Ammonium Chloride → 6-[2-(2,6-Dichloro-4-methyl-phenoxy)-ethoxy]-5',6'-dihydro-2'H-[3,4']bipyridinyl-1',3'-dicarboxylic acid 1'-tert-butyl ester 3'-methyl ester

HRID 1715445Notes

Reaction equation

HRID 1715445 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[CH2:31][N:32]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:33][CH2:34][C:35]=1OS(C(F)(F)F)(=O)=O)=[O:29].[NH4+].[Cl-]>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[CH2:31][N:32]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:33][CH2:34][C:35]=1[C:7]1[CH:12]=[N:11][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])=[CH:9][CH:8]=1)=[O:29]

Participants

8

Reactant 4

HCID 25517Ammonium ChlorideHCID 152219361-Tert-butyl 3-methyl 4-(trifluoromethanesulfonyloxy)-1,2,5,6-tetrahydropyridine-1,3-dicarboxylateHCID 448166685-Bromo-2-(2-(2,6-dichloro-4-methylphenoxy)ethoxy)pyridineHCID 178418339Butyllithium

Product 1

HCID 671490666-[2-(2,6-Dichloro-4-methyl-phenoxy)-ethoxy]-5',6'-dihydro-2'H-[3,4']bipyridinyl-1',3'-dicarboxylic acid 1'-tert-butyl ester 3'-methyl esterYield 70.4%

Reagents, catalysts & solvents 3

HCID 3007855ZincchlorideCatalystHCID 178418397HCID 178418397, compoundCatalystHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-78 °C

Procedure

BuLi (1.6M in hexane, 39.3 mL, 45.2 mmol) was added to a sol. of 5-bromo-2-[2-(2,6-dichloro-4-methyl-phenoxy)-ethoxy]-pyridine (13.0 g, 34.5 mmol) in THF (700 mL) at −78° C. The mixture was stirred for 1 h at −78° C., and ZnCl2 (0.72M in THF, 78.6 mL, 56.5 mmol) was added. The mixture was allowed to warm up to rt. 4-Trifluoromethanesulfonyloxy-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (WO 2004/002957, 11.0 g, 28.3 mmol) and Pd(PPh3)4 (813 mg, 0.704 mmol) were added. The mixture was stirred for 30 min at 70° C., then overnight at rt. Aq. sat. NH4Cl was added, and the mixture was extracted with EtOAc (2×). The org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (heptane/EtOAc 9:1→5:5) yielded the title compound (10.7 g, 70%). LC-MS: tR=1.16 min; ES+: 537.33.

Workup

  1. temperatureto warm up to rt
  2. stirringThe mixture was stirred for 30 min at 70° C.
  3. customovernight
  4. customat rt
  5. extractionthe mixture was extracted with EtOAc (2×)
  6. dry with materialextracts were dried over MgSO4
  7. filtrationfiltered
  8. customthe solvents were removed under reduced pressure
  9. customPurification of the crude by FC (heptane/EtOAc 9:1→5:5)

Sources & evidence

ORD record
ord-1378380a336e4fcc917a0ef6d6c31942
Source dataset
uspto-grants-2010_09
Patent number
US07799805B2

Reaction notes

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