反応 #541611

反応方程式

triethylamine

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

HATU

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

→

title compound

収率 93.5%

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

収率 93.5%

溶媒

CH2Cl2

反応条件

後処理

1. 1
   濃縮The reaction was concentrated in vacuo
2. 2
   その他the residue purified by silica gel chromatography
3. 3
   洗浄eluting with 15-80% hexanes/EtOAc
4. 4
   濃縮concentrated 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
   その他partitioned between EtOAc and water (50 mL each)
10. 10
    抽出The aqueous layer was extracted with ethyl acetate (50 mL)
11. 11
    乾燥dried (MgSO4)
12. 12
    濃縮concentrated in vacuo
13. 13
    その他The residue was triturated in diethyl ether
14. 14
    濃縮concentrated in vacuo

実験手順

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.

出典