Reaktion #541611

Reaktionsgleichung

triethylamine

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

HATU

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

→

title compound

Ausbeute 93.5%

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

Ausbeute 93.5%

Lösungsmittel

CH2Cl2

Reaktionsbedingungen

Aufarbeitung

1. 1
   EinengenThe reaction was concentrated in vacuo
2. 2
   Sonstigethe residue purified by silica gel chromatography
3. 3
   Wascheneluting with 15-80% hexanes/EtOAc
4. 4
   Einengenconcentrated 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
   Sonstigepartitioned between EtOAc and water (50 mL each)
10. 10
    ExtraktionThe aqueous layer was extracted with ethyl acetate (50 mL)
11. 11
    Trocknendried (MgSO4)
12. 12
    Einengenconcentrated in vacuo
13. 13
    SonstigeThe residue was triturated in diethyl ether
14. 14
    Einengenconcentrated in vacuo

Vorschrift

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.

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