Ammonium Chloride → 1-(Tert-butyl) 3-methyl 4-(4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)phenyl)-5,6-dihydropyridine-1,3(2h)-dicarboxylate

HRID 658230Notes

Reaction equation

HRID 658230 reaction equation
[Si:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li]CCCC.[CH3:24][O:25][C:26]([C:28]1[CH2:29][N:30]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:31][CH2:32][C:33]=1OS(C(F)(F)F)(=O)=O)=[O:27].[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.CCOC(C)=O>[CH3:24][O:25][C:26]([C:28]1[CH2:29][N:30]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:31][CH2:32][C:33]=1[C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[CH:13][CH:14]=1)=[O:27]

Participants

9

Reactant 4

HCID 25517Ammonium ChlorideHCID 150978074-[2-(Tert-butyldimethylsilanyloxy)ethoxy]bromobenzeneHCID 152219361-Tert-butyl 3-methyl 4-(trifluoromethanesulfonyloxy)-1,2,5,6-tetrahydropyridine-1,3-dicarboxylateHCID 178418339Butyllithium

Product 1

HCID 684912491-(Tert-butyl) 3-methyl 4-(4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)phenyl)-5,6-dihydropyridine-1,3(2h)-dicarboxylateYield 82.4%

Reagents, catalysts & solvents 4

HCID 3007855ZincchlorideCatalystHCID 178418397HCID 178418397, compoundCatalystHCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
-78 °C

Procedure

To a sol. of 4-[2-(tert-butyldimethylsilanyloxy)ethoxy]bromobenzene (WO 03/093267, 7.95 g, 24 mmol) in THF (200 mL) at −78° C. was added BuLi (1.6M in hexane, 17.12 mL, 27.4 mmol). The sol. was stirred at −78° C. for 30 min, then ZnCl2 (1M in THF, 30 mL, 30 mmol) was added. The resulting sol. was allowed to warm to rt, and 4-trifluoromethanesulfonyloxy-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (WO 2004/002957, 7.79 g, 20 mmol) in THF (20 mL) and Pd(PPh3)4 (0.69 g, 0.60 mmol) were added. The reaction mixture was heated to 50° C. for 1 h, and stirred 16 h at rt. The mixture was cooled to 0° C., and aq. sat. NH4Cl was added. EtOAc was added, and the org. phase was washed with brine, dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 2:8→1:0) yielded the title compound (8.1 g, 82%). LC-MS: tR=1.23 min, ES+: 506.47.

Workup

  1. temperatureto warm to rt
  2. temperatureThe reaction mixture was heated to 50° C. for 1 h
  3. stirringstirred 16 h at rt
  4. temperatureThe mixture was cooled to 0° C.
  5. washphase was washed with brine
  6. dry with materialdried over MgSO4
  7. filtrationfiltered
  8. customthe solvents were removed under reduced pressure
  9. customPurification of the residue by FC (EtOAc/heptane 2:8→1:0)

Sources & evidence

ORD record
ord-0f98cd4c79cc43459a5a141e034a4541
Source dataset
uspto-grants-2011_12
Patent number
US08076359B2

Reaction notes

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