反应详情

2-(Phenylamino)-2-(thiophen-2-yl)acetic acid hydrochloride (I29) (359 mg, 1.33 mmol), DCC (330 mg, 1.60 mmol), and HOBT (245 mg, 1.60 mmol) were dissolved in THF (15 ml). (R)-quinuclidin-3-ol (339 mg, 2.66 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. HOBT (20.4 mg, 0.13 mmol) and DCC (33.0 mg, 0.16 mmol) were added again and the mixture was stirred for additional 8 hours. HOBT (20.4 mg, 0.13 mmol), DCC (33.0 mg, 0.16 mmol), (R)-quinuclidin-3-ol (16.9 mg, 0.13 mmol) were added, and the mixture is stirred for additional 16 hours. THF is evaporated, and the resulting crude oil was dissolved in EtOAc and washed with water and brine. The organic phase was recovered, dried over Na2SO4, filtered and evaporated. The crude was first purified by flash chromatography (DCM/MeOH=9/1) and then by preparative HPLC. The pure fractions were collected and evaporated. The resulting TFA salt was dissolved in THF and passed through a PL-HCO3 cartridge (Varian, 200 mg, 1.8 mmol/g HCO3−). THF was evaporated, and the product was dissolved in dioxane (2 ml) and 4M HCl in dioxane (2 ml) was added. The solvent was evaporated, and the residue was dried under vacuum for 24 hours to obtain the title compound (33 mg, 7% yield, mixture of diastereomers).

1. stirringthe mixture was stirred for additional 8 hours
2. stirringthe mixture is stirred for additional 16 hours
3. customTHF is evaporated
4. dissolutionthe resulting crude oil was dissolved in EtOAc
5. washwashed with water and brine
6. customThe organic phase was recovered
7. dry with materialdried over Na2SO4
8. filtrationfiltered
9. customevaporated
10. customThe crude was first purified by flash chromatography (DCM/MeOH=9/1)
11. customThe pure fractions were collected
12. customevaporated
13. dissolutionThe resulting TFA salt was dissolved in THF
14. customTHF was evaporated
15. dissolutionthe product was dissolved in dioxane (2 ml)
16. addition4M HCl in dioxane (2 ml) was added
17. customThe solvent was evaporated
18. customthe residue was dried under vacuum for 24 hours