Potassium Carbonate → 2,6-Dichloro-4-pyrimidinepropanoic Acid

HRID 23194Notes

Reaction equation

HRID 23194 reaction equation
[O-][Mn](=O)(=O)=O.[K+].[C:7]([O-:10])([O-])=[O:8].[K+].[K+].[Cl:13][C:14]1[N:19]=[C:18]([Cl:20])[CH:17]=[C:16]([CH2:21][CH2:22]C=C(C)C)[N:15]=1>O.C(O)(C)(C)C>[Cl:13][C:14]1[N:19]=[C:18]([Cl:20])[CH:17]=[C:16]([CH2:21][CH2:22][C:7]([OH:10])=[O:8])[N:15]=1

Participants

6

Reactant 3

HCID 11430Potassium CarbonateHCID 516875Potassium PermanganateHCID 224884832,4-Dichloro-6-(4-methylpent-3-en-1-yl)pyrimidine

Product 1

HCID 224883372,6-Dichloro-4-pyrimidinepropanoic AcidYield 49.8%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6386tert-ButanolSolvent

Procedure

The above synthesis may be carried out as follows: To a solution of LDA (1.28 g, 12 mmol) in THF (30 mL) at −78° C. was added 2,4-dichloro-6-methylpyrimidine (1.96 g, 12 mmol) in THF (15 mL). After stirring for 15 minutes, 3,3-dimethylallyl bromide (1.79 g, 12 mmol) in THF (5 mL) was added dropwise. After the reaction warmed to ambient temperature, water and ethyl acetate was added. The organic layer was separated, the solvent was removed in vacuo, and the residue was chromatographed (ethyl acetate/hexane, 1/19) to give 2.06 g (74%) of 2,4-dichloro-6-(4-methyl-3-pentenyl)pyrimidine (1H NMR (CDCl3) δ 7.15 (s, 1), 5.10 (t, 1), 2.80 (t, 2), 2.45 (m, 2), 1.70 (s, 3), 1.55 (s, 3). To a solution of NaIO4 (17 g, 81 mmol) and KMnO4 (251 mg, 1.59 mmol) in water was added K2CO3 (1.29 g, 9.38 mmol) and 2,4-dichloro-6-(4-methyl-3-pentenyl)pyrimidine (2.06 g, 8.9 mmol) in t-butanol. After stirring for 16 hours, the reaction was acidified to pH 3 and extracted with ethyl acetate. The organic layer was extracted with aqueous NaHCO3. The aqueous layer was acidified to pH 3 and extracted with ethyl acetate. The organic layer was dried and the solvent removed in vacuo to give 980 mg of 3-(2,4-dichloropyrimidin-6-yl)propionic acid (the compound of formula (XIX)), 1H NMR (CDCl3) δ 7.30 (s, 1), 3.05 (t, 2), 2.90 (t, 2). The acid was coupled to piperonylamine under standard conditions with isobutyl chloroformate and N-methylmorpholine to give the compound of formula (XX). Imidazole was added under standard conditions (1-trimethylsilylimidazole and CsF in DMF at 60° C.) to give N-[(1,3-benzodioxol-5-yl)ethyl]-6-chloro-2-(1H-imidazol-1-yl)pyrimidine-4-propionamide (the compound of formula (Ihh)); MS: 386 (M+H)+.

Workup

  1. extractionextracted with ethyl acetate
  2. extractionThe organic layer was extracted with aqueous NaHCO3
  3. extractionextracted with ethyl acetate
  4. customThe organic layer was dried
  5. customthe solvent removed in vacuo

Sources & evidence

ORD record
ord-05df2ec397ec4ffb8a4805020deb2680
Source dataset
uspto-grants-2005_02
Patent number
US06849739B2

Reaction notes

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