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CAS No. : | 822-36-6 | MDL No. : | MFCD00005201 |
Formula : | C4H6N2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | XLSZMDLNRCVEIJ-UHFFFAOYSA-N |
M.W : | 82.10 | Pubchem ID : | 13195 |
Synonyms : |
|
Num. heavy atoms : | 6 |
Num. arom. heavy atoms : | 5 |
Fraction Csp3 : | 0.25 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 23.55 |
TPSA : | 28.68 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.47 cm/s |
Log Po/w (iLOGP) : | 0.77 |
Log Po/w (XLOGP3) : | 0.46 |
Log Po/w (WLOGP) : | 0.72 |
Log Po/w (MLOGP) : | -0.47 |
Log Po/w (SILICOS-IT) : | 1.56 |
Consensus Log Po/w : | 0.61 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.26 |
Solubility : | 4.56 mg/ml ; 0.0555 mol/l |
Class : | Very soluble |
Log S (Ali) : | -0.63 |
Solubility : | 19.2 mg/ml ; 0.234 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -1.51 |
Solubility : | 2.55 mg/ml ; 0.0311 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.0 |
Signal Word: | Danger | Class: | 8 |
Precautionary Statements: | P501-P260-P270-P202-P201-P264-P280-P308+P313-P303+P361+P353-P301+P330+P331-P363-P301+P312+P330-P304+P340+P310-P305+P351+P338+P310-P405 | UN#: | 3263 |
Hazard Statements: | H302-H314-H351 | Packing Group: | Ⅲ |
GHS Pictogram: |
* 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 |
---|---|---|
99% | With N-Bromosuccinimide In tetrahydrofuran at 20℃; for 1 h; | [0229] To a solution of 3-1 (3.4 g, 40 mmol) in THF (50 mL) at r.t. was added NBS ( 14 g, 80 mmol). The mixture was stirred for 1 h. The solvent were removed under reduced pressure. Purification by column chromatography on silica gel (PE:EA=2: 1 ) provided 3-2 as white solid (9.6 g, 99percent). +E SI-MS: m/z 239.0 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With trans-N,N'-dimethyl-1,2-cyclohexyldiamine; potassium phosphate; copper(l) iodide In 1,4-dioxane at 115℃; for 72 h; Molecular sieve | Coupling reaction: A reaction flask was charged with 3-bromo-5-trifluoromethylbenzoic acid (compound 2, 2.7 g, 0.01 mol), 4-methyl-1H- imidazole (1.64 g, 1), trans- N, N'-dimethylcyclohexanediamine (0.28 g, 0.002 mol), 1,4-dioxane (10 vol./g), anhydrous potassium phosphate , 0.03mol) and 4A molecular sieves (0. lg / g), to form a mixed system; the mixed system is purged with nitrogen to have an oxygen content of 500ppm, finally adding cuprous iodide (0.38g, 0.002mol) The system was heated to 115 ° C, the reaction was stirred for 72 hours, TLC showed compound 2 disappeared to give the product system; and then the system was cooled to room temperature, transferred to 2M hydrochloric acid quenched, concentrated filtered without fraction To be purified solution. Adding n-butanol, extracting and separating the organic phase, extracting with n-butanol twice, and combining the organic phases; concentrating the organic phase to remove n-butanol to obtain 3- (4-methyl- -5- (trifluoromethyl) benzoic acid (Compound 3) crude. Recrystallization from methanol (4: 1 ./g) gave 1.76 g of a khaki-colored solid in 65percent yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15% | With caesium carbonate In N,N-dimethyl-formamide at 100℃; for 1 h; Inert atmosphere | 4-Fluoro-3-methoxybenzaldehyde (85 g, 0.55 mol), 4-methyl-1 /-/-imidazole (90.5 g,1.1 mol) and cesium carbonate (268.8 g, 0.82 mol) were combined in dimethylformamide (1.7 L) and stirred at 100 0C for 1 hour. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated in vacuo. The residue was dissolved in water (2 L) and extracted with ethyl acetate (3 x 2 L). The combined organic layers were washed with water and brine, dried over sodium sulfate, and concentrated under reduced pressure. Chromatography on silica (Eluant: 2:1 petroleum ether: ethyl acetate) afforded a yellow solid, which was recrystallized from ethyl acetate (300 mL) to provide the title compound as a white solid. Yield: 17.8 g, 0.082 mol, 15percent. 1H NMR (300 MHz, CDCI3) δ 2.31 (d, J=1.0 Hz, 3H), 3.97 (s, 3H), 7.01 (m, 1H), 7.45 (d, J=7.8 Hz, 1 H), 7.54-7.58 (m, 2H), 7.83 (d, J=1.3 Hz, 1 H), 10.01 (s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 96 h; Inert atmosphere | 4-Methylimidazole (249 mg, 3.03 mmol), 4-fluoro-3-methoxybenzonitrile (417 mg, 2.76 mmol), and cesium carbonate (1.89 g, 5.80 mmol) were placed in a reaction vessel in a nitrogen gas atmosphere, N,N-dimethylformamide (5.0 mL) was added to the vessel and the resultant mixture was stirred at room temperature for 96 hours. To the reaction mixture were successively added water (2 mL) and ethyl acetate (6 mL) to perform an extraction, and the aqueous layer was separated and then, the organic layer was washed with water (5 mL). To the organic layer were added ethyl acetate (5 mL) and water (5 mL) to perform an extraction, and the aqueous layer was separated and then, the organic layer was washed with water (5 mL) and concentrated under a reduced pressure to obtain 499 mg of a crude product. To the crude product was added tert-butyl methyl ether (2.5 mL) to obtain a suspension, and the solids collected by filtration of the suspension were washed with tert-butyl methyl ether/heptane (2.5 ml; 1 :3) three times to obtain 431 mg of a crude product. To the obtained crude product was added tert-butyl methyl ether (4.3 mL) in a nitrogen gas atmosphere, and the resultant mixture was stirred at 50°C for 30 minutes and then naturally cooled to room temperature, and the solids collected by filtration were washed with tert-butyl methyl ether/heptane (2.1 mL; 1 :3) twice and dried under a reduced pressure to obtain 310 mg of a title compound. Yield: 53percent. |
49.9% | With potassium carbonate In dimethyl sulfoxide at 120℃; for 1 h; | Example Al a) Preparation of intermediate 1. K2CO3 (112 g, 0.81 mol) was added to a stirred sol. of 4-methylimidazole (66.0 g, 0.804 mol) in DMSO (600 ml). The r.m. was heated at 120 0C. Subsequently 4-fluoro- 3-methoxybenzonitrile (60.0 g, 0.397 mol) was added portionwise (internal reaction temperature increased to 140 0C). The r.m. was maintained at 120 0C for 1 h, was cooled, and was then poured onto ice-water (3 1). This mixture was stirred for 30 min. The precipitated solid was collected by filtration and washed with H2O. The off-white solid was recrystallised from MeCN to yield 30.0 g of intermediate 1. A second crop of product was obtained from the mother liquor. Yield: 12.3 g of intermediate 1(combined yield; 49.9 percent). |
39% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 135 - 140 h; Inert atmosphere | 4-Fluoro-3-methoxybenzonitrile (98.2 g, 0.65 mol) was combined with 4-methyl-1 /-/- imidazole (53.4 g, 0.65 mol) and anhydrous potassium carbonate (138.2 g, 1 mol, 1.54 eq) in dimethylformamide (650 ml_), and the reaction mixture was stirred for 16 hours at 135-140 0C (internal temperature). The mixture was cooled to room temperature and filtered; the salts were washed with dichloromethane (3 x 30 ml_). The combined filtrates were evaporated in vacuo to afford a brown semisolid, which was suspended in water (500 ml_) and left to stand at 5 0C for 24 hours. The mixture was filtered, and the solid was washed with ice water (2 x 50 ml_), then dried in vacuo to afford a yellow solid (105.5 g). Crystallization from methanol (106 ml_) provided purified product (66.3 g) as yellowish crystals. These were boiled with acetone (100 ml_) for 5 minutes and the mixture was left to cool overnight. The mixture was filtered, and the crystals were washed with acetone (2 x 10 ml_) to afford the title compound as a white solid. Yield: 54.6 g, 0.256 mmol, 39percent. 1H NMR (400 MHz, CDCI3) δ 2.31 (d, J=1.0 Hz, 3H), 3.94 (s, 3H), 6.97 (m, 1 H), 7.30 (m, 1 H), 7.37 (m, 2H), 7.79 (d, J=1.4 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid; nitric acid; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; | A. 4-Methylimidazole (10 g, 0.12 moles), was cooled in a flask, and fuming nitric acid (11 ml, 0.24 moles) was added dropwise. This was followed by the addition of sulfuric acid (11 ml). The reaction was then heated with stirring at 100 C. for 21/2 hours. The cooled reaction mixture was then added to 500 ml of ice water, and the precipitate was filtered off. The filtrate was neutralized with ammonium hydroxide, and filtered again. The combined precipitates were then recrystallized from water to give 6.35 g of 4-methyl-5-nitroimidazole. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.18% | With copper(l) iodide; (+)-D-glucosamine hydrochloride; caesium carbonate; In water; dimethyl sulfoxide; at 90℃; for 12h; | In a reaction vessel, 24 g (0.1 mol) of 3-bromo-5-trifluoromethylaniline,8.2 g (0.1 mol) of 4-methylimidazole,58.7 g (0.18 mol) Cs2CO3,0.95 g (0.005 mol) CuI, 1.1 g (0.005 mol) D-glucosamine hydrochloride,Then 60 mL DMSO and 80 mL water were added,Stirring to dissolve, the reaction temperature was controlled at 90 ,The reaction was continued for 12 hours. After the reaction was completed, 120 mL of ethyl acetate was added,After centrifugation to take the supernatant,Concentration and drying gave 3- (4-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) aniline.The HPLC purity was 98.66% and the yield was 96.18% |
91% | With copper(l) iodide; 1-(5,6,7,8-tetrahydroquinolin-8-yl)ethan-1-one; caesium carbonate; In N,N-dimethyl-formamide; at 110℃; for 18h;Inert atmosphere; Sealed tube; | In a pressure tube with one end sealed, add 190mg CuI (1mmol), 1.64g 4-methyl-1H-imidazole (20mmol), 3.25g Cs2CO3(10mmol), and after Nitrogen replacement, add 2.40g 3-bromo-5-(trifluoromethyl)aniline (10 mmol), 350mg 1-(5,6,7,8-tetrahydroquinolin-8-yl)ethanone (2mmol) and 30mL DMF was added into a flask. The mixture was stirred at 110C for 18 h under sealing. After cooling to room temperature, the solvent was removed under vacuum and the residue was purified by column chromatography to afford 2.19 g desired product (91 %).; 1H NMR (400 MHz, d-DMSO), delta 8.06 (s, 1H), 7.35 (s, 1 H), 6.97 (s, 1 H), 6.93 (s, 1 H), 6.81 (s, 1H), 5.87 (br, 2H), 2.15 (s, 3H). MS (ESI), m/z: 242 (M+ + H+). |
91% | With copper(l) iodide; 1-(5,6,7,8-tetrahydroquinolin-8-yl)ethan-1-one; caesium carbonate; In N,N-dimethyl-formamide; at 110℃; for 18h;Sealed tube; Inert atmosphere; | In a pressure tube with one end sealed, add 190 mg CuI (1 mmol), 1.64 g 4-methyl-1H-imidazole (20 mmol), 3.25 g Cs2CO3 (10 mmol), and after Nitrogen replacement, add 2.40 g 3-bromo-5-(trifluoromethyl)aniline (10 mmol), 350 mg 1-(5,6,7,8-tetrahydroquinolin-8-yl)ethanone (2 mmol) and 30 mL DMF was added into a flask. The mixture was stirred at 110 C. for 18 h under sealing. After cooling to room temperature, the solvent was removed under vacuum and the residue was purified by column chromatography to afford 2.19 g desired product (91%). 1H NMR (400 MHz, d-DMSO), delta 8.06 (s, 1H), 7.35 (s, 1H), 6.97 (s, 1H), 6.93 (s, 1H), 6.81 (s, 1H), 5.87 (br, 2H), 2.15 (s, 3H). MS (ESI), m/z: 242 (M++H+). |
77.3% | With copper(l) iodide; 8-quinolinol; In dimethyl sulfoxide; at 120℃;Inert atmosphere; | To the solution of Bromo-5-trifluoromethyl-phenylamine (500 mg, 2.1 mmol, 1.0 eq), 4-methyl-1H-imidazole (20.5 mg, 2.5 mmol, 1.2 eq), cuprous iodide (0.14 eq) and 8-hydroxyquinoline (44 mg, 0.3 mmol, 0.14 eq) in 3 mL dimethylsulfoxide was purged with nitrogen 3 times and the solution was heated to 120 C., the mixture was diluted with water after completion of the reaction. Then the organic layer was washed successively with dilute aqueous ammonia solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was isolated by column chromatography to give the title product as a yellow solid (392 mg, 77.3% yield). 1H NMR (400 MHz, CDCl3) delta7.73 (s, 1H), 6.98 (s, 1H), 6.92 (s, 1H), 6.83 (s, 1H), 6.77 (s, 1H), 4.14 (s, 2H), 2.27 (s, 3H). MS m/z (ESI): 242.1 [M+H]. |
71% | With copper(l) iodide; 1-(5,6,7,8-tetrahydroquinolin-8-yl)ethan-1-one; caesium carbonate; In N,N-dimethyl-formamide; at 130℃; for 24h;Inert atmosphere; | General procedure: A mixture of CuI (190mg, 1mmol), 4-methyl-1H-imidazole (1.64g, 20mmol), Cs2CO3(3.25g, 10mmol), 3-bromo-5-(trifluoromethyl)aniline (2.40g, 10 mmol), 1-(5,6,7,8-tetrahydroquinolin-8-yl)ethanone (350mg, 2mmol) and DMF (30mL) was added to a bottom, the bottom was evacuated and backfilled with argon (this procedure was repeated three times), then the mixture was heated to 130 C for 24 h under argon. After cooling to room temperature, the solvent was removed under vacuum and the residue was purified by column chromatography on silica gel to afford the crude product. The crude product was recrystallized as a white solid (1.7 g, 71%) |
71% | With copper(l) iodide; 1-(5,6,7,8-tetrahydroquinolin-8-yl)ethan-1-one; caesium carbonate; In N,N-dimethyl-formamide; at 130℃; for 24h;Inert atmosphere; | CuI (190 mg, 1 mmol), 4-methyl-1H-imidazole (1.64 g, 20 mmol), Cs2CO3 (3.25 g, 10 mmol), 3-bromo-5- (trifluoromethyl) aniline 2.40 g, 10 mmol), 1- (5,6,7,8-tetrahydroquinoline-8-substituted) ethanone (350 mg, 2 mmol) was dissolved in DMF (30 mL), protected with argon, heated to 130 C., and reacted for 24 hours.After the reaction was completed, it was cooled to room temperature, spin-dried, and separated by silica gel column chromatography. The white solid obtained by recrystallization was the target product (1.7 g, yield: 71%) |
70% | With copper(l) iodide; 8-quinolinol; In dimethyl sulfoxide; at 120℃; for 24h;Inert atmosphere; | 3-bromo-5-trifluoromethylaniline (48 g, 0.2 mol) was added to a three-necked flask equipped with argon,4-methylimidazole (19.7 g, 0.24 mol), cuprous iodide (5.7 g, 0.03 mol)8-hydroxyquinoline (4.4 g, 0.03 mol)(30g, 0.22mol) and 300ml of DMSO, stirred and heated to 120 C for 24 h, followed by TLC. After the reaction was completed, the mixture was cooled to 50 C. 200 ml of 14% aqueous ammonia was added and stirring was continued for 1 h. Water and ethyl acetate were extracted three times. The organic phases were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and the solvent was removed by rotary distillation.Then, the solvent was cooled in a refrigerator, and the precipitated crystals were filtered and dried to obtain 33.7 g of pale green needle-like crystals in a yield of 70%. |
67% | With copper(l) iodide; copper; potassium carbonate; In N,N-dimethyl acetamide; at 140℃; for 48h; | 3-Bromo-5-(trifluoromethyl)aniline (0.2 mL, 1.43 mmol) was stirred in a solvent of dimethylacetamide (10 mL). The reaction solution was added with 4-methyl-1H-imidazole (0.35 g, 4.26 mmol), K2CO3 (0.20 g, 5.23 mmol), Cu (0.022 g, 0.346 mmol) and CuI (0.068 g, 0.115 mmol), and stirred for about 2 days at 140C. The reaction mixture was diluted with ethyl acetate, and washed with a saturated aqueous sodium bicarbonate solution and saline. The organic layer thus obtained was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (0.23 g, 67%). 1H-NMR Spectrum (300 MHz, DMSO-d6): delta 8.06 (s, 1H), 7.36 (s, 1H), 6.96 (s, 1H), 6.92 (s, 1H), 6.80 (s, 1H), 5.86 (s, 2H), 2.14 (s, 3H). MS (ESI+, m/z): 242 [M+H]+ |
67% | With copper(l) iodide; copper; potassium carbonate; In N,N-dimethyl acetamide; at 140℃; for 48h; | 3-Bromo-5-(trifluoromethyl)aniline (0.2 mL, 1.43 mmol) was stirred in a solvent of dimethylacetamide (10 mL). The reaction solution was added with 4-methyl-1H-imidazole (0.35 g, 4.26 mmol), K2CO3 (0.20 g, 5.23 mmol), Cu (0.022 g, 0.346 mmol) and CuI (0.068 g, 0.115 mmol), and stirred for about 2 days at 140 C. The reaction mixture was diluted with ethyl acetate, and washed with a saturated aqueous sodium bicarbonate solution and saline. The organic layer thus obtained was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (0.23 g, 67%). 1H-NMR Spectrum (300 MHz, DMSO-d6): delta 8.06 (s, 1H), 7.36 (s, 1H), 6.96 (s, 1H), 6.92 (s, 1H), 6.80 (s, 1H), 5.86 (s, 2H), 2.14 (s, 3H). MS (ESI+, m/z): 242 [M+H]+ |
59.1% | With copper(l) iodide; 8-quinolinol; ammonia; potassium carbonate; In water; dimethyl sulfoxide; at 50 - 120℃; for 16h;Sealed tube; Inert atmosphere; | Step 1. 3-(4-Methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline A suspension of 3-bromo-5-(trifluoromethyl)aniline (4.8 g, 20 mmol), 4-methylimidazole (1.97 g, 24 mmol), K2CO3 (3.04 g, 22 mmol), CuI (0.57 g, 3 mmol) and 8-hydroxyquinoline (0.44 g, 3 mmol) in 20 mL DMSO was stirred at 120 C. in a sealed tube under Ar2 for 16 hrs. The mixture was cooled down to 50 C. and 28% aq ammonia (10 mL) was added. The mixture was maintained at this temperature for 1 h. After cooling to rt, H2O and EtOAc were added. The aqueous layer was extracted with EtOAc (60 mL*3) and the organic layer was washed with brine, dried with Na2SO4, after filtration, the filtrate was concentrated under reduced pressure and purified by chromatography on silica gel (CH2Cl2/CH3OH 97:3) to give 2.85 g product as pale yellow solid (59.1%). 1H NMR (300 MHz, CDCl3) delta: 7.76 (1H, s), 7.01 (1H, s), 6.94 (1H, s), 6.84 (1H, s), 6.78 (1H, s), 4.11 (2H, brs), 2.29 (3H, s). LCMS: m/z [M+H]+ 242.0966. |
58% | With 8-quinolinol; potassium carbonate; In dimethyl sulfoxide; at 120℃;Inert atmosphere; | A suspension of 1(3.0 g, 36 mmol), 2 (4.8 g, 20 mmol), K2C03 (4.5 g, 33 mmol), Cul (1.14 g, 6 mmol) and 8-hydroxyquinoline (0.56 g, 4 mmol) in DMSO (20 mL) was heated at 120 C overnight under nitrogen. After cooling, water was added and the mixture was extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by silica gelcolumn chromatography to give 3 (2.8 g, 58%) as a yellow solid. LCMS (m/z: m+1):242.2. |
47.5% | With copper(l) iodide; 8-quinolinol; sodium hydroxide; calcium oxide; In dimethyl sulfoxide; at 120℃; for 69h;Inert atmosphere; | Example 1; Preparation of 3-(trifluoromethyl)-5-(4-methyl-1H-imidazole-1-yl)-benzeneamine of formula I2000 g of 3-bromo-5-trifluoromethylaniline of formula II, 1368 g of 4-methylimidazole of formula III, 181 g of 8-hydroxyquinoline, 238 g of CuI, 666.6 g of NaOH, 933 g of CaO and 7000 ml of DMSO were loaded into a 10 L of 3-neck flask. The reaction mixture was protected with nitrogen and was then stirred at 120 C. for 69 hours while monitoring for the consumption of 3-bromo-5-trifluoromethyaniline by HPLC. Heating was stopped when 3-bromo-5- trifluoromethyaniline/4-methylimidazole is not more than 5%. The reaction mixture was cooled down to 45-50 C. and poured into a 50 L reactor. 8.4 L of 14% ammonia was added dropwise and then stirred for 1 hour at 45-50 C. The mixture was cooled down to room temperature. 16.8 L of water and 10 L of ethyl acetate were added to the extract. The upper organic layer was separated and filtered through the filter aid. The lower aqueous layer was washed with 7.5L of ethyl acetate and combined with the above filtrate. The combined organic layer was washed with 5 L×3 of 5% of brine for three times. The upper organic layer was separated and dried over 1 kg of anhydrous Na2SO4 overnight. The mixture was filtered and concentrated to obtain 2.3 kg of solid. The residue was dissolved in 2 L of ethyl acetate at 45 C. To the solution was then added 8 L of petroleum ether dropwise at 45 C. The mixture was cooled down slowly to 0-15 C. and stirred for 1 hour. A large amount of precipitate was formed and filtered. The filtered cake was dissolved in 2 L of ethyl acetate at 45 C. The solution was then added 8 L of petroleum ether dropwise at 45 C. The mixture was cooled down slowly to 15-0 C. and stirred for 1 hour. A large precipitate was formed and filtered. The filter cake was dried at 45 C. and 954 g of 3-(trifluoromethyl)-5-(4-methyl-1H-imidazole-1-yl)-benzeneamine of formula I were obtained. (Yield: 47.5%). The obtained compound of formula I had purity of 99.7% on area by HPLC and contained 0.13% on area by HPLC, of the 5 methyl isomer impurity. |
47.5% | Example 1: Preparation of 3-(trifluoromethyl)-5-(4-methyl-1H-imidazole-1-yl)-benzeneamine of formula I 2000g of 3-bromo-5- trifluoromethylaniline of formula II, 1368g of 4-methylimidazole of formula III , 181 g of 8-hydroxyquinoline, 238g of CuI, 666.6g of NaOH, 933g of CaO and 7000ml of DMSO were loaded into a lOL of 3-neck flask. The reaction mixture was protected with nitrogen and was then stirred at 120C for 69 hours while monitoring for the consumption of 3-bromo-5- trifluoromethyaniline by HPLC. Heating was stopped when 3-bromo-5- trifluoromethyaniline / 4-methylimidazole is not more than 5%. The reaction mixture was cooled down to 45-50C and poured into a 50L reactor. 8.4L of 14% ammonia was added dropwise and then stirred for 1hour at 45-50C. The mixture was cooled down to room temperature.16.8L of water and 10L of ethyl acetate were added to the extract. The upper organic layer was separated and filtered through the filter aid. The lower aqueous layer was washed with 7.5L of ethyl acetate and combined with the above filtrate. The combined organic layer was washed with 5Lx3 of 5% of brine for three times. The upper organic layer was separated and dried over 1kg of anhydrous Na2S04 overnight. The mixture was filtered and concentrated to obtain 2.3kg of solid. The residue was dissolved in 2L of ethyl acetate at 45C. To the solution was then added 8L of petroleum ether dropwise at 45C. The mixture was cooled down slowly to 0-15C and stirred for 1hour. A large amount of precipitate was formed and filtered. The filtered cake was dissolved in 2L of ethyl acetate at 45C. The solution was then added 8L of petroleum ether dropwise at 45C. The mixture was cooled down slowly to 15-0C and stirred for 1hour. A large precipitate was formed and filtered. The filter cake was dried at 45C and 954g of 3-(trifluoromethyl)-5-(4-methyl-1H-imidazole-l-yl)-benzeneamine of formula I were obtained. (Yield: 47.5%). The obtained compound of formula I had purity of 99.7% on area by HPLC and contained 0.13% on area by HPLC, of the 5 methyl isomer impurity. | |
With copper; potassium carbonate; copper(II) iodide; In ISOPROPYLAMIDE; at 140 - 150℃; for 16h; | Preparation 30; [229] Preparation of 3-(4-methyl-imidazol- 1 - yl)-5-trifluoromethyl-phenylamine; [230] 3-amino-5-bromo-benzotrifluoride (17.1g,71.24mmol), 4-methylimidazole (17.6g,213.72mmol), potassium carbonate (9.8g, 71.24mmol), cupper (1. Ig, 17.81mmol), and cupper iode (II) (3.4g, 17.81mmol) were added to N,N-dimethylacetamide (100ml) at room temperature, and mixed therewith at 140~150C for 16 hr. After the reaction was completed, the temperature of the reaction vessel was cooled to RT. Then, ethyl acetate (200ml) was added thereto and mixed therewith for 30 min. The reaction mixture was filtered with Celite, and an organic layer of the filtered solution was washed with water, dried with magnesium sulfate, distilled under vacuum, and washed with n- hexane to give the titled compound as pale white solid.[231] 1H-NMR (CDCl3 delta)= 2.28 (s,3H), 4.04 (br,2H), 6.79 (s,lH), 6.83 (s,lH), 6.92(s,lH), 7.00 (s,lH), 7.77 (s.lH) | |
With potassium carbonate;copper(l) iodide; 8-quinolinol; In dimethyl sulfoxide; at 120℃; for 15h; | B) 3-(4-Methyl-1W-imidazol-1-yl)-5-(trifluoromethyl)benzenamine; A suspension of 3-bromo-5-(trifluoromethyl)aniline (4.80 g, 20 mmol), 4-methylimidazole (1.97 g, 24 mmol), potassium carbonate (3.04 g, 22 mmol), CuI (0.57 g, 3 mmol), and 8-hydroxyquinoline(0.44 g, 3 mmol,) in dry DMSO (20 mL) in a pressure tube was degassed by bubbling N2 into the suspension for 10 minutes while stirring. The tube was sealed tightly. The mixture was heated at 120 0C (oil bath temperature) for 15 h. The mixture was cooled down to 45- 50 0C and 14% aq. NH4OH (20 mL) was added. The mixture was maintained at this temperature for 1 h. After cooling to rt, water and ethyl acetate were added. The aqueous layer was extracted with ethyl acetate and the combined organic layers were passed through a short silica gel column to remove most of green/biue Cu salt. The filtrate was dried over sodium sulfate and concentrated on a rotavap. The crude product was EPO <DP n="39"/>recrystallized from EtOAc/hexanes, giving pure pale yellow needles. The mother liquor was concentrated and the residue was purified on silica gel column (5% methanol/methylene chloride), yielding a second crop as pale yellow needles. | |
A suspension of 3- bromo-5-(trifiuoromethyl)aniline (4.8 g, 20 mmol), 4-methylimidazole (1.97 g, 24 mmol), potassium carbonate (3.04 g, 22 mmol), CuI (0.57 g, 3 mmol), and 8-hydroxyquinoline (0.44 g, 3 mmol,) in dry DMSO (20 mL) in a pressure tube was degassed by bubbling N2 into the suspension for 10 minutes while stirring. The tube was sealed tightly. The mixture was heated at 120 0C (oil bath temperature) for 15 h. The mixture was cooled down to 45- 50 0C and 14% aq. NH4OH (20 mL) was added. The mixture was maintained at this temperature for 1 h. After cooling to rt, water and ethyl acetate were added. The aqueous layer was extracted with ethyl acetate and the combined organic layers were passed through a short silica gel column to remove most of green/blue Cu salts. The filtrate was dried over sodium sulfate and concentrated on a rotavap. The crude product was recrystallized from EtOAc/hexanes, giving pure pale yellow needles. The mother liquor was concentrated and the residue was purified on silica gel column (5% methanol/methylene chloride), yielding a second crop as pale yellow needles. | ||
With copper(l) iodide; caesium carbonate; rac-diaminocyclohexane; In diethylene glycol dimethyl ether; at 20 - 150℃; for 24h;Product distribution / selectivity; | Example 9 5-(4-Methyl-1 H-imidazol-1 -yl)-3-trifluoromethyl-phenylamine (I) EPO <DP n="23"/>To a single neck flask fitted with a condenser are added CuI (89.5 mg, 0.47 mmol), cyclohexanediamine (107.3 mg, 0.94 mmol) and diglyme (10 ml_). The mixture is stirred for 10 minutes at ambient temperature. To the purple heterogeneous mixture, 3-bromo-5- trifluoromethyl-phenylamine (XVI) (1.13 g, 4.7 mmol), 4-methyl-1 /-/-imidazole (0.77 g, 9.4 mmol) and Cs2CO3 (1.53 g, 4.7 mmol) are added. The mixture is heated at 1500C and stirred for an additional 24 hours. The mixture is cooled to 250C and purified by column chromatography (silica gel; EtOAc/MeOH 95:5) to afford (I) as the major product (840 mg). | |
With copper(l) iodide; 8-quinolinol; potassium carbonate; In dimethyl sulfoxide; at 40 - 120℃; for 16h;Inert atmosphere; Sealed tube; | 3-(4-MetIzyI-1H-imidazo1-1-y1)5-(trifluorornethy1)ani1ine: A suspension of 3-bromo-5-(trifluorornethyl)aniline (4.8 g, 20 mmol), 4-methylimidazole (1.97 g, 24 mmol), potassium carbonate (3.04 g, 22 mmol), Cu (0.57 g, 3 mmol), and 8-hydroxyquinoline (0.44 g, 3 mrnol,) in dry DMSO (20 mL) in a pressure tube was degassed by bubbling N2 into the suspension for 10minutes while stirring. The tube was sealed tightly. The mixture was heated at 120 C (oil bath temperature) for 15 h. The mixture was cooled down to 45- 50C and 14% aq. NH4OH (20 mL) was added. The mixture was maintained at this temperature for I h. After cooling to rt, water and ethyl acetate were added. The aqueous layer was extracted with ethyl acetate and the combined organic layers were passed through a short silica gel column to remove most of green/blue Cusalts. The filtrate was dried over sodium sulfate and concentrated on a rotavap. The crude product was recrystallized from EtOAc/hexanes, giving pure pale yellow needles. The motherliquor was concentrated and the residue was purified on silica gel column (5% methanol/methylene chloride), yielding a second crop as pale yellow needles. |
Yield | Reaction Conditions | Operation in experiment |
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75.3% | Example 6 5-(4-Methyl-imidazol-1 -yl)-3-trif luoromethyl-benzonitril (XXII)A solution of 4-methyl-1H-imidazole (1.98 g, 24.11 mmol) in Lambda/-methyl pyrrolidinone (NMP) (18 ml.) is added to a solution of sodium hydride (0.82 g, 60%, 20.5 mmol) in NMP (18 mL) at 20-250C under an atmosphere of nitrogen. The mixture is stirred for 1 hour, before a solution of 3-fluoro-5-trifluoromethyl benzonitrile (XXI) (3.2 g, 16.4 mmol) in NMP (8 mL) is added. The reaction mixture is stirred for 2 hours at 20-250C and then water (120 mL) is added within 20 minutes and the resulting suspension is stirred for 16 hours.The precipitate is filtered, washed with water (20 mL), dissolved in ethyl acetate (70 mL) and the organic layer is washed with water (50 mL). The aqueous phase is extracted with ethyl acetate (2 x 40 mL) and the combined organic layers are reduced to a volume of 50 mL in vacuo. Following a heptane (68 mL) addition the crystallization of the product occurs. The suspension is cooled to 00C and stirred for 2 hours before being filtered. The filter cake is washed with cold heptane (2 x 15 mL) and dried in vacuo to give 3.1 g of the title compound (75.3%) as white crystals (73.7% area by HPLC). | |
74% | In N,N-dimethyl acetamide; at 145℃; for 3h; | General procedure: General procedure for nucleophilic substitution: A solution of <strong>[149793-69-1]3-fluoro-5-trifluoromethyl-benzonitrile</strong> (1 eq) and the corresponding amine (3eq) in DMA was stirred at 145C during 3h. NaCl(aq) was added. The product was taken off into ethyl acetate. The organic layer was washed two times with water then dried over Na2S04 and evaporated under reduced pressure to give a white solid. 3 -(4-Methyl-imidazo 1- 1 -yl)-5 -trifluoromethyl-benzonitrile Yield: 74%. HPLC: 100% ESI-MS: [M+H]+= 252 Da. |
74% | In N,N-dimethyl acetamide; at 145℃; for 3h; | General procedure: General procedure for nucleophilic substitution: A solution of <strong>[149793-69-1]3-fluoro-5-trifluoromethyl-benzonitrile</strong> (1 eq) and the corresponding amine (3eq) in DMA was stirred at 145C during 3h. NaCl(aq) was added. The product was taken off into ethyl acetate. The organic layer was washed two times with water then dried over Na2S04 and evaporated under reduced pressure to give the intermediate compounds. |
In ISOPROPYLAMIDE; at 145℃; for 19h; | Preparation of the intermediate 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline: To a flask was added <strong>[149793-69-1]3-fluoro-5-(trifluoromethyl)benzonitrile</strong> (17 g, 89 mmol), 4-methylimidazole (22.2 g, 270 mmol), N,N-dimethylacetamide (80 mL) and the reaction mixture was stirred at 145C for 19 hours. The solvent was removed under reduced pressure and ethyl acetate (200 mL) was added. The solution was washed with brine (2 x200 mL), dried, filtered, concentrated and recrystallized from ethyl ether and petroleum ether to give an intermediate: 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzonitrile. To a flask was added the intermediate of the previous step (16.7 g, 66 mmol), 1,4-dioxane (300 mL) and 1M NaOH aqueous solution (275 mL) and the reaction mixture was stirred at 95C for 18 hours. After the solvent was removed by concentration, the reaction mixture was neutralized by 1N HCl, and then extracted with n-butanol (250 mL x 2). The organic phase was dried and concentrated to give a intermediate: 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzoic acid. To a solution of the intermediate of the previous step (6.8 g, 25 mmol) in t-butanol (200 mL) was added triethylamine (5.23 mL, 37.5 mmol) and diphenyl phosphoryl azide (DPPA) (7.6 g, 27.5 mmol) and the reaction mixture was stirred at 80C for 16 hours. The solvent was removed under reduced pressure and water (100 mL) was added. The solution was extracted with ethyl acetate (2 × 100 mL) and the combined organic phase was washed with brine, dried, filtered, concentrated, purified through column chromatography, and recrystallized from ethyl ether and petroleum ether to give an intermediate: 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)-N-(tert-butoxycarbonyl) aniline. To a flask was added the intermediate of the previous step (5 mmol) and HCl/isopropanol (30 mL, 4M) and the reaction mixture was stirred at 60C for 5 hours. The solvent was removed under reduced pressure and saturated sodium bicarbonate solution (80 mL) was added. The solution was extracted with ethyl acetate (3 x80 mL) and the combined organic phase was washed with brine, dried, filtered, concentrated and recrystallized from ethyl ether and petroleum ether to give the intermediate 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline. |
Yield | Reaction Conditions | Operation in experiment |
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EXAMPLE 5 8-(4-Methyl-1H-imidazol-1-yl)-7-trifluoromethyl[1,2,4]triazolo-[4,3-a]quinoxaline-1,4(2H,5H)-dione The title compound was prepared from 4-amino-2-chloro-5-nitrobenzotrifluoride and 4-methylimidazole by a method analogous to the method described in example 4. M.p. 320 C. (decomp.). 1 H-NMR (DMSO-d6): delta12.5 (2H, broad s), 8.50 (1H, s), 7.70 (1H, s), 7.65 (1H, s), 7.10 (1H, s), 2.20 (3H, s). MS (m/e): 350 (M+, 100%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81.8% | With potassium carbonate; In acetonitrile; for 6h;Reflux; | Step 1. 4-Methyl-1-(2-(trifluoromethyl)-4-nitrophenyl)-1H-imidazole A mixture of 4-methylimidazole (0.63 g, 7.67 mmol), 1-fluoro-2-(trifluoromethyl)-4-nitrobenzene (1.06 g, 5.1 mmol), and K2CO3 (1.06 g, 7.67 mmol) in acetonitrile (20 mL) was refluxed for 6 hs. The mixture was filtered through Celite and filtrate was evaporated in vacuo and the residue was purified by chromatography on silica gel (PE/EtOAc 1:1) to give 1.13 g product as light green oil (81.8percent). 1H NMR (300 MHz, CDCl3) delta: 8.71 (1H, s), 8.52-8.55 (1H, d, J=8.4 Hz), 7.59-7.62 (2H, m), 6.90 (1H, s), 2.32 (3H, s). LCMS: m/z [M+H]+ 272.0660. |
With potassium carbonate; In acetonitrile; for 18h;Heating / reflux; | B. To a solution of compound 18e (0.70 mL, 5.10 mmol) in 30 mL CH3CN was added 4-methyl-1H-imidazole (0.630 g, 7.67 mmol) and K2CO3 (1.06 g, 7.89 mmol). The mixture was heated at reflux for 18 hours, cooled, and filtered over a pad of Celite. The filtrate was evaporated in vacuo and the resulting residue was purified via silica gel chromatography (60-100percent EtOAc/heptane) to give the product compound 19b as a green oil. MS: M+H+=272.1, 1H NMR (d6-DMSO): delta8.66-8.61 (m, 2H), 7.88 (d, 1H), 7.80 (s, 1H), 7.20 (s,1 H), 2.18 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78.2% | With isoquinolin-8-ol; copper(l) iodide; potassium carbonate; triethylamine; In N,N-dimethyl-formamide; at 100 - 140℃; for 5h; | 13.5 g of <strong>[630125-49-4]3-bromo-5-nitro-trifluorotoluene</strong> (13.5 g, 0.05 mol), 5.0 g of 4-methyl-1H-imidazole (5.0 g, 0.06 mol), 1.42 g of cuprous iodide (1.42 g, 7.5 mmol), 2.2 g of 8-hydroxyisoquinoline (2.2 g, 7.5 mmol), 7.6 g of potassium carbonate (0.055 mol) and 50 mL of N,N-dimethylformamide were added to a 250 mL three-necked bottle, heated to 100 C., stirred to dissolve. Added with 0.75 g of triethylamine (0.75 g, 7.5 mmol), continued to heat to 140 C., reacted for 5 hours, to complete the reaction detected by TLC. Cooled down to 50-60 C., filtered, and the filter cake was washed with ethyl acetate, the filter liquor was washed with saline water and water, concentrated, then recrystallized by ethyl acetate and n-hexane (1:1), to get 10.6 g of yellow solid 3-(4-methyl-1H-imidazol-1-yl)-5-nitro-trifluorotoluene, with a yield of 78.2%, melting point 118-120 C., MS-ESI (m/z): 272(M+H), 1H NMR (400 MHz, CDCl3) delta 8.45(s, 2H), 7.95(s, 1H), 7.93(s, 1H), 7.16(s, 1H), 2.33(s, 3H). |
53.3% | Example 13 4-Methyl-1 -(3-nitro-5-tiotaf luoromethyl-phenyl)-1 H-imidazole (IX) (by aromatic substitution)4-Methylimidazole (10.5 g, 125.5 mmol) and potassium carbonate (12.0 g, 119.6 mmol) is suspended in Lambda/,Lambda/-dimethylformamide (80 mL) and stirred at 1000C for 1 hour. A solution of 1-fluoro-3-nitro-5-trifluoromethyl-benzene (12.5 g, 59.8 mmol) in EPO <DP n="26"/>ty/V-dimethylformamide (20 mL) is added over 10 minutes. The mixture is stirred at 1080C internal temperature for 3 hours. HPLC analysis shows complete consumption of the fluoride starting material. The mixture is cooled down to about 200C and water (200 mL) is added over 1 hour. The resulting suspension is filtered to give 17.5 g of wet solid (HPLC: 88.8 area% desired isomer, 8.9 area% undesired isomer/byproduct). A suspension of this material in water (100 mL) is stirred for 1 hour at room temperature. The solid is filtered, washed with water (100 mL) and dried at 50C under reduced pressure to give the crude product. HPLC analysis shows more than 90 area% of the desired product. Re-crystallization: A solution of above crude product (9.5 g) in ethyl acetate (50 mL) is treated for 2 hours at 700C with activated carbon (1 g) and filter aid (1 g) and, thereafter, is filtered, and the filtrate is evaporated to dryness to give 11.1 g of a residue. This material is dissolved in ethyl acetate (3.25 g) and heptane (50 mL) under reflux. The solution is seeded at 65C with 4-methyl-1-(3-nitro-5-trifluoromethyl-phenyl)-1H-imidazole and allowed to cool down to room temperature over night and afterwards stirred at 00C for 3 hours. The solid formed is filtered, washed with heptane (20 mL) and dried at 500C under reduced pressure to give 4-methyl-1-(3-nitro-5-trifluoromethyl-phenyl)-1 /-/-imidazole as a solid. Yield overall: 53.3% (HPLC purity: 98.2 area%), Melting point: 117-118C | |
21.1% | With copper(l) iodide; potassium carbonate; ethylenediamine; In N,N-dimethyl-formamide; at 110℃; for 23h;Product distribution / selectivity; | Example 10 4-Methyl-1-(3-nitro-5-trifluoromethyl-phenyl)-1H-imidazole (IX) (by catalyzed coupling)To a stirred suspension of <strong>[630125-49-4]1-bromo-3-nitro-5-trifluoromethyl-benzene</strong> (4.05 g, 15 mmol), 4-methyl-1 W-imidazole (2.01 g, 24 mmol, 98%) and potassium carbonate (3.73 g, 27 mmol) in Lambda/,Lambda/-dimethylformamide (10 mL) are added ethylenediamine (0.141 mL, 2.1 mmol) and copper(l) iodide (0.204 g, 1.05 mmol). The vigorously stirred mixture is heated to 110 0C for 23 hours. After that, most of the 1-bromo-3-nitro-5-trifluoromethyl- benzene is converted, and the suspension is allowed to cool down to room temperature. The mixture is diluted with terf-butyl methyl ether (30 mL) and 5% aqueous NaCI solution (30 mL) and isopropyl acetate (15 mL) are added. The aqueous layer is separated and extracted with a mixture of tert-buty methyl ether (10 mL) and isopropyl acetate (5 mL). The organic layers are combined and filtered. The filtrate is washed with water (10 mL), treated for 5 minutes with ethylenediamine (0.303 mL), washed with water (10 mL), 5% aqueous sodium EPO <DP n="24"/>metabisulfite solution (10 mL) and water (10 ml.) before it is treated with activated carbon (1.2 g) at room temperature for 1 hour. The suspension is filtered using filter aid, and the filtrate is evaporated to dryness under reduced pressure to give a clear, red-brown oil which solidifies upon standing at room temperature. The obtained solid is purified by column chromatography on silica gel eluting with a 4:5 mixture of ethyl acetate and hexane (in the presence of 0.5 volume% of triethylamine) to afford mainly 4-methyl-1-(3-nitro- 5-trifluoromethyl-phenyl)-1 /-/-imidazole as a pale yellow solid. Yield: 21.1% (HPLC purity: 96.7 area%) Melting point: 118-119C. |
Yield | Reaction Conditions | Operation in experiment |
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85% | With potassium hydroxide; In dimethyl sulfoxide; at 80℃; for 8h;Inert atmosphere; | Synthesis of l-(2-Methoxy-4-nitrophenyl)-4-methyl-lH-imidazole [0304] To a stirred solution of <strong>[1009-36-5]<strong>[1009-36-5]2-chloro-5-nitroanisol</strong>e</strong> (3 g, 16.0 mmol) in DMSO (15 mL) under argon atmosphere were added 4-methyl imidazole (5.2 g, 64.0 mmol), and KOH (1.34 g, 24.0 mmol) at RT. The reaction mixture was stirred at 80 C for 8 h. After the consumption of the starting materials (monitored by TLC), the reaction was diluted with water (50 mL) to afford the solid which was filtered and dried in vacuo to afford l-(2- Methoxy-4-nitrophenyl)-4-methyl-lH-imidazole (3.2 g, 85%) as a yellow solid. 1H-NMR (DMSO-de, 400 MHz): delta 7.98-7.95 (m, 3H), 7.72-7.67 (m, 1H), 7.28 (s, 1H), 3.98 (s, 3H), 2.16 (s, 3H); TLC: 100% EtOAc (R 0.3). |
85% | With potassium hydroxide; In dimethyl sulfoxide; at 20 - 80℃; for 8h;Inert atmosphere; | To a stirred solution of <strong>[1009-36-5]<strong>[1009-36-5]2-chloro-5-nitroanisol</strong>e</strong> (3 g, 16.0 mmol) in DMSO (15 mL) under an argon atmosphere were added 4-methyl imidazole (5.2 g, 64.0 mmol), KOH (1.34 g, 24.0 mmol) at RT. The reaction mixture was stirred at 80 oC for 8 h. After the completion of the starting material (monitored by TLC), the reaction was diluted with water (50 mL) to afford the solid which was filtered and dried in vacuo to afford 1-(2-Methoxy-4- nitrophenyl)-4-methyl-1H-imidazole (3.2 g, 85%) as a yellow solid. 1H-NMR (DMSO-d6, 400 MHz): delta 7.98-7.95 (m, 3H), 7.72-7.67 (m, 1H), 7.28 (s, 1H), 3.98 (s, 3H), 2.16 (s, 3H); TLC: 100% EtOAc (Rf: 0.3). |
85% | With potassium hydroxide; In dimethyl sulfoxide; at 80℃; for 8h;Inert atmosphere; | Synthesis of 1-(2-Methoxy-4-nitrophenyl)-4-methyl-1H-imidazole To a stirred solution of <strong>[1009-36-5]<strong>[1009-36-5]2-chloro-5-nitroanisol</strong>e</strong> (3 g, 16.0 mmol) in DMSO (15 mL) under an argon atmosphere were added 4-methyl imidazole (5.2 g, 64.0 mmol), KOH (1.34 g, 24.0 mmol) at RT. The reaction mixture was stirred at 80 C. for 8 h. After the completion of the starting material (monitored by TLC), the reaction was diluted with water (50 mL) to afford the solid which was filtered and dried in vacuo to afford 1-(2-Methoxy-4-nitrophenyl)-4-methyl-1H-imidazole (3.2 g, 85%) as a yellow solid. 1H-NMR (DMSO-d6, 400 MHz): delta 7.98-7.95 (m, 3H), 7.72-7.67 (m, 1H), 7.28 (s, 1H), 3.98 (s, 3H), 2.16 (s, 3H); TLC: 100% EtOAc (Rf: 0.3). |
45% | With potassium hydroxide; In dimethyl sulfoxide; at 80℃; for 5h; | A solution of <strong>[1009-36-5]2-chloro-5-nitroanisol</strong> (187 mg, 1 mmol), of 4-methylimidazol (335 mg, 4 mmol) and of potassium hydroxide (99 mg, 1.5 mmol) in DMSO (0.86 mL) was stirred for 5 hours at 80 under an atmosphere of nitrogen. After cooling to room temperature the reaction was poured onto ice/water. A precipitation was formed and the suspension was stirred for 15 minutes. The solid was filtered off, washed with water, dissolved in dichloromethane, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure to yield a yellow solid. The crude product was purified on silica gel using dichloromethane/methanol (19:1 v/v) as eluent to yield the title compound (106 mg, 45%) as a pale-yellow solid. Alternatively the product can be also crystallized from the crude material from diethyl ether. MS ISP (m/e): 234.3 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): delta (ppm)=7.97 (d, 1H), 7.96 (s, 1H), 7.83 (s, 1H), 7.42 (d, 1H), 7.00 (s, 1H), 4.00 (s, 3H), 2.31 (s, 3H). |
45% | With potassium hydroxide; In dimethyl sulfoxide; at 80℃; for 5h;Inert atmosphere; | a) 1-(2-Methoxy-4-nitro-phenyl)-4-methyl-1H-imidazole; A solution of <strong>[1009-36-5]<strong>[1009-36-5]2-chloro-5-nitroanisol</strong>e</strong> (187 mg, 1 mmol), of 4-methyl-1H-imidazole (335 mg, 4 mmol) and of potassium hydroxide (99 mg, 1.5 mmol) in DMSO (0.86 mL) was stirred for 5 h at 80 C. under an atmosphere of nitrogen. After cooling to 20 C. the reaction was poured onto ice-water. A precipitation was formed and the suspension was stirred for 15 min. The solid was filtered off, washed with water, dissolved in dichloromethane, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure to yield a yellow solid. The crude product was purified on silica gel using dichloromethane/methanol (19:1 v/v) as eluent to yield the title compound (106 mg, 45%) as a pale-yellow solid. Alternatively the product can be also crystallized from the crude material from diethyl ether.MS ISP (m/e): 234.3 (100) [(M+H)+].1H NMR (CDCl3, 300 MHz): delta (ppm)=7.97 (d, 1H), 7.96 (s, 1H), 7.83 (s, 1H), 7.42 (d, 1H), 7.00 (s, 1H), 4.00 (s, 3H), 2.31 (s, 3H). |
45% | With potassium hydroxide; In dimethyl sulfoxide; at 80℃; for 5h;Inert atmosphere; | Example 1 (4,6-Dimethoxy- [ 1 ,3,5] triazin-2-yl)- [3-methoxy-4-(4-methyl-imidazol- l-yl)-phenyl] -aminea) 1 -(2-Methoxy-4-nitro-phenyl)-4-methyl- 1 H-imidazole A solution of <strong>[1009-36-5]<strong>[1009-36-5]2-chloro-5-nitroanisol</strong>e</strong> (187 mg, 1 mmol), of 4-methyl-l H-imidazole (335 mg, 4 mmol) and of potassium hydroxide (99 mg, 1.5 mmol) in DMSO (0.86 mL) was stirred for 5 h at 80 0C under an atmosphere of nitrogen. After cooling to 20 0C the reaction was poured onto ice- water. A precipitation was formed and the suspension was stirred for 15 min. The solid was filtered off, washed with water, dissolved in dichloromethane, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure to yield a yellow solid. The crude product was purified on silica gel using dichloromethane/methanol (19:1 v/v) as eluent to yield the title compound (106 mg, 45 %) as a pale-yellow solid. Alternatively the product can be also crystallized from the crude material from diethyl ether. MS ISP (m/e): 234.3 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): delta (ppm) = 7.97 (d, IH), 7.96 (s, IH), 7.83 (s, IH), 7.42 (d, IH), 7.00 (s, IH), 4.00 (s, 3H), 2.31 (s, 3H). |
45% | With potassium hydroxide; In dimethyl sulfoxide; at 80℃; for 5h;Inert atmosphere; | a) 1-(2-Methoxy-4-nitro-phenyl)-4-methyl-1H-imidazole A solution of <strong>[1009-36-5]<strong>[1009-36-5]2-chloro-5-nitroanisol</strong>e</strong> (187 mg, 1 mmol), of 4-methyl-1H-imidazole (335 mg, 4 mmol) and of potassium hydroxide (99 mg, 1.5 mmol) in DMSO (0.86 mL) was stirred for 5 h at 80 C. under an atmosphere of nitrogen. After cooling to 20 C. the reaction was poured onto ice-water. A precipitation was formed and the suspension was stirred for 15 min. The solid was filtered off, washed with water, dissolved in dichloromethane, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure to yield a yellow solid. The crude product was purified on silica gel using dichloromethane/methanol (19:1 v/v) as eluent to yield the title compound (106 mg, 45%) as a pale-yellow solid. Alternatively the product can be also crystallized from the crude material from diethyl ether. MS ISP (m/e): 234.3 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): delta (ppm)=7.97 (d, 1H), 7.96 (s, 1H), 7.83 (s, 1H), 7.42 (d, 1H), 7.00 (s, 1H), 4.00 (s, 3H), 2.31 (s, 3H). |
45% | With potassium hydroxide; In dimethyl sulfoxide; at 80℃; for 5h; | A solution of 187 mg (1 mmol) <strong>[1009-36-5]2-chloro-5-nitroanisol</strong>, 335 mg (4 mmol) 4-methylimidazol and 99 mg (1.5 mmol) potassium hydroxide in DMSO (0.86 ml) was stirred for 5 hours at 80 under an atmosphere of nitrogen. After cooling to room temperature the reaction was poured onto ice/water. A precipitation was formed and the suspension was stirred for 15 minutes. The solid was filtered off, washed with water, dissolved in methylene chloride, dried over sodium sulphate, filtered and the solvent was evaporated under reduced pressure to yield a yellow solid. The crude product was purified on silica gel with methylene chloride/methanol 19/1 yielding 106 mg (45%) 1-(2-methoxy-4-nitro-phenyl)-4-methyl-1H-imidazole as a light yellow solid. Alternatively the product can be also crystallized from the crude material from diethyl ether. MS ISP (m/e): 234.3 (100) (M+H)+. 1H NMR (CDCl3, 250 MHz): 6 (ppm)=7.97 (d, 1H), 7.96 (s, 1H), 7.83 (s, 1H), 7.42 (d, 1H), 7.00 (s, 1H), 4.00 (s, 3H), 2.31 (s, 3H). |
26.0% | With potassium carbonate; In dimethyl sulfoxide; at 150℃; for 6h;Inert atmosphere; | A mixture of l-chloro-2-methoxy-4-nitrobenzene (50 g, 0.26 mol), 4-methyl-lH- imidazole (43.77 g, 0.53 mol) and K2CO3 (36.84 g, 0.26 mol) in DMSO (500 ml) was reacted in an autoclave under a N2 atmosphere for 6 h at 150 0C. This reaction was performed 3 times with 50 g of l-chloro-2-methoxy-4-nitrobenzene. Subsequently, the three r.m. were worked up together. The mixture was poured into 6 1 of ice-water. The solid was filtered off and washed with H2O. The solid was dissolved in DCM and this solution was washed with H2O. The separated organic layer was dried (MgSO4), filtered and the solvent was evaporated in vacuo. The residue was purified over silicagel on a glass filter (eluent: DCM/MeOH from 100/0 to 97/3). The product fractions were collected and the solvent was evaporated. The residue was suspended in DIPE, filtered off and dried in the oven. Yield: 48.54 g of intermediate 1 (26.0 %). |
26% | With potassium carbonate; In dimethyl sulfoxide; at 150℃; for 6h;Autoclave; Inert atmosphere; | a) Preparation of intermediate 1 A mixture of l-chloro-2-methoxy-4-nitrobenzene (50 g, 0.26 mol), 4-methyl-lH- imidazole (43.77 g, 0.53 mol) and K2CO3 (36.84 g, 0.26 mol) in DMSO (500 ml) was reacted in an autoclave under N2 atmosphere for 6 h at 150 0C. This reaction was repeated twice with 50 g of l-chloro-2-methoxy-4-nitrobenzene each. Subsequently, the 3 r.m. (150 g of l-chloro-2-methoxy-4-nitrobenzene in total) were worked up together. The mixture was poured out into 6 1 of ice-water. The solid was filtered off and washed with H2O. The solid was dissolved in DCM and this sol. was washed with H2O. The separated organic layer was dried (MgSO4), filtered and the solvent was evaporated. The residue was purified over silica gel on a glass filter (eluent:DCM/MeOH from 100/0 to 97/3). The product fractions were collected and the solvent was evaporated. The residue was suspended in DIPE, filtered off and dried in the oven. Yield: 48.54 g of intermediate 1 (26 %). |
26% | With potassium carbonate; In dimethyl sulfoxide; at 150℃; for 6h;Inert atmosphere; Autoclave; | Example Al a) Preparation of intermediate 1A mixture of l-chloro-2-methoxy-4-nitrobenzene (50 g, 0.26 mol), 4-methyl-lH- imidazole (43.77 g, 0.53 mol) and K2CO3 (36.84 g, 0.26 mol) in DMSO (500 ml) was reacted in an autoclave under N2 atmosphere for 6 h at 150 0C. This reaction was repeated twice with 50 g of l-chloro-2-methoxy-4-nitrobenzene each (150 g in total). The 3 r.m. were combined and poured out into ice-water (6 1). The solid was filtered off and washed with H2O. The solid was dissolved in DCM and this solution was washed with H2O. The separated organic layer was dried (MgSO4), filtered and the solvent was evaporated. The residue was purified over silica gel on a glass filter (eluent:DCM/MeOH from 100/0 to 97/3). The product fractions were collected and the solvent was evaporated. The residue was suspended in DIPE, filtered off and dried in the oven. Yield: 48.54 g of intermediate 1 (26.0 %). |
20% | With potassium hydroxide; In dimethyl sulfoxide; at 110℃; for 24h; | A mixture of 4-methyl-lH-imidazole (18.0 g, 53.5 mmol), 1- chloro-2-methoxy-4-nitrobenzene (10.0 g, 53.5 mmol)5 and potassium hydroxide (4.5 g, 80.3 mmol) in DMSO (50 mL) was heated at 1100C for 24 h. The reaction mixture was allowed to cool to it and was poured into 1000 mL of water. The aqueous mixture was extracted with dichloromethane (3 x 250 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude reaction mixture was purified using silica gel chromatography (33O g silica cartridge, 0-2% MeOH/chloroform, linear gradient over 72 min, flow 25 mL/min) to afford l-(2-methoxy-4-nitrophenyl)-4-methyl-lH- imidazole (2.56 g, 20 % yield) as a yellow/orange solid. LC-MS (M+H)+ = 234.1. 1H NMR (500 MHz5 chloroform-^ delta ppm 7.97 - 8.00 (m, 1 H) 7.93 - 7.97 (m, 2 H) 7.45 (d, J-8.85 Hz5 1 H) 7.02 (s, 1 H) 4.02 (s, 3 H) 2.35 (s, 3 H). |
20% | With potassium hydroxide; In dimethyl sulfoxide; at 110℃; for 24h; | A mixture of 4-methyl-lH-imidazole (18.0 g, 53.5 mmol), l-chloro-2-methoxy-4- nitrobenzene (10.0 g, 53.5 mmol), and potassium hydroxide (4.5 g, 80.3 mmol) in DMSO (50 mL) was heated at 110 0C for 24 h. The reaction mixture was allowed to cool to rt and was poured into 1000 mL of water. The aqueous mixture was extracted with dichloromethane (3 x 250 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude reaction mixture was purified using silica gel chromatography (330 g silica cartridge, 0-2% MeOH/chloroform, linear gradient over 72 min, flow 25 mL/min) to afford l-(2- methoxy-4-nitrophenyl)-4-methyl-lH-imidazole (2.56 g, 20 % yield) as a yellow/orange solid. LC-MS (M+H)+ = 234.1. 1H NMR (500 MHz, CDCl3) delta ppm 7.97 - 8.00 (m, 1 H) 7.93 - 7.97 (m, 2 H) 7.45 (d, J=8.85 Hz, 1 H) 7.02 (s, 1 H) 4.02 (s, 3 H) 2.35 (s, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydride; In N,N-dimethyl-formamide; at 0 - 70℃; for 3h; | Sodium hydride (743 mg) was added to a solution of <strong>[77337-82-7]<strong>[77337-82-7]2-bromo-5-nitroanisol</strong>e</strong> (3.00 g) and 4-methyl-1H-imidazole (1.27 g) in DMF (20 mL) under ice-cooling, and the reaction solution was stirred at 70C for three hours. The reaction solution was left to cool to room temperature. Then, water and ethyl acetate were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system -> ethyl acetate-methanol system) to obtain 477.0 mg of the title compound. The property values of the compound are as follows. 1H-NMR (CDCl3) delta (ppm): 2.31 (s, 3H), 4.00, (s, 3H), 6.99-7.00 (m, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.84 (d, J = 1.2 Hz, 1H), 7.93-7.98 (m, 2H). | |
With caesium carbonate;2,4-dimethyl-heptane-3,5-dione; In N,N-dimethyl-formamide; at 25 - 90℃; | Reference 4; Synthesis of 3 -methoxy-4-(4-methyl-imidazol- 1 -yl)phenylamineSteplTo a stirred solution of 3,methoxy-4-bromo nitrobenzene(5g, 0.026mol) in DMF (50ml) were added 4-methylimidazole (32g, 0.038mol), CuI (0.49g, 0.0026mol) and Cs2CO3 (2 Ig, 0.065mol) at 25C. Reaction mixture was stirred at this temperature for 30 min. To this 2,4-dimethyl hepta- 3,5-dione (catalytic) was added and stirred at 900C overnight (modified procedures from Buchwald group J. Am. Chem. Soc, 2006, 128, 8742-8743). Reaction was cooled, partitioned between ethyl acetate (200ml) and water. Aqueous part was extracted with ethyl acetate (200ml). Organics combined, dried over sodium sulfate and concentrated under vacuum. Product was purified by column chromatography using silica gel(100-200mesh) and 0-2% methanol, dichloromethane as eluent to obtain 2.1g of l-(2-methoxy-4-nitro-phenyl)-4- methyl- 1 H-imidazole |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; PEG;copper(I) oxide; 4,7-dimethoxy-1,10-phenanthroline; In 1-methyl-pyrrolidin-2-one; at 120℃; for 48h; | Step B:; A mixture of compound 55.1c' (2.03 g, 10 mmol), Cu2O (0.288 g, 2 mmol), PEG (4.0), Cs2CO3 (9.77 g, 30 mmol), 4-methylimidazole (0.98 g, 12 mmol) and 55.1c" (0.72 g, 3 mmol) in NMP (15 ml_) was vacuum-nitrogen exchange degassed and stirred in a sealed tube at 120 0C for 48 hours. The mixture was cooled to room temperature and diluted with CH2CI2 followed with addition of silica gel. The mixture was stirred for 20 minutes and filtered. The organic layer was washed with water (3x), brine, dried over MgSO4, and concentrated to give the crude product. The crude residue was purified by column chromatography eluting with CH2CI2/MeOH to yield compound 55.1c (0.2 g). | |
With caesium carbonate;copper(I) oxide; 4,7-dimethoxy-1,10-phenanthroline; In 1-methyl-pyrrolidin-2-one; PEG; at 120℃; for 48h;Sealed tube; | Step A: A mixture of compound E2a (2.03 g, 10 mmoi), Cu2O (0.288 g, 2 mmol), PEG(4.0), Cs2CO3 (9,77 g, 30 mmol), 4-methyiimidazGie (0.98 g, 12 mmol) and E2b (0.72 g, 3 mmol) in HMP (15 mL) was vacuum-nitrogen exchange degassed and stirred in a sealed tube at 120 0C for 48 hours. The mixture was cooled to room temperature and diluted with CH2CI2 followed with addition of sica gel. The mixture was stirred for 20 minutes and filtered. The organic layer was washed with water (3x), brine, dried over MgSO4, and concentrated to give the crude product. The crude residue was purified by column chromatography eluting with CH2CI2/MeOH to yield compound E2c (0.2 g). | |
With 1-methyl-pyrrolidin-2-one; copper(I) oxide; 4,7-dimethoxy-1,10-phenanthroline; caesium carbonate; at 120℃; for 48h;Inert atmosphere; | EXAMPLE 2Step A: A mixture of compound 2a (2.03 g, 10 mmol), Cu2O (0.288 g, 2 mmol), PEG (4.0), Cs2CO3 (9.77 g, 30 mmol), 4-methylimidazole (0.98 g, 12 mmol) and 2b (0.72 g, 3 mmol) in NMP (15 mL) was vacuum-nitrogen exchange degassed and stirred in a sealed tube at 120 C for 48 hours. The mixture was cooled to room temperature and diluted with CH2CI2 followed with addition of silica gel. The mixture was stirred for 20 minutes and filtered. The organic layer was washed with water (3x), brine, dried over <n="279"/>MgSO4, and concentrated to give the crude product. The crude residue was purified by column chromatography eluting with CH2CbZMeOH to yield compound 2c (0.2 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With potassium carbonate; In dimethyl sulfoxide; at 125℃; for 16h;Autoclave; Inert atmosphere; | 2-Fluoro-5-nitroanisole (50 g, 0.29 mol) was added to a solution of 4-methyl-lH- imidazole (36.0 g, 0.44 mol) and K2C03 (40.38 g, 0.29 mol) in DMSO (150 ml) in a stainless steel autoclave under a N2 atmosphere. The vessel was closed and the r.m. was heated at 125 °C for 16 h. Subsequently, the mixture was cooled and the solvent was evaporated under reduced pressure. H20 (q.s.) was added to the residue and the precipitated product was collected by filtration. This solid was then triturated with DIPE and collected by filtration to yield a light-brown solid. Yield: 53.8 g of intermediate 40(79 percent). |
79% | With potassium carbonate; In dimethyl sulfoxide; at 125℃; for 16h;Inert atmosphere; | 2-Fluoro-5-nitroanisole (50 g, 0.29 mol) was added to a solution of 4-methyl-lH- imidazole (36.0 g, 0.44 mol) and K2C03 (40.38 g, 0.29 mol) in DMSO (150 ml) in a stainless steel autoclave under a N2 atmosphere. The vessel was closed and the r.m. was heated at 125 °C for 16 h. Subsequently, the mixture was cooled and the solvent was evaporated under reduced pressure. H20 (q.s.) was added to the residue and the precipitated product was collected by filtration. This solid was then triturated with DIPE and collected by filtration to yield a light-brown solid. Yield: 53.8 g of intermediate 40 (79 percent). |
79% | With potassium carbonate; In dimethyl sulfoxide; at 125℃; for 16h;Inert atmosphere; | 2-Fluoro-5-nitroanisole (50 g, 0.29 mol) was added to a solution of 4-methyl-1H-imidazole (36.0 g, 0.44 mol) and K2CO3 (40.38 g, 0.29 mol) in DMSO (150 ml) in a stainless steel autoclave under a N2 atmosphere. The vessel was closed and the r.m. was heated at 125° C. for 16 h. Subsequently, the mixture was cooled and the solvent was evaporated under reduced pressure. H2O (q.s.) was added to the residue and the precipitated product was collected by filtration. This solid was then triturated with DIPE and collected by filtration to yield a light-brown solid. Yield: 53.8 g of intermediate 40 (79percent). |
78.9% | With potassium carbonate; In dimethyl sulfoxide; at 125℃; for 16h;Inert atmosphere; Autoclave; | Example A2 a) Preparation of intermediate 3. (NOTE: this reaction was carried out in 4 batches of 50 g of <strong>[454-16-0]2-fluoro-5-nitroanisole</strong>). A mixture of <strong>[454-16-0]2-fluoro-5-nitroanisole</strong> (200 g, 1.17 mol), 4-methyl- IH- imidazole (143.9 g, 1.75 mol) and K2CO3 (161.5 g, 1.17 mol) in DMSO (600 ml) was prepared in a stainless steel autoclave under a N2 atmosphere. The vessel was closed and the r.m. heated at 125 0C for 16 h. The contents were allowed to cool and the solvent was evaporated under reduced pressure. H2O (q.s.) was added to the residue and the precipitated product was collected by filtration. This solid was then triturated with DIPE and collected by filtration to yield a light-brown solid. Yield: 215 g ofintermediate 3 (78.9 percent). |
With potassium carbonate; In acetonitrile; at 20℃; | Step C:; Two equivalent of 4-methylimidazole, 1 equivalent of 3-methoxy-4-fluoro- nitrobenzene and 5 eq. of K2CO3 were stirred in CH3CN at room temperature over night. The reaction mixture was filtered and concentrated under reduced pressure. The crude product was recrystalized with EtOAc to give desired product 5.1 d. | |
With potassium carbonate; In acetonitrile; at 20℃; | Step F: Two equivalent of 4-methylimidazofe, 1 equivalent of 3-rnethoxy-4-fluoro- nitrobenzene and 5 eq. of K2CO3 were stirred in CH3CN at room temperature over night. The reaction mixture was filtered and concentrated under reduced pressure. The crude product was recrystalized with EtOAc to give desired product E1i. | |
With potassium carbonate; In acetonitrile; at 20℃; | 4-methylimidazole (2.0 mmol), <strong>[454-16-0]3-methoxy-4-fluoro-nitrobenzene</strong> (1.0 mmol) and K2CO3 (5 mmol) were stirred in CH3CN (10 mL) at room temperature over night. The reaction mixture was filtered and concentrated under reduced pressure. The crude product was recrystallized with EtOAc to give desired product 1a. | |
With potassium carbonate; In acetonitrile; at 20℃; | EXAMPLE 1Step A: 4-methylimidazole (2.0 mmol), <strong>[454-16-0]3-methoxy-4-fluoro-nitrobenzene</strong> (1.0 mmol) and K2CO3 (5 mmoi) were stirred in CH3CN (10 mL) at room temperature over night. The reaction mixture was filtered and concentrated under reduced pressure. The crude product was recrystalized with EtOAc to give desired product 1a. | |
With potassium carbonate; In N,N-dimethyl-formamide; at 85℃;Sealed tube; | Example 34 a. 3-methoxy-4-(5-methyl-lH-imidazol-l-yl)anilineA mixture of 4-methyl imidazole (500 mg, 6.1 mmol), 2-fluoro-5-nitro anisole (1.02 g, 5.9 mmol) and potassium carbonate (1.68 g, 12 mmol) in DMF (15 mL) was heated overnight at 85°C in a sealed tube. The reaction mixture was cooled, transferred into a round bottom flask using ethyl acetate and concentrated under high vacuum to 5 mL volume. The residue was suspended in water and extracted with dichloromethane. The organic extracts were combined, washed with brine, dried over anhydrous MgSO4, filtered and concentrated. The residue was dissolved in dichloromethane (10 mL) and diluted with hexane until the solution became slightly turbid. The turbid solution was left at room temperature. The separated solid was filtered, washed with hexane to give l-(2-methoxy-4-nitro-phenyl)-4- methyl-lH-imidazole. The mother liquor was purified by preparative HPLC giving 0.20 g of l-(2-methoxy-4-nitro-phenyl)-5-methyl-lH-imidazole.10 percent Pd/C (0.28 g, 2.6 mmol) was added to a solution of l-(2-methoxy-4-nitro-phenyl)-5- methyl-lH-imidazole (0.61 g, 2.6 mmol) in ethyl acetate (20 mL). The mixture was hydrogenated at 35 psi over night. The mixture was filtrated through celite and concentrated to about 10 mL. Diethylether (50 mL) was added and the solution was cooled to 00C. 4M HCl in dioxane (2 mL) was added and the solution was stirred for 15 min then warmed up to rt and stirred for 30 min. The excess solvent was decanted off and more diethylether was added and the mixture stirred for 15 min. This was repeated once more with a large amount of diehtylether. The wet solid was dried under vacuum giving 0.60 g of the title compound (16 percent Yield).1H NMR (400 MHz, METHANOL-d4) ppm 2.15 (s, 3 H), 3.92 (s, 3 H), 7.07 (dd, 1 H), 7.19 (d, 1 H), 7.49 (s, 1 H), 7.59 (d, 1 H), 9.03 (d, 1 H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With potassium hydroxide; In N,N-dimethyl-formamide; at 0 - 20℃;Product distribution / selectivity; | Method A 6-Methoxy-2-(4-methyl-1H-imidazol-1-yl)-3-nitropyridine (1B) To a N,N-dimethylformamide (500 mL) solution of 4-methylimidazole (8.5 g, 103 mmol) was added freshly powdered KOH (6.72 g, 120 mmol) in two portions under N2 at 0 C., followed by addition of <strong>[38533-61-8]2-chloro-6-methoxy-3-nitropyridine</strong> (18.9 g, 100 mmol). The resulting solution was warmed to room temperature and stirred for 2 hours. Majority of solvent was removed under vacuum and the residue was diluted with water and extracted with ethyl acetate three times. The organic layer was combined and washed two more times with water to remove additional dimethyl formamide and dried over magnesium sulfate. Solvent was evaporated under vacuum and the residue was purified by column (15-25% gradient eluent of ethyl acetate in dichloromethane) to provide compound 1B as a yellow oil (21.9 g, 93% yield) which becomes yellow solid after standing on bench. |
93% | To 4.02 g (1.6 eq.) 4-methylimidazole dissolved in CHCl3 (8 mL, instead of DMF [38]) a solution of 4-(dimethylamino) pyridine (DMAP, 0.37 g, 10 mol %) in CHCl3 (2 mL) was added dropwise. The reaction mixture was stirred at 0 C for 10 min followed by the addition of triethylamine (TEA, 12.73 mL, 3 eq.; instead of solid KOH [38]) and stirring at 0 C for further 10 min. To this reaction mixture was added dropwise <strong>[38533-61-8]2-chloro-6-methoxy-3-nitropyridine</strong> (5.77 g, 1 eq.) in CHCl3 (14 mL). After 30 min at 0 C the mixture was stirred at ambient temperature overnight. The mixture was washed twice with water and aq. NaCl saturated solution (20 mL). The aqueous phase was extracted with CHCl3 (20 mL). The organic phase was dried over Na2SO4 and filtered. Evaporation of the solvent and subsequent purification by column chromatography (EtOAc/n-hexane, 1:2, v/v) afforded 1 as a yellow solid (6.65 g, 93%). 1H-NMR (400 MHz, CDCl3): delta (ppm) = 2.27 (s, 3H); 4.03 (s, 3H); 4.75 (s, 2H); 6.78 (d, 3J = 8.8, 1H); 6.90 (dd, 4J = 2.0, 4J = 1.2, 1H); 7.94 (d,4J = 1.2, 1H); 8.23 (d, 3J = 8.8, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30.8% | With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 8h; | A suspension of 4-methyl-1H-imidazole (1.178 g, 14.35 mmol) in DMF (15 mL) was added to a solution of <strong>[454-73-9]1-fluoro-3-nitro-5-(trifluoromethyl)benzene</strong> (2 g, 9.56 mmol) in DMF (15 mL). Cs2CO3 (6.23 g, 19.13 mmol) was added and the mixture was stirred at 80 C. for 8 h. The mixture was cooled to rt and then the solution was concentrated and distributed between EA and saturated NaHCO3 solution. The combined organic extract was washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by silica column chromatography (PE/EA=5:1). All fractions found to contain product by TLC (PE/EA=1:1, Rf=0.5) were combined and concentrated to yield a light yellow solid of 4-methyl-1-(3-nitro-5-(trifluoromethyl)phenyl)-1H-imidazole (800 mg, 2.95 mmol, 30.8% yield): 1H NMR (400 MHz, CD3OD) delta 8.61-8.78 (m, 1H), 8.44-8.51 (m, 1H), 8.31-8.39 (m, 2H), 7.55 (s, 1H), 2.27 (s, 3H); ES-LCMS m/z 272.0 (M+H). |
30.8% | With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 8h; | A suspension of 4-methyl-lH-imidazole (1.178 g, 14.35 mmol) in DMF (15 mL) was added to a solution of l-fluoro-3-nitro-5-(trifluoromethyl)benzene (2 g, 9.56 mmol) in DMF (15 mL). CS2CO3 (6.23 g, 19.13 mmol) was added and the mixture was stirred at 80 C for 8 h. The mixture was cooled to rt and then the solution was concentrated and distributed between EA and saturated NaHC03 solution. The combined organic extract was washed with brine, dried over MgSO/i, filtered and concentrated. The crude material was purified by silica column chromatography (PE/EA = 5: 1). All fractions found to contain product by TLC (PE/EA = 1: 1, Rf = 0.5) were combined and concentrated to yield a light yellow solid of 4-methyl-l-(3-nitro-5- (trifluoromethyl)phenyl)-lH-imidazole (800 mg, 2.95 mmol, 30.8% yield): l NMR (400 MHz, CD3OD) delta 8.61-8.78 (m, 1H), 8.44-8.51 (m, 1H), 8.31-8.39 (m, 2H), 7.55 (s, 1H), 2.27 (s, 3H); ES-LCMS m/z 272.0 (M+H). |
30.8% | With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 8h; | A suspension of 4-methyl-1H-imidazole (1.178 g 14.35 mmol) in DMF (15 mL) was added to a solution of 1-fluoro-3-nitro-5- (trifluoromethyl) benzene (2 g 9.56 mmol) in DMF (15 mL) . Cs2CO3(6.23 g 19.13 mmol) was added and the mixture was stirred at 80 for 8 h. The mixture was cooled to rt and then the solution was concentrated and distributed between EA and saturated NaHCO3solution. The combined organic extract was washed with brine dried over MgSO4 filtered and concentrated. The residue was purified by silica column chromatography (PE/EA 51) . All fractions found to contain product by TLC (PE/EA 11 Rf 0.5) were combined and concentrated to yield a light yellow solid of 4-methyl-1- (3-nitro-5- (trifluoromethyl) phenyl) -1H-imidazole (800 mg 2.95 mmol 30.8yield) 1HNMR(400 MHz CD3OD) delta 8.61-8.78 (m 1H) 8.44-8.51 (m 1H) 8.31-8.39 (m 2H) 7.55 (s 1H) 2.27 (s 3H) ES-LCMS rn/z 272.0 (M+H) |
In dimethyl sulfoxide; at 140℃; | Tetramethylammonium fluoride (200 g, 2.15 mol) was added to a solution of 1,3- dinitro-5-trifluoromethyl-benzene (200 g, 0.847 mol) in DMSO (2 L). The mixture was heated to 100-110 0C for 4 h. TLC (Petroleum ether: EtOAc=20:l) showed -50% of starting material has been converted into mono fluoro substituted intermediate. 4-Methyl- IH- imidazole (200 g, 2.43 mol) was added to the reaction mixture, and the resulting solution was heated to 140 0C overnight. TLC (Petroleum ether: EtOAc=20:l) showed the aforementioned intermediate disappeared. The reaction mixture was cooled to room temperature, and then added with water (10 L). The resulting mixture was extracted with DCM (2 L x 2). The combined organic layers were concentrated to give a crude product, which was purified by chromatography (silica, elute; Petroleum ether: EtOAc = 5:1?3:1) to give the title compound (34 g, 15%) as a yellow solid. | |
With potassium carbonate; | : In post-3-nitro-5-trifluoromethyl-fluorophenyl and 4-methylimidazole,obtained by stannous chloride reduction of the nitro |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With caesium carbonate; In acetonitrile;Heating / reflux; | A mixture of 2-chloro-5-nitro-toluene (2.0 g, 12 mmol), of 4-methylimidazole (1.0 g, 12 mmol) and of cesium carbonate (5.7 g, 17.5 mmol) in acetonitrile (20 mL) was refluxed overnight. The reaction mixture was cooled, quenched by addition of water and extracted with ethyl acetate. The solvent was removed under reduced pressure and the crude material was purified by column chromatography on silica gel using ethyl acetate as eluent to yield the title compound (1.27 g, 50%) as a slightly brownish solid. MS ISP (m/e): 218.3 (100) [(M+H)+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17.2% | In acetonitrile; at 90℃; for 3h; | 2-cyano-4-fiuoronitrobenzene (29.5 g, 177.6 mmol) and 4-methylimidazole (29.1g, 354.4 mmol) were dissolved in acetonitrile (300 mL), the reaction mixture was then heated at 900C for 3 hours.The solution was cooled at r.t. and the solvent evaporated, the residue (constituted of about 85:15 regioisomeric mixture of 4/5 methyl-isomers) was partitioned between AcOEtZH2O (5/2), the separated organic layer was washed with water, brine and then evaporated. The orange residue was crystallized from acetone/heptane. This gave a first crop of the titled product 25.0 g (62%), the mother liquor was concentrated and the residue was chroma- tographed over silica gel (acetone/heptane 1 :3 to 1:1, to 3:1) to provide further 7.0 g (17.2%) of the pure title compound.TLC: (SiO2, 245 nm) acetone/heptane (3:1) Rf: 0.50; C11H10N4O2, MW: 230.23; 1H-NMR (300 MHz, CDCl3) ppm: 2.3 (s, 3H), 7.10 (t, IH), 7.63 (d, IH), 7.75 (dd, IH), 7.86 (d, IH), 7.91 (d, IH), 8.44 (d, IH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | With potassium hydroxide; In N,N-dimethyl-formamide; at 20.0℃; for 16.0h; | 4-methoxy-2-(4-methyl-1H-imidazol-1-yl)-3-nitropyridine To a mixture of <strong>[6980-09-2]2-chloro-3-nitro-4-methoxypyridine</strong> (2.0 g, 10.6 mmol) and 4-methylimidazole (1.3 g, 15.9 mmol) in 20 mL of DMF was added freshly powdered KOH (0.9 g, 15 mmol). The resulting mixture was stirred at rt for 16 h. The reaction was poured into water and extracted with ethyl acetate (3*). Standard work-up followed by column chromatography using 50% ethyl acetate in hexane provided the product (0.65 g, 28% yield). MS (ESI) 235.0 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; | <strong>[66684-61-5]1,5-difluoro-3-methoxy-2-nitrobenzene</strong> (7 g, 37.0 mmol) and 4-methyl-1H-imidazole (3.04 g, 37.0 mmol) were dissloved in DMF (100 mL). To this was added potassium carbonate (10 g, 74 mmol)). The reaction was stirred at RT overnight then poured into water and extracted with ethyl acetate. The organic layer was separated, washed with water, brine, then dried over MgSO4 and filtered. The solvent was removed under reduced pressure and the crude purified by flash chromatography on silica gel in 50% to 70%. Ethyl acetate/hexane 4.5 g of a pale yellow solid was recovered. MS [(+)ESI] m/z=252.1 [M-H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 85℃; | A mixture of 4-methyl imidazole (500 mg, 6 mmol), 2-fluoro-5-nitro anisole (1.02 g, 5.9 mmol) and potassium carbonate (1.68 g, 12 mmol) in DMF (15 mL) was heated overnight at 850C in a sealed tube. The reaction mixture was cooled, transferred into a round bottom flask using ethyl acetate and concentrated under high vacuum to 5 mL volume. The residue was suspended in water and extracted with dichloromethane (3 x 25 mL). The organic extracts were combined, washed with brine, dried over anhydrous MgSO4, filtered and concentrated to give an orange solid. The solid was dissolved in dichloromethane (10 mL) and diluted with hexane until the solution became slightly turbid. The turbid solution was left at room temperature. The separated orange solid was filtered, washed with hexane to give l-(2-methoxy-4-nitro-phenyl)-4-methyl-lH-imidazole and l-(2-methoxy-4-nitro- phenyl)-5 -methyl- lH-imidazole (577 mg, 43 percent).1H NMR (400 MHz, methanol- d4) delta ppm 2.25 (s, 3 H) 4.02 (s, 3 H) 7.21 (s, 1 H) 7.62 (d, 1 H) 7.92 - 8.02 (m, 2 H) 8.04 (s, 1 H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15% | With caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 1h;Inert atmosphere; | 4-Fluoro-3-methoxybenzaldehyde (85 g, 0.55 mol), 4-methyl-1 /-/-imidazole (90.5 g,1.1 mol) and cesium carbonate (268.8 g, 0.82 mol) were combined in dimethylformamide (1.7 L) and stirred at 100 0C for 1 hour. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated in vacuo. The residue was dissolved in water (2 L) and extracted with ethyl acetate (3 x 2 L). The combined organic layers were washed with water and brine, dried over sodium sulfate, and concentrated under reduced pressure. Chromatography on silica (Eluant: 2:1 petroleum ether: ethyl acetate) afforded a yellow solid, which was recrystallized from ethyl acetate (300 mL) to provide the title compound as a white solid. Yield: 17.8 g, 0.082 mol, 15%. 1H NMR (300 MHz, CDCI3) delta 2.31 (d, J=1.0 Hz, 3H), 3.97 (s, 3H), 7.01 (m, 1H), 7.45 (d, J=7.8 Hz, 1 H), 7.54-7.58 (m, 2H), 7.83 (d, J=1.3 Hz, 1 H), 10.01 (s, 1 H). |
With potassium carbonate; In dimethyl sulfoxide; at 100℃; for 72h; | General procedure: A solution of 4-fluoro-3-methoxybenzaldehyde (100mg, 0.65mmol), 1-methylpiperazine (65mg, 0.65mmol) and potassium carbonate (90mg, 0.65mmol) in DMSO (0.6mL) was stirred at 100C for 3 days. The reaction mixture was diluted with water and extracted with diethyl ether (3 x 15mL). The combined organic layers were dried over MgSO4, filtrated and concentrated in vacuum to give 85mg (56%) as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 96h;Inert atmosphere; | 4-Methylimidazole (249 mg, 3.03 mmol), 4-fluoro-3-methoxybenzonitrile (417 mg, 2.76 mmol), and cesium carbonate (1.89 g, 5.80 mmol) were placed in a reaction vessel in a nitrogen gas atmosphere, N,N-dimethylformamide (5.0 mL) was added to the vessel and the resultant mixture was stirred at room temperature for 96 hours. To the reaction mixture were successively added water (2 mL) and ethyl acetate (6 mL) to perform an extraction, and the aqueous layer was separated and then, the organic layer was washed with water (5 mL). To the organic layer were added ethyl acetate (5 mL) and water (5 mL) to perform an extraction, and the aqueous layer was separated and then, the organic layer was washed with water (5 mL) and concentrated under a reduced pressure to obtain 499 mg of a crude product. To the crude product was added tert-butyl methyl ether (2.5 mL) to obtain a suspension, and the solids collected by filtration of the suspension were washed with tert-butyl methyl ether/heptane (2.5 ml; 1 :3) three times to obtain 431 mg of a crude product. To the obtained crude product was added tert-butyl methyl ether (4.3 mL) in a nitrogen gas atmosphere, and the resultant mixture was stirred at 50C for 30 minutes and then naturally cooled to room temperature, and the solids collected by filtration were washed with tert-butyl methyl ether/heptane (2.1 mL; 1 :3) twice and dried under a reduced pressure to obtain 310 mg of a title compound. Yield: 53%. |
49.9% | With potassium carbonate; In dimethyl sulfoxide; at 120℃; for 1h; | Example Al a) Preparation of intermediate 1. K2CO3 (112 g, 0.81 mol) was added to a stirred sol. of 4-methylimidazole (66.0 g, 0.804 mol) in DMSO (600 ml). The r.m. was heated at 120 0C. Subsequently 4-fluoro- 3-methoxybenzonitrile (60.0 g, 0.397 mol) was added portionwise (internal reaction temperature increased to 140 0C). The r.m. was maintained at 120 0C for 1 h, was cooled, and was then poured onto ice-water (3 1). This mixture was stirred for 30 min. The precipitated solid was collected by filtration and washed with H2O. The off-white solid was recrystallised from MeCN to yield 30.0 g of intermediate 1. A second crop of product was obtained from the mother liquor. Yield: 12.3 g of intermediate 1(combined yield; 49.9 %). |
39% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 135 - 140h;Inert atmosphere; | 4-Fluoro-3-methoxybenzonitrile (98.2 g, 0.65 mol) was combined with 4-methyl-1 /-/- imidazole (53.4 g, 0.65 mol) and anhydrous potassium carbonate (138.2 g, 1 mol, 1.54 eq) in dimethylformamide (650 ml_), and the reaction mixture was stirred for 16 hours at 135-140 0C (internal temperature). The mixture was cooled to room temperature and filtered; the salts were washed with dichloromethane (3 x 30 ml_). The combined filtrates were evaporated in vacuo to afford a brown semisolid, which was suspended in water (500 ml_) and left to stand at 5 0C for 24 hours. The mixture was filtered, and the solid was washed with ice water (2 x 50 ml_), then dried in vacuo to afford a yellow solid (105.5 g). Crystallization from methanol (106 ml_) provided purified product (66.3 g) as yellowish crystals. These were boiled with acetone (100 ml_) for 5 minutes and the mixture was left to cool overnight. The mixture was filtered, and the crystals were washed with acetone (2 x 10 ml_) to afford the title compound as a white solid. Yield: 54.6 g, 0.256 mmol, 39%. 1H NMR (400 MHz, CDCI3) delta 2.31 (d, J=1.0 Hz, 3H), 3.94 (s, 3H), 6.97 (m, 1 H), 7.30 (m, 1 H), 7.37 (m, 2H), 7.79 (d, J=1.4 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 110℃; for 1h; | 5-ethynyl-2-(4-methyl-1H-imidazol-1-yl)-1,3-thiazole. A mixture of 2-bromo-1,3-uuazole-5-carbaldehyde (10 mg, 0.068 mmol), 4-methyl-1H-imidazole (7.23 mg,0.088mmol), potassium carbonate (28.1 mg, 0.203 mmol) and DMF (5 ml) were heated at 1100C for 1h. The mixture was purified on silica gel (EtOAc/hexane 8:2) to afford 2-(4-methyl-1H-imidazol-1-yl)-1,3-thiazole-5-carbaldehyde (38.4 mg, 0.199 mmol) as a yellow solid. This aldehyde (38.4 mg, 0.199 mmol) and anhydrous potassium carbonate (110 mg, 0.795 mmol) were placed in a 25-ml flask and placed on high vacuum for 10 min. Under N2, anhydrous MeOH (2 ml) was added. To the suspension was added dimethyl (1-diazo-2- oxopropyl) phosphonate (40 mul, 0.256 mmol). The reaction was stirred at rt for 22 h. The mixture was diluted with DCM, washed with water, dried over sodium sulfate, concentrated to afford crude product, which was used in next step directly. MS calc'd 190.0 (MH+), exp 190.0 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 5 3-(4-Wlethyl-imidazol-1-yl)-5-trifluoromethyl-phenylamine (I)Sodium hydride (12.18g, 55-65% m/m, Fluka 71620) is suspended in tetrahydrofuran (60 mL) and a solution of 4-methylimidazole (24.5 g) in tetrahydrofuran (65 mL) is slowly added to the stirred suspension at 20-250C. Gentle cooling is necessary to maintain the temperature at 20-250C during the addition. After completion of the addition, the reaction mixture is stirred for additional 15 minutes at 20-250C, until gas evolution had ceased. A solution of <strong>[454-67-1]3-fluoro-5-trifluoromethyl-phenylamine</strong> (XlX) (25 g) in 1-methyl-2-pyrrolidone (125 mL) is added slowly to the reaction mixture and the mixture is stirred for additional 15 minutes at 20-250C. Then, the reaction mixture is heated at an oil bath temperature of 1000C to distill off the volatile solvent (tetrahydrofuran). Finally, the temperature is raised to 165C (oil bath) and the reaction mixture is stirred for 22 hours at this temperature. For work up, the reaction mixture is poured onto water (500 mL) and the water phase is extracted with f-butyl methyl ether (2 x 500 mL). The f-butyl methyl ether phases are combined and are extracted with water (2 x 500 mL). The organic layer is dried on anhydrous magnesium sulfate (19 g) and the solvent is evaporated at 45C under reduced pressure to obtain crude 3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenylamine as a yellowish solid. The crude product is contaminated with at least 1 regioisomer. The crude product is dissolved in toluene (93.4 g) at 80-90C and the solution is allowed to cool down to room temperature. Crystallization occurred at ca. 35-40C. The suspension is stirred for additional 2 hours at room temperature and the product is isolated by filtration. The filter cake is washed with ice- cold toluene (25 mL) and dried in vacuo at 5O0C to obtain pure 5-(4-methyl-imidazol-1-yl)-3- trifluoromethyl-phenylamine (I). GC-MS: m/z 241 , 222, 213, 200, 186, 172, 160.1H-NMR (400 MHz, DMSO-d6): delta 2.15 (3H), 5.85 (2H), 6.79 (1 H), 6.91 (1H), 6.95(1 H), 7.34 (1H), 8.04 (1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | Example 1 Synthesis of 1-[3-Bromo-5-(trifluoromethyl)phenyl]-4-methyl-1H- imidazole (XXVI)Scheme 12(XXVI)A 2 L, 4-neck, round-bottom flask equipped with a mechanical stirrer, a digital thermometer, heatingZcooling capacity, an addition funnel, and a nitrogen inlet/outlet is EPO <DP n="16"/>charged 1-methyl-2-pyrrolidinone (113 g) and sodium hydride (8.0 g, 60% in oil) under nitrogen purge. The mixture is stirred at 20-250C for 15 minutes. A solution of 4-methylimidazole (17.6 g) and 1-methyl-2-pyrrolidinone (181 g) is slowly added to the mixture over 30 minutes, maintaining the batch temperature between 20-25C. After the addition, the mixture is stirred at 20-250C for 2 hours. A solution of 3-bromo-5- fluorobenzotrifluoride (XXV) (40 g) and 1-methyl-2-pyrrolidinone (76 g) is slowly added into the mixture over 10 minutes, maintaining the batch temperature between 20-250C. After the addition, the mixture is stirred at 20-250C for 16 hours.Water (720 g) is slowly added to the mixture over 3 hours, maintaining the batch temperature between 20-250C. After the addition, the mixture is stirred at 20-25C for 1 hour. Any solid is isolated by filtration, rinsed with a solution of 1-methyl-2-pyrrolidinone (41 g) and water (100 g), and then rinsed with water (100 g). The solid is air-dried in the funnel for 1 hour.A 2 L, 4-neck , round-bottom flask under nitrogen purge is charged with the solid (~50 g) and ethyl acetate (361 g). The mixture is stirred for 5 minutes at 20-25C until a solution is obtained. The solution is washed with water (2 x 100 g). The organic layer is distilled at 100 mm Hg at 400C until a residual volume of 100 ml_ is reached. Heptane (342 g) is added, and the mixture is distilled at 400 mm Hg at 60C until a residual volume of 300 ml. is reached. This operation is repeated one more time. The residue is cooled from 55C to 200C over 5 hours, and stirred for an additional 1 hour at 200C. The mixture is cooled to 5C over 1 hour and stirred for an additional 1 hour at 5C. Any solid is isolated by filtration and rinsed with cold (50C) heptane (68 g). The cake is dried at 5 mm Hg/20-25C for 4 hours to yield (XXVI) (24.3 g, 48% yield) as a white solid:1H NMR 300 MHz, DMSOd6), delta 8.45 (s, 1 H), 8.30 (s, 1H), 8.10 (s, 1H), 7.90 (s, 1H), 7.70 (s, 1 H), 2.10 (s, 3H). EPO <DP n="17"/> |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydride; potassium iodide; In N,N-dimethyl-formamide; at 20 - 80℃; | Example 2; N-(5-tert-butyl~2-methylphenyl)-7-rnethyl-2- {4-[2-(4-methyl- 1 H-imidazol- 1 -yl)ethyl]piperidin- 1 -yl } -7H-purin-6-amine; To a solution of 4-methyI-l //-imidazole (100 mg, 1.22 mmol) and sodium hydride (60 mg, 1.49 mmol) in DMF (6 niL) was added /erf-butyl-4-(2-bromoethyl)rhoiperidine-l-carboxylale (427 mg, 1.46 mmol) and potassium iodide (40 mg, 0.24 mmol). The reaction mixture was heated at 80 0C for 2h and then cooled to RT and stirred overnight. The reaction mixture was diluted with CH2Cl2 (10 mL) and washed with H2O (1 x 10 mL). The aqueous layer was further extracted with CH2Cl2 (1 x 10 mL) and the combined organics dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash chromatography (2-10% MeOH/CH2Cl2) to give an inseparable mixture of imidazole regioisomers confirmed by MS (ESI+): cal'd [M+H]+ 294.2, obs. 294.2. The mixture was treated with TFA (1 mL) in CH2Cl2 (2 mL) and stirred overnight at RT. The reaction mixture was then concentrated and purified by flash chromatography (5-15% MeOH/ CH2Cl2) to give 236 mg (99%) of a 2: 1 mixture of isomers favoring the external methyl imidazole confirmed by MS (ESH-): cal'd [M+H]+ 194.2, obs. 194.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 2; N-(5-tert-butyl~2-methylphenyl)-7-rnethyl-2- {4-[2-(4-methyl- 1 H-imidazol- 1 -yl)ethyl]piperidin- 1 -yl } -7H-purin-6-amine; To a solution of 4-methyI-l //-imidazole (100 mg, 1.22 mmol) and sodium hydride (60 mg, 1.49 mmol) in DMF (6 niL) was added /erf-butyl-4-(2-bromoethyl)rhoiperidine-l-carboxylale (427 mg, 1.46 mmol) and potassium iodide (40 mg, 0.24 mmol). The reaction mixture was heated at 80 0C for 2h and then cooled to RT and stirred overnight. The reaction mixture was diluted with CH2Cl2 (10 mL) and washed with H2O (1 x 10 mL). The aqueous layer was further extracted with CH2Cl2 (1 x 10 mL) and the combined organics dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash chromatography (2-10% MeOH/CH2Cl2) to give an inseparable mixture of imidazole regioisomers confirmed by MS (ESI+): cal'd [M+H]+ 294.2, obs. 294.2. The mixture was treated with TFA (1 mL) in CH2Cl2 (2 mL) and stirred overnight at RT. The reaction mixture was then concentrated and purified by flash chromatography (5-15% MeOH/ CH2Cl2) to give 236 mg (99%) of a 2: 1 mixture of isomers favoring the external methyl imidazole confirmed by MS (ESH-): cal'd [M+H]+ 194.2, obs. 194.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 2; N-(5-tert-butyl~2-methylphenyl)-7-rnethyl-2- {4-[2-(4-methyl- 1 H-imidazol- 1 -yl)ethyl]piperidin- 1 -yl } -7H-purin-6-amine; To a solution of 4-methyI-l //-imidazole (100 mg, 1.22 mmol) and sodium hydride (60 mg, 1.49 mmol) in DMF (6 niL) was added /erf-butyl-4-(2-bromoethyl)rhoiperidine-l-carboxylale (427 mg, 1.46 mmol) and potassium iodide (40 mg, 0.24 mmol). The reaction mixture was heated at 80 0C for 2h and then cooled to RT and stirred overnight. The reaction mixture was diluted with CH2Cl2 (10 mL) and washed with H2O (1 x 10 mL). The aqueous layer was further extracted with CH2Cl2 (1 x 10 mL) and the combined organics dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash chromatography (2-10% MeOH/CH2Cl2) to give an inseparable mixture of imidazole regioisomers confirmed by MS (ESI+): cal'd [M+H]+ 294.2, obs. 294.2. The mixture was treated with TFA (1 mL) in CH2Cl2 (2 mL) and stirred overnight at RT. The reaction mixture was then concentrated and purified by flash chromatography (5-15% MeOH/ CH2Cl2) to give 236 mg (99%) of a 2: 1 mixture of isomers favoring the external methyl imidazole confirmed by MS (ESH-): cal'd [M+H]+ 194.2, obs. 194.1.; Step 2:; A mixture of the imidazole regioisomers (88 mg, 0.46 mmol), Hnig's base (1.5 niL), and the chloro methyl purine of Example 1 Step 1 (100 mg, 0.303 mmol) in 2-prorhoanol (1.5 mL) was heated for 2h at 190 0C in the microwave. The reaction mixture was then concentrated and purified by flash chromatography (2-10% MeOH/CH2CI2, D - 210 nM) to give 87 mg (59%) of a 2:1 mixture of amino methyl purine imidazole regioisomers, which were separated by HPLC (Chiralcel OJ, 30% EtOH/heptane, flow rate = 0.75 mL/min, D = 254 nM, tR = 8.76 min. (major); tR = 12.76 min. (minor)) and confirmed by MS (ESI+): cal'd [M+H]+ 487.3, obs. 487.2 and 1H NMR (CDCI3) D 7.83 (d, IH5 J= 1.1 Hz), 7.62 (s, IH), 7.53 (s, IH), 7.14 (d, IH, J= 8.0 Hz), 7.08 (dd, IH, J, = 7.9 Hz, J2 = 1.5 Hz), 6.62 (s, IH), 6.34 (s, IH), 4.78 (d, 2H, J- 13.1), 3.91 (t, 2H, J= 7.4), 3.81 (s, 3H), 2.76 (t, 2H, J- 12.0 Hz), 2.28 (s, 3H), 2.22 (s, 3H), 1.70 (q, 2H, J= 7.5 Hz), 1.67 (br d, 2H, J = 12.7 Hz), 1.56-1.37 (m, IH), 1.31-1.11 (m, 13H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With potassium carbonate; In dimethyl sulfoxide; at 20 - 45℃; | Example 43 b. 3-methoxy-2-(4-methyl-lH-imidazol-l-yl)-5-nitropyridine To a suspension of 4-methyl-lH-imidazole (0.522 g, 6.36 mmol) and potassium carbonate (1.832 g, 13.26 mmol) in DMSO (20 mL) at room temperature was added 2-chloro-3- methoxy-5-nitropyridine (1.0 g, 5.30 mmol). The reaction mixture was stirred at 45C overnight. About 20 mL warm water (heated to 500C) was added to the reaction mixture and the precipitated solid was immediately filtrated and washed with warm water. The solid was dried in the dry vacuum oven at 400C for two days giving 0.914 g of the title compound as an isomeric mixture (74 % Yield). 1H NMR (400 MHz, DMSO-J6) delta ppm 8.90 - 8.94 (m, 1 H), 8.45 (s, 1 H), 8.32 - 8.37 (m, 1 H), 7.66 - 7.70 (m, 1 H), 4.10 (s, 3 H), 2.15 - 2.20 (m, 3 H). MS m/z 235 [M+H] +. |
72% | With potassium carbonate; In dimethyl sulfoxide; at 45℃; for 16h;Inert atmosphere; | Synthesis of 3-methoxy-2-(4-methyl-lH-imidazol-l-yl)-5-nitropyridine [0328] To a stirred solution of <strong>[75711-00-1]2-chloro-3-methoxy-5-nitropyridine</strong> (2 g, 10.60 mmol) in DMSO (40 mL) under argon atmosphere were added potassium carbonate (3.65 g, 26.51 mmol) and 4-methyl-lH-imidazole (1 g, 12.72 mmol) at RT. The reaction mixture was stirred at 45 C for 16 h. After consumption of the starting materials (monitored by TLC), the reaction was diluted with hot water (40 mL). The obtained solid was filtered and dried in vacuo to afford 3-methoxy-2-(4-methyl-lH-imidazol-l-yl)-5-nitropyridine (1.8 g, 72%) as a yellow solid. 1H-NMR (DMSO-<, 400 MHz): delta 8.92-8.90 (m, 1H), 8.45 (s, 1H), 8.36-8.32 (m, 1H), 7.68 (s, 1H), 4.10 (s, 3H), 2.20 (s, 3H); LC-MS: 235 (M+l); (column; X-Bridge C- 18 (50 3.0 mm, 3.5 mu); RT 2.09 min. 0.05% aq TFA: ACN; 0.80 mL/min); TLC: 5% MeOH:CH2Cl2 (R 0.4). |
72% | With potassium carbonate; In dimethyl sulfoxide; at 20 - 45℃; for 16h;Inert atmosphere; | To a stirred solution of <strong>[75711-00-1]2-chloro-3-methoxy-5-nitropyridine</strong> (2 g, 10.60 mmol) in DMSO (40 mL) under an argon atmosphere were added potassium carbonate (3.65 g, 26.51 mmol) and 4-methyl-1H-imidazole (1 g, 12.72 mmol) at room temperature. The reaction mixture was stirred at 45 oC for 16 h. After consumption of the starting material (monitored by TLC), the reaction mixture was diluted with water (40 mL) to obtain solid which was filtered and dried in vacuo to afford 3-methoxy-2-(4-methyl-1H-imidazol-1 -yl)-5- nitropyridine (1.8 g, 72%) as a yellow solid. 1H-NMR (DMSO-d6, 400 MHz): delta 8.92-8.90 (m, 1H), 8.45 (s, 1H), 8.36-8.32 (m, 1H), 7.68 (s, 1H), 4.10 (s, 3H), 2.20 (s, 3H); LC-MS: 235 (M+1); (column; X-Bridge C-18 (50 × 3.0 mm, 3.5 mum); RT 2.09 min. 0.05% aq TFA: ACN; 0.80 mL/min); TLC: 5% MeOH/ CH2Cl2 (Rf: 0.4). |
72% | With potassium carbonate; In dimethyl sulfoxide; at 45℃; for 16h;Inert atmosphere; | Synthesis of 3-methoxy-2-(4-methyl-1H-imidazol-1-yl)-5-nitropyridine To a stirred solution of <strong>[75711-00-1]2-chloro-3-methoxy-5-nitropyridine</strong> (2 g, 10.60 mmol) in DMSO (40 mL) under an argon atmosphere were added potassium carbonate (3.65 g, 26.51 mmol) and 4-methyl-1H-imidazole (1 g, 12.72 mmol) at room temperature. The reaction mixture was stirred at 45 C. for 16 h. After consumption of the starting material (monitored by TLC), the reaction mixture was diluted with water (40 mL) to obtain solid which was filtered and dried in vacuo to afford 3-methoxy-2-(4-methyl-1H-imidazol-1-yl)-5-nitropyridine (1.8 g, 72%) as a yellow solid. 1H-NMR (DMSO-d6, 400 MHz): delta 8.92-8.90 (m, 1H), 8.45 (s, 1H), 8.36-8.32 (m, 1H), 7.68 (s, 1H), 4.10 (s, 3H), 2.20 (s, 3H); LC-MS: 235 (M+1); (column; X-Bridge C-18 (50*3.0 mm, 3.5 mum); RT 2.09 min. 0.05% aq TFA: ACN; 0.80 mL/min); TLC: 5% MeOH/CH2Cl2 (Rf: 0.4). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | With caesium carbonate;copper(l) iodide; In N,N-dimethyl-formamide; at 140 - 150℃; for 2h;Inert atmosphere; Microwave; | Example 6a 6-Methoxy-5-(4-methylimidazol-1-yl)pyridin-2-ylamine A mixture of <strong>[1211533-83-3]5-bromo-6-methoxypyridin-2-amine</strong> (CAS 1211533-83-3, 573 mg, 2.82 mmol), 4-methyl-1H-imidazole (CAS 822-36-6, 324 mg, 3.95 mmol), copper(I)iodide (107 mg, 0.56 mmol) and cesium carbonate (1839 mg, 5.64 mmol) in DMF (5 mL) was heated to 140 C. under argon atmosphere in a microwave reactor for 1 h and then at 150 C. for 1 h. The reaction mixture was diluted with DCM and MeOH and filtered through a plug of Celite. The solvent was evaporated and the residue was purified by HPLC to give the title product (128 mg, 22%). 1H NMR (500 MHz, DMSO-d6) delta ppm 2.11 (m, 3H) 3.77 (s, 3H) 6.05 (d, 1H) 6.19 (s, 2H) 6.92 (t, 1H) 7.33 (d, 1H) 7.54 (d, 1H). MS m/z 205.1 [M+H]+. |
22% | With copper(l) iodide; caesium carbonate; In N,N-dimethyl-formamide; at 140 - 150℃; for 2h;Inert atmosphere; Microwave reactor; | Example 9d. 6-methoxy-5 -(4-methyl- 1 H-imidazol- 1 -yl)pyridin-2-amineA mixture of <strong>[1211533-83-3]5-bromo-6-methoxypyridin-2-amine</strong> (573 mg, 2.82 mmol), 4-methyl-lH- imidazole (324 mg, 3.95 mmol), copper iodide (107 mg, 0.56 mmol) and CS2CO3 (1839 mg, 5.64 mmol) in DMF (5 mL) was heated to 1400C under argon atmosphere in a microwave reactor for 1 h and then at 1500C for 1 h. The reaction mixture was diluted with dichloromethane and methanol and filtered through a plug of Celite. The solvent was evaporated and the residue was purified by preparative HPLC to give 128 mg of the title product (22 % Yield).1H NMR (500 MHz, DMSO-J6) delta ppm 7.54 (d,l H) 7.33 (d, 1 H) 6.92 (t, 1 H) 6.19 (s, 2 H) 6.05 (d, 1 H) 3.77 (s, 3 H) 2.11 (m, 3 H).MS m/z 205 [M+H]+ 203 [M-H]" |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With copper(l) iodide; 1-(5,6,7,8-tetrahydroquinolin-8-yl)ethan-1-one; caesium carbonate; In N,N-dimethyl-formamide; at 130℃; for 24h;Inert atmosphere; | General procedure: A mixture of CuI (190mg, 1mmol), 4-methyl-1H-imidazole (1.64g, 20mmol), Cs2CO3(3.25g, 10mmol), 3-bromo-5-(trifluoromethyl)aniline (2.40g, 10 mmol), 1-(5,6,7,8-tetrahydroquinolin-8-yl)ethanone (350mg, 2mmol) and DMF (30mL) was added to a bottom, the bottom was evacuated and backfilled with argon (this procedure was repeated three times), then the mixture was heated to 130 C for 24 h under argon. After cooling to room temperature, the solvent was removed under vacuum and the residue was purified by column chromatography on silica gel to afford the crude product. The crude product was recrystallized as a white solid (1.7 g, 71%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | Step 1 . Preparation of methyl 5-chloro-6-(4-methyl-1 /-/-imidazol-1 - yl)nicotinate (C4). Methyl 5,6-dichloronicotinate (800 mg, 3.88 mmol), 4-methyl-1 H- imidazole (638 mg, 7.77 mmol) and cesium fluoride (1 .18 g, 7.77 mmol) were combined and the flask was purged with nitrogen. Dimethyl sulfoxide (9.7 mL) was added and the reaction was heated to 100 C for 15 minutes. The reaction mixture was then partitioned between aqueous sodium bicarbonate solution (100 mL) and ethyl acetate (100 mL), and the aqueous layer was extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with aqueous sodium bicarbonate solution (50 mL) and brine (50 mL), dried over magnesium chloride, filtered and concentrated in vacuo. Chromatography on silica (Gradient: 40% to 80% ethyl acetate in heptane) afforded the title compound as a white solid. Yield: 604 mg, 2.40 mmol, 62%. LC S m/z 252.4, 254.4 (M+1 ). 1 H NMR (400 MHz, CDCI3) delta 2.32 (br s, 3H), 4.00 (s, 3H), 7.48 (m, 1 H), 8.32 (d, J=1 .2 Hz, 1 H), 8.47 (d, J=1 .9 Hz, 1 H), 8.98 (d, J=1 .9 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | Synthesis of 4-methoxy-5-(4-methyl-lH-imidazol-l-yl) picolino nitrile [0324] To a stirred solution of 4-methyl-lH-imidazole (580 mg, 7.04 mmol) in acetonitrile (24 mL) under argon atmosphere were added potassium carbonate (1.3 g, 9.38 mmol) and 18 crown-6 (2.47 g, 9.38 mmol) at RT. The reaction mixture was stirred at 60 C for 2 h. Then <strong>[1256823-07-0]5-bromo-4-methoxypicolinonitrile</strong> (1 g, 4.69 mmol) was added to the reaction mixture and stirred at reflux for 18 h. After consumption of the starting materials (monitored by TLC), the reaction was diluted with water (20 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography using 90%> EtOAc:hexanes to afford 4-methoxy-5-(4-methyl-lH-imidazol-l-yl) picolino nitrile (250 mg, 25%) as a yellow solid. 1H-NMR (CDC13, 500 MHz): delta 8.58 (s, 1H), 7.82 (s, 1H), 7.39 (s, 1H), 6.99 (s, 1H), 401 (s, 3H), 2.23 (s, 3H); LC-MS: 215 (M+l); (column; X-Bridge C-18 (50 3.0 mm, 3.5 mu); RT 2.45 min. 0.05% Aq TFA: ACN; 0.8 mL/min); TLC: EtOAc (R 0.2). | |
25% | To a stirred solution of 4-methyl-1H-imidazole (580 mg, 7.04 mmol) in acetonitrile (24 mL) under an argon atmosphere were added potassium carbonate (1.3 g, 9.38 mmol) and 18-crown-6 (2.47 g, 9.38 mmol) at room temperature. The reaction mixture was stirred at 60 oC for 2 h. Then <strong>[1256823-07-0]5-bromo-4-methoxypicolinonitrile</strong> (1 g, 4.69 mmol) was added to the reaction mixture at room temperature. The reaction mixture was stirred at reflux for 18 h. After consumption of the starting material (monitored by TLC), the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by column chromatography using 90% EtOAc:hexanes to afford 4- methoxy-5-(4-methyl-1H-imidazol-1-yl) picolinonitrile (250 mg, 25%) as a yellow solid. 1H- NMR (CDCl3, 500 MHz): delta 8.58 (s, 1H), 7.82 (s, 1H), 7.39 (s, 1H), 6.99 (s, 1H), 401 (s, 3H), 2.23 (s, 3H); LCMS: 215 (M+1); (column; X-Bridge C-18 (50 × 3.0 mm, 3.5 mum); RT 2.45 min. 0.05% Aq TFA: ACN; 0.8 mL/min); TLC: EtOAc (Rf: 0.2). | |
25% | Synthesis of 4-methoxy-5-(4-methyl-1H-imidazol-1-yl) picolinonitrile To a stirred solution of 4-methyl-1H-imidazole (580 mg, 7.04 mmol) in acetonitrile (24 mL) under an argon atmosphere were added potassium carbonate (1.3 g, 9.38 mmol) and 18-crown-6 (2.47 g, 9.38 mmol) at room temperature. The reaction mixture was stirred at 60 C. for 2 h. Then <strong>[1256823-07-0]5-bromo-4-methoxypicolinonitrile</strong> (1 g, 4.69 mmol) was added to the reaction mixture at room temperature. The reaction mixture was stirred at reflux for 18 h. After consumption of the starting material (monitored by TLC), the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2*30 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by column chromatography using 90% EtOAc:hexanes to afford 4-methoxy-5-(4-methyl-1H-imidazol-1-yl) picolinonitrile (250 mg, 25%) as a yellow solid. 1H-NMR (CDCl3, 500 MHz): delta 8.58 (s, 1H), 7.82 (s, 1H), 7.39 (s, 1H), 6.99 (s, 1H), 401 (s, 3H), 2.23 (s, 3H); LCMS: 215 (M+1); (column; X-Bridge C-18 (50*3.0 mm, 3.5 mum); RT 2.45 min. 0.05% Aq TFA: ACN; 0.8 mL/min); TLC: EtOAc (Rf: 0.2). |
16% | Step 3. Preparation of 4-methoxy-5-(4-methyl-1 /-/-imidazol-1 -yl)pyridine-2- carbonitrile (C3). 4-Methyl-1 /-/-imidazole (15 g, 0.18 mol), potassium carbonate (34 g, 0.25 mol) and 18-crown-6 (64 g, 0.24 mol) were combined in acetonitrile (600 mL), and the reaction mixture was heated to 60 C for 2 hours. 5-Bromo-4- methoxypyridine-2-carbonitrile (C2) (25 g, 0.12 mol) was added in one portion, and the reaction was heated to reflux for 18 hours. After being combined with an identical reaction mixture, the reaction was partitioned between water (500 mL) and ethyl acetate (500 mL). The aqueous layer was extracted with ethyl acetate (2 x 300 mL), and the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by chromatography on silica (Gradient: 1 :10 to 1 :2 ethyl acetate: petroleum ether) provided the title product as a white solid. Yield: 8.2 g, 0.038 mol, 16%. NMR (400 MHz, CDCI3) delta 2.30 (d, J=1 Hz, 3H), 4.02 (s, 3H), 6.96-6.97 (m, 1 H), 7.38 (s, 1 H), 7.82 (d, J=1.5 Hz, 1 H), 8.53 (s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | With potassium phosphate;copper(l) iodide; trans-1,2-Diaminocyclohexane; In 1,4-dioxane; for 0.5h;Inert atmosphere; Reflux; | Step 1 . Synthesis of 5-bromo-3-methoxy-2-(4-methyl-1 /-/-imidazol-1 - yl)pyrazine (C11 ). A solution of <strong>[476622-89-6]5-bromo-2-iodo-3-methoxypyrazine</strong> (which may be prepared according to Garg, N . K. et al., J. Am. Chem. Soc. 2002, 124, 13179- 13184) (92 g, 0.29 mol), 4-methyl-1 H-imidazole (38.5 g, 0.47 mol), K3P04 (157 g, 0.74 mol) and trans- ,2-diaminocyclohexane (15 mL, 0.12 mol) in dioxane (300 mL) was heated at reflux under a stream of argon for 15 minutes. Copper(l) iodide (5.5 g, 29 mmol) was added, and the reaction mixture was heated at reflux for an additional 30 minutes. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (1 .0 L) and chromatographed on silica (Gradient: 0% to 16% methanol in ethyl acetate) to provide the title compound. Yield: 21.7 g, 0.081 mol, 28%. 1 H N MR (400 MHz, CDCI3) delta 2.28 (s, 3H), 4.15 (s, 3H), 7.53 (s, 1 H), 8.08 (s, 1 H), 8.38 (s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
According to the described general procedure (GP11), N-alkylation of commercially available 4(5)-methylimidazole (4.343 g ; 52.90 mmol) with <strong>[53844-02-3](2-bromo-ethyl)-carbamic acid benzyl ester</strong> (15.019 g ; 58.19 mmol), and subsequent purification by FC (DCM /MeOH =10/1) afforded a mixture of [2-(4-methyl-imidazol-1-yl)-ethyl]-carbamic acid benzyl ester, and [2-(5-methyl-imidazol-1-yl)ethyl]-carbamic acid benzyl ester (ratio of regioisomers close to 1/1, according to 1H-NMR) as a yellow oil (4.270 g ; 31%). LC-MS: tR=0.68 min. (2 regioisomers); [M+H]+: 260.46 g/mol. A mixture of [2-(4-methyl-imidazol-1-yl)-ethyl]carbamic acid benzyl ester, [2-(5-methyl-imidazol-1-yl)-ethyl]-carbamic acid benzyl ester (1.198 g; 4.62 mmol; ratio of regioisomers close to 1/1, according to 1H-NMR), and 10% palladium on activated charcoal (240 mg; 20% in mass) was placed under nitrogen before addition of anh. MeOH (20 ml). The resulting mixture was placed under vacuum, and then under hydrogen (1 atm), and stirring at rt was continued for 2.5 h. Filtration over a pad of celite, concentration to dryness under reduced pressure afforded a mixture of 2-(4-methyl-imidazol-1-yl)-ethylamine, and 2-(5-methyl-imidazol-1-yl)-ethylamine as a slightly yellow oil (540 mg; 93%). LC-MS: tR=0.17 min. (2 regioisomers); [M+H]+: no ionisation. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
According to the described general procedure (GP11), N-alkylation of commercially available 4(5)-methylimidazole (4.343 g ; 52.90 mmol) with <strong>[53844-02-3](2-bromo-ethyl)-carbamic acid benzyl ester</strong> (15.019 g ; 58.19 mmol), and subsequent purification by FC (DCM /MeOH =10/1) afforded a mixture of [2-(4-methyl-imidazol-1-yl)-ethyl]-carbamic acid benzyl ester, and [2-(5-methyl-imidazol-1-yl)ethyl]-carbamic acid benzyl ester (ratio of regioisomers close to 1/1, according to 1H-NMR) as a yellow oil (4.270 g ; 31%). LC-MS: tR=0.68 min. (2 regioisomers); [M+H]+: 260.46 g/mol. A mixture of [2-(4-methyl-imidazol-1-yl)-ethyl]carbamic acid benzyl ester, [2-(5-methyl-imidazol-1-yl)-ethyl]-carbamic acid benzyl ester (1.198 g; 4.62 mmol; ratio of regioisomers close to 1/1, according to 1H-NMR), and 10% palladium on activated charcoal (240 mg; 20% in mass) was placed under nitrogen before addition of anh. MeOH (20 ml). The resulting mixture was placed under vacuum, and then under hydrogen (1 atm), and stirring at rt was continued for 2.5 h. Filtration over a pad of celite, concentration to dryness under reduced pressure afforded a mixture of 2-(4-methyl-imidazol-1-yl)-ethylamine, and 2-(5-methyl-imidazol-1-yl)-ethylamine as a slightly yellow oil (540 mg; 93%). LC-MS: tR=0.17 min. (2 regioisomers); [M+H]+: no ionisation. These primary amines were converted to the corresponding chlorhydrate salt by treatment of a solution of regioisomeric amines (540 mg ; 4.31 mmol) in dichloromethane (5 ml) with 4N HCl in 1,4-dioxane (3.25 ml ; 3 eq.). Concentration to dryness under reduced pressure afforded a beige solid which was further dried under HV. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With triethylamine; In acetonitrile; at 70℃; for 20h; | a) 1-(2,6-difluoro-4-nitrophenyl)-4-methyl-1H-imidazole; A mixture of <strong>[66684-58-0]1,2,3-trifluoro-5-nitrobenzene</strong> (15.0 g, 84.7 mmol), 4-methylimidazole (6.95 g, 84.7 mmol) and triethylamine (8.57 g, 11.8 mL, 84.7 mmol) in acetonitrile (85 mL) was stirred for 20 h at 70° C. Then it was diluted with ethyl acetate (200 mL) and washed with aqueous NaHCO3 (saturated, 60 mL) and brine (60 ml). The aqueous layers were extracted with further ethyl acetate (100 mL). The organic layers were combined, dried over sodium sulfate, filtered off and evaporated. Recrystallization with a mixture of ethyl acetate (50 mL) and heptane (30 mL) afforded the title compound as light yellow crystals (8.76 g, 43percent).MS ISP (m/e): 240.2 [(M+H)+]1H NMR (CDCl3, 300 MHz): delta (ppm)=8.04-8.01 (m, 2H), 7.74 (s, 1H), 6.98 (s, 1H), 2.32 (s, 3H). |
43% | With triethylamine; In acetonitrile; at 70℃; for 20h; | A mixture of l,2,3-trifluoro-5-nitrobenzene (15.0 g, 84.7 mmol), 4-methylimidazole (6.95 g, 84.7 mmol) and triethylamine (8.57 g, 11.8 mL, 84.7 mmol) in acetonitrile (85 mL) was stirred for 20 h at 70 °C. Then it was diluted with ethyl acetate (200 mL) and washed with aqueous NaHCC"3 (saturated, 60 mL) and brine (60 ml). The aqueous layers were extracted with further ethyl acetate (100 mL). The organic layers were combined, dried over sodium sulfate, filtered off and evaporated. Recrystallization with a mixture of ethyl acetate (50 mL) and heptane (30 mL) afforded the title compound as light yellow crystals (8.76g, 43percent).MS ISP (m/e): 240.2 [(M+H)+]1H NMR (CDCI3, 300 MHz): delta (ppm) = 8.04-8.01 (m, 2H), 7.74 (s, 1H), 6.98 (s, 1H), 2.32 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; triethylamine;copper (I) acetate; In dichloromethane; at 20℃; for 24.0h; | Example 136 (S)-N2-[1-(4-Fluorophenyl)ethyl]-4-(4-methyl-1H-imidazol-1-yl)-N6-(pyrazin-2-yl)pyridine-2,6-diamine dihydrochloride 1.10 g of 2,6-dichloro-4-(4,4,5,5,-tetramethyl-1,3,2-dioxaboran-2-yl)pyridine, 164 mg of 4-methylimidazole, 0.56 ml of triethylamine and 0.32 ml of pyridine were dissolved in 4 ml of methylene chloride, and 545 mg of copper acetate was added thereto, and the mixture was stirred at room temperature for 24 hours. The reaction solution was diluted with water, and chloroform and concentrated ammonia aqueous solution were added thereto, and the mixture was subjected to extraction. The aqueous layer was further subjected to extraction with chloroform, and the obtained organic layers were combined, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 117 mg of 2,6-dichloro-4-(4-methyl-1H-imidazol-1-yl)pyridine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With potassium carbonate; In dimethyl sulfoxide; at 55℃; for 16h;Product distribution / selectivity; | To a solution of 4-methylimidazole 4 (28.5 g, 347 mmole) in DMSO (200 ml), K2C03 (132 g, 955 mmol) and l-(3,4-difluoro-phenyl)-ethanone 7 (50.0 g, 320 mmole) were added. The reaction mixture was heated and stirred at 55C for 16 h. The reaction mixture was allowed to cool to room temperature and water (600 mL) was added. The reaction mixture was stirred for another 60 min. The precipitate was collected, washed with water (~ 2L) and dried under vacuum overnight to yield the crude product. Recrystallization of the crude product afforded the desired product 8 (32.5 g, 59% yield). |
58% | With potassium carbonate; In dimethyl sulfoxide; at 55℃; for 18h;Inert atmosphere; | To a solution of 4-methylimidazole (65, 3.50 g, 42.6 mmol) in DMSO (25 mL)was added potassium carbonate (16.35 g, 0.118 mol). 3,4-Difluoroacetophenone (49, 6.16 g, 39.5 mmol) was added to theresulting suspension and the reaction mixture was heated to 55 C for 18h. The reaction was cooled to roomtemperature, water (80 mL) was added, and the resulting mixture stirred for 1 hat room temperature. The resultingprecipitate was collected by filtration, washed with water (500 mL), and then driedovernight in a vacuum oven at 50 C to afford an orange solid. The solid was further triturated with diethylether to afford 1-(3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl)ethanone(50) as a light brown solid (4.98 g,58%) that was suitable for use without further purification: 1H NMR (500 MHz, DMSO-d6) delta 8.03 (s, 1H), 8.01-7.96 (m, 1H), 7.92-7.89 (m,1H), 7.82-7.78 (m, 1H), 7.38 (s, 1H), 2.63 (s, 3H), 2.18 (s, 3H). |
With potassium carbonate; In dimethyl sulfoxide; at 80℃; | In a similar procedure as described above, 1-(3, 4-difluoro-phenyl)-propan-1-one was reacted with 4-methyl-imidazole to give compound 13. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With potassium carbonate; In dimethyl sulfoxide; at 110℃; for 22h;Product distribution / selectivity; | l-(6-chloro-pyridin-3-yl)-ethanone 5(7.0 g, 45.2 mmof} and 4-methyliminazole 4 (11.1 g, 135.5 mmole) were combined in DMSO (35 mL), followed by addition of K2C03. The mixture was heated at 110DC for 22 h. The reaction mixture was then cooled to room temperature and poured into ice water (400 mL) with vigorous stirring for 15 min. The resulting precipitate was collected on a filter and washed with water. The resulting material was dried in vacuo to yield 6 as a tan solid (6.1 g, 67%). LC/MS: [m+l]+=202.2, lH NMR (DMSOd6) 300 MHz 52.18 (3H,s), 2.63 (3H, s), 7.72 (1H, s), 7.87 (1H, d, J=9.0 Hz), 8.41 (1H, d, J=9.0 Hz), 8.51 (1H, s), 8.98 (1H, s). |
67% | With potassium carbonate; In dimethyl sulfoxide; at 110℃; for 22h; | 1. 1-[6-(4-methyl-imidazole-1-yl)-pyridin-3-yl]-ethanone (19) <strong>[55676-22-7]1-(6-chloro-pyridin-3-yl)-ethanone</strong> (7.00 g, 45.16 mmol) and 4-methylimidazole (11.11 g, 135.50 mmol) were combined in DMSO (35 ml), before addition of K2CO3. The mixture was heated at 110 C for 22 h with rapid stirring. The reaction was then cooled to room temperature and poured into ice water (400 ml) with vigorous stirringfor 15 min. The resulting precipitate was collected on a filter and washed generously with water. The resulting material was dried in vacuo to yield 19 as a tan solid (6.1 g, 67%). LC/MS: [M+1]+ = 202.2. C11H11N3O = 201.2. 1H NMR (DMSO-d6) 300 MHz delta 2.18 (3H, s), 2.63 (3H, s), 7.72 (1H, s), 7.87 (2H, d, J=9.0 Hz), 8.41 (2H, d, J=9.0 Hz), 8.5.1 (1H,s), 8.98 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetonitrile; at 20℃; for 48h; | To 2.50 g (7.69 mmol) 2-bromo-1 -(4-iodo-phenyl)-ethanone in 30 mL ACN are added 1 .90 g (23.1 mmol) 4-methylimidazole and the mixture is stirred at rt for 48 h. After that time, the solvent is evaporated and the residue is taken up in EtOAc. The mixture is washed with water and brine (2x) and the organic layer is dried over magnesium sulphate. The solvent is evaporated and the residue is recrystallized from diethyl ether to yield the desired product.C12H11 IN2O (M = 326.13 g/mol)ESI-MS: 327 [M+H]+ | |
In acetonitrile; at 20℃; for 48h; | Example IXExample IX.11-(4-Iodo-phenyl)-2-(4-methyl-imidazol-1-yl)-ethanoneTo 2.50 g (7.69 mmol) <strong>[31827-94-8]2-bromo-1-(4-iodo-phenyl)-ethanone</strong> in 30 mL ACN are added 1.90 g (23.1 mmol) 4-methylimidazole and the mixture is stirred at rt for 48 h. After that time, the solvent is evaporated and the residue is taken up in EtOAc. The mixture is washed with water and brine (2×) and the organic layer is dried over magnesium sulphate. The solvent is evaporated and the residue is recrystallized from diethyl ether to yield the desired product.C12H11IN2O (M=326.13 g/mol)ESI-MS: 327 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; | l-(4-Ethynyl-2-phenoxyphenyl)-4-methyl-l//-iinidazole.A mixture of <strong>[68359-57-9]4-fluoro-3-phenoxybenzaldehyde</strong> (1.0 g, 4.6 mmol) in 10 mL of DMF was treated with 4-methylimidazole (1.0 g, 12 mmol) and warmed to 100 C. Stirred overnight. Diluted with EtOAc, washed with sat'd NaHCO3, dried (Na2SO4), concentrated. Dissolved in 10 mL of MeOH, treated with K2CO3 (1.0 g, 7.2 mmol) and dimethyl (l-diazo-2-oxopropyl)phosphonate (1.0 g, 5.2 mmol) and stirred overnight. Diluted with DCM and washed with water. Dried (Na2SO4), cone. Chromatography on silica (0-20% MeOH/DCM) gave the desired alkyne (1.1 g; 87% overall yield): 1H NMR (600 MHz, CDCl3) delta 7.23-7.31 (m, 4 H), 7.11-7.12 (m, 2 H), 6.88-6.95 (m, 4 H), 3.1 1 (s, 1 H), 2.29 (s, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | In acetonitrile; at 100℃; for 16h; | 4-Methylimidazole (6.14 g, 73.3 mmol) was added to a sol. of 2-chloro-5-nitro-6- picoline (4.3 g, 24.42 mmol) in CH3CN (64.5 mL). The r.m. was stirred at 100 °C in a pressure tube for 16 h. The r.m. was cooled to r.t. and the solvents evaporated in vacuo. The residue was washed with water and extracted with DCM. The o.l. was separated, dried (MgSC^), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; eluent: DCM/MeOH from 100/0 to 95/5). The product fractions were collected and the solvent evaporated in vacuo. The product was precipitated from DIPE, filtered off and dried in vacuo. Yield: 4.4 g of intermediate 20 (82percent yield) as a pale yellow solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.71 g | Example 43: N-(5-Fluorothiazol-2-yl)-5-(2-(5-methyl-lH-imidazol-l-yl)-4- (trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(lH)-sulfonamide Step 1 : l-(2-Bromo-5-(trifluoromethyl)phenyl)-5-methyl-lH-imidazole A solution of 4-methyl-lH-imidazole (1.352 g, 16.46 mmol) in 20 mL THF was treated with lithium tert-butoxide IN in hexane (16.46 ml, 16.46 mmol) and was allowed to stir for one hour. The reaction mixture was concentrated and then transferred to a microwave vial charged with l-bromo-2-fluoro-4-(trifluoromethyl)benzene (2.360 ml, 16.46 mmol) and 10 mL dioxane. The reaction mixture was heated to 180 C in a microwave reactor for one hour. After cooling to room temperature, the reaction mixture was poured into saturated NH4CI solution and was extracted with DCM. The organics were concentrated, then purified directly by silica gel column chromatography (0 to 50% EtO Ac/heptane) yielding l-(2- bromo-5-(trifluoromethyl)phenyl)-5-methyl-lH-imidazole (0.710 g, 2.327 mmol). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.435 g | Example 42: N-(5-Fluorothiazol-2-yl)-5-(2-(4-methylpiperazin-l-yl)-4- (trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(lH)-sulfonamide Step 1 : 5-(2-(4-Methyl-lH-imidazol-l-yl)-4-(trifluoromethyl)phenyl)isoquinoline A suspension of sodium hydride 60% (0.330 g, 13.75 mmol) in 8 mL DMF was cooled to 0 C and was treated with 4-methyl-lH-imidazole (0.676 g, 8.23 mmol). After stirring for 40 minutes, l-bromo-2-fluoro-4-(trifluoromethyl)benzene (1.180 ml, 8.23 mmol) was added, and the reaction mixture was heated to 120 C for 90 minutes. At this point Cl2Pd(AmPhos) (Sigma-Aldrich, St. Louis, MO, 0.291 g, 0.412 mmol), isoquinolin-5- ylboronic acid (1.424 g, 8.23 mmol), potassium phosphate (6.99 g, 32.9 mmol), 16 mL dioxane and 12 mL water were added, and the reaction mixture was heated to 120 C overnight. The reaction mixture was poured into saturated aHC03 solution and was extracted with DCM. The organics were concentrated then purified by reverse phase column chromatography [RediSep Gold C18 150g, 15 to 100% (0.1% NH40H in MeOH)/(0.1% NH40H in water)] yielding 5-(2-(4-methyl-lH-imidazol-l-yl)-4- (trifluoromethyl)phenyl)isoquinoline (1.435 g, 4.06 mmol) as an about 4: 1 mixture of isomers. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | General procedure: The respective methylimidazole (385 mg, 4.70 mmol) was dissolved in acetonitrile(30 mL) and cooled to 0 °C. NaH (60percent in mineral oil, 271 mg, 5.64 mmol, 1.2 equiv.)was added to the solution and the suspension was stirred at 0 °C for 30 min. Afteradding Hoffers chloro sugar (2.19 g, 5.64 mmol, 1.2 equiv.) in 4 portions during 60min the reaction was stirred for further 3 h and allowed to reach ambient temperature.The solvent was removed under reduced pressure and the residue was dissolved inCH2Cl2. The organic layer was washed with water (3 × 30 mL) and dried (MgSO4).The crude product was purified by column chromatography on silica gel (cyclohexane: CH2Cl2 : NEt3, 50 : 30 : 8). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With N-Bromosuccinimide; In tetrahydrofuran; at 20℃; for 1h; | [0229] To a solution of 3-1 (3.4 g, 40 mmol) in THF (50 mL) at r.t. was added NBS ( 14 g, 80 mmol). The mixture was stirred for 1 h. The solvent were removed under reduced pressure. Purification by column chromatography on silica gel (PE:EA=2: 1 ) provided 3-2 as white solid (9.6 g, 99%). +E SI-MS: m/z 239.0 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79.6% | With potassium carbonate; In dimethyl sulfoxide; at 20℃; for 12h;Inert atmosphere; | Synthesis of 2-(4-Methyl-lH-imidazol-l-yl)-5-nitropyridine [0318] To a stirred solution of <strong>[4487-59-6]2-bromo-5-nitropyridine</strong> (5 g, 50.0 mmol) in DMSO (50 mL) were added 4-methyl imidazole (8.1 g, 200.0 mmol), and K2C03 (10.2 g, 150.0 mmol) at RT under argon atmosphere. The reaction mixture was stirred at RT for 12 h. After the consumption of the starting materials (monitored by TLC), the reaction was diluted with water (50 mL), the precipitate was filtered and dried under vacuo to afford 2-(4-Methyl-lH- imidazol-l-yl)-5-nitropyridine (4 g, 79.6%) as a yellow solid. 1H-NMR (CDC13, 400 MHz): delta 9.32 (s, IH), 8.62 (d, IH), 8.36 (s, IH), 7.42-7.38 (m, 2H), 2.32 (s, 3H); Mass (ESI): 205 [M+1]; LC-MS: 205 (M+1); (column; Zorbax SB C-18, (50x4.6 mm, 1.8mu); RT 4.42 min. 5mM AA in water: ACN; 0.5 ml/min); TLC: 100% EtOAc (Rf. 0.3). |
8 g | With potassium carbonate; In dimethyl sulfoxide; at 20℃; for 12h;Inert atmosphere; | To a stirred solution of <strong>[4487-59-6]2-bromo-5-nitropyridine</strong> (10 g, 0.05 mol) in DMSO (100 mL) under an argon atmosphere were added 4-methyl imidazole (16.3 g, 0.2 mol) and potassium carbonate (20.5 g, 0.15 mol) at room temperature. The reaction mixture was stirred for 12 h at room temperature. After consumption of the starting material (monitored by TLC), the reaction was diluted with water (100 mL) and the solid was filtered. The filtrate was extracted with EtOAc (2 x 200 mL), the combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain 2-(4-methyl-1 H-imidazol-1-yl)-5- nitropyridine (8 g) as a yellow solid used in the next step without further purification. TLC: 30% EtOAc:hexane (Rf: 0.45). |
8 g | With potassium carbonate; In dimethyl sulfoxide; at 20℃; for 12h;Inert atmosphere; | Synthesis of 2-(4-methyl-1H-imidazol-1-yl)-5-nitropyridine To a stirred solution of <strong>[4487-59-6]2-bromo-5-nitropyridine</strong> (10 g, 0.05 mol) in DMSO (100 mL) under an argon atmosphere were added 4-methyl imidazole (16.3 g, 0.2 mol) and potassium carbonate (20.5 g, 0.15 mol) at room temperature. The reaction mixture was stirred for 12 h at room temperature. After consumption of the starting material (monitored by TLC), the reaction was diluted with water (100 mL) and the solid was filtered. The filtrate was extracted with EtOAc (2*200 mL), the combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain 2-(4-methyl-1H-imidazol-1-yl)-5-nitropyridine (8 g) as a yellow solid used in the next step without further purification. TLC: 30% EtOAc:hexane (Rf: 0.45). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With potassium carbonate; In N,N-dimethyl-formamide; at 4 - 20℃; | To a solution of <strong>[147808-42-2]4-bromo-2,6-difluoronitrobenzene</strong> (8.0 g, 33.6 mmol, 1.3 eq) in DMF (20 mL) potassium carbonate (7.4 g, 53.8 mmol, 2.0 eq) was added. The suspension was cooled to 4 C and a solution of 4-methylimidazole (2.4 g, 26.9 mmol, 1.0 eq) in DMF (45 mL) was added over 5 h. After the addition the mixture was stirred an additional hour at 4 C and 17 h at room temperature. Half of the DMF was removed and the residue was poured into water (150 mL). The precipitate was filtered off. Ethyl acetate (25 mL) was used to dissolve the solid and the organic layer was extracted with 1 N HCl (4 x 25 mL). During neutralization with Na2CO3- solution (pH 8) a precipitate was formed. It was filtered off and dried. Crystallization from ethanol (3 times) gave a pale yellow solid (3.40 g, 42%). TLC [Silica, CHCl3/MeOH/30% aqueous NH3 (10:1:0.1)]: Rf = 0.56. 1H NMR (300 MHz, CDCl3): delta = 7.55 (d, J = 1.6 Hz, 1H), 7.53 (dd, J = 8.6, 1.8 Hz, 1H), 7.42 (t, J = 1.8 Hz, 1H), 6.89-6.60 (m, 1H), 2.25 (d, J = 1.0 Hz, 3H). 13C NMR (75 MHz, CDCl3): delta = 154.1 (d, J = 264.3 Hz), 140.8, 136.1, 131.8 (d, J = 1.4 Hz), 125.8, 125.7 (d, J = 3.7 Hz), 120.4 (d, J = 22.1 Hz), 115.9, 13.6, [C-NO2 is not detected]. 19F NMR (282 MHz, CDCl3): delta = - 118.61 (dd, J = 8.3, 1.5 Hz). LRMS (ESI+): m/z = 322.0 (calcd. 322.0 for C10H279BrF2N3NaO2 [M+Na]+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With iron(III) chloride; potassium phosphate; In N,N-dimethyl-formamide; at 130℃; for 16h;Inert atmosphere; | General procedure: FeCl3 (8 mg, 0.05 mmol, 10 mol%), K3PO4 (212 mg, 1 mmol), N-heterocycles 1 (0.50 mmol), and o-fluorobenzaldehydes 2(0.50 mmol) were added to an oven-dried Schlenk tube (with a magnetic stirrer bar within) equipped with a Teflon valve. The tube was repeatedly evacuated and back-filled with N2 (3 times). Under a counter flow of N2, DMF (2.0 mL) was added by a syringe, and the mixture was stirred for about 16 h at 130 C. When the reaction was complete, the mixture was extracted with ethyl acetate (3 15 mL), and the organic layer was washed with brine(3 10 mL) and dried over anhydrous Na2SO4. Subsequently,the solvent was removed and the product was purified by column chromatography on silica gel (PE:EA = 5:1-1:1, v/v) to give the desired product 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31.6% | In N,N-dimethyl-formamide; at 130℃; for 0.5h;Sealed tube; Microwave irradiation; | Step 1 (1143) 4-Chloro-3-nitro-pyridin-2-amine (LXXXI) (3.00 g, 17.3 mmol, 1.0 eq) and 4-methyl-1H-imidazole (XCI) (2.84 g, 34.6 mmol, 2.0 eq) were taken up into a microwave tube in DMF (20 mL). The sealed tube was heated at 130 C. for 30 min under microwave. TLC showed the starting material was consumed, LC/MS showed the desired product was found. 10% NH4Cl (60 mL) were added. The aqueous layer was extracted with DCM (2×100 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, concentrated in vacuum. The residue was purified by chromatography on silica gel (PE:THF=1:1) to give the product 4-(4-methylimidazol-1-yl)-3-nitro-pyridin-2-amine (XCII) (1.20 g, 5.47 mmol, 31.6% yield) as a yellow solid. 1H NMR (CDCl3, 400 MHz) delta ppm 2.30 (d, J=0.75 Hz, 3H), 5.96-6.26 (m, 2H), 6.68 (d, J=5.02 Hz, 1H), 6.72-6.75 (m, 1H), 7.57 (d, J=1.0 Hz, 1H), 8.32 (d, J=5.14 Hz, 1H); ESIMS found C9H9N5O2 m/z 219.1 (M+H). |
31.6% | In N,N-dimethyl-formamide; at 130℃; for 0.5h;Sealed tube; Microwave irradiation; | 4-Chloro-3-nitro-pyridin-2-amine (LXXXII) (3.00 g, 17.3 mmol, 1.0 eq) and 4-methyl-lH-imidazole (XCIII) (2.84 g, 34.6 mmol, 2.0 eq) were taken up into a microwave tube in DMF (20 mL). The sealed tube was heated at 130C for 30 min under microwave. TLC showed the starting material was consumed, LC/MS showed the desired product was found. 10% NH4CI (60 mL) were added. The aqueous layer was extracted with DCM (2 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SC>4, concentrated in vacuum. The residue was purified by chromatography on silica gel (PE:THF = 1 : 1) to give the product 4-(4- methylimidazol-l-yl)-3-nitro-pyridin-2 -amine (XCIV) (1.20 g, 5.47 mmol, 31.6% yield) as a yellow solid. NMR (CDC13, 400 MHz) delta ppm 2.30 (d, J=0.75Hz, 3H), 5.96-6.26 (m, 2H), 6.68 (d, J=5.02Hz, 1H), 6.72-6.75 (m, 1H), 7.57 (d, J=1.0Hz, 1H), 8.32 (d, J=5.14Hz, 1H); ESIMS found C9H9N502 m/z 219.1 (M+H). |
31.6% | In N,N-dimethyl-formamide; at 130℃; for 0.5h;Microwave irradiation; Sealed tube; | Preparation of intermediate 4-(2-fluorophenyl)-3-nitropyridin-2-amine (XCII) is depicted below in Scheme 18. Step 1 (0877) 4-Chloro-3-nitro-pyridin-2-amine (LXXX) (3.00 g, 17.3 mmol, 1.0 eq) and 4-methyl-1H-imidazole (XC) (2.84 g, 34.6 mmol, 2.0 eq) were taken up into a microwave tube in DMF (20 mL). The sealed tube was heated at 130 C. for 30 min under microwave. TLC showed the starting material was consumed, LC/MS showed the desired product was found. 10% NH4Cl (60 mL) were added. The aqueous layer was extracted with DCM (2×100 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, concentrated in vacuum. The residue was purified by chromatography on silica gel (PE:THF=1:1) to give the product 4-(4-methylimidazol-1-yl)-3-nitro-pyridin-2-amine (XCI) (1.20 g, 5.47 mmol, 31.6% yield) as a yellow solid. 1H NMR (CDCl3, 400 MHz) delta ppm 2.30 (d, J=0.75 Hz, 3H), 5.96-6.26 (m, 2H), 6.68 (d, J=5.02 Hz, 1H), 6.72-6.75 (m, 1H), 7.57 (d, J=1.0 Hz, 1H), 8.32 (d, J=5.14 Hz, 1H); ESIMS found C9H9N5O2 m/z 219.1 (M+H). |
31.6% | In N,N-dimethyl-formamide; at 130℃; for 0.5h;Microwave irradiation; Sealed tube; | Step 1 (0901) 4-Chloro-3-nitro-pyridin-2-amine (XCV) (3.00 g, 17.3 mmol, 1.0 eq) and 4-methyl-1H-imidazole (CV) (2.84 g, 34.6 mmol, 2.0 eq) were taken up into a microwave tube in DMF (20 mL). The sealed tube was heated at 130 C. for 30 min under microwave. TLC showed the starting material was consumed, LC/MS showed the desired product was found. 10% NH4Cl (60 mL) were added. The aqueous layer was extracted with DCM (2×100 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, concentrated in vacuum. The residue was purified by chromatography on silica gel (PE:THF=1:1) to give the product 4-(4-methylimidazol-1-yl)-3-nitro-pyridin-2-amine (CVI) (1.20 g, 5.47 mmol, 31.6% yield) as a yellow solid. 1H NMR (CDCl3, 400 MHz) delta ppm 2.30 (d, J=0.75 Hz, 3H), 5.96-6.26 (m, 2H), 6.68 (d, J=5.02 Hz, 1H), 6.72-6.75 (m, 1H), 7.57 (d, J=1.0 Hz, 1H), 8.32 (d, J=5.14 Hz, 1H); ESIMS found C9H9N5O2 m/z 219.1 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With copper acetylacetonate; [bis(acetoxy)iodo]benzene; dihydrogen peroxide; oxygen; nickel diethyldithiocarbamate; ferric nitrate; In ethanol; at 70℃; under 760.051 Torr; for 1.5h; | Dissolve 4-methylimidazole in ethanol, concentration is 5g/L. Add oxidant iodobenzene diacetate, hydrogen peroxide, and catalyst mixture of cupric acetylacetonate, ferric nitrate, and nickel diethyldithiocarbamate where in the molar ratio of cupric acetylacetonate, ferric nitrate, and nickel diethyldithiocarbamate is 3:5:1. Stir completely. Heat to 70C at normal pressure. Introduce oxygen at a rate of 100mL/min. Reflux reaction for 90min. After reaction, add acetone and shock extract. Vacuum concentration. Vacuum distill the solvent. After, obtain the crude product. Recrystallize to obtain the desired product 1H-imidazolo-4-carboxylic acid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With iodine; sodium hydroxide; In 1,4-dioxane; for 1h; | A solution of 4-methyl-1H-imidazole (5.4 g, 65.8 mmol) and iodine (16.69 g, 65.8 mmol) in dioxane (51 ml) was treated with NaOH (132 ml, 132 mmol) for 1 h. Most organic solvent was removed under reduced pressure. It was neutralized by saturated ammonium chloride and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was triturated in 50 mL of diethyl ether and aged for 10 min. The white solids were collected by filtration and dried under vacuum to give the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | The reaction flask was charged with <strong>[328-67-6]3-bromo-5-trifluoromethyl benzoic acid</strong> (compound 2, 2.7 g, 0.01 mol)Methyl-1H-imidazole (1.64 g, 0.02 mol),Trans-N, N'-dimethylcyclohexanediamine (0.28 g, 0.002 mol),DMF (10vol./g), anhydrous potassium phosphate (6.3g, 0.03mol) and 4A molecular sieves (0. lg / g) to form a mixed system; the mixture was purged with nitrogen until the oxygen content 500ppm, The reaction system was heated to 115 C, the reaction was stirred for 72 hours, TLC showed compound 2 disappeared to give the product system;Dimethyl sulfate (2.7 g, 0.021 mol) was added dropwise to the product system,TLC was followed by complete methyl esterification of the coupled carboxylic acid generated in situ. The system was cooled to room temperature, transferred to 2M hydrochloric acid to quench, ethyl acetate was added and the organic phase was extracted and separated; the aqueous phase was extracted twice with ethyl acetate and the organic phases were combined; the organic phase was concentrated to remove the ethyl acetate solvent to obtain Methyl 3- (4-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) benzoate (Compound 3) crude. Methanol (4 vol./g) was recrystallized to give 1.9 g of a khaki-colored solid in a yield of 70%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With trans-N,N'-dimethyl-1,2-cyclohexyldiamine; potassium phosphate; copper(l) iodide; In 1,4-dioxane; at 115℃; for 72h;Molecular sieve; | Coupling reaction: A reaction flask was charged with <strong>[328-67-6]3-bromo-5-trifluoromethylbenzoic acid</strong> (compound 2, 2.7 g, 0.01 mol), 4-methyl-1H- imidazole (1.64 g, 1), trans- N, N'-dimethylcyclohexanediamine (0.28 g, 0.002 mol), 1,4-dioxane (10 vol./g), anhydrous potassium phosphate , 0.03mol) and 4A molecular sieves (0. lg / g), to form a mixed system; the mixed system is purged with nitrogen to have an oxygen content of 500ppm, finally adding cuprous iodide (0.38g, 0.002mol) The system was heated to 115 C, the reaction was stirred for 72 hours, TLC showed compound 2 disappeared to give the product system; and then the system was cooled to room temperature, transferred to 2M hydrochloric acid quenched, concentrated filtered without fraction To be purified solution. Adding n-butanol, extracting and separating the organic phase, extracting with n-butanol twice, and combining the organic phases; concentrating the organic phase to remove n-butanol to obtain 3- (4-methyl- -5- (trifluoromethyl) benzoic acid (Compound 3) crude. Recrystallization from methanol (4: 1 ./g) gave 1.76 g of a khaki-colored solid in 65% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34.3% | With potassium carbonate; In dimethyl sulfoxide; at 20℃; for 0.5h; | To a solution of <strong>[933702-55-7]2-chloropyrimidine-5-carbaldehyde</strong> (3.00 g, 21.05 mmol) in DMSO (20 mnL) was added K2C03 (7.27 g, 52.60 mmoi) and 4-methyi-IH-imidazoie (2.59 g, 31.6 mmol).The resulting mixture was stirred at ambient temperature for 30 minutes. The reaction mixture was poured into ice cold water (50 ml.) and extracted with ethyl acetate (3 xIOO mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (Redi sep-24 g, 80% EtOAc/n-hexane) to obtain Intermediate 104 (1.40 g, 34.30%) as a white solid. ?HNMR (400 MHz, DMSO-d6) ppm 2.20 (s, 3 H), 7.72 (t, J 1.2 Hz 1 H), 8.56 (d, J1.2 Hz, 1 H), 9.26 (s. 2 H) 10.09 (s. 1 H). LCMS MethodD): retention time 1.07 mm, [M±H]1891. |
34.30% | With potassium carbonate; In dimethyl sulfoxide; at 20℃; for 0.5h; | To a stirring solution of <strong>[933702-55-7]2-chloropyrimidine-5-carbaldehyde</strong> (3.00 g, 21.05 mmol) in DMSO (20 mL) was added K2CO3 (7.27 g, 52.60 mmol) followed by 4-methyl-1H- imidazole (2.59 g, 31.6 mmol) and the resulting mixture was stirred at ambient temperature for 30 minutes. The reaction mixture was poured into ice cold water (50 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (Redisep-24 g, 80 % EtOAc/n-hexane) to obtain Intermediate 138 (1.40 g, 34.30%) as a white solid.1H NMR (400 MHz, DMSO- d6) G ppm 2.20 (s, 3 H), 7.72 (t, J = 1.2 Hz 1 H), 8.56 (d, J = 1.2 Hz, 1 H), 9.26 (s, 2 H) 10.09 (s, 1 H). LCMS (Method-D): retention time 1.07 min, [M+H] 189.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54.1% | With tris-(dibenzylideneacetone)dipalladium(0); potassium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100.0℃; for 16.0h;Inert atmosphere; | General procedure: To a solution of Intermediate 47B (1.00g. 8.92 mrnol) and 6bromo4 methylnicotinonitrile (1.76 g, 8.92 mmol) in dioxane (20 mL) was added K2C03 (308 g. 22.30mmol) and XANTPHOS (1.03 g, 1.78 mmol) and the resulting reaction mixture was degassed with nitrogen for 5 minutes. Pd2(dha)3 (0.82 g, 089 mmol) was added and the resulting mixture was degassed again for 5 minutes then heated at 100 C for 16 h. The reaction mixture was cooled to ambient temperature, filtered t1i?ough Celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (Redisep40 g, 22. 5%MeOHDCM) to obtain Intermediate 47C (120 g, 59.0%) as a pale yellow solid. 1H NMR (300 MHz, DMSO-d6) ppm 2.57 (s. 3 H) 2.65 (t, J= 6.61 Hz, 2 H) 3.55 3.67 (m, 2 H) 4.71 (br. s., I H) 7.80 (s, I H) 7.96 (d, J= 0.76 Hz, I H) 8.47 (s, I H) 8.82 (s, I H). LCMS Qvlethod-D):retention time 086 mm, [M±ij 229.3. |
54.10% | With tris-(dibenzylideneacetone)dipalladium(0); potassium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100.0℃; for 16.0h;Inert atmosphere; | General procedure: To a solution of Intermediate 15B (0.50 g, 4.46 mmol) and 6bromo4methoxynicotinonitrile (0.95 g, 4.46 mmol) in dioxane (20 mL) was added K2CO3 (1.54 g, 11.15 mmol) and XANTPHOS (0.52 g, 0.89 mmol) and the resulting reaction mixture was degassed with nitrogen for 5 minutes. Pd2(dba)3(0.41 g, 0.45 mmol) was added and the resulting mixture was degassed again for 5 minutes then heated at 100 C for 16 h. The reaction mixture was cooled to ambient temperature, filtered through Celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (Redisep24 g, 2 2.5 % MeOH in DCM), to obtain Intermediate 15C (0.40 g, 36.70%) as a pale yellow solid.1H NMR (400 MHz, DMSOd6) G ppm 2.65 (t, J = 6.78 Hz, 2 H), 3.61 (td, J = 6.78, 5.02 Hz, 2 H), 4.10 (s, 3 H), 4.62 4.76 (m, 1 H), 7.58 (s, 1 H), 7.81 (s, 1 H), 8.47 (s, 1 H), 8.73 (s, 1 H). LCMS (MethodI): retention time 0.83 min, [M+H] 245.3 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | With copper(l) iodide; 8-quinolinol; potassium carbonate; In dimethyl sulfoxide; at 110℃;Inert atmosphere; | To a solution of 60 (1.0 g, 4.1 mmol) in MeOH (30 mL) was added dropwise H2S04 (5 mL). The reaction was refluxed overnight before concentrated. The residue was treated with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na2SO4 and evaporated under reduced pressure togive 61(1.1 g, 100%) as an off-white solid. A suspension of 61(900 mg, 3.46 mmol), 1 (853 mg, 10.4 mmol), K2C03 (955 mg, 6.92 mmol), Cul (198 mg, 1.04 mmol) and 8- hydroxyquinoline (100 mg, 0.69 mmol) in DMSO (9 mL) was heated at 110 C overnight under nitrogen. After cooling, water was added and the mixture was acidified by aqueous KHSO4, and extracted with EtOAc 3 times. The product was in the waterphase. The water layer was directly purified by reverse prep-HPLC to give 62 (310 mg,36%) as a white solid. LCMS (m/z: m+1): 248.1. |
36% | With copper(l) iodide; 8-quinolinol; potassium carbonate; In dimethyl sulfoxide; at 110℃;Inert atmosphere; | To a solution of 43 (1.0 g, 4.1 mmol) in MeOH (30 mL) was added H2SO4 (5 mL)dropwise. The reaction was heated at reflux overnight before concentrated. The residue wastreated with water and extracted with EtOAc twice. The combined organic layers were washedwith brine, dried over Na2SO4 and evaporated under reduced pressure to give 44 (1.1 g, 100%)as an off-white solid. A suspension of 44 (900 mg, 3.46 mmol), 1 (853 mg, 10.4 mmol), K2CO3(955 mg, 6.92 mmol), CuI (198 mg, 1.04 mmol) and 8-hydroxyquinoline (100 mg, 0.69 mmol)in DMSO (9 mL) was heated at 110C overnight under nitrogen. After cooling, water wasadded and the mixture was acidified by aqueous KHSO4 and extracted with EtOAc 3 times.The product was in the water phase. The water layer was directly purified by reverse prep-HPLC to give 45 (310 mg, 36%) as a white solid. LCMS (m/z: m+1): 248.1. To a mixture of 45 (310 mg, 1.26 mmol) in MeOH (30 mL) was added dropwise H2SO4 (2 mL). The reactionwas heated at reflux overnight before being concentrated. The residue was treated with water,basified by 2N NaOH under ice-water bath and extracted with CH2Cl2 3 times. The combinedorganic layers were washed with brine, dried over Na2SO4, and evaporated under reducedpressure to give 46 (260 mg, 79%) as a slightly yellow solid. LCMS (m/z: m+1): 262.1. Amixture of 46 (260 mg, 1.0 mmol) and Pd/C (80 mg) in THF (10 mL) was stirred at roomtemperature under hydrogen atmosphere overnight. The reaction mixture was filtered and thefiltrate was concentrated under reduced pressure to give 47 (231 mg, 100%) as a slightly yellowoil. LCMS (m/z: m+1): 232.3. A mixture of 47 (231 mg, 1.0 mmol), 41 (323 mg, 1.0 mmol),HATU (760 mg, 2.0 mmol) and DIEA (646 mg, 5.0 mmol) in DMF (3 mL) was heated at 70Covernight. After cooling, the reaction was directly purified by reverse prep-HPLC and thensilica gel prep-TLC to give 48 (148 mg, 28%) as a slightly yellow solid. LCMS (m/z: m+1):537.3. To a solution of 48 (148 mg, 0.28 mmol) in THF (5 mL) was added LAH (42 mg, 1.10mmol). The mixture was stirred at room temperature overnight before being quenched withwater (100 mg). The resulting mixture was filtered through Celite and washed withCH2Cl2/MeOH (10/1). The filtrate was evaporated under reduced pressure to give the fullyreduced benzylic alcohol (145 mg, 100%) as a slightly yellow solid which was used in nextstep without purification. A mixture of this material (125 mg, 0.25 mmol) and MnO2 (427 mg,4.9 mmol) in CH2Cl2/MeOH (20/1, 30 mL) was heated at reflux overnight. The reactionmixture was filtered and washed with CH2Cl2/MeOH (20/1, 60 mL). The filtrate wasevaporated under reduced pressure to give aldehyde 49 (123 mg, 99%) as a slightly yellowsolid. This material was also used in the next step without intermediate purification. To asolution of 49 (103 mg, 0.20 mmol) and (S)-piperidine-2-carboxylic acid (129 mg, 1.0 mmol)in DMF (2 mL) was added AcOH (2 drops) and then NaBH3CN (63 mg, 1.0 mmol) at 5C.The mixture was stirred at room temperature for 4 h. The reaction mixture was directly purifiedby reverse prep-HPLC to give crude product (48 mg, ~60% purity). 23 mg of the crude productwas further purified by silica gel prep-TLC to give pure 2b (12 mg, 20%) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With copper(l) iodide; potassium carbonate; L-proline; In dimethyl sulfoxide; at 130℃; for 3h;Inert atmosphere; | To a solution of 112 (14 g, 60.34 mmol) in DMSO (200 mL), 1 (17 g, 211.18 mmol), L10 proline (3.47 g, 30.17 mmol), Cul (9.2 g, 48.27 mmol) and K2C03 (20.8 g, 150.8 mmol) weresequentially added at room temperature under N2. The reaction mixture was heated at 130 C for 3 h. After cooling at room temperature, water (200 mL) was added and reaction mixture was filtered through a pad of Celite, washed with EtOAc (3 x 50 mL). The filtrate was extracted with ethyl acetate (2 x 100 mL). The organic layer washed with brine solution (200 mL) anddried (Na2SO4), concentrated in vacuo to give the crude residue. This material was trituratedwith diethyl ether to give 113 (8 g, 57%) as a light brown solid. MS (ESl +ve): 234.21. 1H-NMR(400 MHz; DMSO-d6): 58.34 - 8.30 (m, 2H), 8.12 (s, 1H), 8.01 (s, 1H), 7.64 (bs, 1H), 5.64 (t, J =5.7 Hz, 1H), 4.67 (d, J = 5.6 Hz, 2H), 2.17 (s, 3H). |
45.9% | With copper(l) iodide; potassium carbonate; L-proline; In N,N-dimethyl-formamide; at 130℃; for 18h;Inert atmosphere; | To a solution of 65 (26 g, 112 mmol) in DMF (364 mL), 1 (32.2 g,392 mmol), L-proline (6.45 g, 56 mmol), CuI (17.07 g, 89.6 mmol) andK2CO3 (38.7 g, 280 mmol) were sequentially added at room temperatureunder N2. The reaction mixture was then heated at 130 C for 18 h.Following the consumption of starting material, the reaction mixturewas cooled to room temperature and water (1000 mL) was added to it.The reaction mass was then filtered through a celite pad and thenwashed with EtOAc (2 × 500 mL). The filtrate was subsequently extractedwith ethyl acetate (2 × 500 mL), washed with brine(2 × 500 mL), dried (Na2SO4) and concentrated under vacuo to givecrude residue. The residue was triturated by EtOAc (3 × 250 mL) togive 66 (12 g, 45.9%) as a light brown solid. 1H NMR (400 MHz; DMSOd6):delta 8.34-8.30 (m, 2H), 8.12 (s, 1H), 8.01 (s, 1H), 7.64 (bs, 1H), 5.64(t, 1H), 4.67 (d, 2H), 2.17 (s, 3H). LCMS: m/z 234.1 (M + H)+, 93.9%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; | A mixture of 31(0.66 g, 3 mmol), 1(0.8 g, 10 mmol) and K2C03 (0.8 g, 6 mmol)in DMF (5 mL) was heated at 100 C overnight. After cooling, water was added and themixture was extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography to give 32 (0.76 g, 90%) as a yellow solid. LCMS (m/z: m+1):282.0, 284.0. |
90% | With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; | A mixture of 23 (0.66 g, 3 mmol), 1 (0.8 g, 10 mmol), and K2CO3 (0.8 g, 6 mmol) inDMF (5 mL) was heated at 100C overnight. After cooling, water was added and the mixturewas extracted with EtOAc twice. The combined organic layers were washed with brine, driedover Na2SO4 and concentrated. The residue was purified by silica gel column chromatographyto give 24 (0.76 g, 90%) as a yellow solid. LCMS (m/z: m+1): 282.0, 284.0. A mixture of 24(1 g, 3.5 mmol), methyl acrylate (0.45 g, 5.25 mmol), Et3N (0.7 g, 7 mmol), Pd(OAc)2 (0.07 g,0.35 mmol) and TOTP (0.2 g, 0.7 mmol) in DMF (5 mL) was heated at 100C overnight undernitrogen. After cooling, water was added and the mixture was extracted with EtOAc twice. Thecombined organic layers were washed with brine, dried over Na2SO4 and concentrated. Theresidue was purified by silica gel column chromatography to give 25 (0.8 g, 80%) as a yellowsolid. LCMS (m/z: m+1): 288.2. A mixture of 25 (200 mg, 0.70 mmol) and Fe (195 mg, 3.5mmol) in EtOH (3 mL) and AcOH (1 mL) was heated at 60C for 4 h. After cooling, water was added, basified with aqueous NaHCO3 and the mixture was extracted with EtOAc twice. Thecombined organic layers were washed with brine, dried over Na2SO4 and concentrated. Theresidue was purified by silica gel column chromatography to yield 26 (150 mg, 84%) as ayellow oil. LCMS (m/z: m+1): 258.2. To a solution of 7 (119 mg, 0.39 mmol) in NMP (2 mL)was added SOCl2 (70 mg, 0.59 mmol). The reaction was heated at 60C for 1 h before 26 (100mg, 0.39 mmol) and Et3N (158 mg, 1.6 mmol) were added. The resulting mixture was stirredat 60C for 3 h. The reaction was directly purified by reverse prep-HPLC and then silica gelprep-TLC to give the methyl ester of 1e (80 mg, 38%) as a slight yellow solid. LCMS (m/z,m+1): 545.3. This material (80 mg, 0.15 mmol) was dissolved in MeOH/H2O (3/1 mL) andwas treated with NaOH (18 mg, 0.45 mmol). The mixture was stirred at room temperatureovernight. The reaction was diluted with water and acidified with aqueous KHSO4. Theprecipitate was filtered and washed with water. The cake was collected and dried to give 1e(62 mg, 80%) as a slightly yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95.6% | In N,N-dimethyl acetamide; at 145℃;Inert atmosphere; | To a stirred solution of <strong>[149793-69-1]3-fluoro-5-(trifluoromethyl)benzonitrile</strong> (13A) (10.0 g, 52.9 mmol, 1.0 equiv) in N,N-dimethylacetamide (50.0 mL, 5.0 vol. equiv) was added 5-methyl-lH- imidazole (13B) (13.5 g, 164.0 mmol, 3.1 equiv) at RT. The resulting mixture was stirred for 3 h at 145 C. The completion of reaction was monitored by TLC. The reaction mixture was quenched with water and extracted with ethyl acetate (3 x 200.0). The combined organic extract was washed with brine (200.0 mL), dried over sodium sulphate and concentrated under vacuum to get crude. The crude was purified with column chromatography eluted with ethyl acetate in n- hexane (0 to 40%) to afford titled compound (13C) (12.7 g, 95.6%) as an off white solid. (0485) MR (300 MHz, OMSO-d6) delta 8.28-8.24 (t, 3H), 8.05-7.99 (d, 2H), 2.49-2.37 (m, 3H). MS (ES+): 252.2 (M+l); MS (ES-): 250.4 (M-l). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 100℃; for 12h; | To a mixture of <strong>[460081-20-3]ethyl 2-bromooxazole-4-carboxylate</strong> (1 g, 4.5 mmol) and 4-methyl- lH-imidazole (448 mg, 5.45 mmol) in N,N-dimethylformamide (1 mL) was added N,N- diisopropylethyl amine (1.59 mL, 9.09 mmol) and the mixture was heated and stirred at 100 C for 12 h. The mixture was purified by silica gel column (eluting gradien petroleum ether / ethyl acetate = 10: 1 to 0: 1) to give ethyl 2-(4-methyl-lH-imidazol-l-yl)oxazole-4- carboxylate (0.3 g, crude) as a light brown solid. LCMS (ESI): m/z = 222.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | With copper(l) iodide; potassium tert-butylate; (1S,2S)-N,N'-dimethyl-1,2-diaminocyclohexane; In N,N-dimethyl-formamide; at 120℃; for 4h; | 1. A mixture of 1 (Key Organics, 1.00 g, 3.20 mmol), (S,S)-N,N'-dimethyl-l,2- diaminocyclohexane (91.0 mg, 0.64 mmol), 4-methyl- lH-imidazole (525 mg, 6.39 mmol), Cul (304 mg, 1.60 mmol) and t-BuOK (1.07 g, 9.60 mmol) in DMF (5 mL) was stirred at 120 C for 4 h. After cooling to RT, the mixture was directly purified by prep-HPLC to give 2 (320 mg,31% yield) as an off-white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63 g | In N,N-dimethyl acetamide; at 80 - 85℃; for 12h; | Example 18: Preparation of 3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl benzoic acid : In 3 lit four necked round bottom flask equipped with mechanical stirrer, thermometer, reflux condenser and an addition funnel, <strong>[161622-05-5]3-fluoro-5-(trifluoromethyl)benzoic acid</strong> (80 g), 4-methylimidazole (47.2 g) and dimethylacetamide (400 ml) was added, heated to 80-85C and stirred for 12 hrs at the same temperature. The reaction mass was cooled to room temperature, diluted with water (500 ml) and extracted with ethyl acetate (1000 ml). The solvent from organic layer was distilled off under vacuum and th obtained residue was titrated with water to get the title compound. Yield: 63 g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99 mg | With potassium carbonate; In N,N-dimethyl-formamide; at 110℃; for 2h; | Mix 4-methylimidazole (82mg, 1mmol), 5-fluoro, 2-nitropyridine (170mg, 1.2mmol) and potassium carbonate (300mg, 2.2mmol) with 5mL DMF, stir at 110 C for 2 hours, add 20mL It was diluted with ethyl acetate, washed with saturated sodium chloride three times, and the organic phase was dried over anhydrous sodium sulfate. After spinning, it was purified with a normal phase silica gel column to obtain YC028 (99 mg). |
Tags: 822-36-6 synthesis path| 822-36-6 SDS| 822-36-6 COA| 822-36-6 purity| 822-36-6 application| 822-36-6 NMR| 822-36-6 COA| 822-36-6 structure
[ 53316-51-1 ]
4,5-Dimethyl-1H-imidazole hydrochloride
Similarity: 0.83
[ 66247-84-5 ]
(1H-Imidazol-4-yl)methanamine hydrochloride
Similarity: 0.83
[ 38585-61-4 ]
4-(Chloromethyl)-1H-imidazole hydrochloride
Similarity: 0.81
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H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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