تفاعل #5478

معادلة التفاعل

n-butyllithium hexane

1-azabicyclo[3.2.1]octane-5-methanol

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

1,1'-carbonyldiimidazole

→

colorless solid

المردود 47.3%

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

المردود 47.3%

المذيبات

tetrahydrofuran

tetrahydrofuran

ظروف التفاعل

المعالجة

1. 1
   أخرىdegassed under a stream of nitrogen over 10 minutes
2. 2
   workup.STIRRINGstirred for 30 minutes
3. 3
   تركيزconcentrated in vacuo
4. 4
   أخرىThe above degassed solution
5. 5
   أخرىwas 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
   تركيزconcentrated in vacuo
8. 8
   أخرىThe residue was partitioned between toluene (100 mL)
9. 9
   workup.ADDITIONcontaining a little 2-propanol and saturated aqueous sodium carbonate (50 mL)
10. 10
    أخرىthe organic layer was separated
11. 11
    استخلاصThe aqueous solution was extracted with toluene (2×50 mL)
12. 12
    workup.ADDITIONcontaining a little 2-propanol
13. 13
    تجفيفthe combined organic solution was dried (Na2SO4)
14. 14
    تركيزconcentrated in vacuo
15. 15
    ترشيحThe residue was filtered through alumina (
16. 16
    غسيلeluted with 2% methanol/tetrahydrofuran
17. 17
    أخرىwith 35% methanol/tetrahydrofuran to collect product), and the filtrate
18. 18
    تركيزwas concentrated in vacuo
19. 19
    أخرىtriturated from cold ether
20. 20
    أخرىRecrystallization from ethyl acetate/hexane

الإجراء التجريبي

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.

المصدر