Methyl acetoacetate → Methyl 4-(2-Chloro-4-fluorophenyl)-6-methyl-2-(2-thiazolyl)-1,4-dihydropyrimidine-5-carboxylate

HRID 1778457Notes

Reaction equation

HRID 1778457 reaction equation
[ClH:1].[S:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]([NH2:9])=[NH:8].[C:10]([O:16][CH3:17])(=[O:15])[CH2:11][C:12]([CH3:14])=O.Cl[C:19]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:20]=1C=O.[C:28]([O-])(=O)C.[K+]>C(CO)(F)(F)F>[CH3:17][O:16][C:10]([C:11]1[CH:28]([C:19]2[CH:20]=[CH:23][C:24]([F:27])=[CH:25][C:26]=2[Cl:1])[N:8]=[C:7]([C:3]2[S:2][CH:6]=[CH:5][N:4]=2)[NH:9][C:12]=1[CH3:14])=[O:15]

Participants

6

Reactant 4

HCID 7757Methyl acetoacetateHCID 517044Potassium AcetateHCID 27791842-Chloro-5-FluorobenzaldehydeHCID 186795841,3-Thiazole-2-carboximidamide hydrochloride

Product 1

HCID 9820500Methyl 4-(2-Chloro-4-fluorophenyl)-6-methyl-2-(2-thiazolyl)-1,4-dihydropyrimidine-5-carboxylate

Reagents, catalysts & solvents 1

HCID 64092,2,2-TrifluoroethanolSolvent

Procedure

To a stirred solution of thiazole-2-carboxamidine hydrochloride (0.13 g, 1.0 mmol), methyl acetoacetate (0.12 g, 1.0 mmol) and 2-chloro-5-fluorobenzaldehyde (0.16 g, 1.0 mmol) in CF3CH2OH (8 mL) was added potassium acetate (0.20 g, 2.0 mmol). The reaction mixture was refluxed for 16 hours. After it was cooled to room temperature, the reaction mixture was concentrated and the residue was dissolved in ethyl acetate and then washed with brine. The organic layer was dried over sodium sulfate. The solvent was concentrated, and the residue was purified by column chromatography (ethyl acetate/petroleum ether is from ¼ to ½) to afford 4-(2-chloro-4-fluoro-phenyl)-6-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester (Compound B) as a yellow solid. MS: calc'd (MH+) 366, measured (MH+) 366. 1H NMR (DMSO-d6, 400 MHz): δ ppm 9.98 (s, 1H), 7.97 (d, J=4.0 Hz, 1H), 7.90 (d, J=4.0 Hz, 1H), 7.41 (dd, J=8.0, 4.0 Hz, 1H), 7.35 (dd, J=8.0, 8.0 Hz, 1H), 7.18 (td, J=8.0, 4.0 Hz, 1H), 5.98 (s, 1H), 3.53 (s, 3H), 2.47 (s, 3H).

Workup

  1. temperatureThe reaction mixture was refluxed for 16 hours
  2. concentrationthe reaction mixture was concentrated
  3. dissolutionthe residue was dissolved in ethyl acetate
  4. washwashed with brine
  5. dry with materialThe organic layer was dried over sodium sulfate
  6. concentrationThe solvent was concentrated
  7. customthe residue was purified by column chromatography (ethyl acetate/petroleum ether is from ¼ to ½)

Sources & evidence

ORD record
ord-b8728a6a8efa446fbbef6fd22e5bc5bc
Source dataset
uspto-grants-2016_02
Patent number
US09266904B2

Reaction notes

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