Acetic Acid → 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

HRID 932160Notes

Reaction equation

HRID 932160 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:24][CH3:25])[CH:22]=O)[C:11](=[O:26])[C@:10]([CH2:28][C:29]([OH:31])=[O:30])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH:32]12[O:39][CH:36]([CH2:37][CH2:38]1)[CH2:35][NH:34][CH2:33]2.Cl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[CH:36]12[O:39][CH:32]([CH2:38][CH2:37]1)[CH2:33][N:34]([CH2:22][C@@H:21]([N:12]1[C@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[C@@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[CH2:9][C@@:10]([CH2:28][C:29]([OH:31])=[O:30])([CH3:27])[C:11]1=[O:26])[CH2:24][CH3:25])[CH2:35]2

Participants

7

Reactant 5

HCID 176Acetic AcidHCID 313Hydrochloric AcidHCID 5049666Sodium triacetoxyborohydrideHCID 120692318-Oxa-3-azabicyclo[3.2.1]octaneHCID 585738802-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-oxobutan-2-yl)piperidin-3-yl)acetic acid

Product 1

HCID 585739502-((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

Reagents, catalysts & solvents 1

HCID 111,2-DichloroethaneSolvent

Procedure

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.

Workup

  1. customthe mixture was partitioned between 5% aq. HCl and ethyl acetate
  2. washThe organic layer was washed with sat. aq. NaCl solution
  3. dry with materialdried over Na2SO4
  4. concentrationconcentrated
  5. customThe residue was purified by reversed phase preparatory HPLC (eluent: 0-100% MeCN +0.1% TFA in water +0.1% TFA, over 20 minutes)
  6. additionFractions containing the product
  7. customwere transferred to a separatory funnel
  8. additionsat. aq. NaHCO3 and dichloromethane were added
  9. extractionThe aqueous layer was back extracted with dichloromethane
  10. washThe combined organic layers were washed with sat. aq. NaCl solution
  11. dry with materialdried over anhydrous Na2SO4
  12. filtrationfiltered
  13. concentrationthe filtrate was concentrated

Sources & evidence

ORD record
ord-b5372235c7424764980b33982797b6c5
Source dataset
uspto-grants-2016_03
Patent number
US09296736B2

Reaction notes

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