Ethyl Acetate → (rac.)-(1R*,5S*)-3-{4-[2-(2,6-Dichloro-4-methyl-phenoxy)-ethoxy]-phenyl}-8-methyl-8-aza-bicyclo[3.2.1]oct-2-ene-2-carboxylic Acid Methyl Ester

HRID 2428177Notes

Reaction equation

HRID 2428177 reaction equation
Br[C:2]1[CH:20]=[CH:19][C:5]([O:6][CH2:7][CH2:8][O:9][C:10]2[C:15]([Cl:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[Cl:18])=[CH:4][CH:3]=1.[Li]CCCC.[CH3:26][O:27][C:28]([C:30]1[C@@H:31]2[N:45]([CH3:46])[C@H:34]([CH2:35][C:36]=1OS(C(F)(F)F)(=O)=O)[CH2:33][CH2:32]2)=[O:29].CCOC(C)=O>C1COCC1.[Cl-].[Cl-].[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:26][O:27][C:28]([C:30]1[C@@H:31]2[N:45]([CH3:46])[C@H:34]([CH2:35][C:36]=1[C:2]1[CH:20]=[CH:19][C:5]([O:6][CH2:7][CH2:8][O:9][C:10]3[C:15]([Cl:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[Cl:18])=[CH:4][CH:3]=1)[CH2:33][CH2:32]2)=[O:29]

Participants

8

Reactant 4

HCID 8857Ethyl AcetateHCID 11695595(1beta,5beta)-3-(Trifluoromethylsulfonyloxy)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene-2-carboxylic acid methyl esterHCID 498559311-(4-Bromophenoxy)-2-(2,6-dichloro-4-methylphenoxy)ethaneHCID 178418339Butyllithium

Product 1

HCID 91150596(rac.)-(1R*,5S*)-3-{4-[2-(2,6-Dichloro-4-methyl-phenoxy)-ethoxy]-phenyl}-8-methyl-8-aza-bicyclo[3.2.1]oct-2-ene-2-carboxylic Acid Methyl EsterYield 87%

Reagents, catalysts & solvents 3

HCID 3007855ZincchlorideCatalystHCID 178418397HCID 178418397, compoundCatalystHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

1-[2-(4-Bromo-phenoxy)-ethoxy]-2,6-dichloro-4-methyl-benzene (10.5 g, 28.0 mmol) was dissolved in THF (90 mL), and the sol. was cooled to −78° C. BuLi (1.6M in hexane, 18.2 mL, 29.1 mmol) was added, and the sol. was stirred at −78° C. for 1 h. ZnCl2 (1M in THF, 30.8 mL, 30.8 mmol) was added, and the mixture was allowed to warm to rt. A sol. of (rac.)-(1R*,5S*)-8-methyl-3-trifluoromethanesulfonyloxy-8-aza-bicyclo[3.2.1]oct-2-ene-2-carboxylic acid methyl ester (WO 2004/096799; 4.60 g, 14.0 mmol) in THF (10 mL), and then Pd(PPh3)4 (324 mg, 0.280 mmol) were added. The mixture was heated rapidly to 55° C., and stirred at this temperature for 30 min. The mixture was cooled to 0° C., and EtOAc (250 mL) was added. This mixture was washed with cold aq. 1M NaOH (1×), and brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (MeOH/CH2Cl2 5:95) yielded the title compound (5.77 g, 87%). LC-MS: tR=0.86 min; ES+: 476.26.

Workup

  1. temperatureto warm to rt
  2. temperatureThe mixture was heated rapidly to 55° C.
  3. stirringstirred at this temperature for 30 min
  4. temperatureThe mixture was cooled to 0° C.
  5. washThis mixture was washed with cold aq. 1M NaOH (1×), and brine
  6. dry with materiallayer was dried over MgSO4
  7. filtrationfiltered
  8. customthe solvents were removed under reduced pressure
  9. customPurification of the crude by FC (MeOH/CH2Cl2 5:95)

Sources & evidence

ORD record
ord-50de09f60204472388467d261300ccba
Source dataset
uspto-grants-2011_06
Patent number
US07968720B2

Reaction notes

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