* 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.
Reference：
[1] Polish Journal of Chemistry, 1981, vol. 55, # 7/8, p. 1659 - 1665
3
[ 1003-91-4 ]
[ 25676-75-9 ]
Yield
Reaction Conditions
Operation in experiment
571 mg
for 24 h; Reflux
To a solution of N-methylimidazole (1.64 g, 19.97 mmol) and sodium acetate (25 g, 300 mmol) in acetic acid (180 mL) at room temperature was added bromine (9.6 g, 60.07 mmol) dropwise as a solution in 20 mL acetic acid. The resulting mixture was stirred for 2.5 h at room temperature. Acetic acid was removed in vacuo, the residue was suspended in 500 mL water and stirred at room temperature for 10 minutes. The resultant precipitate was filtered, washed with water and dried under high vacuum to give 2,4,5-tribromo-l-methyl- lH-imidazole (1.82 g, 29percent - some product remained in the mother liquor) as a light yellow powder. Used without further characterization. To a suspension of the tribromide (1.82 g, 5.71 mmol) in 45 mL water was added sodium sulfite (13 g, 103 mmol) and the resulting mixture was stirred at rapid reflux for 24 h. After cooling to room temperature, organics were extracted with ether (3 χ 75 mL), dried over magnesium sulfate, filtered and concentrated to give 1.61 g of a mixture of tri-, di- and monobromoimidazoles. This mixture was re-subjected to the reduction conditions (same quantity of sodium sulfite) using 15 mL of 3: 1 water/acetic acid as solvent and heating in a sealed vessel at 130 °C for 60 h. After cooling to room temperature, the pH of the reaction mixture was adjusted to 9-10 by addition of 2 N sodium hydroxide. Organics were extracted with ether (3 χ 50 mL), dried over magnesium sulfate, filtered and concentrated to give crude 4-bromo-l -methyl- lH-imidazole (571 mg, ca. 62percent). Used without further characterization.. 4-Butyl-l -methyl- lH-imidazole (95 mg, 22 percent) was synthesized as in Example 3.1 using 4-bromo-l -methyl- lH-imidazole (571 mg, ca. 3.53 mmol) in place of 5-bromo-2- formylfuran and propylboronic acid (372 mg, 4.24 mmol) in place of hexylboronic acid. Used without further characterization. To a solution of diisopropylamine (0.13 mL, 0.918 mmol) in 2 mL anhydrous tetrahydrofuran at - 0°C was added -butyllithium (0.34 mL, 2.5 M in hexanes) dropwise. The solution was stirred while warming to -20 °C over 20 minutes. After cooling to -78 °C, 4-butyl-l -methyl- lH-imidazole (95 mg, 0.765 mmol) was added dropwise as a solution in 2 mL anhydrous tetrahydrofuran. The resulting solution was stirred for 40 minutes at -78 °C. Dimethylformamide (0.24 mL, 3.06 mmol) was added and the solution stirred while warming to room temperature. The reaction mixture was poured into 15 mL of 1 N hydrochloric acid and stirred for 5 minutes. The pH of the reaction mixture was adjusted to 7-8 by careful addition of saturated sodium bicarbonate solution. Organics were extracted with dichloromethane (3 χ 20 mL), dried over magnesium sulfate, filtered and concentrated. The crude residue was subjected to chromatography on silica gel with gradient elution (5-50percent ethyl acetate in hexanes) to give l -methyl-4-propyl-lH-imidazole-2-carbaldehyde (9 mg, 8percent) as an off-white solid. Used without further characterization.
Reference：
[1] Bulletin des Societes Chimiques Belges, 1988, vol. 97, # 8-9, p. 573 - 598
[2] Chemical and Pharmaceutical Bulletin, 1994, vol. 42, # 9, p. 1784 - 1790
[3] Acta Chemica Scandinavica, 1990, vol. 44, # 10, p. 1050 - 1057
[4] Acta Chemica Scandinavica, 1990, vol. 44, # 10, p. 1050 - 1057
5
[ 2302-25-2 ]
[ 77-78-1 ]
[ 25676-75-9 ]
[ 1003-21-0 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1983, # 4, p. 735 - 739
6
[ 141524-72-3 ]
[ 25676-75-9 ]
[ 1003-21-0 ]
Reference：
[1] Heterocycles, 1992, vol. 33, # 1, p. 21 - 26
[2] Chemical and Pharmaceutical Bulletin, 1994, vol. 42, # 9, p. 1784 - 1790
[3] Journal of the Chemical Society, 1924, vol. 125, p. 1569
7
[ 2302-25-2 ]
[ 77-78-1 ]
[ 25676-75-9 ]
[ 1003-21-0 ]
Reference：
[1] Journal of the Chemical Society, 1924, vol. 125, p. 1569
[2] Journal of the Chemical Society, 1924, vol. 125, p. 1569
[3] Journal of the Chemical Society, Chemical Communications, 1981, # 21, p. 1095 - 1097
8
[ 77-78-1 ]
[ 25676-75-9 ]
[ 1003-21-0 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1989, p. 1139 - 1145
9
[ 2302-25-2 ]
[ 74-88-4 ]
[ 25676-75-9 ]
[ 1003-21-0 ]
Reference：
[1] Bulletin des Societes Chimiques Belges, 1988, vol. 97, # 8-9, p. 573 - 598
[2] Chemical and Pharmaceutical Bulletin, 1994, vol. 42, # 9, p. 1784 - 1790
[3] Acta Chemica Scandinavica, 1990, vol. 44, # 10, p. 1050 - 1057
[4] Acta Chemica Scandinavica, 1990, vol. 44, # 10, p. 1050 - 1057
10
[ 2302-25-2 ]
[ 77-78-1 ]
[ 25676-75-9 ]
[ 1003-21-0 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1983, # 4, p. 735 - 739
11
[ 141524-72-3 ]
[ 25676-75-9 ]
[ 1003-21-0 ]
Reference：
[1] Heterocycles, 1992, vol. 33, # 1, p. 21 - 26
[2] Chemical and Pharmaceutical Bulletin, 1994, vol. 42, # 9, p. 1784 - 1790
[3] Journal of the Chemical Society, 1924, vol. 125, p. 1569
12
[ 2302-25-2 ]
[ 77-78-1 ]
[ 25676-75-9 ]
[ 1003-21-0 ]
Reference：
[1] Journal of the Chemical Society, 1924, vol. 125, p. 1569
[2] Journal of the Chemical Society, 1924, vol. 125, p. 1569
[3] Journal of the Chemical Society, Chemical Communications, 1981, # 21, p. 1095 - 1097
13
[ 77-78-1 ]
[ 25676-75-9 ]
[ 1003-21-0 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1989, p. 1139 - 1145
tetrakis(triphenylphosphine) palladium(0); In toluene; for 24h;Heating / reflux;Product distribution / selectivity;
Starting from the compound 98 (scheme 19), following the procedure describedabove for the synthesis of compound 10 (scheme 2, step 2, example 12) but replacing 2-bromothiazole with 4-bromo-l-methyl-l.H-imidazole, title compound 224 was obtained in29% yield. MS (m/z): 250.1 (100%), 252.1 (37%) (M+l).
1,1-dimethylethyl 3-methyl-1-(1-methyl-1H-imidazol-4-yl)-2-oxo-4-imidazolidinecarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
With potassium phosphate; copper(l) iodide; trans-N,N-dimethyl-cyclohexane-1,2-diamine; In 1,4-dioxane; for 3h;Heating / reflux;
The 3-methyl-1-(1-methyl-1 H-imidazol-4-yl)-2-oxo-4-imidazolidinecarboxylic acid trifluoroacetate salt used in the method described above was prepared as follows: (i) To a stirred mixture of 1 ,1 -dimethylethyl 3-methyl-2-oxo-4- imidazolidinecarboxylate (200 mg, 0.999 mmol) (prepared as described in step (iii) of Example 13, starting from (4S)-2-oxo-3-[(phenylmethyl)oxy]carbonyl}-4- imidazolidinecarboxylic acid) and 4-bromo-1-methyl-1 H-imidazole (193 mg, 1.199 mmol) in 1 ,4-dioxane (8 ml) was added potassium phosphate (1060 mg, 4.99 mmol), copper(l) iodide (190 mg, 0.999 mmol) and trans-N,N-dimethylcyclohexane-1 ,2- diamine (0.158 ml, 0.999 mmol) and the reaction mixture was stirred at reflux under argon for 3 hours. The mixture was cooled to room temperature and diluted with dichloromethane (2OmL) and filtered and washed through with dichloromethane. The filtrate was concentrated under vacuum and taken up in dichloromethane. The solution was washed with 0.880 ammonia (x3), water then brine and separated by hydrophobic frit and the organic layer was reduced under vacuum. The residue was purified by Flashmaster automated silica gel chromatography eluting with 0-20% methanol in dichloromethane to leave an oil which crystallised on standing. The residue was dried under vacuum overnight to give 1 ,1-dimethylethyl 3-methyl-1-(1- methyl-1 H-imidazol-4-yl)-2-oxo-4-imidazolidinecarboxylate (285 mg, 87 % yield). LC/MS [M+H]+ = 281.
With potassium phosphate; copper(l) iodide; trans-N,N-dimethyl-cyclohexane-1,2-diamine; In 1,4-dioxane; for 1h;Heating / reflux;
Example 39 N-[(2-Chloro-3,4-difluorophenyl)methyl]-3-methyl-1 -(1 -methyl-1 H- imidazol-4-yl)-2-oxo-4-imidazolidinecarboxamide (E39) (in a form obtainable or prepared from (4S)-2-oxo-3-[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid); To a stirred mixture of N-[(2-chloro-3,4-difluorophenyl)methyl]-3-methyl-2-oxo-4- imidazolidinecarboxamide (100 mg, 0.33 mmol) (prepared as described in Example 28), 4-bromo-1 -methyl-1 H-imidazole (63.8 mg, 0.396 mmol) in 1 ,4-dioxane (6 ml) was added potassium phosphate (350 mg, 1.65 mmol), copper (I) iodide (62.8 mg, 0.33 mmol) and trans-N,N-dimethylcyclohexane-1 ,2-diamine (0.052 ml, 0.33 mmol) and the mixture was heated at reflux under argon for 1 h. The mixture was cooled to room temperature and partitioned between saturated sodium hydrogen carbonate solution and dichloromethane. The organic extracts were separated, washed with water and brine, dried and evaporated. The residue was purified by silca gel chromatography eluting with 0-20% methanol in dichloromethane, followed by mass- directed automated HPLC to give N-[(2-chloro-3,4-difluorophenyl)methyl]-3-methyl-1- <n="68"/>(1-methyl-1 H-imidazol-4-yl)-2-oxo-4-imidazolidinecarboxamide (15 mg, 12%). LC/MS [M+H]+ = 384 , retention time = 1.71 minutes.
In tetrahydrofuran; diethyl ether; n-heptane; ethylbenzene; at -10 - 0℃; for 1h;
c) To a dry, N2 purged, 500 mL three neck flask equipped with a stir bar is added 200 mL of dry diethyl ether and 4-bromo-N-methylimidazole (50.0 g, 311 mmol). The flask is then cooled to -10 C. with an acetone/ice bath. A 2.0 M heptane/THF/ethylbenzene solution of lithium diisopropylamide (171 mL, 342 mmol) is then added via syringe while maintaining the reaction temperature at 0 C. or lower. After 1 hour, dimethylformamide (DMF) (36.1 mL, 466 mmol) is added dropwise over 5 minutes. The reaction mixture is allowed to stir for 45 minutes at or below 5 C. and then quenched with a saturated aqueous solution of citric acid. The resulting mixture is stirred vigorously until the two phases separate. The organic layer is recovered and washed (3*200 mL) with water. The solvent is removed in vacuo to give the desired product, 2-formyl-4-bromo-(1) N-methylimidazole, as a brown crystalline solid (yield: 55.7 g, 95 percent, 86 percent purity by GC). Additional purification may be achieved by elution through alumina using methylene chloride solvent.
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; toluene; for 16h;Reflux;
Example 831 -Methylethyl [(2S,4/?)-1 -acetyl-2-methyl-6-(1 -methyl-1 H-imidazol-4-yl)-1 ,2,3,4- tetrahydro-4-quinolinyl]carbamate h drochlorideA mixture of 1 -methylethyl [(2S,4R)-1 -acetyl-2-methyl-6-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 ,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation, see Intermediate 52) (150 mg, 0.36 mmol), 4-bromo-1 -methylimidazole (0.43 mmol), tetrakis(triphenylphosphine)palladium(0) (42 mg, 10 mol%) and potassium carbonate (199 mg, 1 .44 mmol) in toluene (2 mL) and ethanol (2 mL) was refluxed for 16 h then cooled to room temperature and concentrated in vacuo. The residue was partitioned between AcOEt (10 mL) and water (10 mL) and the layers were separated. The organic phase was dried over MgS04 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient: 0 to 6% MeOH in DCM) gave a residue which was treated with 1 M HCI in Et20 (0.5 mL, slight excess). The solvent was evaporated and the residue triturated with Et20 to give 1 -methylethyl [(2S,4R)-1 -acetyl-2-methyl-6-(1 -methyl- 1 /-/-imidazol-4-yl)-1 ,2,3,4-tetrahydro-4-quinolinyl]carbamate hydrochloride (8 mg, 0.02 mmol, 5%) as a colourless solid. LCMS (method G): Retention time 0.56 min, [M+H]+ = 371.1
With sodium hydroxide; In tetrahydrofuran; at 7 - 20℃;
(c) 4-Bromo-l-methyl-lH-imidazole[00357] To a solution of 5-bromo-lH-imidazole (70 g, 0.48 mol) in THF (220 mL) in an ice bath was added 25% NaOH (70 mL). Mel (81 g, 0.57 mol) was then added dropwise at 7-8 C. The mixture was stirred at ambient temperature for 5 min, and then the solvent was removed under reduced pressure. The title compound (15 g) was obtained by fractional distillation. GC-MS: 160 (M+).
With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; water; at 150℃; for 0.666667h;Inert atmosphere; Microwave irradiation;
General procedure: A mixture of 4-methyl-3-(4-(pyridin-2-ylmethoxy)benzamido)phenyl boronic acid (50 mg, 0.14 mmol), Cs2CO3 (135 mg, 0.41 mmol), Pd(PPh3)4(23.93 mg, 0.02 mmol) and 4-bromo-1H-imidazole (26 mg, 0.18 mmol) was purged with nitrogen before adding degassed dioxane (690 muL) and water (230 muL) and heating in a microwave for 40 min at 150 C. After cooling, the aqueous layer was removed with a pipette, and the organic layer was diluted with DMSO (1 mL) and filtered through a 0.2 mum filter. The filtrate was concentrated to a volume of 1 mL and purified by Gilson HPLC (20-75% MeCN/10 mM NH4OAc in water). The fractions were concentrated and lyophilized to yield the product (19 mg, 0.049 mmol, 35%). 1H NMR (DMSO-d6) delta ppm 12.11 (s, 1H), 9.76 (s, 1H), 8.59 (d, 1H), 7.97 (d, 2H), 7.85 (td, 1H), 7.70 (s, 1H), 7.67 (s, 1H), 7.56 (m, 2H), 7.36 (dd, 1H), 7.21 (d, 1H), 7.15 (d, 2H), 5.27 (s, 2H), 2.18 (s, 3H). LCMS (M+H) = 385.
A mixture of 1-methylethyl [(2S,4R)-1-acetyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation, see Intermediate 52) (150 mg, 0.36 mmol), <strong>[25676-75-9]4-bromo-1-methylimidazole</strong> (0.43 mmol), tetrakis(triphenylphosphine)palladium(0) (42 mg, 10 mol %) and potassium carbonate (199 mg, 1.44 mmol) in toluene (2 mL) and ethanol (2 mL) was refluxed for 16 h then cooled to room temperature and concentrated in vacuo. The residue was partitioned between AcOEt (10 mL) and water (10 mL) and the layers were separated. The organic phase was dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient: 0 to 6% MeOH in DCM) gave a residue which was treated with 1M HCl in Et2O (0.5 mL, slight excess). The solvent was evaporated and the residue triturated with Et2O to give 1-methylethyl [(2S,4R)-1-acetyl-2-methyl-6-(1-methyl-1H-imidazol-4-yl)-1,2,3,4-tetrahydro-4-quinolinyl]carbamate hydrochloride (8 mg, 0.02 mmol, 5%) as a colourless solid.LCMS (method G): Retention time 0.56 min, [M+H]+=371.1
With bis(di-tert-?butyl(4-?dimethylaminophenyl)?phosphine)?dichloropalladium(II); sodium carbonate; In 1,2-dimethoxyethane; water; at 80℃; for 4h;Inert atmosphere;
General procedure: Reactions were carried out in a Bohdan XT 24 position block using the appropriate halide indicated.2M Sodium carbonate (0.680 mL, 1.36 mmol) was added to a stirred mixture of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (10, 151 mg, 0.62 mmol), the appropriate halide (0.74 mmol) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (Pd(Amphos)Cl2) (26.3 mg, 0.04 mmol) in DME (4 mL) under nitrogen. The resulting mixture was stirred at 80 C for 4 h, allowed to cool, diluted with water (10 mL), extracted with EtOAc (2×25 mL) and the organic layer was evaporated to afford crude products. Unless otherwise stated the crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5 mu silica, 19 mm diameter, 100 mm length, 5-95% MeCN/1% NH3 in H2O).
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; water; at 130℃; for 0.5h;Inert atmosphere; Microwave irradiation;
General procedure for preparation of Compound 10-6: A solution of Compound 10-3 (169 mg, 0.3 mmol) in a mixture of dioane (10 mL)-H20 (1 mL), was added Compound 10-5 (55.8 mg, 0.3 mmol), Cs2C03 (195 mg, 0.6 mmol) and Pd(dppf)Cl2 (22 mg, 0.03 mmol) and heated under irradiation of M W at 130C for 30 min under N2. Catalyst was filtered through diatomite and concentrated in vacuum to give the crude product (100 mg, yield 61.3%).
To a solution of N-methylimidazole (1.64 g, 19.97 mmol) and sodium acetate (25 g, 300 mmol) in acetic acid (180 mL) at room temperature was added bromine (9.6 g, 60.07 mmol) dropwise as a solution in 20 mL acetic acid. The resulting mixture was stirred for 2.5 h at room temperature. Acetic acid was removed in vacuo, the residue was suspended in 500 mL water and stirred at room temperature for 10 minutes. The resultant precipitate was filtered, washed with water and dried under high vacuum to give 2,4,5-tribromo-l-methyl- lH-imidazole (1.82 g, 29percent - some product remained in the mother liquor) as a light yellow powder. Used without further characterization. To a suspension of the tribromide (1.82 g, 5.71 mmol) in 45 mL water was added sodium sulfite (13 g, 103 mmol) and the resulting mixture was stirred at rapid reflux for 24 h. After cooling to room temperature, organics were extracted with ether (3 chi 75 mL), dried over magnesium sulfate, filtered and concentrated to give 1.61 g of a mixture of tri-, di- and monobromoimidazoles. This mixture was re-subjected to the reduction conditions (same quantity of sodium sulfite) using 15 mL of 3: 1 water/acetic acid as solvent and heating in a sealed vessel at 130 °C for 60 h. After cooling to room temperature, the pH of the reaction mixture was adjusted to 9-10 by addition of 2 N sodium hydroxide. Organics were extracted with ether (3 chi 50 mL), dried over magnesium sulfate, filtered and concentrated to give crude 4-bromo-l -methyl- lH-imidazole (571 mg, ca. 62percent). Used without further characterization.. 4-Butyl-l -methyl- lH-imidazole (95 mg, 22 percent) was synthesized as in Example 3.1 using 4-bromo-l -methyl- lH-imidazole (571 mg, ca. 3.53 mmol) in place of 5-bromo-2- formylfuran and propylboronic acid (372 mg, 4.24 mmol) in place of hexylboronic acid. Used without further characterization. To a solution of diisopropylamine (0.13 mL, 0.918 mmol) in 2 mL anhydrous tetrahydrofuran at - 0°C was added -butyllithium (0.34 mL, 2.5 M in hexanes) dropwise. The solution was stirred while warming to -20 °C over 20 minutes. After cooling to -78 °C, 4-butyl-l -methyl- lH-imidazole (95 mg, 0.765 mmol) was added dropwise as a solution in 2 mL anhydrous tetrahydrofuran. The resulting solution was stirred for 40 minutes at -78 °C. Dimethylformamide (0.24 mL, 3.06 mmol) was added and the solution stirred while warming to room temperature. The reaction mixture was poured into 15 mL of 1 N hydrochloric acid and stirred for 5 minutes. The pH of the reaction mixture was adjusted to 7-8 by careful addition of saturated sodium bicarbonate solution. Organics were extracted with dichloromethane (3 chi 20 mL), dried over magnesium sulfate, filtered and concentrated. The crude residue was subjected to chromatography on silica gel with gradient elution (5-50percent ethyl acetate in hexanes) to give l -methyl-4-propyl-lH-imidazole-2-carbaldehyde (9 mg, 8percent) as an off-white solid. Used without further characterization.
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; at 85℃; for 16h;Inert atmosphere;
To the solution of methyl 4-(6-bromo- 1 -(2-chloro-6-(trifluoromethyl)benzoyl) - 1 H-indazol-3 -yl)-3 -fluor obenzoate (Y-2) (50 mg, 0.083 mmol) in dioxane (5 mL) was added 4-bromo-l-meth yl-lH-imidazole (20 mg, 0.1 mmol) , K2C03 (30 mg, 0.2 mmol) and (PPh3)4Pd (10 mg, 0.0083 mmol) under N2 protection. The mixture was protected by N2 and stirred at 85 C for 16 h. The solution was cooled down, concentrated, and purified by Prep-HPLC (ACN:H20) to afford 5 mg of product (yield: 7.2 %). LCMS (ESI) calc'd [M+H]+: 557, found: 557
7.2%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; at 85℃; for 16h;Inert atmosphere;
To the solution of methyl 4-(6-bromo- 1 -(2-chloro-6-(trifluoromethyl)benzoyl) -1 H-indazol-3 -yl)-3 -fluorobenzoate (Y-2)(50 mg, 0.083 mmol) in dioxane (5 mL) was added <strong>[25676-75-9]4-bromo-1-methyl-1H-imidazole</strong> (20 mg,0.1 mmol), K2C03(30 mg, 0.2 mmol) and (PPh3)4Pd (10mg, 0.0083 mmol) under N2protection. The mixture was protected by N2 and stirred at 85 C for 16 h. The solution was cooled down, concentrated, and purified by Prep-HPLC (ACN:H20) to afford 5 mg of product (yield: 7.2 %). LCMS (ESI) calc?d [M+H]: 557, found: 557.
To a solution of methyl 2-(tert-butoxy)-2-[2-(3,4-dihydro-2H-1-benzopyran-6-yl)-3- (tetramethyl-1 ,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)phenyl]acetate (35a) (100 mg, 0.182 mmol) in dioxane (1 mL) was added <strong>[25676-75-9]4-bromo-1-methylimidazole</strong> (36 muIota_, 0.36 mmol) and sodium carbonate saturated aqueous solution (1. mL). This mixture was stirred at room temperature for 20 minutes while passing a stream of argon. [1 ,1 - Bis(diphenylphosphino) ferrocene]dichloropalladium(ll), complex with dichloromethane (14 mg, 0.018mmol) was added and the resulting mixture was stirred at 80 C for 24 hours. Further 4-bromo-1 -methylimidazole (36 mu, 0.36 mmol) and [1 ,1 '-Bis(diphenylphosphino) ferrocene]dichloropalladium(ll), complex with dichloromethane (14 mg, 0.018mmol) were added and the resulting mixture was stirred at 80 C for 24 hours. Water (10 mL) was added and the mixture was extracted with ethyl acetate (2x10 mL). The organic phase were washed with brine (10 mL), dried over sodium sulfate and concentrated in vacuo. The crude residue was purified on preparative TLC (dichloromethane/ethyl acetate: 90/10).
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In water; N,N-dimethyl-formamide; at 80 - 100℃;Sealed tube;
a) 6- (1-Methyl-i H-imidazol-4-yl)-8- ((2- (trimethylsilyl)ethoxy)methoxy)-3- ((2- (trimethylsilyl)ethoxy)methyl)guinazolin-4(3H)-oneA suspension of <strong>[25676-75-9]4-bromo-1-methyl-1H-imidazole</strong> (0.02 g, 0.1 mmol), (6-(4,4,5,5-tetramethyl-1,3 ,2-dioxaborolan-2-yl)- 8- ((2- (trimethylsilyl)ethoxy)methoxy)-3- ((2- (trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one (0.05 g, 0.08 mmol, example 28), bis(diphenylphosphino)feffocene-palladium(II)dichloride (0.01 g, 0.01 mmol), potassium carbonate (0.03 g, 0.25 mmol) and water (0.2 ml) in dimethylformamide (1 ml) was stirred in asealed tube at 100 C for 2 hours and then at 80 C overnight. Filtration and chromatography (C18 reverse phase HPLC, methanol / water (0.1 % formic acid) = 40:60 to 100:0) yielded the title compound as white solid (0.01 g, 20 %). MS: mle = 503.7 [M+Hf?.
4-(1-methyl-1H-imidazol-4-yl)-2-nitroaniline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,2-dimethoxyethane; water; at 100℃; for 4h;Inert atmosphere;
Intrmdiate Example 11.5-(I-Methyl-1H-imidazol-4-yl)-1H-benzo[d]imidazolea) 4-(1-Methyl-1H-imidazol-4-yl)-2-nitroanilineA solution, of <strong>[833486-94-5]2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline</strong>(1.45 g, 5.55 mmol, 1.1 eq) in 1 ,2-dimethoxyethane (15 ml) was degassed by N2bubbling for 5 mi 4-Bromo-1-methyi-1H-imidazole (0.81 g, 5 mmol, 1 eq) was added and the mixture was degassed for another 5 mm. Pd(dppf)Cl2 (0.4 g, 0.5 mmol, 0.1 eq) and aqueous sodiumcarbonate (1.59 g, 15 mmol, 3 eq) were added, sequentially using the procedure of Intermediate Example 1 and then heated at 100 C for 4 h. The reactionmixture was then quenched and extracted as in Intermediate Example 1. The solvent was distilled off to afford the crude residue which was purified by columnchromatography (60-120 silica gel, 50 % ethyl acetate in hexane) to afford the title product in 60 % yield (0.6 g). LC-MS (ESI): Calculated mass: 218.08; Observed mass:219.2 [M+HJ (rt: 0.09 mm).
N-(2',4'-difluoro-5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-1-yl)-[1,1'-biphenyl]-3-yl)acetamide[ No CAS ]
N-(2',4'-difluoro-5-(5-(1-methyl-1H-imidazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1'-biphenyl]-3-yl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
11%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,2-dimethoxyethane; water; at 90℃; for 2h;Inert atmosphere;
b) A solution of the compound of Example 297(a) (0.1 g, 0.204 mmol) in 1,2-dimethoxyethane (15 ml) was degassed by N2 bubbling for 5 min. 4-Bromo-1-methyl imidazole (49 mg, 0.306 mmol, 1.5 eq.) was added and the mixture was degassed for another 5 min. Pd(dppf)Cl2 (16 mg, 0.0204 mmol, 0.1 eq.) and aqueous sodium carbonate (65 mg, 0.612 mmol, 3.0 eq.) were added and the procedure of Example 1(d) was followed. The crude residue of the product was purified by column chromatography (60-120 silica gel, 5% methanol in chloroform) to yield the title product in 11% yield (10 mg). 1H NMR (400 MHz, DMSO-d6): delta 10.5 (s, 1H), 9.05-9.0 (br S, 1H), 8.8 (s, 1H), 8.26 (s, 1H), 8.18 (s, 1H), 8.13 (s, 1H), 7.87-7.76 (m, 5H), 7.56 (s, 1H), 7.48 (dt, 1H), 7.3-7.29 (dt, 1H), 3.9 (s, 3H), 2.15 (s, 3H); LC-MS (ESI): Calculated mass: 443.45; Observed mass: 444.1 [M+H]+ (rt: 0.632 min).
(7-methoxy-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinolin-3-yl)boronic acid[ No CAS ]
6-(7-methoxy-3-(1-methyl-1H-imidazol-4-yl)quinolin-6-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
25 mg
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 130℃; for 1h;Microwave irradiation;
7-Methoxy-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinolin-3- yl)boronic acid (0.24 g, 0.53 mmol), 4-bromo-1 -methyl-1 H-imidazole (0.26 g, 1.6 mmol), and Na2C03 (0.20 g, 1 .9 mmol) were added to a microwave vial. Pd(PPh3)4 (0.05 g, 0.04 mmol) was then added followed by addition of 1 ,4-dioxane (2.2 ml.) and water (0.6 ml_). The reaction mixture was sealed and heated in a Biotage Initiator microwave reactor at 130 C for 1 h. A solution of NaHC03was added to the reaction and the aqueous phase was extracted with DCM (3x). The combined organic phases were dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (1-10% 7 M ammonia in MeOH gradient, in DCM) to give 6-(7-methoxy-3-(1 -methyl-1 H-imidazol-4-yl)quinolin-6- yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine as a yellow solid (25 mg). MS (M+1 ) = 486.6
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; N-benzyl-N,N,N-triethylammonium chloride; cesium fluoride; In water; toluene; for 48h;Inert atmosphere; Reflux;
General procedure: A deaerated mixture of <strong>[25676-75-9]4-bromo-1-methyl-1H-imidazole</strong> (10) (0.800g, 5.00mmol), an arylboronic acid 7 (10.0mmol), CsF (2.28g, 15.0mmol), PdCl2(dppf) (0.183g, 0.25mmol), and BnEt3NCl (0.057g, 0.25mmol) in toluene (30mL) and water (30mL) was heated at reflux under argon for 48h. The mixture was then cooled to room temperature and partitioned between water and AcOEt, and the organic extract was dried and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel to provide the desired product. This procedure was used to prepare compounds 9a and 9b, both in 95% yield.
60.11%
With bis(tri-t-butylphosphine)palladium(0); caesium carbonate; In 1,4-dioxane; water; at 50℃; for 19h;Inert atmosphere;
To a solution of 4-bromo-l -methyl- l//-imidazole (300 mg, 1.86 mmol), (4-methoxyphenyl)boronic acid (283 mg, 1.86 mmol) in dioxane (15 mL) was added to a solution of Cs2C03 (1.2 g, 3.73 mmol) in H20 (3 mL) followed with Pd(t-Bu3P)2 (95 mg, 186.34 umol). The mixture was stirred at 50 C for l9h under N2. The mixture was diluted with water (30 mL), extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine (15 mL), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was purified by silica gel column (petroleum : ethyl acetate = ( 1:0 to 2:3) to afford compound 39A (232.2 mg, yield 60.11%) as light red solid. 1H NMR (CD OD, 400 MHz) d 7.64 - 7.57 (m, 3H), 7.30 (s, 1H), 6.90 (br d, / = 8.3 Hz, 2H), 3.79 (s, 3H), 3.73 (s, 3H). MS (ESI) m/z (M+H)+ 188.9.
4-(3,5-dimethoxyphenyl)-1-methyl-1H-imidazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; N-benzyl-N,N,N-triethylammonium chloride; cesium fluoride; In water; toluene; for 48h;Reflux; Inert atmosphere;
General procedure: A deaerated mixture of <strong>[25676-75-9]4-bromo-1-methyl-1H-imidazole</strong> (10) (0.800g, 5.00mmol), an arylboronic acid 7 (10.0mmol), CsF (2.28g, 15.0mmol), PdCl2(dppf) (0.183g, 0.25mmol), and BnEt3NCl (0.057g, 0.25mmol) in toluene (30mL) and water (30mL) was heated at reflux under argon for 48h. The mixture was then cooled to room temperature and partitioned between water and AcOEt, and the organic extract was dried and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel to provide the desired product. This procedure was used to prepare compounds 9a and 9b, both in 95% yield.
Lithium diisopropylamide (2 M solution in heptane I tetrahydrofuran I ethylbenzene, 24 mL, 48 mmol) was added to a -10 00 solution of 4-bromo-1 -methyl15 IH-imidazole (7.0 g, 43 mmol) in tetrahydrofuran (250 mL). After 1 hour, N,Ndimethylformamide (4.8 g, 66 mmol) was added at 0 C, and the reaction mixture was stirred for an additional hour. Saturated aqueous citric acid solution (50 mL) was then added, and the organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the product as a yellow solid. This material was used in the following step without further purification. Yield: 7.0 g, 37 mmol, 86%. 1H NMR (400 MHz, DMSOd 6) 9.61 (s, I H), 7.77 (s, I H), 3.92 (s, 3H).
61.7%
b) 4-Bromo-1-methyl-1H-imidazole-2-carbaldehyden-buthyllithium 1.6M in hexane (1.83 ml, 2.93 mmol, Eq: 1.05) was stirred in Diethyl ether (2.5 ml) and cooled to -78C in a dry-ice bath. 4-bromo-l -methyl- IH-imidazole (450 mg, 2.8 mmol, Eq: 1.00) solved in Diethyl ether (0.75 ml) was added via syringe in ca.4-5 portions over 20min. After stirring for ca. 60min at -78C, DMF (215 mg, 226 mu, 2.93 mmol, Eq: 1.05) in Diethyl ether (0.5 ml) was added via syringe in portions over ca. 15min. The reaction mixture was stirred at -78C for 2.5h. Water was added and extracted three times with ethyl acetate, dried over magnesium sulfate, filtered and evaporated. The crude material was purified by column chromatography using heptane / ethyl acetate (0-100% ethyl acetate) as eluent affording 4- Bromo-1 -methyl- lH-imidazole-2-carbaldehyde (326 mg, 61.7%) as light yellow solid. MS: m/z=191.3 (M+H+)
2-(((1R,5S,8r)-3-benzyl-3-azabicyclo[3.2.1]octan-8-yl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide[ No CAS ]
2-(((1R,5S,8r)-3-benzyl-3-azabicyclo[3.2.1]octan-8-yl)oxy)-5-(1-methyl-1H-imidazol-4-yl) benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
62%
With tris-(dibenzylideneacetone)dipalladium(0); sodium carbonate; tri tert-butylphosphoniumtetrafluoroborate; In 1,4-dioxane; water; at 100℃; for 16h;Inert atmosphere; Sealed tube;
Preparation 1452-(((i R,55,8r)-3-benzyl-3-azabicyclo[3.2. iloctan-8-yl)oxy)-5-(i-methyl-i H-imidazol-4-VI) benzam ide To a solution of 2-((( i R, 5S, 8r)-3-benzyl-3-azabicyclo[3.2. i ]octan-8-yl)oxy)-5-(4,4, 5,5- tetramethyl-i,3,2-dioxaborolan-2-yl)benzamide (Preparation 151, 300 mg, 0.65 mmol) and 4- bromo-i-methyl-iH-imidazole (0.i6 mL, 0.97 mmol) in dioxane (8 mL) was added a solution of sodium carbonate (i72 mg, i.62 mmol) in water (2 mL) and the mixture was degassed with10 argon for i5 minutes. Pd2(dba)3 (29 mg, 0.032 mmol) followed by tBu3HPBF4 (37 mg, 0.i3 mmol) were added and the reaction was heated at iOOC in a sealed tube for i6 hours. The reaction was cooled, washed with water, brine, dried over sodium sulphate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 6% MeOH in DCM to afford the title compound (i70 mg, 62%).15 MSm/z4i7[M+H]
4-(aminomethyl)phenylboronic acid hydrochloride[ No CAS ]
[ 25676-75-9 ]
(4-(1-methyl-1H-imidazol-4-yl)phenyl)methanamine dihydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
0.12 g
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,2-dimethoxyethane; water; at 120℃; for 6h;Inert atmosphere; Microwave irradiation;
A solution of (4-(aminomethyl)phenyl)boronic acid hydrochloride (0.85 g), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.37 g), <strong>[25676-75-9]4-bromo-1-methyl-1H-imidazole</strong> (0.80 g) and sodium carbonate (1.20 g) in DME (12 mL)-water (3 mL) was stirred under an argon atmosphere at 120C for 6 hr under microwave irradiation. To the reaction mixture was added 6N hydrochloric acid, and the mixture was washed with ethyl acetate. The aqueous layer was separated, neutralized with 8N aqueous sodium hydroxide solution, and concentrated under reduced pressure. The residue was washed with THF, and the obtained organic layer was concentrated. The residue was crudely purified by NH silica gel chromatography (hexane-ethyl acetate). The obtained crudely purified product was diluted with ethyl acetate, 4N hydrogen chloride ethyl acetate solution (1 mL) was added, and the resulting precipitate was collected by filtration, and dried to give the title compound (0.12 g). 1H NMR (300 MHz, DMSO-d6) delta 3.90 (3H, s), 4.05-4.10 (2H, m), 7.63 (2H, d, J = 8.3 Hz), 7.90 (2H, d, J = 8.3 Hz), 8.20 (1H, d, J = 1.1 Hz), 8.42 (3H, brs), 9.19 (1H, s), 1H not detected.
1-methyl-4-(prop-1-en-2-yl)-1H-imidazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
22%
General procedure: To a 50 mL round bottle flask was added 1,1?-Bis(diphenylphosphino)ferrocenedichloro Palladium(II) (0.1equiv), bromide (1.0equiv) and vinylboronic acid pinacol ester (2.0equiv) in 20mL dioxane. The mixture was degassed for 5min, and sodium carbonate aqueous solution (2.0M, 10equiv) was added. The mixture was then heated to 85C for 14h. After cooled to rt, the reaction mixture was filtered through a short Celite pad and washed with EtOAc. The organic solution was concentrated under reduced pressure and the residue was loaded into combi flush for purification to afford the product as oil.
3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one[ No CAS ]
3,3-dimethyl-1-(1-methyl-1H-imidazol-4-yl)-6-(2-methylpyrimidin-5-yl)indolin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
59%
With copper(l) iodide; potassium carbonate; N,N`-dimethylethylenediamine; In acetonitrile; at 120℃; for 1.5h;Inert atmosphere; Microwave irradiation;
A suspension of 3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (100 mg) and 4-iodopyridine (97 mg) in acetonitrile (1.5 ml) was flushed with argon, then potassium carbonate(120 mg), copper(I)iodide (8 mg) and N,N?-dimethylethylendiamine (7 mg) were added andstifling was continued in a microwave oven at 120 C for 1.5 h. The mixture was partitionedbetween water and EtOAc, the organic layer was dried, evaporated and the residue purified by flash chromatography (silica gel, 30% to 100% EtOAc in n-heptane). The compound containing fractions were evaporated and the residue crystallized from n-heptane/EtOAc to give the title compound (64 mg, 49%) as a light brown solid. MS (mlz): 331.2 [(M+H)?i:_Example 2 was prepared in analogy to example id using <strong>[25676-75-9]4-bromo-1-methyl-1H-imidazole</strong> togive the title compound (59%) as an off-white solid. MS (mlz): 334.3 [(M+H)41.
tert-butyl 4-([2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl]oxy}methyl)piperidine-1-carboxylate[ No CAS ]
tert-butyl 4-([2-amino-5-(1-methyl-1H-imidazol-4-yl)pyridin-3-yl]oxy}methyl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
42%
With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In ethanol; water; toluene; at 85℃; for 16h;Inert atmosphere;
To a suspension of tert-butyl 4-([2-amino-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-3-yl]oxy}methyl)piperidine-1 -carboxylate (I-55) (1 1 .08 g, 27.2 mmol), 4-bromo-1 -methyl-1 H-imidazole (5.26 g, 32.7 mmol), Cs2C03 (2 N in H20, 27.2 mL, 54.5 mmol) in toluene (50 mL) and EtOH (150 mL) was added Pd(PPh3)4 (4.72 g, 4.08 mmol). The mixture was thoroughly degassed with N2 three times and the brown suspension was then stirred at 85 C for 16 hr under N2. LCMS showed the desired product by mass had formed. The reaction mixture was concentrated under vacuum to give a residue, which was diluted with CH2CI2 (300 mL), washed with water (50 mL), brine (30 mL), dried over Na2S04 and concentrated to give the crude product which was purified twice by silica gel chromatography (0 to 5% MeOH in CH2CI2 followed by CH2CI2/MeOH = 1 /0 to 20/1 ) to give tert-butyl 4-([2-amino-5-(1 -methyl-1 H-imidazol-4-yl)pyridin-3-yl]oxy}methyl)piperidine-1 -carboxylate (~ 5.9 g as a brown solid. ~ 90% purity). This material was diluted with EtOAc / CH2CI2 (5:1 , 60 mL) and heated to 60 C until a clear solution was obtained. Cooling the solution to 25 C with concomitant reduction of the volume under reduced pressure (~10 mL) lead to the appearance of a precipitate. The suspension was filtered, the filter cake was washed with EtOAc/petroleum ether (1 :1 , 10 mL) and dried under vacuum to give tert-butyl 4-([2-amino-5-(1 -methyl-1 H-imidazol-4-yl)pyridin-3-yl]oxy}methyl)piperidine-1 -carboxylate (1-106) (4.38 g, 42%) as a purple solid.
4-(4-fluoro-3-methylphenyl)-1-methyl-1H-imidazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
51%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; ethanol; water; at 150℃; for 0.833333h;Inert atmosphere; Microwave irradiation;
Step 1: A solution of 4-bromo-1-methyl-1H-imidazole (1.0 g, 6.2 mmol), <strong>[139911-27-6](4-fluoro-3-methylphenyl)boronic acid</strong> (1.0 g, 6.5 mmol), tetrakis(triphenylphosphine)-palladium(0) (0.6 g, 0.52 mmol) and aqueous Na2CO3 (2 M, 4 mL, 8.0 mmol) in a mixture of DME/EtOH/H2O (7:3:2, 10 mL) was evacuated and then refilled with nitrogen (three cycles). Resulting reaction mixture was then irradiated in the microwave at 150 C. for 50 min., dried (MgSO4), filtered and concentrated under reduced pressure to give a black residue, which was purified by column chromatography eluting with MeOH/DCM to provide 4-(4-fluoro-3-methylphenyl)-1-methyl-1H-imidazole (0.6 g, 51%). MS m/e: 191 (M+H)+.
(4S)-6,8-dichloro-2-methyl-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,2,3,4-tetrahydroisoquinoline[ No CAS ]
(4S)-6,8-dichloro-2-methyl-4-[3-(1-methyl-1H-imidazol-4-yl)phenyl]-1,2,3,4-tetrahydroisoquinoline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
6.7%
With tris-(dibenzylideneacetone)dipalladium(0); trifuran-2-yl-phosphane; caesium carbonate; In 1,4-dioxane; water; at 90℃; for 24h;Inert atmosphere;
To a solution of (4S)-6,8-dichloro-2-methyl-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,2,3,4-tetrahydroisoquinoline (50 mg) obtained in Reference Example 3-2 in dioxane (1.0 mL) and water (0.25 mL), <strong>[25676-75-9]4-bromo-1-methyl-1H-imidazole</strong> (14 mg), tri(2-furyl)phosphine (17 mg), cesium carbonate (78 mg), and tris(dibenzylideneacetone)dipalladium(0) (11 mg) were added in a nitrogen gas atmosphere, and the mixture was stirred at 90C for 1 day.The reaction solution was allowed to cool, and then, water was added thereto, followed by extraction with ethyl acetate.The organic layer was dried over anhydrous magnesium sulfate and filtered, and then, the filtrate was concentratedunder reduced pressure. The obtained residue was purified by preparative LC-MS (LC (Agilent 1260), ESIMS (6130Quadrupole, ESI), column (YMC-Actus Triart 5 mm C18 50 x 30 mm), mobile phase (0.1% formic acid in H2O:0.1%formic acid in CH3CN = 95:5 ? 50:50 ? 5:95), 50 mL/min.) to obtain the title compound (3.6 mg, yield: 6.7%) as acolorless oil substance. 1H NMR (300 MHz, CD3OD) delta ppm 2.60 (s, 3H), 2.80 (dd, J=11.8, 9.8Hz, 1H), 3.17-3.26 (m, 1H), 3.62-3.71 (m, 1H),3.76 (s, 3H), 4.01-4.12 (m, 1H), 4.37 (dd, J=9.8, 5.8Hz, 1H), 6.79-6.83 (m, 1H), 7.07 (d, J=7.6Hz, 1H), 7.31-7.38 (m,2H), 7.46 (s, 1H), 7.54-7.69 (m, 3H). MS (+): 372 [M+H]+.
4-(benzylamino)-N-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide[ No CAS ]
4-(benzylamino)-N-methyl-3-(1-methyl-1H-imidazol-4-yl)benzenesulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
28%
With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; water; at 90℃; for 16h;Inert atmosphere;
To a solution of compound 121-4 (700 mg, 1.74 mmol, 1.0 eq), compound 121-4a (308 mg, 1.91 mmol, 1.1 eq), Cs2C03 (1.13 g, 3.48 mmol, 2.0 eq) in Dioxane (8 mL) and H20 (2 mL) was added Pd(PPh3)4 (101 mg, 87.0 umol, 0.05 eq) under N2. The reaction mixture was stirred at 90 C for 16 hours. The reaction mixture was concentrated under reduced pressure. The mixture was diluted with water (20 mL) and the resultant mixture was extracted with EA (50 mL * 3). The combined organic layers were dried over Na2SC>4, filtered and concentrated to dryness under reduced pressure. The residue was purified by preparative high performance liquid chromatography. The pure fractions were collected and the volatiles were removed under vacuum. The resulting mixture was lyophilized to dryness to remove the solvent residue completely. The title compound 121-5 (180 mg, 28% yield) was obtained. LCMS (ESI): RT = 0.592 min, mass calcd. for C18H20N4O2S 356.13, m/z found 356.9 [M+H]+, lH NMR (400MHz, CDCI3) delta 9.09 (s, 1H), 7.86 (d, J = 2.3 Hz, 1H), 7.49 (dd, J= 2.3, 8.8 Hz, 1H), 7.46 (s, 1H), 7.41 - 7.30 (m, 4H), 7.29 - 7.26 (m, 2H), 6.62 (d, J = 8.8 Hz, 1H), 4.53 (s, 2H), 4.21 (q, J= 5.4 Hz, 1H), 3.75 (s, 3H), 2.61 (d, J = 5.5 Hz, 3H).
N-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-((3-(trifluoromethyl)phenyl)amino)benzenesulfonamide[ No CAS ]
N-methyl-3-(1-methyl-1H-imidazol-4-yl)-4-((3-(trifluoromethyl)phenyl)amino)benzenesulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
11%
With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; water; at 90℃; for 16h;Inert atmosphere;
To a solution of compound 124-1 (120 mg, 0.26 mmol, 1.0 eq), compound 124-la (1492) (42 mg, 0.26 mmol, 1.0 eq) and CS2CO3 (325 mg, 0.17 mmol, 2.0 eq) in Dioxane (3 mL) and H2O (0.6 mL) was added Pd(PPli3)4 (15 mg, 13 umol, 0.05 eq). The suspension was degassed under vacuum and purged with N2 several times. The reaction mixture was stirred at 90 C for 16 hours. LCMS showed Reactant 124-1 was consumed completely and one main peak with desired MS was detected. The reaction mixture was concentrated under reduced pressure. The mixture was diluted with water (10 mL) and the resultant mixture was extracted with EA (30 mL * 3). The combined organic layers were dried over Na2SC>4, filtered and concentrated to dryness under reduced pressure. The residue was purified by prep-HPLC to obtain Compound 124 (12.40 mg, 11% yield). LCMS (ESI): RT = 0.650 min, mass calcd. for C18H17F3N4O2S 410.10, m/z found 410.9 [M+H]+, NMR (400MHz, CDC13) delta 10.83 (s, 1H), 7.97 (d, J = 2.0 Hz, 1H), 7.56 (dd, J = 2.3, 8.8 Hz, 1H), 7.51 (d, J= 5.8 Hz, 2H), 7.48 - 7.41 (m, 2H), 7.38 - 7.33 (m, 2H), 7.29 (d, J = 6.3 Hz, 1H), 4.33 (q, J= 5.3 Hz, 1H), 3.78 (s, 3H), 2.67 (d, J = 5.5 Hz, 3H).
4-(5-bromobenzimidazol-1-yl)-2,6-dimethoxy-N-(2,2,2-trifluoroethyl)benzamide[ No CAS ]
[ 73183-34-3 ]
2,6-dimethoxy-4-[5-(1-methylimidazol-4-yl)benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Borylation: A flask is charged with Int 39 (458 mg, 1 mmol, 1 eq.), E^pim (381 mg, 1.5 mmol, 1.5 eq.), dioxane previously degassed with N2 (5 mL), potassium acetate (295 mg, 3 mmol, 3 eq.) and Pd(dppf)Cl2-DCM (82 mg, 0.10 mmol, 0.1 eq.). The mixture is stirred to 100 C overnight, concentrated in vacuo. The residue is diluted in DCM and water. The organic layer is separated and concentrated in vacuo, purified by flash chromatography on silica gel (eluting with DCM/MeOH 100/0 to 95/5) to afford the expected boronic ester and boronic acid mixture.LCMS: MW (calcd): 505.3; m/z MW (obsd): 506.3 (M+H).LCMS: MW (calcd): 423.1 ; m/z MW (obsd): 424.1 (M+H).; Suzuki coupling: To a stirred solution of boronic ester and boronic acid mixture (51 mg, 0.10 mmol, 1 eq.) and 4-bromo-l -methyl-imidazole (CAS 25676-75-9; 10 pL, 0.10 mmol, 1 eq.) in dioxane (2 mL) is added CS2CO3 (65 mg, 0.20 mmol, 2 eq.), Pd(PPh3)4 (12 mg, 0.01 mmol, 0.1 eq.) in water (0.5 mL). The mixture is heated to 90 C for 1 h then concentrated in vacuo. The residue is diluted in DCM and water. The organic layer is separated and concentrated in vacuo, purified by flash chromatography on Biotage SNAP KP-NH cartridge (eluting with DCM/MeOH 100/0 to 98/2) to afford the expected compound.
methyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-((4-(trifluoromethyl)phenyl)amino)benzoate[ No CAS ]
methyl 3-(1-methyl-1H-imidazol-4-yl)-4-((4-(trifluoromethyl)phenyl)amino)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
49.9%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; water; at 90℃; for 3h;Inert atmosphere;
To a solution of methyl 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-4-[4- (trifluoromethyl)anilino]benzoate (1.35 g, 3.20 mmol, 1.0 eq), 4-bromo-l -methyl -imidazole (619 mg, 3.85 mmol, 1.2 eq) and CS2CO3 (2.09 g, 6.41 mmol, 2.0 eq) in dioxane (15 mL) and H20 (3 mL) was added Pd(dppf)Cl2 (117 mg, 0.16 mmol, 0.05 eq). The mixture was stirred at 90 C for 3 hr under N2. The reaction mixture was concentrated under reduced pressure .Then the mixture was diluted with water (15 mL) and the resultant mixture was extracted with EA (40 mL * 3). The combined organic layers were dried over Na2S04, filtered and concentrated to dryness under reduced pressure. The residue was purified by column chromatography (Si02) to obtain methyl 3-(l-methylimidazol-4-yl)-4-[4-(trifluoromethyl)anilino]benzoate (600 mg, 49.9% yield).
5-(4-methyl-piperazin-1-ylmethyl)-furan-2-carboxylic acid [8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl]-amide[ No CAS ]
5-(4-methyl-piperazin-1-ylmethyl)-furan-2-carboxylic acid [8-(1-methyl-1H-imidazol-4-yl)-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl]-amide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
16.4%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 110℃; for 1h;Inert atmosphere;
[00288] A mixture of5-(4-methylpiperazin-1-ylmethyl)-furan-2-carboxylic acid [8- (4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl]-amide (98 mg, 0.18 mmol, 1.0 eq), 4-bromo-1 -methyl-1H-imidazole (63 mg, 0.39 mmol, 2.2 eq.) Pd(PPh3)4 (21 mg, 0.017 mmol, 0.1eq), K2CO3 (49 mg, 2.0 eq) in 9:1 dioxane:H20 (5ml_) was purged with N2 for 15 min and the mixture was heated to 110 C for 1 h. The reaction mixture was concentrated under reduced pressure and the residue dissolved in MeOH and loaded onto a SCX-2 cartridge. The cartridge was washed with MeOH, and the compound eluted using 0.5M ammonia in methanol. The product-containing fractions were concentrated under reduced pressure to yield the crude material which was purified by prep HPLC to give 5-(4- methyl-piperazin-1-ylmethyl)-furan-2-carboxylic acid [8-(1 -methyl-1H-imidazol-4-yl)-2,3- dihydro-benzo[1,4]dioxin-2-ylmethyl]-amide (13.3 mg, 16.4 %) as an off-white solid AnalpH9_MeOH_QC_V1 : Rt: 6.93 min, m/z 452.4 [M+H]+ 1H NMR (400MHz, DMSO-d6): d 8.65 (t, J = 6.0Hz, 1H) 7.62-7.57 (m, 3H) 7.13 (d, J = 3.5 Hz, 1H) 6.82 (t, J = 7.3 Hz, 1H) 6.70 (dd, J = 7.8, 1.5 Hz, 1H) 6.46 (d, J = 3.3 Hz, 1H) 4.42-4.35 (m, 2H) 3.97 (dd, J = 1 1.9, 8.6 Hz, 2H) 3.77-3.68 (m, 1H) 3.56 (s, 3H) 3.51 (s, 2H) 2.48-2.20 (m, 8H) 2.16 (s, 3H)
benzyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline-2-carboxylate[ No CAS ]
benzyl 5-(1-methylimidazol-4-yl)isoindoline-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
43 mg
With potassium phosphate; [2?-(amino-kappaN)[1,1?-biphenyl]-2-yl-kappaC][butylbis(tricyclo-[3.3.1.13,7]dec-1-yl)phosphine]chloropalladium; In tetrahydrofuran; water; at 75℃;Inert atmosphere;
Step 2: preparation of benzyl 5-(1-methylimidazol-4-yl)isoindoline-2-carboxylate (compound 45b) To a solution of benzyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline-2-carboxylate (compound 45a, 76 mg, 0.20 mmol) in THF/H2O (4.5 mL, v/v = 8/1) was added <strong>[25676-75-9]4-bromo-1-methyl-1H-imidazole</strong> (32 mg, 0.20 mmol), and K3PO4 (85 mg, 0.40 mmol). The solution was bubbled with N2 for 5 mins, then cataCXium A Pd G2 (134 mg, 0.20 mmol) was added. The mixture was heated at 75 C overnight, then cooled to rt and concentrated to give a crude product which was purified by column chromatography to give compound 45b (43 mg) as an oil. MS: calc'd 334 (MH+), measured 334 (MH+).
1-methyl-4-(3-methyl-4-nitrophenyl)-1H-imidazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
47%
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate In 1,4-dioxane; water at 100℃; for 16h;
General Method D: Suzuki Coupling Reaction Intermediate C-V-4: 1-methyl-4-(3-methyl-4-nitrophenyl)-1H-imidazole
General Method D: Suzuki Coupling Reaction Intermediate C-V-4: 1-methyl-4-(3-methyl-4-nitrophenyl)-1H-imidazole A suspension of 4,4,5,5-tetramethyl-2-(3-methyl-4-nitrophenyl)-1,3,2-dioxaborolane (0.80 g, 3.0 mmol) and 4-bromo-1-methyl-1H-imidazole (0.49 g, 3.0 mmol) in a mixture of 1,4-dioxane (12 mL) and water (0.5 mL) was treated with potassium carbonate (1.26 g, 9.1 mmol) and the suspension was allowed to stir. The reaction mixture was degassed by bubbling argon for two minutes and treated with Pd(dppf)Cl2.DCM adduct (0.50 g, 0.61 mmol). The resulting reaction mixture was heated at 100° C. 16 h. The reaction was diluted with water and extracted with DCM (4*25 mL). The organics were combined and dried over anhydrous Na2SO4, filtered and concentrated to dryness under vacuum to afford a black oil. The black oil was purified using silica gel (0 to 15% MeOH/DCM, 15 CV's) to obtain 1-methyl-4-(3-methyl-4-nitrophenyl)-1H-imidazole (0.31 g, 47% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.02 (d, J=8.6 Hz, 1H), 7.84 (d, J=7.7 Hz, 2H), 7.77 (d, J=8.6 Hz, 1H), 7.72 (s, 1H), 3.70 (s, 3H), 2.57 (s, 3H); LC-MS (ESI) m/z: 218.2 (M+H+).
47%
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate In 1,4-dioxane; water at 100℃; for 16h;
Intermediate C 1 : 1 -methyl -4-(3 -methyl -4-nitrophenyl)- 1 H-imidazol e :
General procedure: A suspension of 4,4,5,5-tetramethyl-2-(3-methyl-4-nitrophenyl)-l,3,2- dioxaborolane (0.80 g, 3.0 mmol) and 4-bromo-l -methyl- lH-imidazole (0.49 g, 3.0 mmol) in a mixture of 1,4-dioxane (12 mL) and water (0.5 mL) was treated with potassium carbonate (1.26 g, 9.1 mmol) and the suspension was allowed to stir. The reaction mixture was degassed by bubbling argon for two minutes and treated with Pd(dppf)Ch.DCM adduct (0.50 g, 0.61 mmol). The resulting reaction mixture was heated at 100 °C 16 h. The reaction was diluted with water and extracted with DCM (4 x 25 mL). The organics were combined and dried over anhydrous NaiSCE, filtered and concentrated to dryness under vacuum to afford a black oil. The black oil was purified using silica gel (0 to 15 % MeOH/DCM, 15 CV's) to obtain l-methyl-4-(3-methyl-4-nitrophenyl)-lH-imidazole (0.31 g, 47 % yield). 1H NMR (400 MHz, DMSO-de): d 8.02 (d, J = 8.6 Hz, 1H), 7.84 (d, J = 7.7 Hz, 2H), 7.77 (d, J = 8.6 Hz, 1H), 7.72 (s, 1H), 3.70 (s, 3H), 2.57 (s, 3H); LC-MS (ESI) m/z: 218.2 (M+H+).
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