반응 #541611

반응 방정식

triethylamine

ethyl (3S)-8,8-difluoro-2-azaspiro[4.5]decane-3-carboxylate

HATU

N-[(methyloxy)carbonyl]-L-valine

→

title compound

수율 93.5%

(3S)-8,8-difluoro-2-{N-[(methyloxy)carbonyl]-L-valyl}-2-azaspiro[4.5]decane-3-carboxylic acid

수율 93.5%

용매

CH2Cl2

반응 조건

후처리

1. 1
   농축The reaction was concentrated in vacuo
2. 2
   기타the residue purified by silica gel chromatography
3. 3
   세척eluting with 15-80% hexanes/EtOAc
4. 4
   농축concentrated in vacuo
5. 5
   workup.DISSOLUTIONThe residue was dissolved in THF/water/methanol (5 mL/2.5 mL/2.5 mL)
6. 6
   workup.ADDITIONlithium hydroxide monohydrate was added (119 mg, 2.8 mmol)
7. 7
   workup.STIRRINGthe solution stirred at room temperature for 30 min
8. 8
   workup.ADDITIONThe reaction was treated with 1N HCl (3.5 mL)
9. 9
   기타partitioned between EtOAc and water (50 mL each)
10. 10
    추출The aqueous layer was extracted with ethyl acetate (50 mL)
11. 11
    건조dried (MgSO4)
12. 12
    농축concentrated in vacuo
13. 13
    기타The residue was triturated in diethyl ether
14. 14
    농축concentrated in vacuo

실험 절차

To a solution of ethyl (3S)-8,8-difluoro-2-azaspiro[4.5]decane-3-carboxylate (115), (380 mg, 1.54 mmol) in anhydrous CH2Cl2 (10 mL) was added HATU (614 mg, 1.6 mmol), N-[(methyloxy)carbonyl]-L-valine (283 mg, 1.6 mmol) followed by triethylamine (0.43 mL, 3.1 mmol) and the reaction stirred at room temperature under nitrogen for 1 h. The reaction was concentrated in vacuo and the residue purified by silica gel chromatography eluting with 15-80% hexanes/EtOAc. Appropriate fractions were combined and concentrated in vacuo. The residue was dissolved in THF/water/methanol (5 mL/2.5 mL/2.5 mL) and lithium hydroxide monohydrate was added (119 mg, 2.8 mmol) and the solution stirred at room temperature for 30 min. The reaction was treated with 1N HCl (3.5 mL) and partitioned between EtOAc and water (50 mL each). The aqueous layer was extracted with ethyl acetate (50 mL), the organic layers were combined and dried (MgSO4) and concentrated in vacuo. The residue was triturated in diethyl ether and concentrated in vacuo to afford the title compound as a white solid (542 mg, 93% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.47 (br. s., 1H) 7.41 (d, J=8.0 Hz, 1H) 4.24 (t, J=8.6 Hz, 1H) 3.95-4.14 (m, 2H) 3.52 (s, 3H) 3.25-3.33 (m, 1H) 2.22 (dd, J=12.3, 8.4 Hz, 1H) 1.79-2.11 (m, 5H) 1.58-1.77 (m, 3H) 1.41-1.59 (m, 2H) 0.93 (dd, J=12.7, 6.6 Hz, 6H). LC-MS ESI (M+H)+=377.23.

출처