* 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 water; sodium hydroxide In ethanol at 105℃; for 16 h;
A 250-mE round-bottom flask was charged with4-(1H-pyrazol-i-yl)benzonitrile (Step 1, 2 g, 11.82 mmol), ethanol (40 mE), water (40 mE) and sodium hydroxide (705 mg, 17.63 mmol). The resulting solution was stirred at 105° C. 16 hand then concentrated under vacuum. The residue was diluted with water (30 mE) and extracted with ethyl acetate (50 mE).12109] ThepHoftheaqueousphasewas adjustedto 5 with hydrochloric acid (6.0 M). The solids were collected by filtration, washed with water (10 mE) and dried in an oven to afford 4-(1H-pyrazol-i-yl)benzoic acid as a light yellow solid (Intermediate 2-60, 1 g, 45percent). LCMS: (ESI)m/z 189 [M+H].
45%
With water; sodium hydroxide In ethanol at 105℃; for 16 h;
A 250-mL round-bottom flask was charged with 4-(1H-pyrazol-1-yl)benzonitrile (Step 1, 2 g, 11.82 mmol), ethanol (40 mL), water (40 mL) and sodium hydroxide (705 mg, 17.63 mmol,). The resulting solution was stirred at 105° C. 16 h and then concentrated under vacuum. The residue was diluted with water (30 mL) and extracted with ethyl acetate (50 mL). The pH of the aqueous phase was adjusted to 5 with hydrochloric acid (6.0 M). The solids were collected by filtration, washed with water (10 mL) and dried in an oven to afford 4-(1H-pyrazol-1-yl)benzoic acid as a light yellow solid (Intermediate 2-13, 1 g, 45percent). LCMS: (ESI) m/z 189 [M+H].
With potassium carbonate In N,N-dimethyl-formamide at 120℃; for 7 h;
4-( 1 H-pyrazol- 1 -yl)- benzonitrile4-Fluorobenzonitrile (204.2 g), pyrazole (138.6 g, 1.22 eq) and potassium carbonate (281.5 g, 1.22 eq) in DMF (1110 ml) were heated at 120 0C for 7 hours. The suspension was cooled to 25 0C and water (2920 ml) added. The reaction was extracted with MTBE (3 x 1460 ml) and the combined extracts were washed with water (3 x 1460 ml) and saturated aqueous sodium chloride (1460 ml). The organic phase was concentrated at atmospheric pressure until the pot temperature rose to 65 0C. Heptane (1700 ml) was added over 30 minutes at 60-65 0C, and then a further 300 ml of distillate was collected. The solution was stirred at 60-65 0C for 15 minutes and then cooled to <5 0C. The slurry was filtered and washed with heptane (2 x 200 ml), and dried under vacuum to constant weight to give the title compound as a solid (245.3 g, 87percent). <n="47"/>1H NMR (400 MHz, CDCl3): 6.51 (q, IH), 7.71 (d, 2H), 7.75 (d, IH), 7.81 (d, 2H), 7.98 (d, IH).
83%
With potassium carbonate In N,N-dimethyl-formamide at 115 - 120℃; for 7 - 8 h; Inert atmosphere
5f: 4-(1H-pyrazol-1-yl)benzonitrile N,N-dimethylformamide (123.25 L) was charged to the vessel and analysed for moisture content (target<0.5percent). Potassium carbonate (34.01 kg) was then charged to the vessel followed by pyrazole (16.76 kg) and 4-fluorobenzonitrile (24.65 kg). The reaction mixture was heated to 115 to 120° C. and stirred at this temperature for between seven and eight hours under a nitrogen atmosphere. The reaction was monitored by GC (target<10percent 4-fluorobenzonitrile). The reaction was then cooled to 20-25° C. and quenched with water (369.7 L). Methyl tert-butyl ether (246.5 L) was then charged and the layers allowed to separate. The aqueous layer was washed with methyl tert-butyl ether (2 x147.9 L) and the organic layers combined. The organic layer was then washed with water (2 x 172.55 L) and aqueous brine (123.25 L, 24 wt percent). The organic phase was then concentrated to approximately 100 L at 60° C. or below at atmospheric pressure. n-Heptane (209 L) was then charged and the mixture concentrated to approximately 100 L at 60° C. or below at atmospheric pressure. The reaction was cooled to 0° C. and stirred for three hours at this temperature. The slurry was then filtered washing the filter cake with n-heptane (24.65 L). The resulting solid was dried under vacuum at 40° C. to yield the title product (28.6 kg, 99.32percent purity, 83percent yield). 1H NMR (300 MHz, DMSO-d6): 6.61 (dd, J=2.4, 1.9 Hz, 1H), 7.83 (d, J=1.4 Hz 1H), 7.94 (d, J=8.7 Hz, 2H), 8.04 (d, J=9.0 Hz, 2H), 8.65 (d, J=2.4 Hz, 1H).
80%
With potassium carbonate In N,N-dimethyl-formamide at 110℃; for 16 h;
Step 1. 4-(lH-Pyrazol-l-yl)benzonitrile (0847) [00269] A mixture of lH-pyrazole (15 g, 220.34 mmol), 4-fluorobenzonitrile (27 g, 222.93 mmol), potassium carbonate (60.7 g, 439.19 mmol) in DMF (200 mL) was stirred for 16 h at 110 °C. After cooling to ambient temperature, the reaction mixture was poured into water (500 mL) and the resulting solids were collected by filtration and dried under vacuum, resulting in 30 g (80percent) of 4-(lH-pyrazol-l-yl)benzonitrile. MS (ESI) m/z 170 [M+H]+.
62%
Stage #1: With sodium hydroxide In N,N-dimethyl-formamide at 80℃; for 0.5 h; Inert atmosphere Stage #2: at 110℃; for 3 h;
Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 1H-pyrazole (422 mg, 6.21 mmol, 1.50 equiv), sodium hydroxide (248 mg, 6.20 mmol, 1.50 equiv), and N,N-dimethylformamide (20 mL). The mixture was stirred and heated to 80° C. for 30 min, then to this was added 4-fluorobenzonitrile (500 mg, 4.13 mmol, 1.00 equiv). The resulting solution was stirred for 3 h at 110° C. in an oil bath. The resulting solution was diluted with 50 mL of H2O. The solids were collected by filtration and dried in an oven. The product was obtained as 0.43 g (62percent) of a white solid.
47%
With caesium carbonate In N,N-dimethyl-formamide for 2 h; Reflux
A 100-mE round-bottom flask was charged with4-fluorobenzonitrile (2 g, 16.51 mmol), cesium carbonate (16 g, 49.11 mmol), N,N-dimethylformamide (20 mE) and 1 H-pyrazole (2.24 g, 32.90 mmol). The resulting solution was refluxed for 2 h. The solids were removed by filtration and the filtrate was concentrated under vacuum. The residue was purified by column chromatography eluting with ethyl acetate/petroleum ether (1:10 to 1:4 v/v) to afford 4-(1H- pyrazol-i-yl)benzonitrile as a yellow oil (1.3 g, 47percent). LCMS: (ESI) mlz 170 [M+H].
47%
With caesium carbonate In N,N-dimethyl-formamide for 2 h; Reflux
A 100-mL round-bottom flask was charged with 4-fluorobenzonitrile (2 g, 16.51 mmol), cesium carbonate (16 g, 49.11 mmol), N,N-dimethylformamide (20 mL) and 1H-pyrazole (2.24 g, 32.90 mmol). The resulting solution was refluxed for 2 h. The solids were removed by filtration and the filtrate was concentrated under vacuum. The residue was purified by column chromatography eluting with ethyl acetate/petroleum ether (1:10 to 1:4 v/v) to afford 4-(1H-pyrazol-1-yl)benzonitrile as a yellow oil (1.3 g, 47percent). LCMS: (ESI) m/z 170 [M+H].
With copper(l) iodide; 1,10-phenanthroline N-oxide; caesium carbonate In N,N-dimethyl-formamide at 120℃; Inert atmosphere
To the three-necked flask, CuI (19 mg, 0.1 mmol, 10 molpercent), 1,10-phenanthroline-N-oxide (39 mg, 0.2 mmol, 20 molpercent) and Cs2CO3 (650 mg, 2.0mmol). The reaction flask was evacuated under argon. p-cyanochlorbenzene (138 mg, 1.0mmol), pyrazole (102 mg, 1.5 mmol) and DMF (2 mL) were added under an atmosphere of argon gas. The reaction was carried out at 120 °C for 72 hours until the starting reaction was complete (the reaction was complete by TLC). After completion of the reaction, a brown oil was obtained which was diluted with ethyl acetate. The inorganic salt was removed by filtration and the solvent was removed by rotary evaporation. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate as eluant to give 1-(4-carbonitrilephenyl)pyrazole as a pale yellow oil in a yield of 51percent.
Reference：
[1] Advanced Synthesis and Catalysis, 2007, vol. 349, # 17-18, p. 2673 - 2676
[2] Chemistry - A European Journal, 2014, vol. 20, # 18, p. 5231 - 5236
[3] Journal of Organic Chemistry, 2011, vol. 76, # 9, p. 3151 - 3159
[4] RSC Advances, 2016, vol. 6, # 64, p. 59550 - 59564
[5] Patent: CN104356131, 2016, B, . Location in patent: Paragraph 0316-0327
4
[ 288-13-1 ]
[ 623-00-7 ]
[ 25699-83-6 ]
Yield
Reaction Conditions
Operation in experiment
98%
at 90℃; for 30 h; sealed tube
Following General Procedure A (90 0C, 30 hours), 1H-pyrazole (205 mg, 3.0 mmol) is coupled with 4-bromobenzonitrile (364 mg, 2.0 mmol). The crude brown oil is purified by flash chromatography on silica gel (eluent: dichloromethane / hexanes = 50/50) to provide 330 mg (98 percent isolated yield) of the desired product as a white solid. identificationMp: 89°C. <n="45"/>1H NMR (400 MHz5 CDCI3): δ 7.92-7.93 (d, 1 H1 H7), 7.75-7.78 (m, 2H, H3l5), 7.65-7.70 (m, 3H, H2,B,9), 6.46-6:47 (dd, 1H1 H8).13C NMR (100 MHz, CDCI3): δ 142.95 (C1), 142.50 (C9), 133.68 (C3,5), 126.94 (C7), 118.93 (C2,6), 118.44 (C10), 109.53 (C4), 109.15 (C8). IR (KBr) : v (cm-1) = 3153, 3136, 3066, 2226(CN), 1610, 1528, 1513, 1392, 1342, 1252, 1199, 1176, 1127, 1030, 934, 834, 813, 749, 650, 572, 545. GC/MS: rt = 18.92 min, M/Z = 169. HRMS: 170.0700 (M+H). Theoretical: 170.0718.
82%
With copper(I) oxide; caesium carbonate; N-phenyl-2-pyridincarboxamide-1-oxide In acetonitrile for 20 h; Inert atmosphere; Reflux
General procedure: In 50 mL round bottom flask, aryl halide (1.0 mmol), pyrazole (1.2 mmol), ligand (0.04 mmol), Cu2O (0.10 mmol), cesium carbonate (2.0 mmol), and dry solvent (20 mL) were placed under nitrogen atmosphere. The reaction mixture was heated in oil bath up to specified temperature under constant stirring for 20 h and then allowed to cool to room temperature. The reaction mixture was filtered through a plug of Celite in a fritted filter funnel and washed with ethyl acetate. If DMSO is used as solvent, it is extracted by washing the filtrate with 25 mL water for three times. The organic phase was dried over anhydrous MgSO4 and was removed under reduced pressure to provide the crude product which was purified by column chromatography on silica gel, using hexane and ethyl acetate in 3:1 ratio, respectively, as an eluent.
78%
With copper(l) iodide; tetrabutylammomium bromide; N-(2-aminoethyl)-N'-{2-[(2-aminoethyl)amino]ethyl}ethane-1,2-diamine In water at 125℃; for 24 h;
General procedure: Iodobenzene (1.0 mmol), imidazole (1.5 mmol), TEPA (2.0 mmol), TBAB (0.3 mmol), CuI (0.1 mmol), and 3 mL H2O were added to a 10 mL flask, which was subsequently capped with a rubber balloon. The mixture was stirred in a preheated oil bath at 125 °C for 12 h. After cooling the mixture to the room temperature, 5 mL water was added and the product was extracted by ethyl acetate (10 mL×3). The combined organic layer was washed by brine (15 mL), dried over anhydrous MgSO4, and evaporated under the reduced pressure. Further purification by silica gel column chromatography (6:1 petroleum ether/ethyl acetate) give the 1-phenyl-1H-imidazole.
Reference：
[1] Angewandte Chemie - International Edition, 2007, vol. 46, # 6, p. 934 - 936
[2] Patent: WO2008/4088, 2008, A2, . Location in patent: Page/Page column 43-44
[3] Journal of Organic Chemistry, 2005, vol. 70, # 13, p. 5164 - 5173
[4] New Journal of Chemistry, 2017, vol. 41, # 8, p. 3082 - 3088
[5] European Journal of Organic Chemistry, 2004, # 4, p. 695 - 709
[6] ChemCatChem, 2014, vol. 6, # 8, p. 2373 - 2383
[7] Chemistry - A European Journal, 2014, vol. 20, # 18, p. 5231 - 5236
[8] Tetrahedron Letters, 2016, vol. 57, # 20, p. 2197 - 2200
[9] Tetrahedron, 2013, vol. 69, # 30, p. 6230 - 6233
[10] Organic and Biomolecular Chemistry, 2011, vol. 9, # 12, p. 4671 - 4684
[11] Angewandte Chemie - International Edition, 2009, vol. 48, # 2, p. 333 - 336
5
[ 288-13-1 ]
[ 3058-39-7 ]
[ 25699-83-6 ]
Reference：
[1] Chemistry - A European Journal, 2014, vol. 20, # 18, p. 5231 - 5236
[2] Catalysis Science and Technology, 2017, vol. 7, # 19, p. 4401 - 4412
Reference：
[1] Chemistry - A European Journal, 2014, vol. 20, # 45, p. 14619 - 14623
12
[ 16209-02-2 ]
[ 25699-83-6 ]
Reference：
[1] Angewandte Chemie - International Edition, 2017, vol. 56, # 49, p. 15693 - 15697[2] Angew. Chem., 2017, vol. 129, p. 15899 - 15903,5
13
[ 25699-83-6 ]
[ 99662-34-7 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 11, p. 2955 - 2959
14
[ 25699-83-6 ]
[ 368870-03-5 ]
Yield
Reaction Conditions
Operation in experiment
83%
With borane-THF In tetrahydrofuran for 16 h; Reflux
To 4-(pyrazol-1-yl)benzonitrile (see WO 2005/095343A) (1.46 g, 8.63 mmol) was added a solution of 1M borane tetrahydrofuran complex in tetrahydrofuran (93 ml, 93 mmol), followed by heating to reflux for 16 hours. After completion of the reaction, methanol (14 ml) was added to the reaction solution, followed by concentration under reduced pressure. 6N Hydrochloric acid (265 ml) was added to the residue, followed by further heating to reflux for 3 hours. After this solution was concentrated under reduced pressure, a small amount of water was added. The resulting solution was adjusted to pH 11 with a 30percent aqueous sodium hydroxide solution under ice cooling, followed by extraction with methylene chloride. The separated organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent; chloroform:methano1:28percent aqueous ammonia=90:10:1 (V/V/V)), and fractions containing the desired compound were concentrated under reduced pressure to afford the title compound (1.24 g) as a pale yellow solid. (Yield: 83percent) Mass spectrum (CI, m/z): 174 (M++1). 1H-NMR spectrum (CDCl3, ppm): 7.91 (dd, J=2.5, 0.5Hz, 1H), 7.72 (d, J=1.6Hz, 1H), 7.69-7.63 (m, 2H), 7.44-7.37 (m, 2H), 6.46 (dd, J=2.5, 1.6Hz, 1H), 3.91 (s, 2H).
83%
Stage #1: With borane-THF In tetrahydrofuran for 16 h; Reflux Stage #2: With methanol In tetrahydrofuran
9-(a) 4-(Pyrazol-1-yl)beilzylamine To 4-(pyrazol-1-yl)benzonitrile (see WO 2005/095343A) (1.46 g, 8.63 mmol) was added a solution of 1M borage * tetrahydrofuran complex in tetrahydrofuran (93 ml, 93 mmol), followed by heating to reflux for 16 hours. After completion of the reaction, methanol (14 ml) was added to the reaction solution, followed by concentration under reduced pressure. 6N Hydrochloric acid (265 ml) was added to the residue, followed by further heating to reflux for 3 hours. After this solution was concentrated under reduced pressure, a small amount of water was added. The resulting solution was adjusted to pH 11 with a 30percent aqueous sodium hydroxide solution under ice cooling, followed by extraction with methylene chloride. The separated organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent; chloroform:methanol:28percent aqueous ammonia=90:10:1 (V/V/V)), and fractions containing the desired compound were concentrated under reduced pressure to afford the title compound (1.24 g) as a pale yellow solid. (Yield: 83percent) Mass spectrum (CI, m/z): 174 (M++1). 1H-NMR spectrum (CDCl3, δppm): 7.91 (dd, J=2.5, 0.5Hz, 1H), 7.72 (d, J=1.6Hz, 1H), 7.69-7.63 (m, 2H), 7.44-7.37 (m, 2H), 6.46 (dd, J=2.5, 1.6H, 1H), 3.91 (s, 2H).
52%
With palladium 10% on activated carbon; hydrogen; lithium hydroxide In ethyl acetate at 20℃; for 16 h;
Step 2. (4-(lH-Pyrazol-l-yl)phenyl)methanamine (0849) [00270] A mixture of 4-(lH-pyrazol-l-yl)benzonitrile (15 g, 88.66 mmol), Raney nickel (10 g), palladium on carbon (10 wt. percent, 1 g) and lithium hydroxide (1 g, 41.75 mmol) in EtOAc (200 mL) was evacuated and back-filled with hydrogen several times and then charged with hydrogen. The resulting mixture was stirred for 16 h at ambient temperature, then was filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with a gradient of 1-10percent DCM/MeOH) resulting in 8 g (52percent) of (4-(lH-pyrazol-l- yl)phenyl)methanamine. MS (ESI) m/z 174 [M+H]+.
With caesium carbonate;iron(III) acetylacetonate; copper(II) oxide; at 90℃; for 30h;sealed tube;Conversion of starting material;
Following General Procedure A (90 0C, 30 hours), 1H-pyrazole (205 mg, 3.0 mmol) is coupled with 4-bromobenzonitrile (364 mg, 2.0 mmol). The crude brown oil is purified by flash chromatography on silica gel (eluent: dichloromethane / hexanes = 50/50) to provide 330 mg (98 % isolated yield) of the desired product as a white solid. identificationMp: 89C. <n="45"/>1H NMR (400 MHz5 CDCI3): delta 7.92-7.93 (d, 1 H1 H7), 7.75-7.78 (m, 2H, H3l5), 7.65-7.70 (m, 3H, H2,B,9), 6.46-6:47 (dd, 1H1 H8).13C NMR (100 MHz, CDCI3): delta 142.95 (C1), 142.50 (C9), 133.68 (C3,5), 126.94 (C7), 118.93 (C2,6), 118.44 (C10), 109.53 (C4), 109.15 (C8). IR (KBr) : v (cm-1) = 3153, 3136, 3066, 2226(CN), 1610, 1528, 1513, 1392, 1342, 1252, 1199, 1176, 1127, 1030, 934, 834, 813, 749, 650, 572, 545. GC/MS: rt = 18.92 min, M/Z = 169. HRMS: 170.0700 (M+H). Theoretical: 170.0718.
82%
With copper(I) oxide; caesium carbonate; N-phenyl-2-pyridincarboxamide-1-oxide; In acetonitrile; for 20h;Inert atmosphere; Reflux;
General procedure: In 50 mL round bottom flask, aryl halide (1.0 mmol), pyrazole (1.2 mmol), ligand (0.04 mmol), Cu2O (0.10 mmol), cesium carbonate (2.0 mmol), and dry solvent (20 mL) were placed under nitrogen atmosphere. The reaction mixture was heated in oil bath up to specified temperature under constant stirring for 20 h and then allowed to cool to room temperature. The reaction mixture was filtered through a plug of Celite in a fritted filter funnel and washed with ethyl acetate. If DMSO is used as solvent, it is extracted by washing the filtrate with 25 mL water for three times. The organic phase was dried over anhydrous MgSO4 and was removed under reduced pressure to provide the crude product which was purified by column chromatography on silica gel, using hexane and ethyl acetate in 3:1 ratio, respectively, as an eluent.
78%
With copper(l) iodide; tetrabutylammomium bromide; N-(2-aminoethyl)-N'-{2-[(2-aminoethyl)amino]ethyl}ethane-1,2-diamine; In water; at 125℃; for 24h;
General procedure: Iodobenzene (1.0 mmol), imidazole (1.5 mmol), TEPA (2.0 mmol), TBAB (0.3 mmol), CuI (0.1 mmol), and 3 mL H2O were added to a 10 mL flask, which was subsequently capped with a rubber balloon. The mixture was stirred in a preheated oil bath at 125 C for 12 h. After cooling the mixture to the room temperature, 5 mL water was added and the product was extracted by ethyl acetate (10 mL×3). The combined organic layer was washed by brine (15 mL), dried over anhydrous MgSO4, and evaporated under the reduced pressure. Further purification by silica gel column chromatography (6:1 petroleum ether/ethyl acetate) give the 1-phenyl-1H-imidazole.
With potassium carbonate; In N,N-dimethyl-formamide; at 120℃; for 7h;
4-( 1 H-pyrazol- 1 -yl)- benzonitrile4-Fluorobenzonitrile (204.2 g), pyrazole (138.6 g, 1.22 eq) and potassium carbonate (281.5 g, 1.22 eq) in DMF (1110 ml) were heated at 120 0C for 7 hours. The suspension was cooled to 25 0C and water (2920 ml) added. The reaction was extracted with MTBE (3 x 1460 ml) and the combined extracts were washed with water (3 x 1460 ml) and saturated aqueous sodium chloride (1460 ml). The organic phase was concentrated at atmospheric pressure until the pot temperature rose to 65 0C. Heptane (1700 ml) was added over 30 minutes at 60-65 0C, and then a further 300 ml of distillate was collected. The solution was stirred at 60-65 0C for 15 minutes and then cooled to <5 0C. The slurry was filtered and washed with heptane (2 x 200 ml), and dried under vacuum to constant weight to give the title compound as a solid (245.3 g, 87%). <n="47"/>1H NMR (400 MHz, CDCl3): 6.51 (q, IH), 7.71 (d, 2H), 7.75 (d, IH), 7.81 (d, 2H), 7.98 (d, IH).
83%
With potassium carbonate; In N,N-dimethyl-formamide; at 115 - 120℃; for 7 - 8h;Inert atmosphere;
5f: 4-(1H-pyrazol-1-yl)benzonitrile N,N-dimethylformamide (123.25 L) was charged to the vessel and analysed for moisture content (target<0.5%). Potassium carbonate (34.01 kg) was then charged to the vessel followed by pyrazole (16.76 kg) and 4-fluorobenzonitrile (24.65 kg). The reaction mixture was heated to 115 to 120 C. and stirred at this temperature for between seven and eight hours under a nitrogen atmosphere. The reaction was monitored by GC (target<10% 4-fluorobenzonitrile). The reaction was then cooled to 20-25 C. and quenched with water (369.7 L). Methyl tert-butyl ether (246.5 L) was then charged and the layers allowed to separate. The aqueous layer was washed with methyl tert-butyl ether (2 x147.9 L) and the organic layers combined. The organic layer was then washed with water (2 x 172.55 L) and aqueous brine (123.25 L, 24 wt %). The organic phase was then concentrated to approximately 100 L at 60 C. or below at atmospheric pressure. n-Heptane (209 L) was then charged and the mixture concentrated to approximately 100 L at 60 C. or below at atmospheric pressure. The reaction was cooled to 0 C. and stirred for three hours at this temperature. The slurry was then filtered washing the filter cake with n-heptane (24.65 L). The resulting solid was dried under vacuum at 40 C. to yield the title product (28.6 kg, 99.32% purity, 83% yield). 1H NMR (300 MHz, DMSO-d6): 6.61 (dd, J=2.4, 1.9 Hz, 1H), 7.83 (d, J=1.4 Hz 1H), 7.94 (d, J=8.7 Hz, 2H), 8.04 (d, J=9.0 Hz, 2H), 8.65 (d, J=2.4 Hz, 1H).
80%
With potassium carbonate; In N,N-dimethyl-formamide; at 110℃; for 16h;
Step 1. 4-(lH-Pyrazol-l-yl)benzonitrile (0847) [00269] A mixture of lH-pyrazole (15 g, 220.34 mmol), 4-fluorobenzonitrile (27 g, 222.93 mmol), potassium carbonate (60.7 g, 439.19 mmol) in DMF (200 mL) was stirred for 16 h at 110 C. After cooling to ambient temperature, the reaction mixture was poured into water (500 mL) and the resulting solids were collected by filtration and dried under vacuum, resulting in 30 g (80%) of 4-(lH-pyrazol-l-yl)benzonitrile. MS (ESI) m/z 170 [M+H]+.
62%
Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 1H-pyrazole (422 mg, 6.21 mmol, 1.50 equiv), sodium hydroxide (248 mg, 6.20 mmol, 1.50 equiv), and N,N-dimethylformamide (20 mL). The mixture was stirred and heated to 80 C. for 30 min, then to this was added 4-fluorobenzonitrile (500 mg, 4.13 mmol, 1.00 equiv). The resulting solution was stirred for 3 h at 110 C. in an oil bath. The resulting solution was diluted with 50 mL of H2O. The solids were collected by filtration and dried in an oven. The product was obtained as 0.43 g (62%) of a white solid.
47%
With caesium carbonate; In N,N-dimethyl-formamide; for 2h;Reflux;
A 100-mE round-bottom flask was charged with4-fluorobenzonitrile (2 g, 16.51 mmol), cesium carbonate (16 g, 49.11 mmol), N,N-dimethylformamide (20 mE) and 1 H-pyrazole (2.24 g, 32.90 mmol). The resulting solution was refluxed for 2 h. The solids were removed by filtration and the filtrate was concentrated under vacuum. The residue was purified by column chromatography eluting with ethyl acetate/petroleum ether (1:10 to 1:4 v/v) to afford 4-(1H- pyrazol-i-yl)benzonitrile as a yellow oil (1.3 g, 47%). LCMS: (ESI) mlz 170 [M+H].
47%
With caesium carbonate; In N,N-dimethyl-formamide; for 2h;Reflux;
A 100-mL round-bottom flask was charged with 4-fluorobenzonitrile (2 g, 16.51 mmol), cesium carbonate (16 g, 49.11 mmol), N,N-dimethylformamide (20 mL) and 1H-pyrazole (2.24 g, 32.90 mmol). The resulting solution was refluxed for 2 h. The solids were removed by filtration and the filtrate was concentrated under vacuum. The residue was purified by column chromatography eluting with ethyl acetate/petroleum ether (1:10 to 1:4 v/v) to afford 4-(1H-pyrazol-1-yl)benzonitrile as a yellow oil (1.3 g, 47%). LCMS: (ESI) m/z 170 [M+H].
4-(lH-Pyrazol-l-yl)benzonitrile (Eur. J. Org. Chem. 2004, 695-709) (1.5 g, 8.87 mmol) in dry TetaF (50 ml) under argon was stirred at -78 C whilst lithium diisopropylamide (1.8M solution in TetaF/hexane/ethyl benzene; 5.2 ml, 9.32 mmol) was added dropwise during 20 min. Stirring and cooling were continued for Ih, triisopropyl borate (8 ml, 34.5 mmol) was added dropwise during 30 min and then the temperature was allowed to rise overnight to RT. The peta of the reaction mixture was adjusted to 5 with IM HCl and the mixture was then concentrated to a minimum volume and extracted with ethyl acetate (200 ml) and brine (3 x 100 ml). The organic phase was collected, dried (Na2SO4), filtered and evaporated to a brown solid (1.32 g) which was used in the next step without further purification.APCI-MS m/z: 214.1 [MH+].
[ 1 -(4-CvanophenylV lH~-pyrazol-5-yriboronic acid 4-(lH-Pyrazol-l-yl)benzonitrile (Eur. J. Org. Chem. 2004, 695-709) (1.5 g, 8.87 mmol) in dry TetaF (50 ml) under argon was stirred at -78 C whilst lithium diisopropylamide (1.8M solution in TetaF/hexane/ethyl benzene; 5.2 ml, 9.32 mmol) was added dropwise during 20 min. Stirring and cooling were continued for Ih, triisopropyl borate (8 ml, 34.5 mmol) was added dropwise during 30 min and then the temperature was allowed to rise overnight to RT. The peta of the reaction mixture was adjusted to 5 with IM HCl and the mixture was then concentrated to a minimum volume and extracted with ethyl acetate (200 ml) and brine (3 x 100 ml). The organic phase was collected, dried (Na2SO4), filtered and evaporated to give a brown solid (1.32 g) which was used in the next step without further purification.APCI-MS m/z: 214.1 [MH+].
Step A 4-Pyrazol-1-yl-benzonitrile. To a solution of 4-fluorobenzonitrile (1.5 g, 12.35 mmol) and pyrazole 0.843 g, 12.38 mmol) in DMF (10 mL) was added NaH (60% in oil, 0.644 g, 16.09 mmol). The reaction was heated to 145 C. for 20 h. The reaction was cooled to room temperature and was diluted with water and EtOAc. The aqueous layer was washed with EtOAc (3*) and the combined organic layers were washed with water (4*). The organic solution was dried (MgSO4), filtered, and concentrated. Medium pressure chromatography (4:1 hexanes:EtOAc) provided 4-pyrazol-1-benzonitrile (1.6 g) as a white solid. 1H NMR (400 MHz, CDCl3) delta 7.97 (d, 1H), 7.82 (d, 2H), 7.73 (m, 3H), 6.87 (d, 1H); MS 170 (M+1).
With copper(l) iodide; 1,10-phenanthroline N-oxide; caesium carbonate; In N,N-dimethyl-formamide; at 120℃;Inert atmosphere;
To the three-necked flask, CuI (19 mg, 0.1 mmol, 10 mol%), 1,10-phenanthroline-N-oxide (39 mg, 0.2 mmol, 20 mol%) and Cs2CO3 (650 mg, 2.0mmol). The reaction flask was evacuated under argon. p-cyanochlorbenzene (138 mg, 1.0mmol), pyrazole (102 mg, 1.5 mmol) and DMF (2 mL) were added under an atmosphere of argon gas. The reaction was carried out at 120 C for 72 hours until the starting reaction was complete (the reaction was complete by TLC). After completion of the reaction, a brown oil was obtained which was diluted with ethyl acetate. The inorganic salt was removed by filtration and the solvent was removed by rotary evaporation. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate as eluant to give 1-(4-carbonitrilephenyl)pyrazole as a pale yellow oil in a yield of 51%.
5g: 4-[5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-benzonitrile To 2,2,6,6-tetramethylpiperidine (24.07 g) was added tetrahydrofuran (115 mL). The reaction mixture was cooled to -20 C. At this temperature 1.6 M n-butyl lithium in hexanes (102 mL) was added, maintaining the temperature at less than 0 C. The reaction mixture was stirred at 0 C. for thirty minutes. The reaction mixture was cooled to -50 C. At this temperature a pre-mixed solution of <strong>[25699-83-6]4-(1H-pyrazol-1-yl)benzonitrile</strong> (23 g) dissolved in tetrahydrofuran (115 mL) was added over approximately ten minutes, maintaining the temperature at less than -50 C. Tetrahydrofuran (12 mL) was added, and the reaction was stirred at -50 C. for at least thirty minutes. 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (35 mL) was charged over approximately twenty-five minutes, whilst maintaining the temperature at less than -50 C. The reaction mixture was stirred for approximately thirty minutes at -50 C., and then allowed to warm to approximately -15 C. Acetic acid (23.5 mL) was added over approximately twenty minutes, maintaining the temperature at less than 0 C. For convenience the reaction mixture was allowed to warm to approximately 20 C. over approximately sixteen hours. The reaction mixture was cooled to 0 C. and water (276 mL) was charged over approximately thirty-five minutes, maintaining the temperature at less than 0 C. The reaction mixture was stirred for an additional thirty minutes. The product was isolated by filtration and washed (on the filter) with water (46 mL) and then with n-heptane (46 mL). The damp solid was then dried in vacuo at 40 C. for approximately twenty-four hours to give the title product (34.62 g, 86.28%); 1H NMR (500 MHz, CDCl3% 1.23 (s, 12H), 6.90 (d, J=1.7 Hz, 1H), 7.69-7.63 (m, 4H), 7.70 (d, J=1.7 Hz, 1H). 13C NMR (125 MHz, CDCl3): 143.4, 140.4, 131.5, 123.8, 118.4, 117.5, 109.7, 83.7, 67.0, 23.6.
64%
4-r5-(4,4,5,5-Tetramethyl-ri,3,21dioxaborolan-2-yl)-pyrazol-l-yll-benzonitrile2,2,6,6-Tetramethylpiperidine (623.4 ml, 1.25 eq) and THF (2.5 L) were added to a flask and cooled to -20 +/- 2 0C. Hexyl lithium (2.3M, 1.542 L, 1.2 eq) was added over 140 minutes whilst maintaining the internal temperature at -20 +/- 2 0C. After complete addition, the reaction mixture was stirred at -20 +/- 2 0C for 30 minutes. The mixture was then cooled to -50 +/- 2 0C, and a solution of benzonitrile (325 ml) in THF (2.4 L) was then added slowly over 143 minutes whilst keeping the temperature at -50 +/- 2 0C. After addition was complete, the mixture was stirred at -50 +/- 2 0C for 2.5 hours. Isopropyl pinacol borate (2- isopropoxy-4,4,5,5-tetramethyl-l,3,2-dioxaborolane) (753.4 ml, 1.25 eq) was added to the reaction mixture over 66 minutes whilst keeping the temperature at -50 +/- 2 0C, followed by a line -wash of THF (0.3 L). After addition was complete, the mixture was left to stir for 45 minutes. The mixture was then allowed to warm to -15 0C. Acetic acid (0.51 L, 1 eq) was added over 45 minutes whilst keeping the temperature <0 0C. The mixture was then stirred for 30 minutes at 0 to -5 0C. Water (1.5 L) was then added over 1.5 hours whilst keeping the temperature between 0 and -5 0C, followed by the further water (4.5 L) over 1 hour. After the water addition was complete, the mixture was stirred between 0 and -5C for 30 minutes. The solid was filtered off, washed four times with cold water (1000 mL) and then dried in a vacuum oven at 40 0C to constant weight to give 4-[5-(4,4,5,5- tetramethyl-[l,3,2]dioxaborolan-2-yl)-pyrazol-l-yl]-benzonitrile (566 g, 64%).1H NMR (300 MHz, CDCl3): 1.30 (s, 12H), 6.97 (d, IH), 7.73 (m, 5H).
Step 2; NaBH4, isobutyric acid, MeLi, THF H N' han 1- (4-Pyrazol-1-vl-phenyl)-ethylamine. A suspension of sodium borohydride (22.3 mg, 0.59 mmol) in tetrahydrofuran (5 mL) is stirred at room temperature. Isobutyric acid (54.8 pL, 0.59 mmol) and 4-pyrazol-1-yl- benzonitrile (100 mg, 0.591 mmol), dissolved in 3 mL tetrahydrofuran, are added. The reaction mixture is stirred at 70C for 6 h and then cooled to-80C. Methyllithium (739 pL, 1.18 mmol, 1.6 M in diethyl ether) is added and the reaction mixture is allowed to warm to room temperature over night. The reaction is quenched by addition of 1 mL water and 2 mL 1 M HCI. The organic solvent is evaporated under reduced pressure and the remaining aqueous phase is adjusted with ammonium hydroxide to pH = 7 and extracted with ethylacetate (three times) and the combined organic layer is washed with water, dried with sodium sulphate, and concentrated in vacuum. Purification of the crude product by preparative HPLC yields the title compound. 'H NMR (d6-DMSO, 300MHz) 8=1. 52 (d, 3H, J = 6. 9 Hz), 4.43 (m, 1 H), 6.51 (m, 1 H), 7.56 (d, 2H, J = 9. 0 Hz), 7.70 (s, 1H), 7.85 (d, 2H, J = 9. 0 Hz), 8.46 (d, 1H, J=2. 7Hz). LC/MS (Vla) rt 3. 63,187 (M).
With borane-THF; In tetrahydrofuran; for 16h;Reflux;
To 4-(pyrazol-1-yl)benzonitrile (see WO 2005/095343A) (1.46 g, 8.63 mmol) was added a solution of 1M borane tetrahydrofuran complex in tetrahydrofuran (93 ml, 93 mmol), followed by heating to reflux for 16 hours. After completion of the reaction, methanol (14 ml) was added to the reaction solution, followed by concentration under reduced pressure. 6N Hydrochloric acid (265 ml) was added to the residue, followed by further heating to reflux for 3 hours. After this solution was concentrated under reduced pressure, a small amount of water was added. The resulting solution was adjusted to pH 11 with a 30% aqueous sodium hydroxide solution under ice cooling, followed by extraction with methylene chloride. The separated organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent; chloroform:methano1:28% aqueous ammonia=90:10:1 (V/V/V)), and fractions containing the desired compound were concentrated under reduced pressure to afford the title compound (1.24 g) as a pale yellow solid. (Yield: 83%) Mass spectrum (CI, m/z): 174 (M++1). 1H-NMR spectrum (CDCl3, ppm): 7.91 (dd, J=2.5, 0.5Hz, 1H), 7.72 (d, J=1.6Hz, 1H), 7.69-7.63 (m, 2H), 7.44-7.37 (m, 2H), 6.46 (dd, J=2.5, 1.6Hz, 1H), 3.91 (s, 2H).
83%
9-(a) 4-(Pyrazol-1-yl)beilzylamine To 4-(pyrazol-1-yl)benzonitrile (see WO 2005/095343A) (1.46 g, 8.63 mmol) was added a solution of 1M borage · tetrahydrofuran complex in tetrahydrofuran (93 ml, 93 mmol), followed by heating to reflux for 16 hours. After completion of the reaction, methanol (14 ml) was added to the reaction solution, followed by concentration under reduced pressure. 6N Hydrochloric acid (265 ml) was added to the residue, followed by further heating to reflux for 3 hours. After this solution was concentrated under reduced pressure, a small amount of water was added. The resulting solution was adjusted to pH 11 with a 30% aqueous sodium hydroxide solution under ice cooling, followed by extraction with methylene chloride. The separated organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent; chloroform:methanol:28% aqueous ammonia=90:10:1 (V/V/V)), and fractions containing the desired compound were concentrated under reduced pressure to afford the title compound (1.24 g) as a pale yellow solid. (Yield: 83%) Mass spectrum (CI, m/z): 174 (M++1). 1H-NMR spectrum (CDCl3, deltappm): 7.91 (dd, J=2.5, 0.5Hz, 1H), 7.72 (d, J=1.6Hz, 1H), 7.69-7.63 (m, 2H), 7.44-7.37 (m, 2H), 6.46 (dd, J=2.5, 1.6H, 1H), 3.91 (s, 2H).
52%
With palladium 10% on activated carbon; hydrogen; lithium hydroxide; In ethyl acetate; at 20℃; for 16h;
Step 2. (4-(lH-Pyrazol-l-yl)phenyl)methanamine (0849) [00270] A mixture of 4-(lH-pyrazol-l-yl)benzonitrile (15 g, 88.66 mmol), Raney nickel (10 g), palladium on carbon (10 wt. %, 1 g) and lithium hydroxide (1 g, 41.75 mmol) in EtOAc (200 mL) was evacuated and back-filled with hydrogen several times and then charged with hydrogen. The resulting mixture was stirred for 16 h at ambient temperature, then was filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with a gradient of 1-10% DCM/MeOH) resulting in 8 g (52%) of (4-(lH-pyrazol-l- yl)phenyl)methanamine. MS (ESI) m/z 174 [M+H]+.
With borane dimethyl sulphide; In tetrahydrofuran; at 20℃; for 16h;
Compound 11 is prepared from compound 10 by reacting (1 eq), Boc2O (1.5 eq), Na2CO3 (2 eq) in DCM at RT for 16 h. After work up and the NMR showed characteristic peaks and was used as such for the next step. In subsequent step compound II (1 eq), and 12 (1.1 eq) in presence of PdCl2(dppf) (0.05 eq), KOAc (3 eq), DMSO was heated to 90 C., 16 h. After column purification LCMS showed 50% of desired mass of compound 11. Key intermediate 14 was prepared was prepared by reacting (1 eq), BH3-DMS (3 eq), THF, RT, 16 h. After work up LCMS showed 96% purity of the compound 14.
With lithium aluminium tetrahydride; In tetrahydrofuran; at 20℃; for 3h;Inert atmosphere;
Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed tetrahydrofuran (15 mL). This was followed by dropwise addition of a 4-(1H-pyrazol-1-yl)benzonitrile (250 mg, 1.48 mmol, 1.00 equiv) in tetrahydrofuran (5 mL) with stirring at 0 C. To this was added LiAlH4 (337 mg, 8.87 mmol, 6.00 equiv). The resulting solution was stirred for 3 h at room temperature. The reaction was then quenched by the addition of NaOH (15%, aq). The resulting solution was extracted with 3*50 mL of dichloromethane and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The product was obtained as 0.251 mg of a white crude solid.
With tetra-n-butylammoniumfluoride hydrate; at 120℃;
General procedure: A mixture of the corresponding 4-substituted benzonitrile (1equiv, 0.43-1.34mmol), trimethylsilyl azide (1.5equiv) and tetrabutylammonium fluoride hydrate (0.5equiv) was heated at 120C for 1.5h-9h. The reaction mixture was dissolved in a small amount of warm toluene and chromatographed on silica gel eluting with hexane/ethyl acetate (9:1-1:1), ethyl acetate and ethyl acetate/formic acid (100:0.2) to obtain the desired product as a solid. Characterization of the compounds seeSupplementary material.
1-[6-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-7-methyl-8-(3-trifluoromethyl-phenyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-3-[3-(piperidin-4-ylamino)-propyl]-urea formic acid salt[ No CAS ]
{3-[6-[2-(4-cyanophenyl)-2H-pyrazol-3-yl]-7-methyl-8-(3-trifluoromethylphenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylcarbamoyl]propyl}methylcarbamic acid tert-butyl ester[ No CAS ]
Hexyl lithium (2.3 M in hexanes) (16.96 mL, 39.01 mmol) was added to a stirred solution of 2,2,6,6-tetramethyl-piperidine (6.85 mL, 40.63 mmol) in dry THF (15 mL) at -30C and the resulting suspension was stirred for 20 minutes. The suspension was allowed to warm to 10C to aid dissolution and was added, via cannula, to a solution of <strong>[25699-83-6]4-pyrazol-1-yl-benzonitrile</strong> (5.50 g, 32.51 mmol, preparedaccording to Bioorganic & Medicinal Chemistry Letters, 2006, 16(11), 2955-2959)THF (85 mL) at -78C, keeping the internal reaction temperature < -50C. The resulting reaction mixture was stirred at -75C for 4 h and tributyl tin(IV) chloride (9.08 mL, 33.49 mmol) was added keeping the internal reaction temperature < - 60C during addition. The reaction mixture was stirred at -60C for 1.5 h thenallowed to warm to RT. The resulting solution was quenched by addition of EtOAc (100 mL) and then washed with water (2 x 50 mL) followed by saturated brine (50 mL). The organic extract was dried (Na2504), filtered and concentrated in vacuo. The resultant residue was purified by flash chromatography, eluting with a gradient of 0-5% EtOAc in pentane to give the title compound as an amber oil thatsolidified on standing (10.11 g).LC-MS (Method 1): Rt = 5.36 mi mlz = 459 [M+H]
10.11 g
Step 3. 4-(5-Tributylstannanyl-pyrazol-1-yl)-benzonitrile (Intermediate 3) Hexyl lithium (2.3 M in hexanes) (16.96 mL, 39.01 mmol) was added to a stirred solution of 2,2,6,6-tetramethyl-piperidine (6.85 mL, 40.63 mmol) in dry THF (15 mL) at -30 C. and the resulting suspension was stirred for 20 minutes. The suspension was allowed to warm to 10 C. to aid dissolution and was added, via cannula, to a solution of <strong>[25699-83-6]4-pyrazol-1-yl-benzonitrile</strong> (5.50 g, 32.51 mmol, prepared according to Bioorganic & Medicinal Chemistry Letters, 2006, 16(11), 2955-2959, which is incorporated herein by reference in its entirety) in THF (85 mL) at -78 C., keeping the internal reaction temperature<-50 C. The resulting reaction mixture was stirred at -75 C. for 4 hrs and tributyl tin(IV) chloride (9.08 mL, 33.49 mmol) was added keeping the internal reaction temperature<-60 C. during addition. The reaction mixture was stirred at -60 C. for 1.5 rsh then allowed to warm to RT. The resulting solution was quenched by addition of EtOAc (100 mL) and then washed with water (2*50 mL) followed by saturated brine (50 mL). The organic extract was dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was purified by flash chromatography, eluting with a gradient of 0-5% EtOAc in pentane to give the title compound as an amber oil that solidified on standing (10.11 g). LC-MS (Method 1): Rt=5.36 min, m/z=459 [M+H]+
{3-[6-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylcarbamoyloxy]-propyl}-trimethyl-ammonium chloride[ No CAS ]
dimethyl 2-(5-cyano-2-(1H-pyrazol-1-yl)phenyl)malonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
53%
With silver hexafluoroantimonate; carbonyl(pentamethylcyclopentadienyl)cobalt diiodide; In 1,2-dichloro-ethane; at 100℃; for 48h;Inert atmosphere; Schlenk technique; Glovebox; Sealed tube;
General procedure: To a 15 mL dry Schlenk tube with a stirring bar, substrate 1 (0.3 mmol), 2 (0.36 mmol), and [Cp*Co(CO)I2] (5 mol%) were added under air. Then the tube was transferred into the glove box. AgSbF6 (10 mol%) was added. After moving out, DCE(2 mL) was injected into the tube under nitrogen. Then the tube was sealed and the mixture was stirred at 100 C for 12-48 hours. After cooling down, the solvents were removed under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate) to give the desired coupling product.
1-{2,6-bis[(E)-2-(butoxycarbonyl)ethenyl]benzamidophenyl}-1H-pyrazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
61%
With C10H14*C10H11O2(1-)*Ru(2+)*C10H6Br2N2; copper(II) acetate monohydrate; In ethanol; at 120℃;Inert atmosphere; Sealed tube;
General procedure: To set up the reaction, 100 mg (2 mol%) Cu(OAc)2·H2O,72 mg (0.5 mmol, 1 equiv.) of 1-phenylpyrazole and alkene(1.25 mmol, 2.5 equiv.) were taken in a cleaned and dried R.B. Then, 5 mol% of Ru(MesCO2)(L) (p-cymene) [L-2,2-bypyridine or 4,4-dibromobipyridine] was added to the R.B. under argon. Thereafter, the reaction was kept under reflux conditions at 100-120 C under a sealed condition. After cooling the reaction mixture at room temperature, 10 mL of water and 15 mL EtOAc were added; separated organic layer was washed with 10 mL of NaHCO3 solution several times and dried over anhydrous Na2SO4. The final crude was obtained by evaporating the solvent under reduced pressure. Finally, the products were purified by column chromatography using EtOAc: Hexane mixture.
With water; sodium hydroxide; In ethanol; at 105℃; for 16h;
A 250-mE round-bottom flask was charged with4-(1H-pyrazol-i-yl)benzonitrile (Step 1, 2 g, 11.82 mmol), ethanol (40 mE), water (40 mE) and sodium hydroxide (705 mg, 17.63 mmol). The resulting solution was stirred at 105 C. 16 hand then concentrated under vacuum. The residue was diluted with water (30 mE) and extracted with ethyl acetate (50 mE).12109] ThepHoftheaqueousphasewas adjustedto 5 with hydrochloric acid (6.0 M). The solids were collected by filtration, washed with water (10 mE) and dried in an oven to afford 4-(1H-pyrazol-i-yl)benzoic acid as a light yellow solid (Intermediate 2-60, 1 g, 45%). LCMS: (ESI)m/z 189 [M+H].
45%
With water; sodium hydroxide; In ethanol; at 105℃; for 16h;
A 250-mL round-bottom flask was charged with <strong>[25699-83-6]4-(1H-pyrazol-1-yl)benzonitrile</strong> (Step 1, 2 g, 11.82 mmol), ethanol (40 mL), water (40 mL) and sodium hydroxide (705 mg, 17.63 mmol,). The resulting solution was stirred at 105 C. 16 h and then concentrated under vacuum. The residue was diluted with water (30 mL) and extracted with ethyl acetate (50 mL). The pH of the aqueous phase was adjusted to 5 with hydrochloric acid (6.0 M). The solids were collected by filtration, washed with water (10 mL) and dried in an oven to afford 4-(1H-pyrazol-1-yl)benzoic acid as a light yellow solid (Intermediate 2-13, 1 g, 45%). LCMS: (ESI) m/z 189 [M+H].
2-(4-cyanophenyl)-2H-pyrazole-3-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
A mechanically stirred solution of 2,2,6,6-tetramethylpiperidine (42.5 mL, 35.57 g, 0.252 mol) in dry THF (100 mL) was cooled to -40 C. and n-butyllithium (2.5M solution in hexanes, 96 mL, 0.24 mol) was added at such a rate that the temperature remained below -30 C. The solution was then stirred for 40 min at around -30 C. and finally cooled to -73 C. A solution of <strong>[25699-83-6]4-pyrazol-1-yl-benzonitrile</strong> (33.84 g, 0.20 mmol) in anhydrous THF (250 mL) was added slowly, keeping the temperature below -65 C. A yellow precipitate formed and the resulting slurry was stirred between -65 C. and -73 C. for 60 min. Carbon dioxide pellets (approximately 100 g, 2.27 mol) were then added to the reaction mixture over 5 min, giving an initial exotherm to -50 C., followed by re-cooling to -70 C. The resulting slurry was allowed to warm slowly to +10 C. over 1.5 hr. The suspension was then poured into vigorously stirred 10% w/w aqueous citric acid solution and EtOAc (500 mL) and 1M hydrochloric acid (300 mL) added to give a two-phase solution with an aqueous layer at pH 3. The aqueous layer was separated and further extracted with EtOAc (2×200 mL). The combined organic extracts were washed with 1M hydrochloric acid (200 mL), saturated brine (100 mL), dried over Na2SO4, and the solvents evaporated to give the crude acid as a yellow solid. This was re-dissolved in 0.5M aqueous sodium hydroxide (600 mL) and the solution washed with DCM (2×150 mL) to give a colorless aqueous solution. This was acidified to pH 1 by the addition of conc. HCl, resulting in the formation of a white precipitate, which was collected by filtration, washed with water (50 mL) and dried in vacuo at 50 C./10 mbar over phosphorus pentoxide to give Intermediate A as a white solid; 34.42 g, 80% yield. LCMS (Method U2): Rt=1.16 min, m/z 214 [M+H]+
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