* 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.
With palladium 10% on activated carbon; hydrogen In methanol at 20℃; for 18 h;
A solution of compound52(0.2 g, 1.03 mmol) in methanol (10 mL) was treated with 10percent palladium on carbon (20 mg) and subjected to a hydrogen atmosphere. The mixture was stirred for a further 18 h and then filtered through a pad of Celite®. The pad was washed with methanol (50 mL) and the combined filtrates evaporatedin vacuoto give the crude residue which was purified by flash chromatography on silica eluting withCH2Cl2-methanol-aqueous ammonia (95:4.5:0.5) to give amine53(0.15 g, 87percent) as a brown solid; mp 89–92 °C (lit mp 94–95 °C); νmax/cm-13333, 3210, 1606, 1586, 1519, 1294, 1181;δH(500 MHz, CDCl3) 8.62 (1 H, dt,J1.0, 5.0 Hz), 7.83 (2 H, d,J8.5 Hz), 7.68–7.61 (2 H, m), 7.11 (1 H, m) 6.75 (2 H, d,J8.5 Hz), 3.83 (2 H, br s);δC(125 MHz, CDCl3) 157.6, 149.5, 147.5, 136.6, 129.8, 128.1, 121.0, 119.4, 115.2;m/z(ESI) 171 ([M + H]+, 100).
Reference：
[1] European Journal of Medicinal Chemistry, 2015, vol. 95, p. 277 - 301
[2] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1988, vol. 24, # 11, p. 1221 - 1225[3] Khimiya Geterotsiklicheskikh Soedinenii, 1988, vol. 24, # 11, p. 1476 - 1480
[4] Molecular crystals and liquid crystals, 1980, vol. 62, # 1-2, p. 103 - 114
[5] Chemische Berichte, 1896, vol. 29, p. 168
[6] Journal of the Chemical Society, 1926, p. 2920[7] Journal of the Chemical Society, 1930, p. 398
[8] Journal of the Chemical Society, 1940, p. 1279,1283
[9] Chemical and Pharmaceutical Bulletin, 2004, vol. 52, # 7, p. 818 - 829
[10] Patent: US2006/94644, 2006, A1, . Location in patent: Page/Page column 22
[11] Patent: WO2007/130743, 2007, A2, . Location in patent: Page/Page column 63
2
[ 109-04-6 ]
[ 214360-73-3 ]
[ 18471-73-3 ]
Yield
Reaction Conditions
Operation in experiment
79%
With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 2 h;
Step 4 [Show Image] 2-bromopyridine 5 (14.53 g, 92.0 mmol) and 4-aminophenylboronic acid pinacol ester (30.20 g, 138.0 mmol) were dissolved in dimethylformamide (200 ml). To the solution were added tetrakis triphenyl phosphine palladium (7.44 g, 6.4 mmol) and 2 M potassium carbonate solution (230 ml, 460 mmol) and the mixture was stirred for 2 hours at 100°C. The reactant was poured into water and filtered and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and then saturated saline, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography. To the obtained solid were added ethyl acetate and hexane and the deposited solid was collected with filtration to give the desired substituted aniline 6 (12.35 g, yield 79 percent). 1H-NMR (DMSO-d6) δppm: 5.42 (s, 2H), 6.63 (m, 2H), 7.14 (m, 1H), 7,69-7.75 (m, 2H), 7.79 (m, 2H), 8.51 (m, 1H).
79%
With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 2 h;
2-bromopyridine 5 (14.53 g, 92.0 mmol) and 4-aminophenylboronic acid pinacol ester (30.20 g, 138.0 mmol) were dissolved in dimethylformamide (200 ml). To the solution were added tetrakis triphenyl phosphine palladium (7.44 g, 6.4 mmol) and 2 M potassium carbonate solution (230 ml, 460 mmol) and the mixture was stirred for 2 hours at 100° C. The reactant was poured into water and filtered and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and then saturated saline, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography. To the obtained solid were added ethyl acetate and hexane and the deposited solid was collected with filtration to give the desired substituted aniline 6 (12.35 g, yield 79percent).1H-NMR (DMSO-d6) δ ppm: 5.42 (s, 2H), 6.63 (m, 2H), 7.14 (m, 1H), 7.69-7.75 (m, 2H), 7.79 (m, 2H), 8.51 (m, 1H).
Reference：
[1] Chemical and Pharmaceutical Bulletin, 2004, vol. 52, # 7, p. 818 - 829
9
[ 110-86-1 ]
[ 18471-73-3 ]
Reference：
[1] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1988, vol. 24, # 11, p. 1221 - 1225[2] Khimiya Geterotsiklicheskikh Soedinenii, 1988, vol. 24, # 11, p. 1476 - 1480
[3] Journal of the Chemical Society, 1926, p. 2920[4] Journal of the Chemical Society, 1930, p. 398
[5] European Journal of Medicinal Chemistry, 2015, vol. 95, p. 277 - 301
10
[ 100-05-0 ]
[ 18471-73-3 ]
Reference：
[1] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1988, vol. 24, # 11, p. 1221 - 1225[2] Khimiya Geterotsiklicheskikh Soedinenii, 1988, vol. 24, # 11, p. 1476 - 1480
11
[ 24067-17-2 ]
[ 18471-73-3 ]
Reference：
[1] European Journal of Medicinal Chemistry, 2015, vol. 95, p. 277 - 301
12
[ 18471-73-3 ]
[ 51035-40-6 ]
Reference：
[1] Zhurnal Russkago Fiziko-Khimicheskago Obshchestva, 1921, vol. 53, p. 217,223[2] Chem. Zentralbl., 1923, vol. 94, # III, p. 1024
[3] Molecular crystals and liquid crystals, 1980, vol. 62, # 1-2, p. 103 - 114
13
[ 18471-73-3 ]
[ 4385-62-0 ]
Reference：
[1] Journal of the Chemical Society, 1940, p. 355,357
With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃; under 760.051 Torr; for 18h;
A solution of compound52(0.2 g, 1.03 mmol) in methanol (10 mL) was treated with 10% palladium on carbon (20 mg) and subjected to a hydrogen atmosphere. The mixture was stirred for a further 18 h and then filtered through a pad of Celite. The pad was washed with methanol (50 mL) and the combined filtrates evaporatedin vacuoto give the crude residue which was purified by flash chromatography on silica eluting withCH2Cl2-methanol-aqueous ammonia (95:4.5:0.5) to give amine53(0.15 g, 87%) as a brown solid; mp 89-92 C (lit mp 94-95 C); numax/cm-13333, 3210, 1606, 1586, 1519, 1294, 1181;deltaH(500 MHz, CDCl3) 8.62 (1 H, dt,J1.0, 5.0 Hz), 7.83 (2 H, d,J8.5 Hz), 7.68-7.61 (2 H, m), 7.11 (1 H, m) 6.75 (2 H, d,J8.5 Hz), 3.83 (2 H, br s);deltaC(125 MHz, CDCl3) 157.6, 149.5, 147.5, 136.6, 129.8, 128.1, 121.0, 119.4, 115.2;m/z(ESI) 171 ([M + H]+, 100).
With hydrazine;palladium 10% on activated carbon; In tetrahydrofuran; ethanol; at 20℃;
Step B: 2-(4-Nitrophenyl)pyridine (1.10 g) and 10% Pd/C (300 mg) were dissolved suspended in 80 mL of an 8:1 solution of 30 mL of THF and 10 mL of ethanol under an atmosphere of dry N2. To this solution was added 1.0 mL of anhydrous hydrazine. The reaction mixture was stirred at room temperature overnight and then filtered. The filtrate was concentrated under vacuum. The residue was partitioned between dichloromethane and water and the organic layer was washed with brine, dried over MgSO4, filtered and concentrated under vacuum. The residue was purified via silica gel chromatography to give 653.3 mg of 4-(pyridin-2-yl)benzenamine.
With hydrazine;palladium 10% on activated carbon; In tetrahydrofuran; ethanol; at 20℃;
2-(4-Nitrophenyl)pyridine (1.10 g) and 10% Pd/C (300 mg) were dissolved suspended in 80 mL of an 8:1 solution of 30 mL of THF and 10 mL of ethanol under an atmosphere of dry N2. To this solution was added 1.0 mL of anhydrous hydrazine. The reaction mixture was stirred at room temperature overnight and then filtered. The filtrate was concentrated under vacuum. The residue was partitioned between dichloromethane and water and the organic layer was washed with brine, dried over MgSO4, filtered and concentrated under vacuum. The residue was purified via silica gel chromatography to give 653.3 mg of 4-(pyridin- 2-yl)benzenamine.
With thionyl chloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; 1,2-dichloro-ethane;
EXAMPLE 46 4-(2-pyridyl)-phenyl 2-(3-cyanophenyl)-cyclopentene-1-carboxamide A solution of 2-(3-cyanophenyl)-cyclopentene-1-carboxylic acid (80 mg, 0.375 mmol) in 1,2-ethylene dichloride (4 mL) was treated with SOCl2 (0.28 mL, 10 eq), then refluxed for 2.5 h. After concentration, the residue dissolved in CH2Cl2 (10 mL) at 0 C. was treated with DIPEA (0.65 mL, 10 eq) and <strong>[18471-73-3]4-(2-pyridyl)aniline</strong> (53 mg, 0.314 mmol), and stirred for 12 h. Concentration, extractive workup followed by flash chromatography with Hex: EA=3:1 afforded 59 mg (51%) of the title compound. 1H-NMR (500 MHz, CDCl3) delta8.64 (m, 1H), 7.91 (d, J=8.3 Hz, 2H), 7.74-7.63 (m, 4H), 7.59 (d, J=7.8 Hz, 1H), 7.46-7.41 (m, 3H), 7.19 (m, 1H), 7.07 (br s, 1H), 2.97 (m, 2H), 2.91 (m, 2H), 2.11 (m, 2H).
ethyl 2-[5-(aminosulphonyl)-4-methyl-1,3-thiazol-2(3H)-ylidene]-3-oxo-3-[4-(2-pyridinyl)phenyl]amino}-propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In 5,5-dimethyl-1,3-cyclohexadiene; dichloromethane;
Example V Ethyl 2-[5-(aminosulphonyl)-4-methyl-1,3-thiazol-2(3H)-ylidene]-3-oxo-3-[4-(2-pyridinyl)phenyl]amino}-propanoate A solution of 2 g (5.95 mmol) of diethyl 2-[5-(aminosulphonyl)-4-methyl-1,3-thiazol-2(3H)-ylidene]malonate and 1.2 g (7.13 mmol) of 4-(2-pyridinyl)-aniline in 20 ml of xylene is stirred under reflux for 16 h. The solvent is removed under reduced pressure and the residue is stirred with dichloromethane, whereupon a solid remains. The dichloromethane phase is washed with 1N HCl solution and concentrated. The two solids obtained in this manner are, together, stirred with petroleum ether, and the solid is filtered off with suction. Yield: 2.2 g (80%) 1H-NMR (300 MHz, d6-DMSO, delta/ppm): 1.4 (t, J=7 Hz, 3H), 2.5 (s, 3H), 4.4 (m, 2H), 7.7-8.8 (m, 10H), 10.6-14.2 (m, 2H). According to the NMR, the product is a mixture of the possible E/Z isomers.
WORKING EXAMPLE 159 (Production of Compound 159) Under nitrogen atmosphere, oxalyl chloride (0.31 ml) was added to a solution of 7-(4-methylphenyl)-2,3-dihydrobenzoxepine-4-carboxylic acid (0.65 g) in tetrahydrofuran (10 ml) at room temperature. To the mixture was added a drop of DMF,and the mixture was stirred for 1 hour. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in tetrahydrofuran (15 ml). To the solution were added triethylamine (0.65 ml) and 2-(4-aminophenyl) pyridine (J. Chem. Soc., p.1511, 1960) (0.44 g) at 0 C., and the mixture was stirred at room temperature for 2 hours. The reaction mixture was added to vigorously stirred water to stop the reaction. The mixture was extracted with ethyl acetate. Precipitated crystal was collected by filtration to give N-[4-(2-pyridyl)phenyl]-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 159) (185.9 mg) as colorless crystals. The mother liquor was concentrated and recrystallized from ethyl acetate-tetrahydrofuran to give N-[4-(2-pyridyl)-phenyl]-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 159) (0.58 g) as pale yellow crystals. m.p. 228-229 C.; 1 H-NMR (200 MHz, CDCl3) delta 2.39 (3H, s), 3.09 (2H, t, J=4.4 Hz), 4.36 (2H, t, J=4.4 Hz), 7.06 (1H, d, J=8.2 Hz), 7.16-7.32 (4H, m), 7.42-7.56 (4H, m), 7.68-7.82 (5H, m), 8.02 (2H, dd, J=8.8, 2.0 Hz), 8.65-8.73 (1H, dt, J=4.8, 1.4 Hz). IR (KBr) 3338, 1645, 1593, 1516, 1493, 1466, 1435, 1323, 1248, 810, 777 cm-1; Elemental Analysis for C29 H24 N2 O2; Calcd. C, 80.53; H, 5.59; N, 6.48: Found. C, 80.46; H, 5.62; N, 6.46.
(E)-N-[4-(pyridin-2-yl)-phenyl]-3-(4-methylphenyl)cinnamamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In tetrahydrofuran; water; N,N-dimethyl-formamide;
WORKING EXAMPLE 188 (Production of Compound 188) Under nitrogen atmosphere, oxalyl chloride (0.27 ml) was added to a solution of (E)-3-(4-methylphenyl)cinnamic acid (0.50 g) in tetrahydrofuran (10 ml) at room temperature. To the mixture was added a drop of DMF, and the mixture was stirred for 1 hour. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in tetrahydrofuran (10 ml). To the solution were added triethylamine (0.60 ml) and <strong>[18471-73-3]2-(4-aminophenyl)pyridine</strong> (0.39 g), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was added to vigorously stirred water to stop the reaction. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate, concentrated under reduced pressure and recrystallized from tetrahydrofuran-hexane (1:1) to give (E)-N-[4-(2-pyridyl)-phenyl]-3-(4-methylphenyl)cinnamamide (Compound 188) (561 mg) as pale yellow crystals. m.p. 220-222 C.; 1 H-NMR (200 MHz, CDCl3) delta 2.42 (3H, s), 6.63 (1H, d, J=15.4 Hz), 7.18-7.31 (3H, m), 7.44-7.63 (6H, m), 7.70-7.83 (5H, m), 7.85 (1H, d, J=15.4 Hz), 8.02 (2H, d, J=8.8 Hz), 8.66-8.72 (1H, m). IR (KBr) 3286, 1657, 1622, 1597, 1524, 1462, 1333, 1180, 970, 787 cm-1; Elemental Analysis for C27 H22 N2 O.0.1H2 O; Calcd. C, 82.67; H, 5.70; N, 7.14: Found. C, 82.45; H, 5.70; N, 7.13.
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 100℃; for 2h;
Step 4 [Show Image] 2-bromopyridine 5 (14.53 g, 92.0 mmol) and 4-aminophenylboronic acid pinacol ester (30.20 g, 138.0 mmol) were dissolved in dimethylformamide (200 ml). To the solution were added tetrakis triphenyl phosphine palladium (7.44 g, 6.4 mmol) and 2 M potassium carbonate solution (230 ml, 460 mmol) and the mixture was stirred for 2 hours at 100C. The reactant was poured into water and filtered and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and then saturated saline, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography. To the obtained solid were added ethyl acetate and hexane and the deposited solid was collected with filtration to give the desired substituted aniline 6 (12.35 g, yield 79 %). 1H-NMR (DMSO-d6) deltappm: 5.42 (s, 2H), 6.63 (m, 2H), 7.14 (m, 1H), 7,69-7.75 (m, 2H), 7.79 (m, 2H), 8.51 (m, 1H).
79%
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 100℃; for 2h;
2-bromopyridine 5 (14.53 g, 92.0 mmol) and 4-aminophenylboronic acid pinacol ester (30.20 g, 138.0 mmol) were dissolved in dimethylformamide (200 ml). To the solution were added tetrakis triphenyl phosphine palladium (7.44 g, 6.4 mmol) and 2 M potassium carbonate solution (230 ml, 460 mmol) and the mixture was stirred for 2 hours at 100 C. The reactant was poured into water and filtered and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and then saturated saline, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography. To the obtained solid were added ethyl acetate and hexane and the deposited solid was collected with filtration to give the desired substituted aniline 6 (12.35 g, yield 79%).1H-NMR (DMSO-d6) delta ppm: 5.42 (s, 2H), 6.63 (m, 2H), 7.14 (m, 1H), 7.69-7.75 (m, 2H), 7.79 (m, 2H), 8.51 (m, 1H).
With caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In butanol, n-; water; toluene;Heating / reflux;
To a solution of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (2.66 g, 12.1 mmol) in toluene (20 mL) and n-butanol (7 mL), a solution of 2-bromopyridine (0.991 g, 6.27 mmol) and Cs2CO3 (6.10 g, 18.7 mmol) in H2O (20 mL) was added. The mixture was degassed three times with Ar / vacuum cycle before being charged with Pd(Ph3P)4 (540 mg, 0.46 mmol, 7% mol). It was then heated at reflux under Ar overnight. The reaction mixture was allowed to cool at room temperature, and then in an ice-bath. The precipitates were collected, dried on vacuum to give a solid (0.840 g)
To a solution of 4-(2-pyridinyl)rhohenylamine (0.840 g, 4.94 mmol) and TEA (2.06 mL, 14.8 mmol) in CH2Cl2 (20 mL), di-t-butyl dicarbonate (1.36 mL, 5.93 mmol) was added. After being stirred at room temperature for 2 days, the mixture was concentrated in vacuo. The residue was purified by a silica gel column to give a solid (1.06 g), which was then dissolved in acetone (20 mL). To the solution, mCPBA (ca. 70%, 1.45 g, 5.87 mmol) was added. After being stirred at room temperature overnight, the mixture was concentrated in vacuo. The residue was purified by a silica gel column to give the desired product as an off- white solid (0.673 g).
Example 8 N-Cyano-N'-[4-(pyridin-2-yl)-phenyl]-formamidine A mixture of 2-(4-amino-phenyl)-pyridine (3.1 g), cyanamide (0.8 g) and triethyl orthoformate (3.6 g) was heated at 150 C. for a few minutes. The product which crystallized out was filtered off, washed with ethanol and dried to give 2.5 g of the title compound; M.p. 150-151 C.
With triethylamine; In tetrahydrofuran; water; ethyl acetate;
EXAMPLE 10 A solution of 4'-(trifluoromethyl)-1,1'-biphenyl-2-carbonyl chloride (854 mg) in tetrahydrofuran (5 ml) was added to a mixture of 4-(2-pyridinyl)phenylamine (510 mg) and triethylamine (606 mg) in tetrahydrofuran (25 ml) at ambient temperature. The mixture was stirred at ambient temperature for 3 hours. The resultant mixture was poured into a mixture of ethyl acetate and water and organic layer was washed with 5% aqueous potassium carbonate solution and brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was recrystallized from a mixture of ethyl acetate and diisopropyl ether to give N-[4-(2-pyridinyl)phenyl]-4'-(trifluoromethyl)-1,1'-biphenyl-2-carboxamide (1.20 g). 1H-NMR (DMSO-d6): delta7.30-7.34 (1H, m), 7.51-7.94 (12H, m), 8.04 (2H, d, J=8.68 Hz), 8.364 (1H, d, J=4.56 Hz), 10.55 (1H, s).
1-[4-(pyrid-2-yl)anilinocarbonyl]-4-(4-fluorobenzoyl)piperidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
33%
To a stirred suspension [OF 4- (2-PYRIDYL)] aniline (172mg, [L.] [OLMMOL)] and PS-DIEA (2 mmol) in DCM (5 ml) was added trichloroacetyl chloride (134 [GL,] 1.2 mmol). The solutions were stirred for 72 hours. The reaction was filtered and the filtrate evaporated in vacuo. The residue was dissolved in DMSO (3 ml), and treated with sodium carbonate (424 mg, 4 mmol) and [4-FLUOROBENZOYLPIPERIDINE] (approx [LMMOL] dissolved in [2ML] DMSO) at [80C] for 6 hours. The reaction mixture was cooled to room temperature, and evaporated under high vacuum. The resultant gum was triturated with EtOAc [(10ML)] and filtration afforded the product as an off-white solid (135mg, [33%).] NMR (DMSO-d6): 1.41-1. 61 (m, 2H), 1.73-1. 88 (br d, 2H), 3.01 (t, 2H), 3.59-3. 77 (m, 1H), 4.08-4. 25 (br d, 2H), 7.18-7. 28 (app t, 1H), 7.36 (t, 2H), 7.57 (d, 2H), 7.73-7. 90 (m, 2H), 7.96 (d, 2H), 8.03-8. 15 (m, 2H), 8.59 (d, 1H), 8.66 (s, 1H); [M/Z] 371.51.
With N-Bromosuccinimide; In methanol; dichloromethane; for 2h;Cooling with ice;
Step 5 [Show Image] Compound 6 obtained in Step 4 (16.13 g, 95.0 mmol) was dissolved in dichloromethane (120 ml) and methanol (120 ml). To the solution was added N-bromosuccinimide (17.71 g, 100.0 mmol) under ice cooling and the mixture was stirred for 2 hours under ice cooling. The reactant was poured into saturated saline and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography to give the desired Compound 7 (19.36 g, yield 82 %) 1H-NMR (DMSO-d6) deltappm: 5.64 (s, 2H), 6.86 (d, 1H, J = 8.4 Hz), 7.20 (ddd, 1H, J = 6.6, 5.1, 1.5 Hz), 7.72-7.84 (m, 3H), 8.12 (d, 1H, J = 2,1 Hz), 8.54 (m, 1H).
82%
With N-Bromosuccinimide; In methanol; dichloromethane; for 2h;Ice cooling;
Compound 6 obtained in Step 4 (16.13 g, 95.0 mmol) was dissolved in dichloromethane (120 ml) and methanol (120 ml). To the solution was added N-bromosuccinimide (17.71 g, 100.0 mmol) under ice cooling and the mixture was stirred for 2 hours under ice cooling. The reactant was poured into saturated saline and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography to give the desired Compound 7 (19.36 g, yield 82%).1H-NMR (DMSO-d6) delta ppm: 5.64 (s, 2H), 6.86 (d, 1H, J=8.4 Hz), 7.20 (ddd, 1H, J=6.6, 5.1, 1.5 Hz), 7.72-7.84 (m, 3H), 8.12 (d, 1H, J=2.1 Hz), 8.54 (m, 1H).
With palladium diacetate; caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 160℃; for 0.666667h;Sealed tube; Microwave irradiation;
General procedure: 3-(Tert-butylamino)-4-(2-(4-(pyridin-4-yl)phenylamino)pyrimidin-4-ylamino)cyclobut-3-ene-1,2-dione (49). To a mixture of 4-pyridin-4-ylphenylamine (170 mg, 1 mmol), Pd(OAc)2 (4.4 mg, 0.02 mmol), Cs2CO3 (650 mg, 2.0 mmol) and 4,5-bis(diphenylphosphiono)-9,9-dimethylxanthene (Xantphos, 17.4 mg, 0.03 mmol) was added 57 (280 mg, 1 mmol) in anhydrous 1,4-dioxane (3 mL). The tube was sealed and heated by microwave at 160 oC for 40 min. After cooling to room temperature, the reaction mixture was diluted with CH2Cl2, filtered and concentrated. The residue was purified by flash column chromatography on silica gel (elution with CH2Cl2/MeOH 30:1) to give 339 mg (82% yield) of 49 as a sold. 1H NMR (300 MHz, DMSO-d6) d 1.38 (s, 9H), 7.25 (d, J = 6 Hz, 1H), 7.67 (d, J = 8 Hz, 2H), 7.77 (d, J = 8 Hz, 2H), 7.87 (d, J = 6 Hz, 2H), 8.29 (s, 1H), 8.35 (d, J = 6 Hz, 1H), 8.59 (d, J = 6 Hz, 2H), 9.61 (s, 1H), 10.49 (s, 1H); MS (ESI): m/z 415 (M+H)+.
With tris[2-phenylpyridinato-C2,N]iridium(III); In N,N-dimethyl-formamide; at 20℃;Inert atmosphere; Irradiation;
Under nitrogen or argon, 0.4 mmol, 0.2mmol, Ir(ppy) 3(2mg) and DMF1 ml was added to the reaction flask, followed by blue LED lights(7W) at room temperature irradiation straight trivalent iodine reagent completeconversion of the reaction. Add 10 ml of saturated Na 2CO 3Aqueous solution, andextracted three times with ethyl acetate, the organic layer was washed with water andonce with saturated brine, dried over anhydrous Na 2SO 4The organic layer was dried.Column chromatography (eluent: petroleum ether 60-90: ethyl acetate = 10: 1-5: 1) togive the product in 64% yield.
General procedure: A solution of 1,2-benzisothiazol-3-one 1 (151 mg, 1 mmol), inTHF (10 ml), K2CO3 (276 mg, 2 mmol) was added at room temperaturefor 30 min, then t-butyl bromoacetate 10 (195 mg, 1 mmol)was added. After the reaction was stirred at room temperaturefor 3 h, the solvent was removed under vacuum. The residualwas isolated by column chromatography (ethyl acetate/petroleumether, 15:1) to yield 11. The intermediate 11 (265 mg, 1 mmol) indry CH2Cl2 (10 ml) was treated with trifluoroacetic acid (TFA,3.3 ml) for 5 h at room temperature and the solvent was removedunder vacuum. The residue washed with ethyl ether (2 25 ml) toyield the desired product 12 as white solid. A solution of compound 12 (209 mg, 1 mmol) in dry THF(10 ml) was added portion wise to a suspension of carbonyldiimidazole(162 mg, 1 mmol) in THF (5 ml) and the mixture was stirredat room temperature for 20 min and then refluxed for 10 min.A solution of primary amine (1 mmol) in THF (5 ml) was addedand the reaction mixture was stirred at room temperature overnight.A white precipitate formed, which was collected by suctionfiltration.
With triethylamine; In dichloromethane; at 20℃; for 0.5h;
General procedure: A solution of triphosgene (2.96 g, 10 mmol) in DCM (20 ml) wasadded dropwise to primary amine (10 mmol) in DCM (20 ml) followedby the dropwise addition of triethylamine (3 ml) in DCM(10 ml). The mixture kept at room temperature for 30 min, thenthe solvent was removed on a rotary evaporator. The resulting residuewas dissolved in DCM (20 ml), and 1, 2-benzisothiazol-3-one(1.51 g, 10 mmol) in THF (20 ml) was added. After the mixture wasstirred at room temperature overnight, the solvent was removedon a rotary evaporator. The residue was dissolved in acetone(30 ml) and mixed with water (30 ml). The precipitate was collectedon a funnel by vacuum filtration and washed with water-acetone (1:1, 4 5 ml) to afford the final compound.
2-(1,3-dimethyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)-N-(4-(pyridin-2-yl)phenyl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 16h;
General procedure: A stirred solution of commercially available 2-(l,3- dimethyl-2,6-dioxo-2,3-dihydro-lH-purin-7(6H)-yl)acetic acid, 1 (1 equiv.) in N,N- dimethylforamide (0.18 M), was added Hunig's base (1.5 equiv.), HOBt (1.5 equiv.), EDCI (1.5 equiv.) and the respective amine (1.5 equiv.). The mixture was stirred at room temperature for 16 h. After consumption of starting material, the reaction mixture was quenched with water and extracted with dichloromethane. The combined organic layers were washed with brine solution, dried over Na2S04 and concentrated under vacuum. The crude compound was purified by column chromatography to afford the product. [000154] Compound 25: 2-(l,3-dimethyl-2,6-dioxo-2,3-dihydro-lH-purin-7(6H)-yl)-N-(4- (pyridin-2-yl) phenyl)acetamide. 1H NMR (400 MHz, DMSO-d6) delta (ppm): 10.57 (s, 1H), 8.61 - 8.62 (m, 1H), 8.05 - 8.08 (m, 3H), 7.91 (d, J = 8.00 Hz, 1H), 7.82 - 7.86 (m, 1H), 7.68 (d, J = 8.00 Hz, 1H), 7.28 - 7.31 (m, 1H), 5.23 (s, 2H), 3.46 (s, 3H), 3.20 (s, 3H).
5-bromo-N-(4-(pyridin-2-yl)phenyl)pentanamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
0.21 g
With triethylamine; In dichloromethane; at -78 - 20℃; for 10h;Inert atmosphere;
5-bromovaleric acid (0.14 g, 0.75 mmol) was suspended in oxalyl chloride (ca.2mL), stirred at ambient temperature for 45 min, and the excess oxalyl chloride evaporated under reduced pressure. The residue was dissolved in CH2Cl2(10 mL), cooled to -78 C, and treated dropwise with a solution of amine53(0.14 g, 0.82 mmol) and triethylamine (115 muL, 0.82 mmol) in CH2Cl2(10 mL). The mixture was warmed to ambient temperature, stirred for 10 h, and CH2Cl2(70 mL) was added. The solution was washed with H2O (50 mL), hydrochloric acid (1 M; 50 mL), saturated aqueous sodium hydrogencarbonate (50 mL), brine (50 mL), dried (MgSO4), filtered, and the solvent evaporated under reduced pressure to give the crude amide which was purified by flash chromatography on silica eluting with CH2Cl2-methanol-aqueous ammonia (98:1.5:0.5) to give amide54(0.21 g, 85%) as a colourless solid; mp 97-98 C; numax/cm-13230, 1718, 1543, 1418, 1375, 1214, 907, 814;deltaH(500 MHz, CDCl3) 8.67 (1 H, d,J5.0 Hz), 7.98 (2 H, d,J8.5 Hz), 7.76-7.70 (2 H, m), 7.64 (2 H, d,J8.5 Hz), 7.21 (1 H, t,J5.5 Hz), 3.46 (2 H, t,J7.0 Hz), 2.43 (2 H, t,J7.0 Hz), 2.01-1.87 (4 H, m), NH proton not observed;deltaC(125 MHz, CDCl3) 170.6, 156.9, 149.8, 138.7, 137.7, 127.6, 120.1, 120.3, 119.9, 115.3, 36.8, 33.3, 32.2, 24.1;m/z(ESI) 333, 335 ([M + H]+, 100);Found: C, 57.74; H, 5.29; N, 8.43. Calc for C16H17BrN2O: C, 57.67, H, 5.14; N, 8.41%
2-(5-phenyl-4-(pyridin-4-yl)-1H-1,2,3-triazol-1-yl)-N-(4-(pyridin-2-yl)phenyl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; benzene; at 50℃; for 6h;
General procedure: The solution of triazole 13 (1.0 equiv) in a mixture of trifluoroacetic acid and methylene chloride (1:2) was stirred at 35 C for 3 h. The solvent was then removed by vacuum and the residue was dissolved in tetrahydrofuran. Triethylamine (1.1 equiv) and methanesulfonyl chloride (1.1 equiv) were subsequently added. After stirring at 23 C for 3 h, a solution of arylamine (1.2 equiv) and Huenig?s base (5.0 equiv) in a mixture of tetrahydrofuran and benzene (1:4) was added. After stirring at 50 C for 16 h, the mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulfate. The solvent was then removed under vacuum and the residue was purified by a flash column chromatography on silica gel to give 14.
3-(4-((2-(1,3-dimethyl-2,6-dioxo-2,3-dihydro-1H-purin-7 (6H)-yl)acetoxy)methyl)-1H-1,2,3-triazol-1-yl)propanoic acid[ No CAS ]
(1-(3-oxo-3-((4-(pyridin-2-yl)phenyl)amino)propyl)-1H-1,2,3-triazol-4-yl)methyl-2-(1,3-dimethyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)acetate[ No CAS ]
2-(4-((2-(1,3-dimethyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)acetoxy)methyl)-1H-1,2,3-triazol-1-yl)acetic acid[ No CAS ]
(1-(2-oxo-2-((4-(pyridin-2-yl)phenyl)amino)ethyl)-1H-1,2,3-triazol-4-yl)methyl-2-(1,3-dimethyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)acetate[ No CAS ]
2-(4-(((2-(1,3-dimethyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)propanoyl)oxy)methyl)-1H-1,2,3-triazol-1-yl)acetic acid[ No CAS ]
(1-(2-oxo-2-((4-(pyridin-2-yl)phenyl)amino)ethyl)-1H-1,2,3-triazol-4-yl)methyl-2-(1,3-dimethyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)propanoate[ No CAS ]
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