Tert-butyl 2-acetyl-3-(dimethylamino)acrylate → tert-butyl 1-(4-chloro-3-fluoro-pyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylate

HRID 1508335Notes

Reaction equation

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

Participants

Conditions

Temperature: 85 °C

Procedure

1-(4-Chloro-3-fluoropyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid: To a solution of tert-butyl 2-((dimethylamino)methylene)-3-oxobutanoate (0.045 g, 0.211 mmol) in acetonitrile (2 mL) was added TEA (0.030 mL, 0.215 mmol) followed by Intermediate 41B (0.038 g, 0.19 mmol). The dark brown solution was stirred for 1 h at 85° C. The reaction was concentrated, and water (1 mL) and CH2Cl2 (1 mL) were added. The organic layer was concentrated and purified by silica gel chromatography to provide tert-butyl 1-(4-chloro-3-fluoro-pyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylate as brown oil. MS(ESI) m/z: 312.1 (M+H). 1H NMR (400 MHz, CDCl3) δ 8.39-8.25 (m, 1H), 8.04 (s, 1H), 7.51 (t, J=5.0 Hz, 1H), 2.57 (s, 3H), 1.48 (s, 9H). The oil was stirred with 4 N HCl in dioxane (2 mL) for 12 h at rt. The solution was evaporated to dryness followed by coevaporation with toluene (2×) to give the desired product (12 mg, 22%). MS(ESI) m/z: 256.1 (M+H)+.

Workup

concentrationThe reaction was concentrated
additionwater (1 mL) and CH2Cl2 (1 mL) were added
concentrationThe organic layer was concentrated
custompurified by silica gel chromatography

Sources & evidence

ORD record: ord-b6e343f34be1401c8831249c8355a1f7
Source dataset: uspto-grants-2015_12
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09221818B2

Reaction notes

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