反应详情

温度

-10 °C

A nitrogen inerted reactor is charged with the sodium salt of tert-butyl acetoacetate (100 mmol). Anhydrous toluene (71.5 mL) and THF (8.2 mL, 101 mmol) are added, and the resulting solution is cooled under a positive pressure of nitrogen to ca. −10° C. A 10 M hexanes solution of n-BuLi (104 mmol) is added at such a rate as to maintain an internal reaction temperature of ≦1° C. The resulting solution is stirred an additional 20 to 30 minutes after complete addition as the temperature is allowed to cool to ca. −6° C. Meanwhile, 5-(4-fluorophenyl)-2-isopropyl-1-(3-morpholin-4-yl-3-oxo-propyl)-4-phenyl-1H-pyrrole-3-carboxylic acid phenylamide (25 mmol) is charged to a second nitrogen inerted reactor. Anhydrous THF (50 mL) is added at room temperature, and the resulting slurry is cooled to ca. −10° C. and stirred for 15 to 90 minutes. The solution of dienolate is added to the slurry of morpholine amide at such a rate as to maintain an internal reaction temperature ca. −5° C. Following this addition, the slurry is stirred at ca. −5° C for ≧2 hours. Water (35 mL) is added with vigorous agitation at such a rate as to maintain an internal reaction temperature of ≦0° C. Concentrated 37% hydrochloric acid (19.0 mL, 229 mmol) is added at such a rate as to maintain an internal reaction temperature of ≦0° C. The two-layered reaction mixture is vacuum distilled, removing >50% of the organic solvents. The distillation is stopped and the lower aqueous layer is discarded. Water (55 mL) is added and the vacuum distillation is continued until a majority of the organic solvents are removed. [Note: It is preferable to drain and replace the aqueous layer before initiating the vacuum distillation.] IPA (100 mL) is added followed by water (100 mL). The mixture is stirred for ≧6 hours, allowing for solidification of the product. The solid is collected via filtration, and the cake is washed with pre-mixed 1:1 IPA:H20. The resulting solid is dried in vacuo at 35° C. to provide 7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-3,5-dioxo-heptanoic acid, tert-butyl ester (14.1 g) as a white solid. This material is carried on to subsequent steps without further purification, or optionally, it can be re-precipitated from toluene.

1. temperatureto maintain an internal reaction temperature of ≦1° C
2. additionafter complete addition as the temperature
3. temperatureto cool to ca. −6° C
4. temperaturethe resulting slurry is cooled to ca. −10° C.
5. stirringstirred for 15 to 90 minutes
6. temperatureto maintain an internal reaction temperature ca. −5° C
7. additionthis addition
8. stirringthe slurry is stirred at ca. −5° C for ≧2 hours
9. temperatureto maintain an internal reaction temperature of ≦0° C
10. additionis added at such a rate as
11. temperatureto maintain an internal reaction temperature of ≦0° C
12. customThe two-layered reaction mixture
13. distillationdistilled
14. customremoving >50% of the organic solvents
15. distillationThe distillation
16. additionWater (55 mL) is added
17. distillationthe vacuum distillation
18. customare removed
19. distillationthe vacuum distillation
20. addition] IPA (100 mL) is added
21. stirringThe mixture is stirred for ≧6 hours
22. filtrationThe solid is collected via filtration
23. washthe cake is washed
24. additionwith pre-mixed 1:1 IPA
25. customThe resulting solid is dried in vacuo at 35° C.