1,1'-Carbonyldiimidazole → 4-Amino-5-chloro-2-methoxybenzoic acid 1-azabicyclo[3.3.1]non-5-ylmethyl ester

A solution of 4-amino-5-chloro-2-methoxybenzoic acid (2.02 g, 10 mmol) in anhydrous tetrahydrofuran (10 mL) under nitrogen was treated with 1,1'-carbonyldiimidazole (1.70 g, 10.5 mmol), stirred for one hour, then degassed with a stream of nitrogen over 10 minutes. Meanwhile, a cooled (-10° C.) solution of 1-azabicyclo[3.3.1]nonane-5-methanol (1.71 g, 11 mmol) in anhydrous tetrahydrofuran (10 mL) under nitrogen was treated (via syringe) with 2.5N n-butyllithium/hexane (10.7 mmol), stirred for 30 minutes, concentrated in vacuo, and taken up in anhydrous tetrahydrofuran (10 mL) under nitrogen. The above prepared suspension was transferred into this solution, and the mixture was stirred overnight (18 hours) and concentrated in vacuo. The residue was partitioned between methylene chloride (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 methylene chloride (2×50 mL), and the combined organic solution was dried (Na2SO4), concentrated in vacuo and recrystallized from acetonitrile (2 crops) to afford 1.94 g (57%) of pale yellow solid; mp 152.5°-154.5° C.

1. customdegassed with a stream of nitrogen over 10 minutes
2. stirringstirred for 30 minutes
3. concentrationconcentrated in vacuo
4. customThe above prepared suspension
5. stirringthe mixture was stirred overnight (18 hours)
6. concentrationconcentrated in vacuo
7. customThe residue was partitioned between methylene chloride (100 mL)
8. additioncontaining a little 2-propanol and saturated aqueous sodium carbonate (50 mL)
9. customthe organic layer was separated
10. extractionThe aqueous solution was extracted with methylene chloride (2×50 mL)
11. dry with materialthe combined organic solution was dried (Na2SO4)
12. concentrationconcentrated in vacuo
13. customrecrystallized from acetonitrile (2 crops)

ORD record

ord-9f608317b9754efda2c9e04eca249eb4

Source dataset

uspto-grants-1993_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US05244907