Sodium Hydroxide → HCID 131728342, compound

HRID 1715446Notes

Reaction equation

HRID 1715446 reaction equation
C([O:3][C:4]([C:6]1[C@@H:7]2[N:33]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C@H:11]([CH2:12][C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][O:23][C:24]3[C:29]([F:30])=[CH:28][CH:27]=[C:26]([F:31])[C:25]=3[Cl:32])=[CH:16][CH:15]=1)[CH2:10][N:9]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:8]2)=[O:5])C.[OH-].[Na+]>CCO>[C:44]([O:43][C:41]([N:9]1[CH2:8][C@H:7]2[N:33]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C@H:11]([CH:12]=[C:13]([C:14]3[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][CH2:22][O:23][C:24]4[C:29]([F:30])=[CH:28][CH:27]=[C:26]([F:31])[C:25]=4[Cl:32])=[CH:18][CH:19]=3)[CH:6]2[C:4]([OH:5])=[O:3])[CH2:10]1)=[O:42])([CH3:45])([CH3:46])[CH3:47]

Participants

4

Reactant 2

HCID 14798Sodium HydroxideHCID 131728343HCID 131728343, compound

Product 1

HCID 131728342HCID 131728342, compound

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Procedure

In a 250 mL round-bottom flask equipped with a magnetic stirrer is dissolved compound A1 (4.72 g, 6.97 mmol) in EtOH (100 mL). To this is then added aq. 1M NaOH (50 mL), and the resulting colorless sol. is heated to 80° C. for 14 h. The resulting pale pink sol. is allowed to cool to rt, and carefully acidified to a pH of 1.5. The volatiles are removed in vacuo and the resulting residue is partitioned between EtOAc (300 mL) and water (300 mL). The aq. phase is separated and back-extracted with EtOAc (3×300 mL). The combined org. extracts are then washed with brine (500 mL), decolorized with activated charcoal and dried over MgSO4. Filtration through a bed of Celite and concentration of the colorless filtrate in vacuo affords a white froth. Separation of (rac.)-(1R*,5S*)-7-{4-[3-(2-chloro-3,6-difluoro-phenoxy)-propyl]-phenyl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid 3,9-di-tert-butyl ester [1.01 g, 22%; Rf=0.55 (1:1 Hex:EtOAc+1% AcOH)] and the title compound (2.77 g, 61%) can be achieved by way of FC (SiO2, 2:1 hexane:EtOAc+1% AcOH). Residual AcOH can be removed quantitatively by first azeotroping with heptane and then toluene. Rf=0.50 (1:1 Hex:EtOAc+1% AcOH); ES−=646.8.

Workup

  1. customIn a 250 mL round-bottom flask equipped with a magnetic stirrer
  2. customThe volatiles are removed in vacuo
  3. customthe resulting residue is partitioned between EtOAc (300 mL) and water (300 mL)
  4. customThe aq. phase is separated
  5. extractionback-extracted with EtOAc (3×300 mL)
  6. washextracts are then washed with brine (500 mL)
  7. dry with materialdried over MgSO4
  8. filtrationFiltration through a bed of Celite and concentration of the colorless filtrate in vacuo
  9. customaffords a white froth
  10. customSeparation of (rac.)-(1R*,5S*)-7-{4-[3-(2-chloro-3,6-difluoro-phenoxy)-propyl]-phenyl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid 3,9-di-tert-butyl ester [1.01 g, 22%; Rf=0.55 (1:1 Hex:EtOAc+1% AcOH)]
  11. customResidual AcOH can be removed quantitatively
  12. customby first azeotroping with heptane

Sources & evidence

ORD record
ord-89fc984983bd4800a79f30b4d7a3c377
Source dataset
uspto-grants-2010_09
Patent number
US07799805B2

Reaction notes

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