Triethylamine → tert-butyl 1-(3-fluoro-4-methylpyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylate

HRID 1508339Notes

Reaction equation

[F:1][C:2]1[C:3]([N:9]2[C:13]([CH3:14])=[C:12]([C:15]([OH:17])=[O:16])[CH:11]=[N:10]2)=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].CN([CH:21]=[C:22]([C:30](=O)C)[C:23](OC(C)(C)C)=O)C.CCN(CC)CC>C(#N)C>[F:1][C:2]1[C:3]([N:9]2[C:13]([CH3:14])=[C:12]([C:15]([O:17][C:22]([CH3:30])([CH3:23])[CH3:21])=[O:16])[CH:11]=[N:10]2)=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8]

Participants

Conditions

Temperature: 85 °C

Procedure

1-(3-Fluoro-4-methylpyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid: To a solution of tert-butyl 2-((dimethylamino)methylene)-3-oxobutanoate (0.123 g, 0.575 mmol) in acetonitrile (2 mL) was added TEA (0.080 mL, 0.575 mmol) and Intermediate 43A (0.073 g, 0.517 mmol). The orange solution was heated to 85° C. for 1 h. Additional tert-butyl 2-((dimethylamino)methylene)-3-oxobutanoate (0.160 mL) and Et3N (0.080 mL) were added into the solution and the reaction was heated at 85° C. for 1 h. The reaction mixture was concentrated and purified by silica gel chromatography to give tert-butyl 1-(3-fluoro-4-methylpyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylate as yellow oil. MS(ESI) m/z: 292.1 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.26 (d, J=4.8 Hz, 1H), 8.02 (s, 1H), 7.29 (t, J=4.8 Hz, 1H), 2.54 (s, 3H), 2.43 (d, J=1.5 Hz, 3H), 1.58 (s, 9H). To the oil was added 4 N HCl in dioxane (2 mL) and the reaction was stirred at rt for 4 h. The clear orange solution was evaporated to dryness followed by coevaporation with toluene (2×) to give the desired product (15 mg, 11%) as sticky pink solid. MS(ESI) m/z: 236.1 (M+H)+.

Workup

temperaturethe reaction was heated at 85° C. for 1 h
concentrationThe reaction mixture was concentrated
custompurified by silica gel chromatography

Sources & evidence

ORD record: ord-23b83cc6602c4d099e50fbefbfa939dd
Source dataset: uspto-grants-2015_12
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09221818B2

Reaction notes

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