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1H-Imidazole-4-carboxylic acid is an organic acid containing an imidazole ring, widely used in organic synthesis and pharmaceutical chemistry research. It has biological activity, especially in immune and enzyme reactions.
Synonyms: 4-Imidazolecarboxylic acid
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CAS No. : | 1072-84-0 |
Formula : | C4H4N2O2 |
M.W : | 112.09 |
SMILES Code : | O=C(C1=CNC=N1)O |
Synonyms : |
4-Imidazolecarboxylic acid
|
MDL No. : | MFCD00082203 |
InChI Key : | NKWCGTOZTHZDHB-UHFFFAOYSA-N |
Pubchem ID : | 14080 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | for 18 h; Reflux | The imidazole-2-carboxylic acid (5 g, 44.6 mmol) in suspensionin thionyl chloride (75 mL) was heated to reflux under agitation for18 h. The reaction mixture was cooled, then filtered, washed withtoluene, and dried under high vacuum. The compound is obtainedas a yellow solid (95percent yield). C8H4N4O2. MW: 188.14 g/mol. Mp265-268 °C. 1H NMR δ (ppm, 300 MHz, DMSO-d6) 8.24 (d, 1H,CHC-CO), 8.32 (d, 1H, CHC-CO, J3 Hz), 8.88 (d, 1H, CHN),9.28 (d, 1H, CHN, J3 Hz). 13C NMR δ (ppm, 100 MHz, DMSO-d6)123.99, 124.52, 125.62, 137.26, 139.73, 150.39, 159.68. MS (ESI+ ,QTof, m/z): 189.0 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With manganese(IV) oxide; sodium nitrate; acetic anhydride; In ethanol;Reflux; | The 4,5-dicarboxylic acid imidazole 40g, acetic anhydride 1200 ml, manganese dioxide solid 5g mixed heating reflux 8h, filtered and the filtrate is concentrated to dry,Added to the resulting solid in 50percent ethanol aqueous solution 600 ml refluxing 2h, heating under reflux is filtered and the filtrate after adding sodium nitrate solid 10g stir, natural cooling sleepovers, sleepovers after filtering to obtain again solid 4 (5)-carboxylic acid imidazole |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With sulfuric acid; at 80℃; for 12h; | 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. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With thionyl chloride; for 18h;Reflux; | The imidazole-2-carboxylic acid (5 g, 44.6 mmol) in suspensionin thionyl chloride (75 mL) was heated to reflux under agitation for18 h. The reaction mixture was cooled, then filtered, washed withtoluene, and dried under high vacuum. The compound is obtainedas a yellow solid (95percent yield). C8H4N4O2. MW: 188.14 g/mol. Mp265-268 °C. 1H NMR delta (ppm, 300 MHz, DMSO-d6) 8.24 (d, 1H,CHC-CO), 8.32 (d, 1H, CHC-CO, J3 Hz), 8.88 (d, 1H, CHN),9.28 (d, 1H, CHN, J3 Hz). 13C NMR delta (ppm, 100 MHz, DMSO-d6)123.99, 124.52, 125.62, 137.26, 139.73, 150.39, 159.68. MS (ESI+ ,QTof, m/z): 189.0 [M+H]+. |
With thionyl chloride;N,N-dimethyl-formamide; In toluene; for 30h;Heating / reflux; | Production Example 24; Production of compound (39) by the production method 8; A mixture consisting of 1.5 g (13 mmol) of 1H-<strong>[1072-84-0]imidazole-4-carboxylic acid</strong> and 5 ml of thionyl chloride and three drops of N,N-dimethylformamide and 10ml of toluene was stirred under heating and refluxing for 30 hours. After the reaction, excess thionyl chloride and the solvent were removed under reduced pressure to obtain crystal of diimidazo[1, 5-a, 1' , 5'-d] pyrazine-5,10-dione. In a separate vessel, 0.10 g (2.5 mmol) of sodium hydride was added at room temperature to a mixture consisting of 0.30 g (2.0 mmol) of 6,6-difluoro-5-methyl-5-hexenol, 0.18 g (1.0 mmol) of diimidazo[1, 5-a, 1', 5'-d]pyrazine-5,10-dione and 5 ml of tetrahydrofuran, followed by stirring at the same temperature for 2 hours, the addition of 0.40 g (2.8 mmol) of methyl iodide and further stirring for 2 hours. To the reaction liquid was added 20 ml of ethyl acetate to filter off solid and the filtrate was concentrated under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate : methanol = 10 : 1) to obtain 0.15 g (yield: 30 percent) of 6,6-difluoro-5-methyl-5-hexenyl 1-methyl-1H-imidazole-4-carboxylate.1H-NMR (CDCl3, TMS) deltappm: 1.47-1.56 (5H, m), 1.70-1.79 (2H, m), 1.98-2.04 (2H, m), 3.75 (3H, s), 4.31 (2H, t), 7.51 (2H, s), 7.56 (1H, s) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With thionyl chloride; In acetonitrile; at 75℃; for 2h; | A solution of 100 mg 4-imidazole carboxylic acid in acetonitrile was treated with thionyl chloride (4.0 eq) and was stirred 2 hr at 75°C. The solvent and excess thionyl chloride was removed to give 4-imidazole carbonyl chloride as a tan solid, which was used directly in the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Using the methods of Examples 5 and 6, substituting imidazole-4-carboxylic acid for pyroglutamic acid, the title compounds were obtained. The compound was characterized as the ester and the carboxylic acid was prepared by in situ hydrolysis. Anal. Calcd for C23 H38 N4 O4 S.1 TFA: C, 51.12; H, 6.66; N. 9.46. Found: C, 50.84; H, 6.74; N, 9.65. | ||
Part E compound was added (0.20 g, 0.49 mmol) and the reaction was run at 85° C. (oil bath temperature) for 2 hours. DMSO was removed in vacuo (vacuum pump, dry ice-cooled receiver flask). Ethyl acetate (30 mL) and 1M HC1 were added. The ethyl acetate layer was washed 3 times with 1M HC1, 3 times with saturated aqueous K2 CO3 solution, brine, dried over Na2 SO4 and concentrated to yield 0.39 g of a viscous yellow oil. Flash chromatography on 27 g of silica gel (99.5/0.5 CH2 Cl2 /CH3 OH) yielded 0.16 g of title compound as a white crystalline solid. Also isolated was 0.16 g of unconsumed Part C compound. | ||
EXAMPLE 10 The reaction of Example 9 was carried out using 10 moles of potassium hydroxide instead of potassium carbonate. 510 g (58percent of theory) of imidazole-4-carboxylic acid of melting point 220° C. were obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99.7% | With pyridine; In N,N-dimethyl-formamide; at 50℃; for 6h; | 1H-<strong>[1072-84-0]imidazole-4-carboxylic acid</strong>(5.0 g, 44.6 mmol) and triphenylchloromethane (13.8 g, 49.1 mmol)It was added to a mixture of 50 ml of DMF and 2.5 ml of pyridine. After the addition, the temperature is raised to 50 ° C for 6 h.The reaction was detected by HPLC. Post-treatment: The system is cooled, and the reaction system is slowly added to 100 ml of water.The gray solid precipitated, and the suspension was stirred for 1 hour and then filtered.The filter cake was washed with a small amount of water, dried for 30 min, and dried under vacuum at 50 ° C to obtain 15.8 g of a gray solid.Yield: 99.7percent. |
95% | With pyridine; In N,N-dimethyl-formamide; at 20℃; | 1-(Triphenylmethyl)-1H-<strong>[1072-84-0]imidazole-4-carboxylic acid</strong> was prepared as described in J. Med. Chem. 2001, 44, 1268. 1 H-lmidazole-4-carboxylic acid (0.50 g, 4.5 mmol) and trityl chloride (1.35 g, 4.9 mmol) were added to a solution of DMF (30 ml.) and pyridine (15 ml.) and stirred overnight. Water and EtOAc were added. The layers were separated and the aqueous layer extracted with EtOAc (2 x 50 ml_). The organic extracts were combined, washed with water and brine, dried over Na2SO4, filtered and evaporated. The oil was triturated with EtOAc to afford the title compound (1.5 g, 95percent) as a white solid. 1H NMR (400 MHz, DMSO-d6): delta ppm 12.40 (br. s., 1 H), 7.42 (t, 9 H), 7.17 - 7.35 (m, 2 H), 7.10 (d, 6 H). MS: m/z 1 11 (M-243). |
79% | With pyridine; In N,N-dimethyl-formamide; at 20℃; | Example 6; To a RT solution of 1H-<strong>[1072-84-0]imidazole-4-carboxylic acid</strong> (1.12 g, 9.99 mmol) in pyridine (15 mL) and DMF (30 mL) was added triphenylmethyl chloride (3.06 g, 11.0 mmol). The reaction mixture was stirred at RT overnight, then was partitioned between EtOAc (500 mL) and H2O (50 mL). The organic phase was washed with H2O (20 mL), 10percent citric acid (20 mL) and brine (5 mL), dried (MgSO4) and concentrated in vacuo. The residue was triturated with EtOAc to afford 1-trityl-1H-<strong>[1072-84-0]imidazole-4-carboxylic acid</strong> (2.78 g, 79percent yield) as a white solid. LCMS Method A (ESI, positive ion spectrum): (M+H)/z=not observed, tR=3.27 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonium nitrate; sulfuric acid; at 100℃; for 12h; | The nitroimidazole carboxylic acid was readily obtained by nitration of imidazole carboxylic acid (Scheme 2) as previously described [11,23]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); at 23℃; for 17h; | To a solid mixture of N-[((5S)-3-{4-[exo-(1R,5S)-3-azabicyclo [3.1. 0] hex-6- yl]-3-fluorophenyl}-2-oxo-1, 3-oxazolidin-5-yl) methyl] acetamide (0.157 g, 0.47 mmol, 1 equivalent), HOBT (85 mg, 0.63 mmol, 1.3 equiv. ), EDCI (120 mg, 0.626 mmol, 1.3 equiv. ) and 4-imidazolecarboxylic acid (68 mg, 0.61 mmol, 1.3 equiv. ) at 23°C was added DMF (5 mL), followed by DIEA (0.7 mL, 4.0 mmol, 8.6 equiv. ). The reaction mixture was stirred at the same temperature for 17 hours, diluted with saturated NaHC03 aqueous and extracted with CHC13 (9x50 mL). The combined organic layers were washed (H20, brine), dried (Na2SO4), filtered and evaporated to dry. The crude product was purified by chromatography on a silica gel column, eluting with a gradient increasing in polarity from 0 to 10percent methanol in methylene chloride (containing 1 percent ET3I . Relevant fractions were combined to evaporate and residue was dissolved in CHC13 (300 mL). The organic layer were washed (NaHC03 aqueous, brine), dried (NA2SO4), filtered and evaporated to dryness. The residue was freeze- dried to give the title compound. Yield 65.6 mg (33percent). MS (m/z): [M+H] + = 428 'H NMR (300 MHz, DMSO-d6): 1.68 (s, 1H), 1.82 (s, 3H), 1.98 (bs, 1H), 2.05 (bs, 1H), 3.39 (t, J=5. 4 Hz, 2H), 3.53 (m, 1H), 3.70 (m, 1H), 3.88 (m, 1H), 4.00 (d, J=12. 0 Hz, 1H), 4.08 (t, J=8. 7 Hz, 1H), 4.48 (m, 1H), 4.71 (m, 1H), 7.09 (t, J=8. 7 Hz, 1H), 7.19 (m, 1H), 7.44 (d, J=12. 9 Hz, 1H), 7.59 (s, 1H), 7.72 (d, J=1. 2 Hz, 1H), 8.24 (t, J=5. 4 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With oxalyl dichloride;N,N-dimethyl-formamide; at 20℃; for 1.5h;Heating / reflux; | Step 1: To a 10 mL solution of oxalyl chloride was added 4-imidazolecarboxylic acid (1.0 g, 8.92 mmol) at room temperature, followed by 2 drops of dimethylformamide. The mixture was heated to reflux for 90 minutes, then cooled to room temperature. Following removal of the solvent by evaporation, toluene was added and evaporated to dryness twice to provide 1.49 g of imidazole-4-carbonyl chloride hydrochloride in quantitative yield as a yellow solid. This was used in the subsequent step without purification. |
94% | With thionyl chloride; for 72h;Heating / reflux; | 1H-Imidazole-4-carbonyl Chloride Hydrochloride As suggested by Moss, et al J. Amer. Chem. Soc., 109, 6209-6210 (1987), a suspension of 1 H-<strong>[1072-84-0]imidazole-4-carboxylic acid</strong> (575 mg, 5. 13 MMOL) in thionyl chloride (25 ml) was heated at reflux for 3 days. The solution was allowed to cool to ambient temperature and concentrated in vacuo to afford 800 mg of yellow powder in 94percent yield, which was used without further purification. H NMR (DMSO-d6) : 5 8. 86 (s, 1 H), 8. 22 (s, 1 H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (benzotriazole-1-yloxy)tris(pyrrolidino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); at 20℃; for 18h; | To a solution containing Intermediate 54 (0. 041g) in N, N-DIMETHYLFORMAMIDE (3ML) were added <strong>[1072-84-0]imidazole-4-carboxylic acid</strong> (0. 012g, ALDRICH), (1H-1, 2, 3-benzotriazol-1-yloxy) (TRI-1- pyrrolidinyl) phosphonium hexafluorophosphate (PyBop) (0. 053g) and N, N- diisopropylethylamine (0. 03ML). The solution was stirred under nitrogen at room temperature for 18h and was then concentrated in vacuo. The residual gum was purified using an aminopropyl SPE cartridge eluting with methanol followed by chromatography on silica gel (SPE cartridge), eluting with a gradient of 0percent to 8percent methanol in chloroform, to give the title compound as a yellow solid (0. 031g). LC/MS Rt 2. 32 min, M/Z 549 [MH+] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
13% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 16h; | WSC (0.16 g) was added to a solution of 1-{3-[(6-chloro-2-naphthyl)sulfonyl]propanoyl}piperidine-4-amine (0.29 g) obtained in Example 50a), <strong>[1072-84-0]imidazole-4-carboxylic acid</strong> (0.08 g) and HOBt (0.13 g) in dichloromethane (30 mL), and the mixture was stirred at room temperature for 16 hours. The reaction solution was made alkaline with an aqueous potassium carbonate solution and then extracted with chloroform. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off. The residue was purified with a basic silica gel column to obtain the title compound (47 mg, 13percent) as white powder. NMR (300 MHz, CDCl3) delta: 1.13-1.45 (2H, m), 1.92-2.08 (2H, m), 2.74 (1H, t, J = 11.7), 2.82-2.89 (2H, m), 3.15 (1H, t, J = 11.7), 3.52-3.57 (2H, m), 3.78-3.82 (1H, m), 4.10-4.13 (1H, m), 4.36-4.41 (1H, m), 7.17-7.20 (1H, br), 7.56-7.59 (3H, m), 7.86-7.94 (4H, m), 8.45 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | for 2h;Heating / reflux; | (NEt4)2[ReBr3(CO)3] (488 mg, 0.63 mmol) was dissolved in water (5 ml) and added to a solution of 4-imidazole carboxylic acid (imc) (71 mg, 0.63 mmol) in water (3 ml). After 2 h under reflux, the product precipitated as a white powder at r. t. Filtration, washing with diethyl ether and drying at high vacuum gave 186 mg of 1 (73percent). 1H NMR (300, DMSO-D6) delta 8.40 (s, 1H, imc), 7.68 (s, 1H, imc), 7.08 (br s, 1H, imc) IR (KBr, cm-1) : 2039,1936 nuC=O (st) MS (ESI+, MeOH) m/z: 764 (2M-2H2O), 382 (M-H2O) + Anal. Calcd for C7H5N2O6Re : C, 21. 05 ; H, 1.26 ; N, 7.02 Found: C, 21.15 ; H, 1.41 ; N, 6.97 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In DMF (N,N-dimethyl-formamide); at 20℃; | Example 85 To a solution of 200 mg of 4-[(E)-2-(2,6-dimethylphenyl)vinyl]piperidine monohydrochloride in 5 ml of dimethylformamide, 111 mul of triethylamine, 107 mg of <strong>[1072-84-0]imidazole-4-carboxylic acid</strong>, 161 mg of 1-hydroxybenzotriazole and 228 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride were added at ambient temperature. After stirring at ambient temperature overnight, the reaction mixture was concentrated under reduced pressure. After 50 ml of chloroform and 15 ml of saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, the organic layer was fractionated and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol-ammonia water) to give 280 mg of colorless oil. The oil obtained was dissolved in 2 ml of ethanol, and 226 mul of 4N hydrochloric acid-ethyl acetate was added to the solution. The precipitated crystals were collected by filtration and washed with diethyl ether. The crystals were recrystallized from ethanol-diethyl ether to give 191 mg of 4-[(E)-2-(2,6-dimethylphenyl)vinyl]-1-(1H-imidazol-4-ylcarbonyl)piperidine monohydrochloride. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); at 20℃; for 15h; | The product of Step A (110 mg, TFA salt, 0.233 mmol), and 1H-<strong>[1072-84-0]imidazole-4-carboxylic acid</strong> (29 mg, 0.26 mmol), were stirred in DMF (1.5 mL) under nitrogen. N,N-Diisopropylethylamine (81 muL, 0.47 mmol) was added, then N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (47 mg, 0.24 mmol) was added and the mixture was stirred at room temperature. After 15 hours, LC/MS showed the desired product, (M+H)+ 451 as the main component. The product was isolated by preparative HPLC/MS to provide the title compound (108 mg, TFA salt, 82percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dihydrogen peroxide;pH 7.2;aqueous phosphate buffer; UV-irradiation;Product distribution / selectivity; | Photooxidation; A 1-cm quartz cuvette, filled with 1.4 mL sample, was placed in the parallel beam of a filtered 1000 W xenon arc lamp (Oriel, Stratford, CT). The samples were magnetically stirred during irradiation. To minimize infrared (heat) and visible radiation, the beam was passed through a water filter (7 cm), reflected by a dichroic mirror and filtered through a 1-mm UG11 filter. Short-wave cut off was achieved by passing the beam through WG280, WG305 or WG335 filters with 3 mm thickness each (Schott-Jena, Mainz, Germany). Xenon lamp emission filtered through WG280 included W-C, UV-B and W-A; through WG305 W-B and W-A and through WG335 only W-A was included. Two narrow bands in the W-B and W-A spectral regions were selected to monitor the xenon-arc emission. The probe of a calibrated EGG 550 radiometer (Salem, MA, USA) was equipped with a neutral density filter and narrow band filter type UV-M-IL (Schott-Jena) with a transmission maximum of 21 percent at 303 nm and a half-width of 11.5 nm to monitor UV-B or with a type UV-PIL (Schott-Jena) with a transmission maximum of 46 percent at 363 nm and a half-width of 7.7 nm to monitor UV-A. Transmission spectra of the optical filters were checked on a Perkin Elmer Lambda 40 UV/VIS spectrometer (Norwalk, CT, USA). Additional irradiations were performed with fluorescent tubes TL12, used as a UV-B source, and TL10R, used as a UV-A source (Philips, Eindhoven, The Netherlands), on samples that were magnetically stirred in small Petri dishes. The UV-B output was measured with an IL 443 phototherapy radiometer, fitted with a SEE 1240 silicon detector probe and the UV-A output with an IL 442A phototherapy radiometer with a SEE 115 detector probe (International Light, Newburyport, MA, USA); UCA photo-oxidation on a preparative scale Concentrations of trans-UCA and hydrogen peroxide were largely increased, as was the UV exposure, to obtain larger amounts of UCA photo-oxidation products as collected fractions from the reversed phase column for further analysis. A typical chromatogram is shown in Fig. 4. Four fractions, designated as Rt 8, Rt 10, Rt 14, Rt 17, were finally selected for identification (peak A, 1-3 in Fig.4). Prior to analysis, tetrabutylammonium was removed by solid phase extraction on C18 silica.Identification Rt 8 was identified as imidazole-4-carboxaldehyde (ImCHO). Its UV-spectrum was identical to the synthesized (see below) reference compound with an absorption maximum of 257 nm. Co-injection of Rt 8 with synthesized imidazole-4-carboxaldehyde resulted in a single chromatographic peak with a retention time of 8.13 minutes. Further evidence is to be collected (peak A in Fig.4). The amount of ImCHO in the photooxidized UCA sample was gradually reduced upon storage at -20°C. Rt 10 was identified as imidazole-4-acetic acid. Its UV-spectrum was identical with an absorption maximum of 213 nm. Mass spectrum was obtained with electrospray technique and the dry sample was treated with methanol/HCl and n-butanol/HCl before analysis. A peak at mass 140 was obtained after methylation and at mass 183 after butylation. Consequently, the mass of the original compound was 126. Co-injection of Rt 10 with commercially available imidazole-4-acetic acid resulted in a single chromatographic peak with a retention time of 8.98 minutes (peak 1 in Fig.4). Rt 14 was identified as imidazole-4-carboxylic acid (ImCOOH). Its UV-spectrum was identical to the commercially obtained reference compound with an absorption maximum of 226 nm. Proton resonance (1H-NMR) analysis was done in D2O, showing imidazolic protons in a ratio 1:1 with shifts of 7.76 and 7.53 ppm. Mass spectrum was obtained with electrospray technique and the dry sample was treated with methanol/HCl and n-butanol/HCl before analysis. A peak at mass 126 was obtained after methylation and at mass 169 after butylation. Consequently, the mass of the original compound was 112. Co-injection of Rt 14 with commercially available ImCOOH resulted in a single chromatographic peak with a retention time of 14.73 minutes (peak 2 in Fig.4). The amount of ImCOOH in the photooxidized UCA sample was gradually increased upon storage at -20° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dihydrogen peroxide;pH 7.2;aqueous phosphate buffer;Product distribution / selectivity; | Fenton oxidation UCA isomers (10 or 40 muM) were oxidized with a hydroxyl-radical- generating system that consisted of various concentrations of ferrous ions (10 - 500 muM) and a fixed hydrogen peroxide concentration of 500 muM (the Fenton reagent), either in a sodium phosphate (10 or 20 mM) medium of pH 7.2, or in ultrapure water. In addition, two hydroxyl-radical-generating systems with copper ions (Cu2+) were used, consisting of 50 muM Cu2+ with either 500 muM hydrogen peroxide or 5 mM ascorbic acid. | |
With dihydrogen peroxide; In water;pH 7.2;Product distribution / selectivity; | Fenton oxidation UCA isomers (10 or 40 muM) were oxidized with a hydroxyl-radical- generating system that consisted of various concentrations of ferrous ions (10 - 500 muM) and a fixed hydrogen peroxide concentration of 500 muM (the Fenton reagent), either in a sodium phosphate (10 or 20 mM) medium of pH 7.2, or in ultrapure water. In addition, two hydroxyl-radical-generating systems with copper ions (Cu2+) were used, consisting of 50 muM Cu2+ with either 500 muM hydrogen peroxide or 5 mM ascorbic acid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With thionyl chloride;SiO2; In methanol; 1,1-dichloroethane; chloroform; water; N,N-dimethyl-formamide; | Part E. 3-[4-[2-(1-Pyrrolidinyl)ethoxy]benzyl]-2-[4-(4-imidazolylcarbonylamino)phenyl]benzo[b]thiophene Dihydrochloride. A slurry of 40 mg (0.35 mmol) of 4-imidazolecarboxylic acid in 5 mL of dichloroethane was treated with 1 drop DMF followed by 0.10 mL (1.37 mmol) of SOCl2. The mixture was heated to mild reflux for 2 h, concentrated in vacuo, and the residue reconstituted in 5 mL dichloroethane. A solution of 300 mg (0.70 mmol) of 2-(4-aminophenyl)-3-[4-[2-(1-pyrrolidinyl)ethoxy]benzyl]benzo[b]thiophene (Part D) in 5 mL of dichloroethane was added and the mixture heated to mild reflux for 16 h. The reaction was diluted with 10 mL of sat'd aq NaHCO3, the two layers were separated, and the aqueous layer extracted with CHCl3 (3*10 mL). The combined organic layers were dried (K2CO3), filtered and concentrated in vacuo. Radial chromatography (SiO2; 2percent then 4percent then 5percent MeOH in CHCl3 sat'd with NH4OH) afforded 90 mg (0.17 mmol; 49percent) of the free base of the title compound as a solid. The product was taken up in 2 mL of H2O and was treated with 1 mL of 1 N aq HCl. The solution was lyophilized to give the title compound. 1H NMR (CDCl3; free base) delta 9.23 (s, 1H), 7.89-7.03 (m, 1H), 5 7.78-7.70 (m, 3H), 7.59-7.46 (m, 4H), 7.35-7.26 (m, 2H), 7.06 (d, J=8.5 Hz, 2H), 6.76 (d, 8.6 Hz, 2H), 4.23 (s, 2H), 4.08 (t, J=5.6 Hz, 2H), 2.94 (t, J=5.6 Hz, 2H), 2.74-2.63 (m, 4H), 1.91-1.80 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
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With N-ethyl-N,N-diisopropylamine; In water; | EXAMPLE 1 4-(3-Cyclopentyloxy-4-methoxybenzyl)-1-(imidazol-4-ylcarbonyl)piperidine A solution containing 2.1 g of 4-(3-cyclopentyloxy-4-methoxybenzyl)piperidine, 2.6 g of 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), 1.1 g of N-hydroxybenzotriazole (HOBT), 1.6 ml of diisopropylethylamine and 1.0 g of 4-imidazole-carboxylic acid is stirred, under an argon atmosphere, at room temperature for 16 hours. The reaction mixture is stirred for a few minutes with a saturated sodium carbonate solution. The organic phase is then taken up in water and subsequently dried over magnesium sulphate and concentrated. The residual oil is purified by flash chromatography using a CH2 Cl2 /ammoniacal CH3 OH mixture (95:5) as elution system. 4-(3-Cyclopentyloxy-4-methoxybenzyl)-1-(imidazol-4-ylcarbonyl)piperidine taken up in ethanolic hydrogen chloride crystallises in the form of the hydrochloride, which melts at 204-207° C. |
Yield | Reaction Conditions | Operation in experiment |
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With lithium hydroxide; In methanol; | lH-<strong>[1072-84-0]Imidazole-4-carboxylic acid</strong> (200 mg, 1.8 mmol) and lithium hydroxide (45 mg, 1.9 mmol) were dissolved in methanol (10 ml) to give a clear solution. Volatile components were removed under reduced pressure and the residue co-evaporated with toluene until a free flowing powder was obtained. To the lithium salt was added dry DMF (10 ml), Ligand 1 (250 mg, 0.95 mmol) and Pybop (510 mg, 0.98 mmol). The mixture was warmed until a clear orange solution was obtained. Heat was then removed and the solution stirred for 16 hours. The solvent was removed by rotary evaporation to leave a viscous orange residue which was purified by chromatography on silica gel eluting with CH3CN/MeOH (95:5). The title compound (100 mg, 29percent) was isolated (rf = 0.3) as a white powder m p > 250 0C.1H NMR (d6 DMSO):- delta H 5.76 (IH, s, NH imid), 7.23 - 7.28 (3H, m, 5-H [x3], 7.44 - 7.47 (3H, m, 3-H [x3], 7.53 (IH, s, C-H, imid), 7.72 (3H, bt, J = 7 Hz, 4-H [x3], 7,82 (IH, s, C-H imid), 8.50 (3H, m, 6-H [x3],), 10.46 (IH, s, NH).Mass Spec (ES) m/e :- Calculated for C20H17N6O (M+H) 357 Found 357.Ligand 7 was prepared in an analogous manner from 4-pyridylacetic acid hydrochloride giving a colourless powder (Yield 40 mg, 11 percent), m pt 134 - 135 0C. 1H NMR (CDCl3) : deltaH 3.70 (2H,s, CH2), 7.13 (3H, m, 5-H [x3], 7.26 (2H,d, J =5.0 3-H, 5-H), 7.43 (3H,d, J = 6 Hz 3-H [x3], 7.57 (3H,t, J = 6 Hz 4-H [x3],8.47 (3H, d, J = 5 Hz, 6-H [x 3], 8.53 (2H, d, J = 5.0 Hz, 2-H, 6-H), 9.49 (IH, bs,NH).Mass Spec (ES) m/e :- Calculated for C23H20N5O (M+H) 382 Found 382 Ligand 8 was prepared in an analogous manner from 3-Pyridyl acetic acid hydrochloride giving a fawn coloured powder (180 mg, 54 percent), m p 165 - 166 °C.1H NMR (CDCl3): deltaH 3.68 (2H,s, CH2) 7.08 (3H, ddd, J = 7.5, 5.0 and 1.0 Hz, 5-H [x3], 7.19 (IH dd, J = 7.5 and 5.0 Hz 5'-H), 7.43 (3H, m, 3-H [x3]), 7.53 (3H, dt, J = 7.5 and 5.0 4-H [x3], 7.64 (IH, bd , J = 7.5 Hz 4'-H), 8.43 (3H, m, 6-H [x3], 8.46 (IH, dd, J = 7.5 and 1.5 Hz, 6'-H), 8.56 (IH, d, J = 1.5 Hz, 2'-H), 9.49(IH, s, NH).Mass Spec (ES) m/e :- Calculated for C23H20N5O (M+H) 382 Found 382. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol; | 1 Methyl (1H-imidazol-4-yl) carboxylate 112.09 g (1 mol) (1H-imidazol-4-yl)carboxylic acid are added to 1.3 l methanol. Dry HCl-gas is bubbled through the mixture which is heated under reflux for 4 hours. Cooling to room temperature and evaporation to 300 ml afford 98 g of the title compound as white crystals. Repeated evaporation leads to 46.5 g additional material (total: 144.5 g, 88.9percent). An analytical sample is recrystallized from methanol, melting point: 173°-174° C. (ref.1) mp: 156° C.). C5 H6 N2 O2.HCl (162.6) Calc.: C 36.94; H 4.34; N 17.23; Found: C 36.93; H 4.44; N 17.23. MS: m/z (rel.int. [percent])=126 (M+, 63), 95 (100), 67 (41), 40 (68). 1 H-NMR data: ([D6]DMSO, TMS as internal standard) delta=12.97 (br) 2H, replaceable by D2 O, 9.29 (d) 1H, 8.37 (d) 1H, 3.90 (s) 3H, ppm. | |
With sulfuric acid; In methanol; | a) Methyl 1H-imidazole-4-carboxylate 1H-<strong>[1072-84-0]Imidazole-4-carboxylic acid</strong> (5 g, 44.6 mmol) was dissolved in MeOH (100 ml). Into the solution, H2SO4 (10 ml) was added at 0° C. The resulting mixture was stirred at 80° C. for overnight. The solvent was concentrated under reduced pressure. The pH was adjusted to 9 with aqueous NaHCO3 solution and extracted with EtOAc. The organic layer was concentrated to give the product. Yield 5.2 g. 1H-NMR (400 MHz; DMSO-d6): delta 3.74 (s, 3H), 7.79 (bs, 2H), 12.75 (bs, 1H). LC-MS: [M+1]=127.23. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In hexane; water; ethyl acetate; N,N-dimethyl-formamide; | PREPARATION 9 N-(Diphenylmethyl)-1H-imidazole-4-carboxamide A mixture of 11.7 g of 4-imidazolecarboxylic acid, 18.7 g of 1,1'-carbonyldiidmidazole, 20 ml of diisopropylethylamine and 600 ml of DMF was heated at 35° C. for approximately 18 hours. Twenty milliters of aminodiphenylmethane were added and the solution stirred at 35° C. for approximately 21/2 days. The mixture was concentrated in vacuo and the residue added to 400 ml of water. The mixture was extracted with ethyl acetate and the organic layer was washed with a saturated sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. Two crystallizations from hot ethyl acetate/hexane provided 11 grams of the desired titled intermediate, m.p. 201°-202° C. Analysis for C17 H15 N3 O: Calc.: C, 73.63; H, 5.45; N, 15.15; Found: C, 73.90; H, 5.58; N, 15.12. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With CO2; potassium carbonate; | EXAMPLE 9 544 g (8 moles) of imidazole, 1,380 g (10 moles) of potassium carbonate and 1,000 ml of liquid CO2 were reacted for 2.5 hours under 120 bar and at 219° C. in an autoclave. The end product was precipitated by acidifying the mixture to pH 3 and slowly heating it to 100° C. in the course of 1 hour. The product was dried to give 606 g (67.6percent of theory) of imidazole-4-carboxylic acid, which melted at 220° C. with decomposition (evolution of CO2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonium hydroxide; triethylamine; In methanol; ethyl acetate; N,N-dimethyl-formamide; | EXAMPLES 15-16 Ethyl chloroformate (0.07 ml.) was added to a mixture of <strong>[1072-84-0]imidazole-4-carboxylic acid</strong> (0.08 g.) and triethylamine (1 min.) in DMF (5 ml.) at -5°. The mixture was stirred at room temperature for 0.5 hours and then treated with a solution of 4-[2-(2,2,2-trifluoroethyl)guanidino]-2-(4-aminobutyl)pyrimidine (0.2 g.) in DMF (2 ml.). The mixture was stirred at room temperature for 4 hours, then evaporated to dryness. The residual gum was partitioned between EtOAc and 2 N aqueous HCl and the acid layer was then basified with 11 N aqueous sodium hydroxide and extracted with EtOAc. The organic layer was dried (MgSO4) and evaporated to dryness. The residual gum was purified by preparative thin layer chromatography on Merck 60 F-254 plates using EtOAc/MeOH/aqueous ammonia (s.g. 0.88) 6:1:1 v/v/v as developing solvent. Two products were obtained by extracting appropriate bands of the chromatogram using MeOH/aqueous ammonia (s.g. 0.88) 10:1 v/v and evaporating to dryness. Both residual gums were dissolved in EtOAc and treated with excess of a solution of maleic acid in EtOAc. The resulting solids were filtered to give the separate products. The more polar band gave N-[4-(4-[2-(2,2,2-trifluoroethyl)guanidino]pyrimid-2-yl)butyl]imidazol-4- ylcarboxamide bis maleate (0.02 g.), m.p. 155°-159° (decomp.). The less polar band gave ethyl N-[4-(4-[2-(2,2,2-trifluoroethyl)guanidino]pyrimid-2-yl)butyl]-carbamate hydrogen maleate monohydrate (0.06 g.), m.p. 152°-156°. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In sulfuric acid; | EXAMPLE 2 A solution of 4-imidazolecarboxylic acid (0.56 g) in 25percent v/v sulphuric acid (25 cc) was placed in the cathodic compartment of a vessel as described in example 1, and 25percent v/v sulphuric acid was placed in the anodic compartment. The mixture was electrolysed for 31/2 hours under conditions similar to those described in Example 1. The solution from the cathodic compartment was neutralised with potassium carbonate (18.5 g) and the mixture was evaporated to dryness. The solid residue was extracted with hot isopropanol (200 cc) and the extract was evaporated to an oil which was crystallized from ether to give 4-(hydroxymethyl)imidazole (0.42 g) m.p. 66°-80°. The picrate derivative of this material was recrystallized from water and had m.p. 205.5°. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of 3-4 (0.2g, 0.5mmol), lH-<strong>[1072-84-0]imidazole-4-carboxylic acid</strong> (0.06g, 0.5mmol), HOBT (0.06g, 0.5mmol), and DffiA (0.2ml, 1.4mmol) in DMF (2ml) was added EDC (O.lg, O.betammol). The solution was stirred at room temperature for 45min and was then heated at 8O0C in the microwave for 15min. The solvent was removed in vacuo. The residue was taken up in DMF (0.5ml) and was treated with glacial AcOH (2.0ml). The reaction mixture was heated at 800C for 45min. The reaction was then quenched with water (10ml) and extracted into EtOAc (3x20ml). The combined organic layers were concentrated in vacuo to give 22-1 as a brown residue. MS calculated M+H: 461.5, found 461.2 |
Tags: 1H-Imidazole-4-carboxylic acid | 4-Imidazolecarboxylic acid | Imidazoles | Carboxylic Acids | Imidazole | Organic Building Blocks | Heterocyclic Building Blocks | Structure | 1072-84-0
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