* 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] Journal of the Chemical Society, Chemical Communications, 1993, # 11, p. 921 - 922
2
[ 350-32-3 ]
[ 34667-88-4 ]
Yield
Reaction Conditions
Operation in experiment
95%
With Hexamethyldisiloxane; phosphorus pentoxide In 1,2-dichloro-ethane at 100℃; for 4 h; Heating / reflux
A mixture of 2-fluoro-4-nitrobenzamide (0.83 g, 4.6 mmol) and phosphorus pentoxide/hexamethyl disiloxane in 1,2-dichloroethane (20 mL) was heated under nitrogen at 100° C. for 4 hours. Upon cooling, the solution was poured onto a plug of silica gel and washed with hexane (200 mL) followed by 5percent methanol/chloroform (400 mL). The methanol/chloroform washes were collected and concentrated under reduced pressure to give 2-fluoro-4-nitrobenzonitrile (0.71 g, 95percent) as a beige solid. 1H NMR (DMSO-d6): δ 8.46 (dd, J=9.5, 2.0 Hz, 1H), 8.37-8.22 (m, 2H).
86.73%
With trichlorophosphate In water; N,N-dimethyl-formamide at 25℃; for 12 h;
To a solution of 15 5 (10g, 54.35mmol) in 63 DMF (100mL) was added 64 phosphorus oxychloride (35mL) dropwisely. And the mixture was stirred at 25°C for 12h. This mixture was treated with 65 ice water (300mL) for 30min. Then the mixture was extracted with EA, and the organic layer was washed with sat, dried with Na2SO4, filtered, and concentrated under reduced pressure to afford 66 product 6 (7.82g, 86.73percent) as a yellow solid. HRMS (ESI): m/z, calculated for C7H3FN2O2 167.0261 (M+H)+, found 167.0283.
Reference：
[1] Journal of Heterocyclic Chemistry, 1997, vol. 34, # 4, p. 1163 - 1172
[2] Patent: US6344459, 2002, B1, . Location in patent: Page column 70-71
[3] European Journal of Medicinal Chemistry, 2018, vol. 143, p. 1325 - 1344
[4] Journal of Medicinal Chemistry, 2001, vol. 44, # 23, p. 3856 - 3871
3
[ 403-24-7 ]
[ 34667-88-4 ]
Reference：
[1] Journal of Medicinal Chemistry, 2001, vol. 44, # 23, p. 3856 - 3871
[2] Journal of Heterocyclic Chemistry, 1997, vol. 34, # 4, p. 1163 - 1172
[3] Patent: US6369227, 2002, B1, . Location in patent: Page column 29
[4] European Journal of Medicinal Chemistry, 2018, vol. 143, p. 1325 - 1344
4
[ 1427-07-2 ]
[ 34667-88-4 ]
Reference：
[1] Journal of Medicinal Chemistry, 2001, vol. 44, # 23, p. 3856 - 3871
[2] Journal of Heterocyclic Chemistry, 1997, vol. 34, # 4, p. 1163 - 1172
[3] European Journal of Medicinal Chemistry, 2018, vol. 143, p. 1325 - 1344
5
[ 403-23-6 ]
[ 34667-88-4 ]
Reference：
[1] Journal of Medicinal Chemistry, 2001, vol. 44, # 23, p. 3856 - 3871
[2] European Journal of Medicinal Chemistry, 2018, vol. 143, p. 1325 - 1344
6
[ 4110-33-2 ]
[ 3939-09-1 ]
[ 34667-88-4 ]
Reference：
[1] Journal of the Chemical Society, Chemical Communications, 1993, # 11, p. 921 - 922
7
[ 4110-33-2 ]
[ 34667-88-4 ]
Reference：
[1] Molecular crystals and liquid crystals, 1984, vol. 109, # 2-4, p. 169 - 178
8
[ 34667-88-4 ]
[ 86776-51-4 ]
Reference：
[1] Molecular crystals and liquid crystals, 1984, vol. 109, # 2-4, p. 169 - 178
9
[ 34667-88-4 ]
[ 82380-18-5 ]
Reference：
[1] Molecular crystals and liquid crystals, 1984, vol. 109, # 2-4, p. 169 - 178
10
[ 34667-88-4 ]
[ 53312-80-4 ]
Yield
Reaction Conditions
Operation in experiment
100%
Stage #1: With tin(II) chloride dihdyrate In ethyl acetate at 25℃; Stage #2: With potassium carbonate In ethyl acetate at 20℃; for 4 h;
Step A. Preparation of 4-amino-2-fluorobenzonitrile [00175] The mixture of 2-fluoro-4-nitrobenzonitrile (8.31 g, 50 mmol) and tin (II) chloride dihydrate (56.4 g, 250 mmol) in 250 mL of EtOAc was stirred at 25 °C overnight. LCMS (78109-084) indicated the reaction was completed. 25 mL of sat. K2CO3 was added to the reaction. The resulting mixture was stirred at room temperature for 2h and was followed by addition of lOOg of solid K2CO3. The mixture was stirred at room temperature for 2 hours. Solid was removed by filtration and further washed with EtOAc (50 mLx2). The filtrate was concentrated to yield 6.81 g (100percent) of 4-amino-2-fluorobenzonitrile as an off white solid. 1H NMR (400 MHz, CDCl3) δ ppm 4.30 (s, 2 H) 6.29 - 6.51 (m, 2 H) 7.27 - 7.40 (m, 1 H). MS (ESI) 137 (M+H).
96%
With iron; acetic acid In ethyl acetate for 2 h; Heating / reflux
A mixture of 4-nitro-2-fluorobenzonitrile (1.83 g, 5 mmol) and iron (1.68 g, 6 mmol) in a mixture of acetic acid (40 ml) and ethyl acetate (40 ml) was refluxed for 2 hours. The solid was filtered off and the filtrate was washed with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, concentrated and chromatographed (dichloromethane:acetone, 95:5) to yield 4- amino-2-fluorobenzonitrile (54a) (0.653 g, 4.8 mmol, 96percent).
96%
With hydrogen In ethanol; ethyl acetate for 1 h;
To 2-fluoro-4-nitrobenzonitrile (8.5 g, 51.2 mmol) was added 10percent palladium on carbon (0.5 g) and EtOAc (42.5 mL) and EtOH (170 mL) and the reaction was hydrogenated at 50 psi for 1 h. The reaction was filtered through Celite and the reaction mixture was concentrated to afford 6.7 g (96percent yield) as a light brown solid. LCMS m/z 135.1[M + H]+.
70%
With palladium 10% on activated carbon; hydrogen In methanol for 3 h;
Reference Example 114 4-Amino-2-fluorobenzonitrile To a solution of 2-fluoro-4-nitrobenzonitrile (2.51 g) in methanol (125 mL) was added 10percent palladium carbon (50percent containing water, 237 mg), and the mixture was stirred under a hydrogen atmosphere for 3 hr. The reaction mixture was filtrated, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=1:1) to give the title compound as a pale-yellow solid (yield 1.43 g, 70percent). 1H-NMR (CDCl3)δ: 4.31 (2H, brs), 6.37-6.45 (2H, m), 7.31-7.36 (1H, m).
Reference：
[1] Journal of Medicinal Chemistry, 2001, vol. 44, # 23, p. 3856 - 3871
[2] Patent: WO2010/9183, 2010, A1, . Location in patent: Page/Page column 84
[3] Patent: WO2006/124118, 2006, A1, . Location in patent: Page/Page column 75
[4] Patent: WO2008/157162, 2008, A1, . Location in patent: Page/Page column 145
[5] Patent: WO2006/36024, 2006, A1, . Location in patent: Page/Page column 153
[6] Patent: EP2336107, 2015, B1, . Location in patent: Paragraph 0288
[7] Molecular crystals and liquid crystals, 1984, vol. 109, # 2-4, p. 169 - 178
[8] Patent: EP1803709, 2007, A1,
[9] Patent: US2008/81802, 2008, A1, . Location in patent: Page/Page column 11
[10] Patent: WO2007/3960, 2007, A1, . Location in patent: Page/Page column 26-27
[11] Patent: WO2013/55984, 2013, A1, . Location in patent: Paragraph 00324
[12] European Journal of Medicinal Chemistry, 2018, vol. 143, p. 1325 - 1344
11
[ 34667-88-4 ]
[ 1027259-01-3 ]
Reference：
[1] Organic Process Research and Development, 2011, vol. 15, # 3, p. 565 - 569
[2] Patent: WO2007/95124, 2007, A2, . Location in patent: Page/Page column 57-58
Step A. Preparation of 4-amino-2-fluorobenzonitrile [00175] The mixture of <strong>[34667-88-4]2-fluoro-4-nitrobenzonitrile</strong> (8.31 g, 50 mmol) and tin (II) chloride dihydrate (56.4 g, 250 mmol) in 250 mL of EtOAc was stirred at 25 °C overnight. LCMS (78109-084) indicated the reaction was completed. 25 mL of sat. K2CO3 was added to the reaction. The resulting mixture was stirred at room temperature for 2h and was followed by addition of lOOg of solid K2CO3. The mixture was stirred at room temperature for 2 hours. Solid was removed by filtration and further washed with EtOAc (50 mLx2). The filtrate was concentrated to yield 6.81 g (100percent) of 4-amino-2-fluorobenzonitrile as an off white solid. 1H NMR (400 MHz, CDCl3) delta ppm 4.30 (s, 2 H) 6.29 - 6.51 (m, 2 H) 7.27 - 7.40 (m, 1 H). MS (ESI) 137 (M+H).
96%
With iron; acetic acid; In ethyl acetate; for 2.0h;Heating / reflux;
A mixture of <strong>[34667-88-4]4-nitro-2-fluorobenzonitrile</strong> (1.83 g, 5 mmol) and iron (1.68 g, 6 mmol) in a mixture of acetic acid (40 ml) and ethyl acetate (40 ml) was refluxed for 2 hours. The solid was filtered off and the filtrate was washed with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, concentrated and chromatographed (dichloromethane:acetone, 95:5) to yield 4- amino-2-fluorobenzonitrile (54a) (0.653 g, 4.8 mmol, 96percent).
96%
With hydrogen;palladium 10% on activated carbon; In ethanol; ethyl acetate; under 2585.81 Torr; for 1.0h;
To <strong>[34667-88-4]2-fluoro-4-nitrobenzonitrile</strong> (8.5 g, 51.2 mmol) was added 10percent palladium on carbon (0.5 g) and EtOAc (42.5 mL) and EtOH (170 mL) and the reaction was hydrogenated at 50 psi for 1 h. The reaction was filtered through Celite and the reaction mixture was concentrated to afford 6.7 g (96percent yield) as a light brown solid. LCMS m/z 135.1[M + H]+.
70%
With palladium 10% on activated carbon; hydrogen; In methanol; for 3.0h;
Reference Example 114 4-Amino-2-fluorobenzonitrile To a solution of <strong>[34667-88-4]2-fluoro-4-nitrobenzonitrile</strong> (2.51 g) in methanol (125 mL) was added 10percent palladium carbon (50percent containing water, 237 mg), and the mixture was stirred under a hydrogen atmosphere for 3 hr. The reaction mixture was filtrated, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=1:1) to give the title compound as a pale-yellow solid (yield 1.43 g, 70percent). 1H-NMR (CDCl3)delta: 4.31 (2H, brs), 6.37-6.45 (2H, m), 7.31-7.36 (1H, m).
palladium-carbon; In methanol;
Reference Example 114 4-Amino-2-fluorobenzonitrile To a solution of <strong>[34667-88-4]2-fluoro-4-nitrobenzonitrile</strong> (2.51 g) in methanol (125 mL) was added 10percent palladium carbon (50percent containing water, 237 mg), and the mixture was stirred under a hydrogen atmosphere for 3 hr. The reaction mixture was filtrated, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=1:1) to give the title compound as a pale-yellow solid (yield 1.43 g, 70percent). 1H-NMR (CDCl3)delta: 4.31 (2H, brs), 6.37-6.45 (2H, m), 7.31-7.36 (1H, m).
With hydrogen;5%-palladium/activated carbon; In methanol; at 20℃; under 1500.15 Torr; for 2.0h;
A solution of <strong>[34667-88-4]2-fluoro-4-nitrobenzonitrile</strong> (5 g, 30 mmol) in 300 mL methanol is stirred in a hydrogenation reactor with palladium (5percent on activated charcoal, 400 mg) for 2 h at RT and 2 bar hydrogen pressure. The reaction mixture is filtered and evaporated down. Yield: 4 g.
With iron; ammonium chloride; In ethanol; water; acetic acid; for 5.0h;Heating / reflux;
Preparation 15: 4-Amino-2-fluorobenzonitrile: Saturated aqueous ammonium chloride (50 mL) and acetic acid (3 mL) were added to a stirred solution of <strong>[34667-88-4]2-fluoro-4-nitrobenzonitrile</strong> (50.0 g, 301 mmol) in EtOH (600 mL) followed by iron powder (2 g, 35.7 mmol). The mixture was heated under reflux and more iron powder (123 g, 2.20 mol) added portionwise over a 4 h period. The reaction heated for a further 1 h then allowed to cool to rt before being filtered through a celite plug. The filtrate was evaporated to dryness and the residual material partitioned between EtOAc (500 mL) and water (200 mL). The organic phase was washed with water (50 mL) and brine (100 mL), then dried (MgSO4) and evaporated to afford the title compound: deltaH (ddelta-DMSO) 6.41-6.46 (2H, m), 6.52 (2H, br s), 7.37- 7.41 (IH, m).
With palladium 10% on activated carbon; hydrogen; In ethanol; acetonitrile; under 2585.81 Torr; for 1.0h;
<strong>[34667-88-4]2-fluoro-4-nitrobenzonitrile</strong> (0.125 g, 0.751 mmol) was hydrogenated at 50 psi in the presence of 10percent Pd/C (40 mg) in EtOH/EtOAc (15mL) for 1 h. Filtered through Celite® and concentrated to an orange solid that was carried onto next step. MS (ESI) m/z: 137 (M+H)+.
With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃; for 12.0h;
A solution of 66 6 (10.0g, 60.24mmol) in 69 methanol (100mL) was hydrogenated with 10percent 70 Pd/C (1.0g) under hydrogen atmosphere at room temperature for 12h. After filtration, the filtrate was evaporated to give the corresponding product. It was obtained as a gray 16 solid in 88percent yield. 7 was ready for the next step without the further purification. HRMS (ESI): m/z, calculated for C7H5FN2 137.0487 (M+H)+, found 137.0452.
With potassium fluoride; In methanol; acetonitrile;
Production Example 6-1 2-(6-bromo-2-naphthyloxy)-4-nitrobenzonitrile After heating to reflux <strong>[34667-88-4]2-fluoro-4-nitrobenzonitrile</strong> (1 g), 6-bromo-2-naphthol (1.41 g), potassium fluoride/alumina (0.7 g) and 18-crown-6 (0.16 g) in acetonitrile, the mixture was reacted for 12 hours. It was then cooled to room temperature, the insoluble portion was filtered using celite, the ethyl acetate layer was washed with water and saturated saline and then dried over magnesium sulfate, and the solvent was distilled off. Methanol was added to the residue for crystallization to obtain 1.43 g of 2-(6-bromo-2-naphthyloxy)-4-nitrobenzonitrile. 1H-NMR (CDCl3) delta:7.31 (1H, dd, J=2.4, 8.8 Hz), 7.54 (1H, d, J=2.0 Hz), 7.62-7.70 (3H, m), 7.88 (1H, s), 7.90 (1H, s), 8.01 (1H, dd, J=2.0, 8.4 Hz), 8.08 (1H, s).
With hydrazine hydrate; In ethanol; at 80℃; for 12.0h;
To a solution of <strong>[34667-88-4]2-fluoro-4-nitrobenzonitrile</strong>, 273 (5 g, 30.1 mmols) in ethanol (50 ml) was added hydrazine hydrate (15 ml). The resulting solution was heated at 80 C for 12 h. The reaction mixture was poured into water. The solid formed, consistent with the title compound was filtered and dried. Yield 2.1 g (39 %). 1 H NMR (400 MHz, DMSO) d 8.13 (d, J = 1.9 Hz, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.72 (dd, J = 8.8, 2.0 Hz, 1H).
With hydrazine; In water; isopropyl alcohol; at 80℃; for 12.0h;
Example 69; Synthesis of 2-(pyridin-2-ylamino)-lH-benzimidazole-5-carboxylic acid (3 -amino- IH- indazol-6-yl)-amideTo a solution of <strong>[34667-88-4]2-fluoro-4-nitrobenzonitrile</strong> (10 mmol) in isopropanol (30 mL) was added aqueous hydrazine (4 mL). The resulting solution was heated at 800C for 12 h. The reaction mixture was then concentrated, water (30 mL) was added, and the solution was extracted with ethyl acetate (2x25 mL). The combined organics were washed with water (30 mL) and brine (30 mL) and dried over anhydrous sodium sulfate. The volatiles were removed in vacuo yielding 3-amino-6-nitroindazole as an orange solid, which was utilized for further transformation without further purification.The nitro compound from above was hydrogenated, following general procedure F, to yield 3,6-diaminoindazole.2-Isothiocyanatopyridine (4 mmol), prepared from 2-aminopyridine employing general procedure A, was reacted with methyl 3,4-diaminobenzoate as described in general procedure B to afford 2-(pyridin-2-ylamino)-lH-benzirnidazole-S-carboxylic acid methyl ester. This ester was hydrolyzed, following general procedure C, to obtain 2-(pyridin-2- ylamino)-lH-benzimidazole-5-carboxylic acid.The cafboxylic acid (0.5 mmol) from above was coupled with aforementioned 3,6- diaminoindazole (0.5 mmol) using HBTU as described in general procedure D to afford 2- <n="60"/>(pyridin-2-ylamino)-lH-benzimidazole-5-carboxylic acid (3-amino-lH-indazol-6-yl)-amide. MS: m/z 385 (M+H)+.
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
