1,1'-Carbonyldiimidazole → 4-Amino-5-chloro-2-methoxybenzoic acid 1-azabicyclo[3.2.1]oct-5-ylmethyl ester

A solution of 4-amino-5-chloro-2-methoxybenzoic acid (1.62 g, 8.0 mmol) in anhydrous tetrahydrofuran (10 mL) under nitrogen was treated with 1,1'-carbonyldiimidazole (1.38 g, 8.5 mmol), stirred 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 (1.20 g, 8.5 mmol) in anhydrous tetrahydrofuran (10 mL) under nitrogen was treated (via syringe) with 2.50N n-butyllithium/hexane (8.25 mmol), stirred for 30 minutes, concentrated in vacuo, and taken up in anhydrous tetrahydrofuran (10 mL) under nitrogen. The above degassed solution was transferred into this solution by syringe, and the mixture was stirred at room temperature for 65 hours and at 50° C. for one hour, then concentrated in vacuo. The residue was partitioned between toluene (100 mL) containing a little 2-propanol and saturated aqueous sodium carbonate (50 mL), and the organic layer was separated. The aqueous solution was extracted with toluene (2×50 mL) containing a little 2-propanol, and the combined organic solution was dried (Na2SO4) and concentrated in vacuo. The residue was filtered through alumina (eluted with 2% methanol/tetrahydrofuran, then with 35% methanol/tetrahydrofuran to collect product), and the filtrate was concentrated in vacuo and triturated from cold ether. Recrystallization from ethyl acetate/hexane afforded 1.23 g (47%) of a colorless solid; mp 131°-133° C.

1. customdegassed under a stream of nitrogen over 10 minutes
2. stirringstirred for 30 minutes
3. concentrationconcentrated in vacuo
4. customThe above degassed solution
5. customwas transferred into this solution by syringe
6. stirringthe mixture was stirred at room temperature for 65 hours and at 50° C. for one hour
7. concentrationconcentrated in vacuo
8. customThe residue was partitioned between toluene (100 mL)
9. additioncontaining a little 2-propanol and saturated aqueous sodium carbonate (50 mL)
10. customthe organic layer was separated
11. extractionThe aqueous solution was extracted with toluene (2×50 mL)
12. additioncontaining a little 2-propanol
13. dry with materialthe combined organic solution was dried (Na2SO4)
14. concentrationconcentrated in vacuo
15. filtrationThe residue was filtered through alumina (
16. washeluted with 2% methanol/tetrahydrofuran
17. customwith 35% methanol/tetrahydrofuran to collect product), and the filtrate
18. concentrationwas concentrated in vacuo
19. customtriturated from cold ether
20. customRecrystallization from ethyl acetate/hexane

ORD record

ord-249065f6497c4fd0a7b024f92416e2ba

Source dataset

uspto-grants-1993_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US05244907