Acetic Acid → Dimethyl 4-(2,6-dichlorophenyl)-2-(2-methoxy-2-oxoethyl)-6-[2-(1,3-thiazol-2-yl)ethyl]-1,4-dihydropyridine-3,5-dicarboxylate

HRID 480404Notes

Reaction equation

HRID 480404 reaction equation
CC(O)(C)C.CC[Mg+].[Br-].[NH2:10][C:11]([CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:12][C:13]([O:15][CH3:16])=[O:14].[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[CH:30]=[C:31]([C:36](=O)[CH2:37][CH2:38][C:39]1[S:40][CH:41]=[CH:42][N:43]=1)[C:32]([O:34][CH3:35])=[O:33].C(O)(=O)C>C1COCC1>[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[CH:30]1[C:31]([C:32]([O:34][CH3:35])=[O:33])=[C:36]([CH2:37][CH2:38][C:39]2[S:40][CH:41]=[CH:42][N:43]=2)[NH:10][C:11]([CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:12]1[C:13]([O:15][CH3:16])=[O:14]

Participants

7

Reactant 5

HCID 176Acetic AcidHCID 6386tert-ButanolHCID 253819Dimethyl 3-aminoglutaconateHCID 69949834Methyl 3-(2,6-dichlorophenyl)-2-[(1,3-thiazol-2-yl)propanoyl]-2-propenoateHCID 178461630HCID 178461630, compound

Product 1

HCID 10165160Dimethyl 4-(2,6-dichlorophenyl)-2-(2-methoxy-2-oxoethyl)-6-[2-(1,3-thiazol-2-yl)ethyl]-1,4-dihydropyridine-3,5-dicarboxylateYield 85%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent4×

Procedure

To a stirred solution of 2-methyl-2-propanol (92.8g, 1252 mmol; 2.1 eq.) in anhydrous THF (1100 ml) was added a 1.0M solution of EtMgBr in THF (1192 ml, 1192 mmol; 2.0 eq.) dropwise slowly at 0° C. under nitrogen atmosphere for 2 h period. The resulting solution was stirred at room temperature for 1 h. Then to the mixture was added a solution of dimethyl 3-amino-2-pentenedioate (113.5 g, 655 mmol; 1.1 eq.) in anhydrous THF (550 ml) dropwise slowly at 0° C. for 20 min. The resulting pale yellow solution was stirred at the same temperature for 1 h, then a solution of methyl 3-(2,6-dichlorophenyl)-2-[(1,3-thiazol-2-yl)propanoyl]-2-propenoate (219.9 g, 594 mmol; 1.0 eq.) in anhydrous THF (550 ml) was added at 0° C. for 30 min. The reaction mixture was stirred at room temperature for 16 h under nitrogen atmosphere, then acetic acid (170 ml; 5.0 eq.) was added at 0° C. The resulting mixture was stirred at room temperature for 6 h. The mixture was poured into 2N NaOHaq. (1000 ml), the organic phase was separated and the aqueous phase was extracted with EtOAc (2000 ml). The combined organic phase was washed with H2O (1000 ml) and brine (1000 ml), dried (Na2SO4) and concentrated to give a crude mixture. Purification on silica gel column chromatography (3 times 1700 g) eluted with hexane/EtOAc (2/1 to 1/2) to afford 246.0 g (85%) of dimethyl 4-(2,6-dichlorophenyl)-2-(2-methoxy-2-oxoethyl)-6-[2-(1,3-thiazol-2-yl)ethyl]-1,4-dihydropyridine-3,5-dicarboxylate as a brown oil

Workup

  1. stirringThe resulting pale yellow solution was stirred at the same temperature for 1 h
  2. stirringThe reaction mixture was stirred at room temperature for 16 h under nitrogen atmosphere
  3. stirringThe resulting mixture was stirred at room temperature for 6 h
  4. additionThe mixture was poured into 2N NaOHaq
  5. custom(1000 ml), the organic phase was separated
  6. extractionthe aqueous phase was extracted with EtOAc (2000 ml)
  7. washThe combined organic phase was washed with H2O (1000 ml) and brine (1000 ml)
  8. dry with materialdried (Na2SO4)
  9. concentrationconcentrated
  10. customto give a crude mixture
  11. customPurification on silica gel column chromatography (3 times 1700 g)
  12. washeluted with hexane/EtOAc (2/1 to 1/2)

Sources & evidence

ORD record
ord-35a9d377c41b41ef90209a6958c63d54
Source dataset
uspto-grants-2003_11
Patent number
US06649767B2

Reaction notes

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