55 L, 55 mol) was introduced at a rate such that the internal temperature remained at 30° C. At the end of the exothermic and foaming addition, the reaction was heated at reflux (67° C.) for 1 hr. The reaction mixture was then cooled to 0° C., and 8.2 L of methanol was slowly added so that the internal temperature remained at 20° C. The mixture was then stirred for 2 hr. at room temperature, and the solvent was evaporated under vacuum to yield a yellow oil, which solidified upon standing. This residue was emulsified with water and cooled to 10° C. A solution of formaldehyde (35%, 2.1 L, 27.5 mol) and formic acid (97%, 990 mL, 18.3 mol) was added to the emulsion, and the exothermic and effervescent reaction was maintained at an internal temperature below 30° C. The mixture was the cooled to 10° C., 1 kg (9.5 mol) of Na2CO3 was added in portions, and the mixture was stirred for 1 hr. NaOH (10%, 2.29 L) was added, followed by 5.5 L of water. The product was isolated by extraction with ethyl acetate, which was dried over MgSO4, filtered and concentrated to dryness. The product was double distilled, dissolved in ethyl acetate, converted to the HCl salt with ethanolic HCl, recrystallized from ethyl acetate, suspended in ethyl acetate, re-converted to the base with treatment with 30% NaOH solution, the layers separated, the organic layer washed with brine, dried and evaporated, to yield the product, which was finally distilled to yield 490 g of the pure title product (e.e.=99.5%).

1. additionAt room temperature, borane-THF complex (55 L, 55 mol) was introduced at a rate such that the internal temperature
2. customremained at 30° C
3. additionAt the end of the exothermic and foaming addition
4. temperaturethe reaction was heated
5. temperatureThe reaction mixture was then cooled to 0° C.
6. customremained at 20° C
7. customat room temperature, and the solvent was evaporated under vacuum
8. customto yield a yellow oil, which
9. temperaturecooled to 10° C
10. customthe exothermic and effervescent reaction
11. temperaturewas maintained at an internal temperature below 30° C
12. temperaturecooled to 10° C.
13. stirringthe mixture was stirred for 1 hr
14. dry with materialwas dried over MgSO4
15. filtrationfiltered
16. concentrationconcentrated to dryness
17. dissolutiondissolved in ethyl acetate
18. customrecrystallized from ethyl acetate
19. customthe layers separated
20. washthe organic layer washed with brine
21. customdried
22. customevaporated
23. customto yield the product, which
24. distillationwas finally distilled