5-Bromo-2-(2-(2,6-dichloro-4-methylphenoxy)ethoxy)pyridine → (rac.)-(1R*,5S*)-3-{6-[2-(2,6-Dichloro-4-methyl-phenoxy)-ethoxy]-pyridin-3-yl}-8-aza-bicyclo[3.2.1]oct-2-ene-2,8-dicarboxylic Acid 8-tert-butyl Ester 2-methyl Ester

HRID 2428187Notes

Reaction equation

HRID 2428187 reaction equation
[Li]CCCC.Br[C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][O:16][C:17]2[C:22]([Cl:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=2[Cl:25])=[N:11][CH:12]=1.[CH3:26][O:27][C:28]([C:30]1[C@@H:31]2[N:45]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[C@H:34]([CH2:35][C:36]=1OS(C(F)(F)F)(=O)=O)[CH2:33][CH2:32]2)=[O:29]>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]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[C@H:34]([CH2:35][C:36]=1[C:7]1[CH:12]=[N:11][C:10]([O:13][CH2:14][CH2:15][O:16][C:17]3[C:22]([Cl:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[Cl:25])=[CH:9][CH:8]=1)[CH2:33][CH2:32]2)=[O:29]

Participants

7

Reactant 3

HCID 448166685-Bromo-2-(2-(2,6-dichloro-4-methylphenoxy)ethoxy)pyridineHCID 131728966(rac.)-(1R*,5S*)-3-Trifluoromethanesulfonyloxy-8-aza-bicyclo[3.2.1]oct-2-ene-2,8-dicarboxylic Acid 8-tert-butyl Ester 2-methyl EsterHCID 178418339Butyllithium

Product 1

HCID 131728977(rac.)-(1R*,5S*)-3-{6-[2-(2,6-Dichloro-4-methyl-phenoxy)-ethoxy]-pyridin-3-yl}-8-aza-bicyclo[3.2.1]oct-2-ene-2,8-dicarboxylic Acid 8-tert-butyl Ester 2-methyl EsterYield 78.3%

Reagents, catalysts & solvents 3

HCID 3007855ZincchlorideCatalystHCID 178418397HCID 178418397, compoundCatalystHCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
-78 °C

Procedure

BuLi (1.6 M in hexane, 12.0 mL, 19.2 mmol) was added to the sol. of 5-bromo-2-[2-(2,6-dichloro-4-methyl-phenoxy)-ethoxy]-pyridine (5.45 g, 14.4 mmol) in THF (120 mL) at −78° C. The mixture was stirred at −78° C. for 60 min, and ZnCl2 (1M in THF, 28.9 mL, 28.9 mmol) was added. The mixture was allowed to warm up to rt, and compound A1 (4.00 g, 9.63 mmol) in dry THF (50 mL) and Pd(PPh3)4 (277 mg, 0.240 mmol) in THF (2 mL) were added. The mixture was heated to 70° C. for 1 h, and was quenched with aq. sat. NH4Cl (70 mL). The mixture was extracted with EtOAc (3×). The combined org. layers were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of crude by FC(CH2Cl2/MeOH 99:1→98:2→97:3→96:4→95:5) yielded the title compound (4.25 g, 78%). LC-MS: tR=1.16 min; ES+: 563.11.

Workup

  1. temperatureto warm up to rt
  2. temperatureThe mixture was heated to 70° C. for 1 h
  3. customwas quenched with aq. sat. NH4Cl (70 mL)
  4. extractionThe mixture was extracted with EtOAc (3×)
  5. dry with materiallayers were dried over MgSO4
  6. filtrationfiltered
  7. customthe solvents were removed under reduced pressure
  8. customPurification of crude by FC(CH2Cl2/MeOH 99:1→98:2→97:3→96:4→95:5)

Sources & evidence

ORD record
ord-50de53571be8418896785652447dc2da
Source dataset
uspto-grants-2011_06
Patent number
US07968720B2

Reaction notes

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