Pyrazole → 2-(2-Chloropyridin-5-yl)-1-(3-methoxy-5-methylphenyl)ethanone

HRID 2390765Notes

Reaction equation

N1C=CC=N1.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([CH3:18])[CH:17]=1)[C:11]([O:13]C)=O.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][N:21]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:11]([C:10]2[CH:15]=[C:16]([CH3:18])[CH:17]=[C:8]([O:7][CH3:6])[CH:9]=2)=[O:13])=[CH:22][N:21]=1

Participants

Reactant 4

HCID 1048Pyrazole

HCID 5813932-Chloro-5-methyl-pyridine

HCID 2733832Lithium Hexamethyldisilazide

HCID 13834966Methyl 3-methoxy-5-methylbenzoate

Product 1

HCID 508989412-(2-Chloropyridin-5-yl)-1-(3-methoxy-5-methylphenyl)ethanone

Procedure

For the synthesis of the pyrazole derivative, first, as illustrated in Reaction Scheme 10, methyl 3-methoxy-5-methylbenzoate of Formula 2a is allowed to undergo a nucleophilic attack at its carboxylic carbon by the activated methylene group of 2-chloro-5-methylpyridine in the presence of lithium hexamethyldisilazide to afford 2-(2-chloropyridin-5-yl)-1-(3-methoxy-5-methylphenyl)ethanone, represented by Formula 28. The compound of Formula 28 is converted into a pyrazole derivative through two successive steps. In this regard, the ethanone compound of Formula 28 is heated with N,N-dimethylformamide dimethylacetal, successively followed by cyclization with hydrazine hydrate into 4-(2-chloropyridin-5-yl)-3-(3-methoxy-5-methylphenyl)-1H-pyrazol, represented by Formula 29. The reaction of the pyrazole compound of Formula 29 with iodoacetonitrile in the presence of potassium carbonate produces two regioisomers 4-(2-chloropyridin-5-yl)-3-(3-methoxy-5-methylphenyl)-1H-pyrazol-1-yl)acetonitrile, represented by Formula 30, and 4-(2-chloropyridin-5-yl)-5-(3-methoxy-5-methylphenyl)-1H-pyrazol-1-yl)acetonitrile, represented by Formula 31. In the presence of a palladium catalyst, the regioisomers of Formulas 31 and 32 are subjected to nucleophilic substitution with various arylboronic acids to synthesize various compounds represented by Formulas 32a-c and 33a-c. Finally, these compounds are demethylated with boron trifluoride dimethyl sulfide to synthesize target pyrazole derivatives of Formulas 34a-c and 35a-c.

Sources & evidence

ORD record: ord-2fb68aaea9534ad6bfd1886c803aca4b
Source dataset: uspto-grants-2012_09
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08273880B2

Reaction notes

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