1,1'-Carbonyldiimidazole → 1-Methyl-1H-indole-3-carboxylic acid 1-azabicyclo[3.2.1]oct-5-ylmethyl ester

A solution of 1-methyl-1H-indole-3-carboxylic acid (1.75 g, 10 mmol) in anhydrous tetrahydrofuran (10 mL) under nitrogen was treated with 1,1'-carbonyldiimidazole (1.79 g, 11 mmol), stirred for one hour, and degassed under a stream of nitrogen over 10 minutes. Meanwhile a cooled (-10° C.) solution of 1-azabicyclo[3.2.1]octane-5-methanol (1.55 g, 11 mmol) in anhydrous tetrahydrofuran (10 mL) under nitrogen was treated (via syringe) with 2.5 N n-butyllithium/hexane (10.5 mmol), stirred for 30 minutes, concentrated in vacuo, and taken up in anhydrous tetrahydrofuran (10 mL) under nitrogen. The suspension of the acid/1,1'-carbonyldiimidazole adduct was transferred into this solution, and the mixture was stirred 18 hours at room temperature and 4 hours at 55° C., and concentrated in vacuo. The residue was partitioned between toluene (150 mL) containing some 2-propanol and saturated aqueous sodium carbonate (100 mL). The organic layer was separated and the aqueous solution was extracted with toluene (2×100 mL) containing some 2-propanol. The combined organic solution was dried (Na2SO4), concentrated in vacuo, and filtered through alumina (eluted with 20% methanol/tetrahydrofuran). The filtrate was concentrated in vacuo, triturated with petroleum ethers (30°-60°), and recrystallized from ether/petroleum ethers (2 crops) to afford 1.72 g (58%) of colorless solid; mp 94.5°-96.5° C.

1. customdegassed under a stream of nitrogen over 10 minutes
2. stirringstirred for 30 minutes
3. concentrationconcentrated in vacuo
4. additionThe suspension of the acid/1,1'-carbonyldiimidazole adduct
5. stirringthe mixture was stirred 18 hours at room temperature and 4 hours at 55° C.
6. concentrationconcentrated in vacuo
7. customThe residue was partitioned between toluene (150 mL)
8. additioncontaining some 2-propanol and saturated aqueous sodium carbonate (100 mL)
9. customThe organic layer was separated
10. extractionthe aqueous solution was extracted with toluene (2×100 mL)
11. additioncontaining some 2-propanol
12. dry with materialThe combined organic solution was dried (Na2SO4)
13. concentrationconcentrated in vacuo
14. filtrationfiltered through alumina (eluted with 20% methanol/tetrahydrofuran)
15. concentrationThe filtrate was concentrated in vacuo
16. customtriturated with petroleum ethers (30°-60°)
17. customrecrystallized from ether/petroleum ethers (2 crops)

ORD-Eintrag

ord-382c1d14b7fd4bbd9be646f9f4d37250

Quelldatensatz

uspto-grants-1993_03

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US05190953