Pyridine, hydrofluoride (1:1) → Ethyl 5-methyl 2-fluoro-6-methyl-4-(p-tolyl)pyridine-3,5-dicarboxylate

HRID 1912592Notes

Reaction equation

N[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[C:5]([C:20]([O:22][CH3:23])=[O:21])=[C:4]([CH3:24])[N:3]=1.N([O-])=O.[Na+].C1C=CN=CC=1.[FH:35].C(=O)(O)[O-].[Na+]>O1CCCC1.C(OCC)(=O)C>[F:35][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[C:5]([C:20]([O:22][CH3:23])=[O:21])=[C:4]([CH3:24])[N:3]=1

Participants

Conditions

Temperature: 0 °C

Procedure

3-Ethyl 5-methyl 2-amino-6-methyl-4-(p-tolyl)pyridine-3,5-dicarboxylate (5.0 g, 15.23 mmol) (Example 1, Step C) was dissolved in tetrahydrofuran (50 mL) and cooled to 0° C. Sodium nitrite (5.25 g, 76.15 mmol) was added followed by HF-Pyridine (4.0 mL, 160 mmol). The reaction was stirred at ambient temperature until complete by LCMS. Ethyl acetate and sodium bicarbonate solution was added, the precipitated solid was filtered, and the filtrate was extracted with ethyl acetate, dried over sodium sulfate, and purified by silica-gel chromatography (0-30% hexanes/ethyl acetate) to afford the title compound as a colorless oil (2.91 g, 58%): 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.18-7.24 (m, 2 H) 7.12-7.18 (m, 2 H) 4.11 (q, J=7.22 Hz, 2 H) 3.55-3.60 (m, 3 H) 2.55-2.59 (m, 3 H) 2.39 (s, 3 H) 1.03 (t, J=7.12 Hz, 3 H); LCMS (m/z) ES+=332 (M+1).

Workup

filtrationthe precipitated solid was filtered
extractionthe filtrate was extracted with ethyl acetate
dry with materialdried over sodium sulfate
custompurified by silica-gel chromatography (0-30% hexanes/ethyl acetate)

Sources & evidence

ORD record: ord-a6674a51828146fbabb273b4638fe62d
Source dataset: uspto-grants-2013_12
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08609653B2

Reaction notes

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