Ammonium Chloride → 4-{4-[2-(2,6-Dichloro-4-methyl-phenoxy)-ethoxy]-phenyl}-5,6-dihydro-2H-pyridine-1,3-dicarboxylic Acid 1-tert-butyl Ester 3-methyl Ester

HRID 2428178Notes

Reaction equation

HRID 2428178 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[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: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)=[O:29]

Participants

8

Reactant 4

HCID 25517Ammonium ChlorideHCID 152219361-Tert-butyl 3-methyl 4-(trifluoromethanesulfonyloxy)-1,2,5,6-tetrahydropyridine-1,3-dicarboxylateHCID 498559311-(4-Bromophenoxy)-2-(2,6-dichloro-4-methylphenoxy)ethaneHCID 178418339Butyllithium

Product 1

HCID 671486554-{4-[2-(2,6-Dichloro-4-methyl-phenoxy)-ethoxy]-phenyl}-5,6-dihydro-2H-pyridine-1,3-dicarboxylic Acid 1-tert-butyl Ester 3-methyl EsterYield 100.1%

Reagents, catalysts & solvents 3

HCID 3007855ZincchlorideCatalystHCID 178418397HCID 178418397, compoundCatalystHCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
-78 °C

Procedure

1-[2-(4-Bromo-phenoxy)-ethoxy]-2,6-dichloro-4-methyl-benzene (16.6 g, 44.2 mmol) was dissolved in THF (150 mL), and the sol. was cooled to −78° C. BuLi (1.6M in hexane, 31.4 mL, 50.3 mmol) was added, and the mixture was stirred at −78° C. for 30 min. ZnCl2 (1M in THF, 56.0 mL, 56.0 mmol) was added, and the mixture was allowed to warm up to rt. The mixture was stirred at rt for 1 h. A sol. of 4-trifluoromethanesulfonyloxy-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (WO 2004/002957; 14.3 g, 36.7 mmol) in THF (30 mL), and then a sol. of Pd(PPh3)4 (1.23 g, 1.06 mmol) in THF (30 mL) were added. The mixture was stirred at 50° C. over 20 min, and cooled to 0° C. Aq. 10% NH4Cl was added. The mixture was extracted with EtOAc. The org. extracts were washed with aq. 10% NH4Cl, water, and brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 1:4→EtOAc) yielded the title compound (19.7 g, quantitative yield). LC-MS: tR=1.20 min; ES+: 536.77.

Workup

  1. temperatureto warm up to rt
  2. stirringThe mixture was stirred at rt for 1 h
  3. stirringThe mixture was stirred at 50° C. over 20 min
  4. temperaturecooled to 0° C
  5. extractionThe mixture was extracted with EtOAc
  6. washextracts were washed with aq. 10% NH4Cl, water, and brine
  7. dry with materiallayer was dried over MgSO4
  8. filtrationfiltered
  9. customthe solvents were removed under reduced pressure
  10. customPurification of the residue by FC (EtOAc/heptane 1:4→EtOAc)

Sources & evidence

ORD record
ord-b188c2b9229f423aa0cd7f825413e170
Source dataset
uspto-grants-2011_06
Patent number
US07968720B2

Reaction notes

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