* 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] Chemische Berichte, 1894, vol. 27, p. 2165
2
[ 60710-80-7 ]
[ 82998-57-0 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1973, p. 2940 - 2948
3
[ 60710-80-7 ]
[ 3816-66-8 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 8, p. 1203 - 1208
[2] Chemische Berichte, 1903, vol. 36, p. 4359[3] Chemische Berichte, 1904, vol. 37, p. 1845
[4] Patent: US5932567, 1999, A,
4
[ 939-79-7 ]
[ 60710-80-7 ]
Yield
Reaction Conditions
Operation in experiment
97%
With hydrogen In palladium-carbon
C.14.b. 3-Amino-4-methylbenzonitrile 120 g of 3-nitro-4-methylbenzonitrile were suspended in 1.2 l of EtOH and hydrogenated in the presence of 7 g of Pd/C(10percent) with 50 l of hydrogen at RT. After removal of the catalyst on Celite, the solvent was stripped off to result in 95 g of pure product (97percent). 1H-NMR (DMSO-d6; δ in ppm): 7.1 (dd, 1H); 6.90 (d, 1H); 6.85 (dd, 1H); 5.35 (s, 2H, NH2); 2.15 (s, 3H)
Reference：
[1] Patent: US6455671, 2002, B1,
[2] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 8, p. 1203 - 1208
[3] Chemische Berichte, 1903, vol. 36, p. 4359[4] Chemische Berichte, 1904, vol. 37, p. 1845
[5] Spectrochimica Acta - Part A: Molecular and Biomolecular Spectroscopy, 1997, vol. 53, # 2, p. 141 - 150
[6] Patent: WO2006/86255, 2006, A2, . Location in patent: Page/Page column 39-40
[7] Patent: US5932567, 1999, A,
[8] Patent: WO2007/88400, 2007, A1, . Location in patent: Page/Page column 13
[9] Patent: WO2009/93049, 2009, A1, . Location in patent: Page/Page column 36-37
[10] RSC Advances, 2015, vol. 5, # 105, p. 86529 - 86535
5
[ 39478-78-9 ]
[ 60710-80-7 ]
Yield
Reaction Conditions
Operation in experiment
75%
With 2-(2-methoxyphenyl)-1-methyl-3-(diphenylphosphino)-1H-indole; potassium <i>tert</i>-butylate; triethylamine; bis(dibenzylideneacetone)-palladium(0) In dichloromethane; water; acetonitrile at 50℃; for 24 h; Inert atmosphere
General procedure: An oven-dried Schlenk tube with the presence of magnetic stir bar which is Teflon-coated was charged with Pd(dba)2 (11.5 mg, 0.02 mmol, 2 molpercent) and ligand L4 (8.4 mg, 0.02 mmol, 2 molpercent). The flask was evacuated and backfilled with nitrogen (3 cycles). Pre-complexation of palladium and ligand was initiated by injecting freshly distilled dry dichloromethane (2.0 mL) and Et3N (0.1 mL) into the tube. The solution was stirred and warmed with hair drier till the solvent condensed on the tube wall. The solvent was removed under vacuum. Aryl bromide (1.0 mmol), KOt-Bu (0.25 mmol), and potassium hexacyanoferrate(II) trihydrate (0.23 mmol) were charged successively to the tube followed by another 3 evacuation-nitrogen refill cycles. Water (1.0 mL) and acetonitrile (1.0 mL) were used as a solvent mixture. The tube was immersed into a preheated 50 °C oil bath for 24 hours. The reaction was quenched by cooling to ambient temperature and added with EtOAc and water. The organic supernatant was analyzed by GC. The organic layer was separated and the remained aqua medium was further extracted with EtOAc (10 mL .x. 3). The combined organic phases were concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (230-400 mesh). The pure fractions were collected, dried under vacuum, and followed by proton (1H) and carbon (13C) NMR characterization
General procedure: Following the amide intermediate Preparation Example A. The reaction vessel is closed (when the amide intermediate has a boiling point at normal pressure equal to or lower than the reaction temperature TB described below) or the reaction vessel is kept open (when the amide intermediate has a boiling point higher than the normal pressure When the reaction temperature is TB), the stirring is continued (600 r/min), the reaction temperature is changed to TB, and after the reaction temperature TB is maintained for TD hours, the reaction is almost complete. Then, the reaction vessel was sealed and connected to a vacuum pump so that the degree of vacuum in the reaction vessel reached 20-50 mbar (according to the type of nitrile product) and the distillate was used as the nitrile product. The yield of the nitrile product was calculated and sampled for nuclear magnetic proteomics and elemental analysis to characterize the nitrile product obtained. Specific reaction conditions and characterization results are shown in Tables A-7, A-8, A-9, A-10 and A-11 below. These characterization results show that the nitrile product obtained has an extremely high purity (above 99percent).In these nitrile product preparation examples, 10 g of diphosphorus pentoxide was optionally added to the reaction vessel as a catalyst at the start of the reaction.
i 2-Chloro-N-(5-cyano-2-methylphenyl)acetamide The subtitle compound was prepared from <strong>[60710-80-7]5-cyano-2-methylaniline</strong> (1.6 g) and chloroacetyl chloride (1.1 ml) by the method of Example 33 step (iii) as a white solid. Yield: 1.85 g MS: APCI (-ve) 207 (M-1)
5-cyano-2-methylbenzenediazonium tetrafluoroborate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
A solution of sodium nitrite (4.14 g, 59.9 mmol, 1.10 equiv) in water (20 mL) was added slowly to a pre-cooled (-10 C) mixture of <strong>[60710-80-7]3-amino-4-methylbenzonitrile</strong> (1-2, 7.2 g, 54.5 mmol, 1 equiv) and concentrated aqueous hydrochloric acid solution (12 M, 13.6 mL, 163 mmol, 3.00 equiv) in water (50 mL) at a rate that kept the reaction mixture temperature below 0 C. Following the addition, the reaction mixture was stirred at -5 C for 30 min, then filtered. A solution of sodium tetrafluoroborate (17.9 g, 163 mmol, 3.00 equiv) in water (100 mL) was immediately added to the cold filtrate. The precipitate was filtered and washed with ice-cold water (30 mL). The remaining solid was air-dried to give 5-cyano-2- methylbenzenediazonium tetrafluoroborate as a white solid. A suspension of this product (11.7 g, 50.7 mmol, 1 equiv), potassium acetate (12.4 g, 127 mmol, 2.50 equiv) and 18-crown-6 (1.34 g, 5.07 mmol, 0.100 equiv) in chloroform (150 mL) was stirred at 23 C for 20 h. The reaction mixture was filtered and concentrated. The residue was partitioned between water and EtOAc (300 mL). The organic layer was washed with brine, dried over sodium sulfate and cocnetrated to give 1H-indazole-6-carbonitrile (1-3) as a light yellow solid. 1H NMR (300 MHz, CDCl3) delta 10.37 (br s, 1H), 8.19 (d, 1H, J = 0.9 Hz), 7.90 (d, 1H, J = 1.5 Hz), 7.88 (dd, 1H, J = 8.5, 0.9 Hz), 7.42 (dd, 1H, J = 8.3, 1.5 Hz). LRMS m/z (M+H + CH3CN) 185.1 found, 185.0 required.
A solution of sodium nitrite (4.14 g, 59.9 mmol, 1.10 equiv) in water (20 mL) was added slowly to a pre- cooled (-10 0C) mixture of <strong>[60710-80-7]3-amino-4-methylbenzonitrile</strong> (1-2, 7.2 g, 54.5 mmol, 1 equiv) and concentrated aqueous hydrochloric acid solution (12 M, 13.6 mL, 163 mmol, 3.00 equiv) in water (50 mL) at a rate that kept the reaction mixture temperature below 0 0C. Following the addition, the reaction mixture was stirred at -5 0C for 30 min, then filtered. A solution of sodium tetrafluoroborate (17.9 g, 163 mmol, 3.00 equiv) in water (100 mL) was immediately added to the cold filtrate. The precipitate was filtered and washed with ice-cold water (30 mL). The remaining solid was air-dried to give 5-cyano-2-methylbenzenediazonium tetrafluoroborate as a white solid. A suspension of this product (11.7 g, 50.7 mmol, 1 equiv), potassium acetate (12.4 g, 127 mmol, 2.50 equiv) and 18-crown-6 (1.34 g, 5.07 mmol, 0.100 equiv) in chloroform (150 mL) was stirred at 23 0C for 20 h. The reaction mixture was filtered and concentrated. The residue was partitioned between water and EtOAc (300 mL). The organic layer was washed with brine, dried over sodium sulfate and cocnetrated to give lH-indazole-6-carbonitrile (1-3) as a light yellow solid. 1H NMR (300 MHz, CDCl3) delta 10.37 (br s, IH), 8.19 (d, IH, J= 0.9 Hz), 7.90 (d, IH, J= 1.5 Hz), 7.88 (dd, IH, J = 8.5, 0.9 Hz), 7.42 (dd, IH, J= 8.3, 1.5 Hz). LRMS m/z (M+H + CH3CN) 185.1 found, 185.0 required.
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 80℃;
To a solution of 2-chloro-4-phenylquinazoline (9.6 g, 40 mmol) in 2-propanol (130 mL) was added 4-aminobenzoic acid (8.2 g, 60 mmol) and the mixture was stirred at reflux for 4 h. The mixture was cooled to it and the precipitate was collected by filtration and washed with 2-propanol. The product, 4-(4-phenylquinazolin-2-ylamino)benzoic acid, was isolated as a yellow solid (12.9 g, 95 %).[00337] To a stirred mixture of 4-(4-phenylquinazolin-2-ylamino)benzoic acid (1.37 g, 4.02 mmol), <strong>[60710-80-7]3-amino-4-methylbenzonitrile</strong> (529 mg, 4.01 mmol), and Hunig's base (2.1 mL, 12 mmol) in dimethyl formamide (10 mL) was added HATU (3.04 g, 8.00 mmol). Thestirred mixture was heated to 80 0C overnight, then cooled to rt. The reaction was diluted with ethyl acetate and extracted with water. The organic layer was washed with saturated sodium bicarbonate and concentrated on a rotary evaporator. The residue was sonicated with acetonitrile and filtered to give a light yellow solid, which was again washed with water, acetonitrile, and dried under reduced pressure to give jV-(5-cyano-2-methylphenyl)-4-[(4- phenylquinazolin-2-yl)amino]benzamide (1.18 g, 65%) as a light yellow solid. 1H NMR (400 MHz, DMSOd6): delta 10.36 (s, IH), 9.87 (s, IH), 8.19 (d, 2H), 8.00 (d, 2H), 7.91-7.78 (m, 6H), 7.66-7.62 (m, 4H), 7.51 (d, IH), 7.42 (ddd, IH), 2.36 (s, 3H). MS (EI) for C29H21N5O: 456.1 (MH+).
With pyridine; for 16h;Product distribution / selectivity;
A solution of 4-(pyridin-2-ylmethoxy)benzoyl chloride hydrochloride (644 mg, 2.60 mmol) and <strong>[60710-80-7]3-amino-4-methylbenzonitrile</strong> (515 mg, 3.90 mmol) in pyridine was stirred for 16h. Concentration of the reaction mixture under reduced pressure afforded a crude residue, which was purified using ISCO MPLC (40-100% EtOAc/hexane) to yield the title compound. MS (M+H+) = 344.
With pyridine; In 18 - 25 C;Product distribution / selectivity;
In a 250 mL round-bottomed flask was dissolved 4-(pyridin-2-ylmethoxy)benzoic acid hydrochloride (6.0 g, 22.58 mmol) in DCM (25 mL) to give a colorless solution. SOCl2 (8.24 mL, 112.91 mmol) was added and the reaction was stirred at RT for 3h. Evaporation in vacuo afforded 4-(pyridin-2-ylmethoxy)benzoyl chloride, which was diluted with pyridine (25 mL). To the reaction mixture was added <strong>[60710-80-7]3-amino-4-methylbenzonitrile</strong> (2.98 g, 22.58 mmol) and the reaction was stirred at RT overnight. After concentration in vacuo, the solid residue was diluted with sat. NaHCO3 (50 mL) and the mixture was stirred at RT for 0.5h. The mixture was filtered and the solid was triturated with MeOH (50 mL) for 0.5h. Filtration afforded the title compound. 1R NMR (DMSO-d6) delta 2.33 (s, 3 H), 5.45 (s, 2 H), 7.21 (m, 2 H), 7.49 (d, 1 H), 7.63 (dd, 1 H), 7.68 (t, 1 H), 7.83 (m, 2 H), 8.01 (m, 2 H), 8.22 (m, 1 H), 8.77 (d, 1 H), 10.00 (s, 1 H).
3-[(1-chloro-9-fluorobenzo[h]isoquinolin-5-yl)amino]-4-methylbenzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium hexamethyldisilazane; In tetrahydrofuran; at 0℃; for 0.25h;
Step l : 3-r(l-Chloro-9-fluorobenzor^1isoquinolin-5-v?amino1-4-methylbenzonitrile; To a solution of l,5-dichloro-9-fluorobenzo[c]-2,6-naphthyridine (Example 1, Step 5) (250 mg, 0.94 mmol) and <strong>[60710-80-7]3-amino-4-methylbenzonitrile</strong> (136mg, 1.03 mmol) in THF (9.3 mL) at 0 0C was added NaHMDS (1.8 mL, 1 M in THF, 1.80 mmol). The reaction stirred at <n="69"/>O0C for 15 minutes and then quenched by the addition of sat. aq. NaHCO3 solution. The precipitated solid was collected by filtration, washed with EtOAc and dried under vacuum. 1H NMR (600 MHz, CD6SO) delta 9.40 (s, IH), 9.15 (dd, IH), 8.78 (d, IH), 8.52 (d, IH), 7.86 (s, IH), 7.62 (dd, IH), 7.50-7.58 (m, 3H), 2.25 (s, 3H). LRMS (ESI) calc'd for (C20H12ClFN4) [M+H]+, 363.1; found 363.1.
potassiumhexacyanoferrate(II) trihydrate[ No CAS ]
[ 39478-78-9 ]
[ 60710-80-7 ]
Yield
Reaction Conditions
Operation in experiment
75%
With 2-(2-methoxyphenyl)-1-methyl-3-(diphenylphosphino)-1H-indole; potassium tert-butylate; triethylamine; bis(dibenzylideneacetone)-palladium(0); In dichloromethane; water; acetonitrile; at 50℃; for 24h;Inert atmosphere;
General procedure: An oven-dried Schlenk tube with the presence of magnetic stir bar which is Teflon-coated was charged with Pd(dba)2 (11.5 mg, 0.02 mmol, 2 mol%) and ligand L4 (8.4 mg, 0.02 mmol, 2 mol%). The flask was evacuated and backfilled with nitrogen (3 cycles). Pre-complexation of palladium and ligand was initiated by injecting freshly distilled dry dichloromethane (2.0 mL) and Et3N (0.1 mL) into the tube. The solution was stirred and warmed with hair drier till the solvent condensed on the tube wall. The solvent was removed under vacuum. Aryl bromide (1.0 mmol), KOt-Bu (0.25 mmol), and potassium hexacyanoferrate(II) trihydrate (0.23 mmol) were charged successively to the tube followed by another 3 evacuation-nitrogen refill cycles. Water (1.0 mL) and acetonitrile (1.0 mL) were used as a solvent mixture. The tube was immersed into a preheated 50 C oil bath for 24 hours. The reaction was quenched by cooling to ambient temperature and added with EtOAc and water. The organic supernatant was analyzed by GC. The organic layer was separated and the remained aqua medium was further extracted with EtOAc (10 mL × 3). The combined organic phases were concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (230-400 mesh). The pure fractions were collected, dried under vacuum, and followed by proton (1H) and carbon (13C) NMR characterization
imidazo[1,2-a]pyridine-3-carbonyl chloride[ No CAS ]
[ 1426135-64-9 ]
Yield
Reaction Conditions
Operation in experiment
With N-ethyl-N,N-diisopropylamine; In 1,2-dichloro-ethane; at 20 - 50℃; for 3h;
To a suspension of imidazo[1,2-a]pyridine-3-carboxylic acid (1) (16.6 g, 102 mmol) in dichloromethane (300 mL) and DMF (0.5 mL) at 0 C. was added oxalyl chloride (45 mL, 510 mmol) dropwise over 10 minutes. The reaction was slowly warmed to room temperature and stirred until complete conversion was detected by LCMS in MeOH. The reaction was subsequently reduced to dryness and suspended in dichloroethane (100 mL) and was added to a solution of <strong>[60710-80-7]3-amino-4-methylbenzonitrile</strong> (7) (15 g, 113 mmol) in dichloroethane (200 mL) and Pr2NEt (55 mL) at 0 C. After the addition, the cold bath was removed and contents were stirred at room temperature for 1 hour and then heated to 50 C. for another 2 hours. After the completion of the reaction, the mixture was cooled and a white precipitate formed. The mixture was filtered and the solid was washed with cold dichloromethane. About 10 g of the desired N-(5-cyano-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (8) was obtained. The filtrate was washed with saturated NH4Cl, saturated NaHCO3, brine, dried over magnesium sulfate, filtered and reduced to dryness. The crude solid was triturated with diethyl ether to remove excess aniline and filtered to afford another crop of N-(5-cyano-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (8) as a white solid. MS m/z 277.1 (M+1).
With N-ethyl-N,N-diisopropylamine; In 1,2-dichloro-ethane; at 0 - 50℃; for 3h;
To a suspension of imidazo[1,2-a]pyridine-3-carboxylic acid (1) (16.6 g, 102 mmol) in dichloromethane (300 mL) and DMF (0.5 mL) at 0 C. was added oxalyl chloride (45 mL, 510 mmol) dropwise over 10 minutes. The reaction was slowly warmed to room temperature and stirred until complete conversion was detected by LCMS in MeOH. The reaction was subsequently reduced to dryness and suspended in dichloroethane (100 mL) and was added to a solution of <strong>[60710-80-7]3-amino-4-methylbenzonitrile</strong> (7) (15 g, 113 mmol) in dichloroethane (200 mL) and Pr2NEt (55 mL) at 0 C. After the addition, the cold bath was removed and contents were stirred at room temperature for 1 hour and then heated to 50 C. for another 2 hours. After the completion of the reaction, the mixture was cooled and a white precipitate formed. The mixture was filtered and the solid was washed with cold dichloromethane. About 10 g of the desired N-(5-cyano-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (8) was obtained. The filtrate was washed with saturated NH4Cl, saturated NaHCO3, brine, dried over magnesium sulfate, filtered and reduced to dryness. The crude solid was triturated with diethyl ether to remove excess aniline and filtered to afford another crop of N-(5-cyano-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (8) as a white solid. MS m/z 277.1 (M+1).; To a stirred and cooled (0 C.) suspension of N-(5-cyano-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (8) (10 g, 36.2 mmol) in EtOH (225 ml) was added NH2OH (6 mL, 50% in water solution). After the addition, the reaction was stirred at room temperature for 2 hours then heated at 50 C. for another 2 hours. After cooling to room temperature, the mixture was stored in the fridge overnight. The resulting precipitate was filtered, washed with cold EtOH and dried under vacuum to afford N-(5-(N?-hydroxycarbamimidoyl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (9) as a white solid. 1H NMR (400 MHz, d6-DMSO) delta 9.40 (dt, J=6.8, 1.2 Hz, 1H), 8.15 (s, 1H), 7.88 (d, J=2.0 Hz, 1H), 7.79 (dt, J=9.2, 1.2 Hz, 1H), 7.76 (dd, J=8.0, 1.6 Hz, 1H), 7.52 (ddd, J=9.2, 9.2, 1.2 Hz, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.17 (td, J=6.8, 1.2 Hz, 1H), 2.49 (s, 3H). MS m/z 310.1 (M+1)+.
With N-ethyl-N,N-diisopropylamine; In 1,2-dichloro-ethane; at 0 - 60℃; for 5h;
Oxalyl chloride (10 mL, 110 mmol) was added dropwise to a stirred suspension of 6-fluoroimidazo[1,2-a]pyridine-3-carboxylic acid (24b) (2 g, 11 mmol) and catalytic amounts of DMF in dichloromethane (20 mL). After 5 hours, the solvent was evaporated and the solid was suspended in dry DCE (20 mL) and added to a stirred solution of <strong>[60710-80-7]3-amino-4-methylbenzonitrile</strong> (1.45 g, 11 mmol) and DIEA (6 mmol) in DCE (10 mL) at 0 C. After the addition, the reaction was heated at 60 C. for 5 hours. The mixture was subjected to standard aqueous work and silica purification to give N-(5-cyano-2-methylphenyl)-6-fluoroimidazo[1,2-a]pyridine-3-carboxamide (39) as a solid. 1H NMR (400 MHz, d6-DMSO) delta 10.14 (s, 1H), 9.45 (dd, J=5.2, 2.0 Hz, 1H), 8.62 (s, 1H), 7.90-7.87 (m, 2H), 7.68-7.63 (m, 1H), 7.53 (d, J=8.0 Hz, 1H), 2.37 (s, 3H). MS m/z 295.1 (M+1)+.
With N-ethyl-N,N-diisopropylamine; at 0 - 60℃; for 5h;
Oxalyl chloride (10 mL, 110 mmol) was added dropwise to a stirred suspension of 6-fluoroimidazo[1,2-a]pyridine-3-carboxylic acid (24b) (2 g, 11 mmol) and catalytic amounts of DMF in dichloromethane (20 mL). After 5 hours, the solvent was evaporated and the solid was suspended in dry DCE (20 mL) and added to a stirred solution of <strong>[60710-80-7]3-amino-4-methylbenzonitrile</strong> (1.45 g, 11 mmol) and DIEA (6 mmol) in DCE (10 mL) at 0 C. After the addition, the reaction was heated at 60 C. for 5 hours. The mixture was subjected to standard aqueous work and silica purification to give N-(5-cyano-2-methylphenyl)-6-fluoroimidazo[1,2-a]pyridine-3-carboxamide (39) as a solid. 1H NMR (400 MHz, d6-DMSO) delta 10.14 (s, 1H), 9.45 (dd, J=5.2, 2.0 Hz, 1H), 8.62 (s, 1H), 7.90-7.87 (m, 2H), 7.68-7.63 (m, 1H), 7.53 (d, J=8.0 Hz, 1H), 2.37 (s, 3H). MS m/z 295.1 (M+1)+.; NH2OH (5 mL, 16.1 mmol) was added in one portion to a stirred suspension of N-(5-cyano-2-methylphenyl)-6-fluoroimidazo[1,2-a]pyridine-3-carboxamide (39) (0.95 g, 3.23 mmol). The resulting suspension was heated at 60 C. overnight and then cooled to 0 C. The product, (Z)-6-fluoro-N-(5-(N?-hydroxycarbamimidoyl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (40) was collected by filtration. MS m/z 328.1 (M+1)+.
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