Ethyl Acetate → HCID 86586655, compound

HRID 2088133Notes

Reaction equation

HRID 2088133 reaction equation
C([N:8]1[C@@H:13]2[CH2:14][CH2:15][C@@:9]1([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C@H:10]([O:16][C:17](=O)[C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=1)[CH2:11][CH2:12]2)C1C=CC=CC=1.[C:39]([O-])([O-])=O.[Na+].[Na+].CO.O.C(OCC)(=O)C>C1(C)C=CC=CC=1.[Pd].C[Ti](C)(C1C=CC=C1)C1C=CC=C1>[F:29][C:28]([F:31])([F:30])[C:20]1[CH:19]=[C:18]([C@H:17]([O:16][C@@H:10]2[CH2:11][CH2:12][C@@H:13]3[NH:8][C@@:9]2([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:15][CH2:14]3)[CH3:39])[CH:23]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:21]=1

Participants

8

Reactant 4

HCID 8857Ethyl AcetateHCID 10340Sodium CarbonateHCID 22242641Methanol--water (1/1)HCID 86586656HCID 86586656, compound

Product 1

HCID 86586655HCID 86586655, compound

Reagents, catalysts & solvents 3

HCID 23938PalladiumCatalystHCID 178477792HCID 178477792, compoundCatalystHCID 1140TolueneSolvent

Conditions

Temperature
82 °C

Procedure

(1R*,2R*,5R*)-8-Benzyl-2-[3,5-bis(trifluoromethyl)benzoyloxy]-1-phenyl-8-azabicyclo[3.2.1]octane (Description 9; 821 mg, 1.54 mmol) was treated with a solution of dimethylbis(cyclopentadienyl)titanium in toluene (0.2M, 30 ml). The reaction mixture was stirred in the dark at 82° C. for 2.5 hours. The mixture was cooled to 40° C., than solid Na2CO3 (2 g) added followed by a mixture of methanol-water (9:1, 20 ml). The mixture was stirred for 1 hour at 40° C. and filtered through a pad of Celite™. The filtrate was dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:ethyl acetate 0-35% containing 0.5% triethylamine) to give a 10:1 mixture of (1R*,2R*,5S*,6R*)-2-{1-[3,5-bis(trifluoromethyl)phenyl]ethenyloxy}-1-phenyl-8-azabicyclo[3.2.1]octane and (1R*,2R*,5S*,6R*)-8-benzyl-2-[3,5-bis(trifluoromethyl)benzoyloxy]-1-phenyl-8-azabicyclo[3.2.1]octane. 2/5 of this crude mixture was treated with I-propanol (8 ml), ethyl acetate (8 ml) and 10% palladium on charcoal (340 mg) and stirred under hydrogen atmosphere (1 atm) at room temperature for 12 hours. The mixture was filtered through a pad of Celite™ and concentrated to give a 7:1 (S*:R*) mixture of the title compounds. The isomers were separated by preparative TLC (dichloromethane:methanol) and converted into hydrochloride salts.

Workup

  1. additionadded
  2. stirringThe mixture was stirred for 1 hour at 40° C.
  3. filtrationfiltered through a pad of Celite™
  4. dry with materialThe filtrate was dried (Na2SO4)
  5. concentrationconcentrated
  6. customThe residue was purified by chromatography on silica gel (iso-hexane:ethyl acetate 0-35% containing 0.5% triethylamine)
  7. customto give
  8. stirringstirred under hydrogen atmosphere (1 atm) at room temperature for 12 hours
  9. filtrationThe mixture was filtered through a pad of Celite™
  10. concentrationconcentrated
  11. customto give
  12. customThe isomers were separated by preparative TLC (dichloromethane:methanol)

Sources & evidence

ORD record
ord-b26880b859e64637bd3d41146b6e0fc6
Source dataset
uspto-grants-2004_04
Patent number
US06727249B2

Reaction notes

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