2-Pyridinecarboxylic acid, 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-6-methoxy-, ethyl ester → HCID 131731316, compound

HRID 2364971Notes

Reaction equation

HRID 2364971 reaction equation
CC1(C)COB([C:8]2[CH:9]=[CH:10][C:11]([C:16]([O:18]CC)=[O:17])=[N:12][C:13]=2[O:14]C)OC1.[Cl:22][C:23]1[N:24]=[CH:25][NH:26][CH:27]=1>CO.[Cu-]=O>[ClH:22].[Cl:22][C:23]1[N:24]=[CH:25][N:26]([C:9]2[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[NH:12][C:13](=[O:14])[CH:8]=2)[CH:27]=1

Participants

5

Reactant 2

HCID 683803982-Pyridinecarboxylic acid, 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-6-methoxy-, ethyl esterHCID 178478287HCID 178478287, compound

Product 1

HCID 131731316HCID 131731316, compound

Reagents, catalysts & solvents 2

HCID 178419072HCID 178419072, compoundCatalyst2×HCID 887MethanolSolvent

Procedure

Synthesis of ethyl 4-(4-chloro-1H-imidazol-1-yl)-6-methoxypyridine-2-carboxylate (C34). 1,1-Bis(diphenylphosphino)ferrocene-palladium(II) dichloride-dichloromethane complex (49.8 mg, 0.068 mmol) was added to a solution of ethyl 5-bromo-6-methoxypyridine-2-carboxylate (prepared in analogous fashion to methyl 5-bromo-6-methoxypyridine-2-carboxylate (C30) in Preparation 10; 254 mg, 0.97 mmol), 5,5,5′,5′-tetramethyl-2,2′-bi-1,3,2-dioxaborinane (264 mg, 1.17 mmol), and potassium acetate (293 mg, 2.92 mmol) in 1,4-dioxane (8 mL). The reaction was stirred at 85° C. for 6 hours, whereupon it was allowed to cool to room temperature. Dichloromethane was added, and the resulting mixture was washed with saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, and concentrated in vacuo to afford intermediate ethyl 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-6-methoxypyridine-2-carboxylate. To a solution of ethyl 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-6-methoxypyridine-2-carboxylate (crude) in methanol (50 mL) was added 4-chloro-1H-imidazole (C33) (100 mg, 0.97 mmol) and copper(I) oxide (14 mg, 0.098 mmol) and the reaction was stirred at ambient temperature overnight. The mixture was heated to 50° C. for 2 hours, and additional copper(I) oxide (14 mg, 0.098 mmol) was added. The reaction was heated to reflux for 2 hours and was then filtered through Celite. The Celite pad was washed with methanol, and the combined filtrate and washings were concentrated in vacuo. Purification was carried out twice via silica gel chromatography (Gradient: 0% to 50% ethyl acetate in heptane, then 0% to 40% ethyl acetate in heptane), affording the title compound as a white solid. Yield: 29.3 mg, 0.104 mmol, 11%. LCMS m/z 282.1 (M+1). 1H NMR (400 MHz, CDCl3) δ 1.44 (t, J=7.1 Hz, 3H), 4.14 (s, 3H), 4.46 (q, J=7.1 Hz, 2H), 7.24 (d, J=1.6 Hz, 1H), 7.67 (d, J=7.8 Hz, 1H), 7.82-7.83 (m, 1H), 7.84 (d, J=7.8 Hz, 1H).

Workup

  1. temperatureThe mixture was heated to 50° C. for 2 hours
  2. temperatureThe reaction was heated
  3. temperatureto reflux for 2 hours
  4. filtrationwas then filtered through Celite
  5. washThe Celite pad was washed with methanol
  6. concentrationthe combined filtrate and washings were concentrated in vacuo
  7. customPurification

Sources & evidence

ORD record
ord-5308afec3d7a4f05814e46364ec3e367
Source dataset
uspto-grants-2014_04
Patent number
US08697673B2

Reaction notes

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