Reaktion #1019342

Reaktionsgleichung

Sodium triacetoxyborohydride

2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-oxobutan-2-yl)piperidin-3-yl)acetic acid

8-oxa-3-azabicyclo[3.2.1]octane

acetic acid

HCl

→

title compound

2-((3R,5R,6S)-1-((2S)-1-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid

Lösungsmittel

DCE

Reaktionsbedingungen

Aufarbeitung

1. 1
   Sonstigethe mixture was partitioned between 5% aq. HCl and ethyl acetate
2. 2
   WaschenThe organic layer was washed with sat. aq. NaCl solution
3. 3
   Trocknendried over Na2SO4
4. 4
   Einengenconcentrated
5. 5
   SonstigeThe residue was purified by reversed phase preparatory HPLC (eluent: 0-100% MeCN +0.1% TFA in water +0.1% TFA, over 20 minutes)
6. 6
   workup.ADDITIONFractions containing the product
7. 7
   Sonstigewere transferred to a separatory funnel
8. 8
   workup.ADDITIONsat. aq. NaHCO3 and dichloromethane were added
9. 9
   ExtraktionThe aqueous layer was back extracted with dichloromethane
10. 10
    WaschenThe combined organic layers were washed with sat. aq. NaCl solution
11. 11
    Trocknendried over anhydrous Na2SO4
12. 12
    Filtrationfiltered
13. 13
    Einengenthe filtrate was concentrated

Vorschrift

To a solution of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-oxobutan-2-yl)piperidin-3-yl)acetic acid (99 mg, 0.215 mmol; Example 210, Step A) in DCE (3 mL) was added 48.7 mg (0.43 mmol) of 8-oxa-3-azabicyclo[3.2.1]octane (Connolly, T.; Considine, J.; Ding, Z.; Forsatz, B.; Jennings, M.; MacEwan, M.; McCoy, K.; Place, D.; Sharma, A.; Sutherland, K. Organic Process Research & Development. 2010, 14(2), 459-465. Note: reference is for the HCl Salt). Sodium triacetoxyborohydride (91 mg, 0.430 mmol) was added followed by acetic acid (1.2 μL, 0.022 mmol). After stirring overnight, the mixture was partitioned between 5% aq. HCl and ethyl acetate. The organic layer was washed with sat. aq. NaCl solution, dried over Na2SO4, and concentrated. The residue was purified by reversed phase preparatory HPLC (eluent: 0-100% MeCN +0.1% TFA in water +0.1% TFA, over 20 minutes). Fractions containing the product were transferred to a separatory funnel and sat. aq. NaHCO3 and dichloromethane were added. The aqueous layer was back extracted with dichloromethane. The combined organic layers were washed with sat. aq. NaCl solution, dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to afford the title compound.

Quelle