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To a stirred solution of 1H-<strong>[1072-84-0]imidazole-4-carboxylic acid</strong> (XLIII; 5 g; 44.64 mmol) in ethanol(100 ml) was added sulfuric acid (3 ml). The reaction mixture was heated at 80°C for 12 h. Thereaction mixture was cooled, concentrated at reduced pressure and diluted with water. Theaqueous layer was extracted with ethyl acetate. The combined organic layers were washed withsodium bicarbonate and brine solution, dried over Na2SO4, filtered and concentrated under vacuum to afford ethyl imidazole-4-carboxylate as a white solid (XLIV, 4.75 g, 76percent yield). ?H NMR (400 MHz, DMSO-d6) 12.75 (bs, 1H), 7.77 (s, 2H), 4.24-4.19 (q, J = 7.2 Hz, 2H), 1.28-1.24 (t,J= 6.8 Hz, 3H). MS (M+1) 141.12.
52%
IH-lmidazole-4-carboxylic acid (3.8 g, 33.8 mmol) and 4 M HCI in dioxane (20 ml_) were taken up in EtOH (100 ml_) and heated at 80 0C for 18 h. The solution was concentrated. The residue was partitioned between EtOAc and water. The mixture was quenched with solid NaHCO3 until the aqueous layer was no longer acidic. The layers were separated. The aqueous layer was , extracted with EtOAc. The combined organic layers were washed with brine and dried (MgSO4). Filtration and concentration of the solution provided 2.47 g (52 percent) of the ethyl ester as a white solid.
Preparation of intermediate II-30; LiHMDS was added to a -10C solution of ethyl imidazole-4-carboxylate in DMF. After 15 min, o-diphenylphosphinylhydroxylamine (CAS: 72804-96-7) was added in one portion and the mixture was stirred at rt for 6 h. The reaction was quenched with water (an exothermic reaction occcurs) until a clear solution is obtained. The solvents were removed under reduced pressure. The residue was dissolved in water and it was extracted with DCM (x3). Combined organic layers were dried and evaporated. The residue was purified on silica gel (biotage, DCM/MeOH 0 to 10% MeOH) to obtain: 356 mg of desired product, intermediate II-30. Yield 65%.
The mass ratio of 1 H-imidazole-4-carboxylic acid ethyl ester to potassium hydroxide solution was 1: 2.2, the reaction temperature was 30 After the completion of the reaction, the sulfuric acid solution is added, the pH is adjusted to 1, and the crude product is recrystallized from the recrystallization solvent to obtain 1H-imidazole-4-carboxylic acid.
87.96%
With potassium hydroxide; In water; at 65℃;
The 2.2g imidazole-4-carboxylic acid ethyl ester in 30 ml water, raising the temperature to 65 °C, stirring next adds by drops 3.3g the mass concentration is 20percent of the reacted with an aqueous solution of KOH to the end point.Adding dilute hydrochloric acid wash filters after adjusting pH to obtain 1H-imidazole-4-carboxylic acid.
With Ni-Cu / SiO2 catalyst; at 20℃; for 2h;
The load Ni-Cu/SiO2 catalyst 8g, ethyl ether 300 ml mixed under the condition of ice bath, then slowly adding 4 (5)-carboxylic acid imidazol diethlyl 28g, stirring at room temperature the reaction 2h, reaction latter adds by drops 25 ml water after-filtration, the filter residue is dissolved in 30OmL methanol and filter, collect the resulting ether and methanol filtrate is concentrated to dry, the resulting solid is dissolved in 30OmL heating to reflux in ethanol, the solution is concentrated to the 30 ml, cooling sleepovers and filter to get 4 (5)-hydroxymethyl-imidazole.
With sodium hydroxide; at 30 - 40℃; for 0.166667h;
The above prepared 1H-imidazole-4-ethyl formate and sodium hydroxide solution was mixed and stirred, reacted at at 30-40 ° C for 10 min, then cooled to room temperature, hydrochloric acid solution was added to adjust the pH of the reaction solution to 1-2, and filtered, recrystallization is then carried out with a mixture of ethanol and petroleum ether to obtain the target product; where in, the mass ratio of 1H-imidazole-4-ethyl formate, to sodium hydroxide solution was 1:1.
With sulfuric acid; iron(II) sulfate; In ethanol; for 2h;Reflux;
The 4 (5)-carboxylic acid imidazol 50g, ethanol l000mL, concentrated sulfuric acid 30 ml and ferric sulfate powder 10g mixed heating reflux 2h, reflux cooling after reaction to room temperature instillment 5percent NaOH aqueous solution the concentration of the mass concentration adjusted to pH 7, concentrated to dryness under reduced pressure to the mixed solid, by adding 30 ml water backflow to the mixed solid entirely dissolved the solution after natural cooling sleepovers and filter to get 4 (5)-carboxylic acid imidazol ethyl ester
Synthesis of Compound 8.1. Into a 100-mL 3-necked round-bottom flask, was placed ethyl lH-imidazole-5-carboxylate (1.4 g, 9.99 mmol, 1.00 equiv) and N,N- dimethylformamide (25 mL) was added. The reaction was cooled in an ice bath and then LiHMDS (IN in tetrahydrofuran) (11 mL, 1.10 equiv) was added. The reaction was stirred at R.T. Then amino diphenylphosphinate (2.8 g, 12.01 mmol, 1.20 equiv) was added at RT. The reaction was stirred for 2 h at 25 C. Then it was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with dichloromethane/methanol (100: 1). This provided 1.0 g (65%) of ethyl 1 -amino- lH-imidazole-5-carboxylate (8.1) as an off-white solid.
Ste -2: (0913) Preparation of ethyl 1-amino-1H-imidazole-5-carboxylate: (0914) [00346] To stirred solution of ethyl 1H-imidazole-5-carboxylate (0.1 g, 0.71 mmol) in N,N-dimethylformamide (10 mL) cooled to -10 C, was added lithium bis(trimethylsilyl)amide (0.78 mL, 0.78 mmol) drop wise and the reaction mixture was stirred at -10 C for 15 min. Then (aminooxy)diphenylphosphine oxide (0.199 g, 0.85 mmol) was added at -10 C and the reaction mixture was stirred at room temperature for 6 h. The reaction mixture was quenched by slow addition of water until the precipitate formed was dissolved to become clear solution. Then it was extracted using ethyl acetate (2 x 50 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to afford the title compound ethyl 1- amino-1H-imidazole-5-carboxylate as off white solid (0.1 g, crude). Calculated (M+H): 156.07; Found (M+H): 156.1.
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