Réaction #5478

Équation de réaction

n-butyllithium hexane

1-azabicyclo[3.2.1]octane-5-methanol

4-amino-5-chloro-2-methoxybenzoic acid

1,1'-carbonyldiimidazole

→

colorless solid

Rendement 47.3%

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

Rendement 47.3%

Solvants

tetrahydrofuran

tetrahydrofuran

Conditions de réaction

Traitement

1. 1
   Autredegassed under a stream of nitrogen over 10 minutes
2. 2
   workup.STIRRINGstirred for 30 minutes
3. 3
   Concentrationconcentrated in vacuo
4. 4
   AutreThe above degassed solution
5. 5
   Autrewas transferred into this solution by syringe
6. 6
   workup.STIRRINGthe mixture was stirred at room temperature for 65 hours and at 50° C. for one hour
7. 7
   Concentrationconcentrated in vacuo
8. 8
   AutreThe residue was partitioned between toluene (100 mL)
9. 9
   workup.ADDITIONcontaining a little 2-propanol and saturated aqueous sodium carbonate (50 mL)
10. 10
    Autrethe organic layer was separated
11. 11
    ExtractionThe aqueous solution was extracted with toluene (2×50 mL)
12. 12
    workup.ADDITIONcontaining a little 2-propanol
13. 13
    Séchagethe combined organic solution was dried (Na2SO4)
14. 14
    Concentrationconcentrated in vacuo
15. 15
    FiltrationThe residue was filtered through alumina (
16. 16
    Lavageeluted with 2% methanol/tetrahydrofuran
17. 17
    Autrewith 35% methanol/tetrahydrofuran to collect product), and the filtrate
18. 18
    Concentrationwas concentrated in vacuo
19. 19
    Autretriturated from cold ether
20. 20
    AutreRecrystallization from ethyl acetate/hexane

Mode opératoire

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.

Source