反应详情

To a stirring solution of toluene-4-sulfonic acid 3-(4-pyrrolidin-1-ylmethyl-phenyl)-cyclobutylmethyl ester (159.9 mg, 0.40 mmol) prepared above (Example 4, General Procedure A, Step G) in 2 mL of THF was added 1-(2-pyrimidyl)piperizine (136.2 mg, 0.8 mmol) followed by a solution of KOtBu (136 uL, 0.8 mmol, 1M THF). The reaction was heated to 70 □C (oil bath). After 1 hour DMF (1 mL) was added along with K2CO3 (2 eq). The reaction was then heated to 100 □C. After 3 hours the reaction was cooled to rt and concentrated under reduced pressure. The resulting mixture was diluted with CH2Cl2, quenched with a saturated aqueous solution of NaHCO3. The two layers were separated and the aqueous layer was back extracted with 3:1 chloroform:isopropyl alcohol. The combined organic layers were dried over MgSO4, filtered through a fritted funnel and concentrated under reduced pressure. Purification of this material was accomplished by flash column chromatography using a 10 g ISCO column, eluting with a gradient of 5%, 10%, 20% MeOH/CH2Cl2 w/0.1% NH4OH. The product containing fractions were collected and concentrated under reduced pressure to give the title compound (70.0 mg, 44%) as a colorless oil, and a mixture of cis:trans isomers. The bis-HCl salt was generated by dissolving the title compound in EtOAc and then a solution of HCl (2 eq, 1M HCl, THF) was added. The colorless solid was collected and dried under reduced pressure.

1. temperatureThe reaction was heated to 70 □C (oil bath)
2. temperatureThe reaction was then heated to 100 □C
3. concentrationconcentrated under reduced pressure
4. additionThe resulting mixture was diluted with CH2Cl2
5. customquenched with a saturated aqueous solution of NaHCO3
6. customThe two layers were separated
7. extractionthe aqueous layer was back extracted with 3:1 chloroform
8. dry with materialThe combined organic layers were dried over MgSO4
9. filtrationfiltered through a fritted funnel
10. concentrationconcentrated under reduced pressure
11. customPurification of this material
12. washeluting with a gradient of 5%, 10%, 20% MeOH/CH2Cl2
13. additionThe product containing fractions
14. customwere collected
15. concentrationconcentrated under reduced pressure