반응 #5478

반응 방정식

n-butyllithium hexane

1-azabicyclo[3.2.1]octane-5-methanol

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

1,1'-carbonyldiimidazole

→

colorless solid

수율 47.3%

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

수율 47.3%

용매

tetrahydrofuran

tetrahydrofuran

반응 조건

후처리

1. 1
   기타degassed under a stream of nitrogen over 10 minutes
2. 2
   workup.STIRRINGstirred for 30 minutes
3. 3
   농축concentrated in vacuo
4. 4
   기타The above degassed solution
5. 5
   기타was 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
   농축concentrated in vacuo
8. 8
   기타The residue was partitioned between toluene (100 mL)
9. 9
   workup.ADDITIONcontaining a little 2-propanol and saturated aqueous sodium carbonate (50 mL)
10. 10
    기타the organic layer was separated
11. 11
    추출The aqueous solution was extracted with toluene (2×50 mL)
12. 12
    workup.ADDITIONcontaining a little 2-propanol
13. 13
    건조the combined organic solution was dried (Na2SO4)
14. 14
    농축concentrated in vacuo
15. 15
    여과The residue was filtered through alumina (
16. 16
    세척eluted with 2% methanol/tetrahydrofuran
17. 17
    기타with 35% methanol/tetrahydrofuran to collect product), and the filtrate
18. 18
    농축was concentrated in vacuo
19. 19
    기타triturated from cold ether
20. 20
    기타Recrystallization from ethyl acetate/hexane

실험 절차

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.

출처