* 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] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 3, p. 561 - 566
[2] Journal of Organic Chemistry, 1953, vol. 18, p. 345,356
2
[ 99584-85-7 ]
[ 96784-54-2 ]
Yield
Reaction Conditions
Operation in experiment
70%
With trichlorophosphate In toluene for 24 h; Reflux
To a stirred solution of 3-methyl-4-nitrobenzamide (5g, 28mmol) in 300 ml of toluene was added POCl3 (22g, 140 mmol). After the addition, the mixture was refluxed for 24h. Then, the reaction mixture was poured into ice-water and extracted with ethyl acetate three times. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by recrystallization with ethanol to give the title compound (3.2g, 70percent yield).
93%
With pyridine; hydrogenchloride; trifluoroacetic anhydride In dichloromethane
B. To a stirred, 0° C. solution of 3-methyl-4-nitrobenzamide (30 g, 0.169 mol) in dichloromethane (900 mL) under nitrogen was added pyridine (29.5 g, 0.373 mol), then dropwise trifluoroacetic anhydride (42.7 g, 0.203 mol) in dichloromethane (90 mL). The reaction mixture was stirred at 0° C. for one hour and then 1N HCl was added. The organic phase was separated, dried (Na2 SO4) and concentrated under reduced pressure to afford 25.5 g (93percent) of the 3-methyl-4-nitrobenzonitrile as a light yellow solid; m.p. 69°-71° C.
Reference：
[1] Patent: WO2014/172871, 2014, A1, . Location in patent: Page/Page column 88
[2] Justus Liebigs Annalen der Chemie, 1867, vol. 144, p. 182
[3] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1973, p. 2940 - 2948
[4] Patent: US5034410, 1991, A,
3
[ 3113-71-1 ]
[ 70-55-3 ]
[ 96784-54-2 ]
Yield
Reaction Conditions
Operation in experiment
23 %
With pyridine; phosphorus pentachloride; trichlorophosphate In dichloromethane
Part A Preparation of the intermediate 4-nitro-3-tolunitrile, represented by the formula: A mixture of PCl5 (200 g, 0.96 mole) and p-toluene sulfonamide (90 g, 0.52 mole) was treated with 3-methyl-4-nitrobenzoic acid (82 g, 0.44 mole). The reaction was stirred at room temperature for 1 hour at which time it was heated to 140°C and the POCl3 (150 ml) distilled from the mixture. The reaction was cooled to 5°C, pyridine (200 ml) was carefully added and the mixture allowed to stand overnight. The reaction was carefully diluted to 1 L with H2O and the mixture stirred for 3 hours. The brown solid was filtered, washed with H2O and triturated with 5 N aqueous NaOH. The remaining solid was filtered, washed with H2O and dried to afford 60.0 g of a powder. The solid was stirred in 1200 ml CH2Cl2 and filtered. The supernatant was evaporated in vacuo and the residue recrystallized from EtOH to give 35.9 g (23 percent) of 4-nitro-3-tolunitrile. MS(FD), m/e 162 (M+).
Reference：
[1] Patent: EP655439, 1995, A2,
4
[ 3113-71-1 ]
[ 96784-54-2 ]
Reference：
[1] Journal of Medicinal Chemistry, 1997, vol. 40, # 18, p. 2843 - 2857
[2] Justus Liebigs Annalen der Chemie, 1867, vol. 144, p. 182
[3] Patent: WO2014/172871, 2014, A1,
5
[ 35675-46-8 ]
[ 96784-54-2 ]
Reference：
[1] Patent: WO2014/172871, 2014, A1,
6
[ 620-22-4 ]
[ 96784-54-2 ]
[ 64113-86-6 ]
[ 124289-22-1 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2003, vol. 1, # 13, p. 2326 - 2335
7
[ 620-22-4 ]
[ 96784-54-2 ]
[ 64113-86-6 ]
[ 124289-22-1 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2003, vol. 1, # 13, p. 2326 - 2335
With palladium 10% on activated carbon; hydrogen In tetrahydrofuran; methanol at 20℃;
To a stirring 100 mL solution of THF at room temperature, added 9.89 g (61 mmol, 1 eq) of the benzonitrile. Then added 1 g palladium over 10percent carbon. Then added 25 mL of methanol. The system was then put under 50 psi of pressure in a hydrogenator. After no more hydrogen consumption was observed, the reaction was stopped and filtered over celite. Performed column chromatography using 1:1 hexane:dichloromethane as the mobile phase. Obtained 7.5 g of a beige powder. Yield was 93percent. 1H-NMR (DMSO): δ 2.27 (3H, s), 6.06 (2H, s), 6.41 (1H, d), 6.46 (1H, s), 7.30 (1H, d).
92%
With hydrogenchloride; tin(ll) chloride In water; acetic acid for 3 h;
4-Cyano-2-methylaniline was synthesized as previously described (J. Med. Chem. (1991), 34, 3295): To a solution of 3-methyl-4-nitrobenzonitrile (2.0 g, 12.34 mmol) in acetic acid (20 L) was added dropwise a solution of SnCl2 (9.6 g, 49.38 mmol) in conc. HCl (20 mL). After stirring for 3 h, the mixture was added carefully to a saturated NH4OH solution (120 mL) at 0° C. The resulting mixture was extracted with EtOAc (4.x.30 mL). The combined organic layers were sequentially washed with H2O (30 mL) and a saturated NaCl solution (30 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by flash chromatography (10percent EtOAc/hex) to give 4-cyano-2-methylaniline as a white solid (1.48 g, 92percent): TLC (30percent EtOAc in hexane) Rf0.23. This material was used without further purification
92%
at 20℃; for 14.1667 h;
4-Amino-3-methyl-benzonitrile: To a solution of 3-methyl-4-nitro-benzonitrile (20 g, 0.123 mol) in HOAc (200 mL) was added iron powder (17.55 g, 0.309 mol). After 10 min, the reaction was exothermic and turned to dark color. The reaction mixture was allowed to stir at room temperature for 14 h and then diluted with EtOAc (200 mL). The brown precipitate was filtered through a pad of celite and the filtercake was rinsed with EtOAc. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography (40percent EtOAc/hexane) to yield the title compound (15.3 g, 92percent). 1H NMR (300 MHz, CDCl3) δ 7.30-7.34 (2H, m), 6.64 (1H, d, J=8.7 Hz), 2.16 (3H, s). LCMS (M+H)+m/z 133 (t=0.93 min).
92%
at 20℃; for 14 h;
To a solution of 3-methyl-4-nitro-benzonitrile (20 g, 0.123 mol) in HOAc (200 mL) was added iron powder (17.55 g, 0.309 mol). After 10 min, the reaction was exothermic and turned to dark color. The reaction mixture was allowed to stir at room temperature for 14 h and then diluted with EtOAc (200 mL). The brown precipitate was filtered through a pad of celite and the filtercake was rinsed with EtOAc. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography (40percent EtOAc/hexane) to yield the title compound (15.3 g, 92percent). 1H NMR (300 MHz, CDCl3) δ 7.30-7.34 (2H, m), 6.64 (1H, d, J=8.7 Hz), 2.16 (3H, s). LCMS (M+H)+ m/z 133 (t=0.93 min).
61%
With ammonium hydroxide In hydrogenchloride; acetic acid
C. To a stirred, 25° C. solution of 3-methyl-4-nitrobenzonitrile (24 g, 0.148 mol) in acetic acid (250 mL) under nitrogen was added dropwise a solution of SnCl2.2H2 O (133.57 g., 0.592 mol) in concentrated HCl (250 mL). After stirring for 3 hours, the reaction mixture was added carefully to excess cold ammonium hydroxide. The reaction mixture was extracted several times with ethyl ether. The organic extracts were then combined, dried (Na2 SO4) and evaporated under reduced pressure to afford 12 g (61percent) of the title compound, 4-cyano-2-methylaniline, as a white solid; m.p. 64°-66° C.
Reference：
[1] Journal of Medicinal Chemistry, 1999, vol. 42, # 18, p. 3572 - 3587
[2] Patent: US2017/44373, 2017, A1, . Location in patent: Paragraph 0227; 0228
[3] Patent: US6353006, 2002, B1, . Location in patent: Page column 23
[4] Patent: US2005/54655, 2005, A1, . Location in patent: Page/Page column 15
[5] Patent: US2004/44203, 2004, A1, . Location in patent: Page 27
[6] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 11, p. 3072 - 3076
[7] Journal of Medicinal Chemistry, 1991, vol. 34, # 11, p. 3295 - 3301
[8] Chemische Berichte, 1919, vol. 52, p. 1083
[9] Patent: US6034093, 2000, A,
[10] Patent: US6034093, 2000, A,
[11] Patent: US5731315, 1998, A,
[12] Patent: US5034410, 1991, A,
10
[ 64-17-5 ]
[ 96784-54-2 ]
[ 78881-21-7 ]
Reference：
[1] Patent: US2012/196824, 2012, A1,
11
[ 620-22-4 ]
[ 96784-54-2 ]
[ 64113-86-6 ]
[ 124289-22-1 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2003, vol. 1, # 13, p. 2326 - 2335
12
[ 96784-54-2 ]
[ 90178-82-8 ]
Reference：
[1] Organic Process Research and Development, 2018, vol. 22, # 11, p. 1534 - 1540
With trichlorophosphate; In toluene; for 24h;Reflux;
To a stirred solution of 3-methyl-4-nitrobenzamide (5g, 28mmol) in 300 ml of toluene was added POCl3 (22g, 140 mmol). After the addition, the mixture was refluxed for 24h. Then, the reaction mixture was poured into ice-water and extracted with ethyl acetate three times. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by recrystallization with ethanol to give the title compound (3.2g, 70% yield).
25.5 g (93%)
With pyridine; hydrogenchloride; trifluoroacetic anhydride; In dichloromethane;
B. To a stirred, 0 C. solution of 3-methyl-4-nitrobenzamide (30 g, 0.169 mol) in dichloromethane (900 mL) under nitrogen was added pyridine (29.5 g, 0.373 mol), then dropwise trifluoroacetic anhydride (42.7 g, 0.203 mol) in dichloromethane (90 mL). The reaction mixture was stirred at 0 C. for one hour and then 1N HCl was added. The organic phase was separated, dried (Na2 SO4) and concentrated under reduced pressure to afford 25.5 g (93%) of the 3-methyl-4-nitrobenzonitrile as a light yellow solid; m.p. 69-71 C.
With palladium 10% on activated carbon; hydrogen; In tetrahydrofuran; methanol; at 20℃; under 2585.81 Torr;
To a stirring 100 mL solution of THF at room temperature, added 9.89 g (61 mmol, 1 eq) of the benzonitrile. Then added 1 g palladium over 10% carbon. Then added 25 mL of methanol. The system was then put under 50 psi of pressure in a hydrogenator. After no more hydrogen consumption was observed, the reaction was stopped and filtered over celite. Performed column chromatography using 1:1 hexane:dichloromethane as the mobile phase. Obtained 7.5 g of a beige powder. Yield was 93%. 1H-NMR (DMSO): delta 2.27 (3H, s), 6.06 (2H, s), 6.41 (1H, d), 6.46 (1H, s), 7.30 (1H, d).
92%
With hydrogenchloride; tin(ll) chloride; In water; acetic acid; for 3h;
4-Cyano-2-methylaniline was synthesized as previously described (J. Med. Chem. (1991), 34, 3295): To a solution of 3-methyl-4-nitrobenzonitrile (2.0 g, 12.34 mmol) in acetic acid (20 L) was added dropwise a solution of SnCl2 (9.6 g, 49.38 mmol) in conc. HCl (20 mL). After stirring for 3 h, the mixture was added carefully to a saturated NH4OH solution (120 mL) at 0 C. The resulting mixture was extracted with EtOAc (4×30 mL). The combined organic layers were sequentially washed with H2O (30 mL) and a saturated NaCl solution (30 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by flash chromatography (10% EtOAc/hex) to give 4-cyano-2-methylaniline as a white solid (1.48 g, 92%): TLC (30% EtOAc in hexane) Rf0.23. This material was used without further purification
92%
With iron; acetic acid; at 20℃; for 14.1667h;
4-Amino-3-methyl-benzonitrile: To a solution of 3-methyl-4-nitro-benzonitrile (20 g, 0.123 mol) in HOAc (200 mL) was added iron powder (17.55 g, 0.309 mol). After 10 min, the reaction was exothermic and turned to dark color. The reaction mixture was allowed to stir at room temperature for 14 h and then diluted with EtOAc (200 mL). The brown precipitate was filtered through a pad of celite and the filtercake was rinsed with EtOAc. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography (40% EtOAc/hexane) to yield the title compound (15.3 g, 92%). 1H NMR (300 MHz, CDCl3) delta 7.30-7.34 (2H, m), 6.64 (1H, d, J=8.7 Hz), 2.16 (3H, s). LCMS (M+H)+m/z 133 (t=0.93 min).
92%
With iron; acetic acid; at 20℃; for 14h;
To a solution of 3-methyl-4-nitro-benzonitrile (20 g, 0.123 mol) in HOAc (200 mL) was added iron powder (17.55 g, 0.309 mol). After 10 min, the reaction was exothermic and turned to dark color. The reaction mixture was allowed to stir at room temperature for 14 h and then diluted with EtOAc (200 mL). The brown precipitate was filtered through a pad of celite and the filtercake was rinsed with EtOAc. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography (40% EtOAc/hexane) to yield the title compound (15.3 g, 92%). 1H NMR (300 MHz, CDCl3) delta 7.30-7.34 (2H, m), 6.64 (1H, d, J=8.7 Hz), 2.16 (3H, s). LCMS (M+H)+ m/z 133 (t=0.93 min).
92.2%
With ammonium chloride; zinc; In methanol; at 15℃; for 16h;
To a solution of 3-methyl-4-nitro-benzonitrile (3 g, 18.50 mmol, 1 eq) in MeOH (30 mL) was added Zn (12.10 g, 185.00 mmol, 10 eq) and NH4Cl (9.90 g, 185.00 mmol, 10 eq). The mixture was stirred at 15 C. for 16 h. The mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was diluted with EtOAc (50 mL), washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield crude 4-amino-3-methyl-benzonitrile (2.3 g, 17.05 mmol, 92.2% yield, 98.0% purity) as a white solid which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) delta ppm 7.32 (dd, J=2.9, 3.9 Hz, 2H), 6.68-6.61 (m, 1H), 4.24-3.90 (m, 2H), 2.16 (s, 3H); ES-LCMS m/z 155.1 [M+Na]+.
With stannous chloride; sodium hydrogencarbonate; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; ethanol;
A. 4-Amino-3-methyl benzonitrile To a solution of 3-methyl-4-nitrobenzonitrile (2.0 g, 12.3 mmol) in 100 mL of EtOH is added SnCl2 (13.9 g, 61.7 mmol). The resulting solution is heated at reflux. After 2 hours, the solution is cooled to ambient temperatures. The solution is poured into 150 mL of ice water. The pH of the solution is adjusted to >7 with a solution of saturated NaHCO3. The solution is diluted with EtOAc and the resulting mixture is filtered through Celite. The filtered solution is separated. The organic layer is dried over MgSO4, filtered and concentrated to give the title compound (1.57 g, 8.7 mmol) as an off-white solid. 1 H NMR (CDCl3, 300 MHz) delta 7.30 (m, 2H), 6.63 (d, 1H), 4.10 (bs, 2H), 2.15 (m, 2H). EI MS, [M]+ =132.
With stannous chloride; sodium hydrogencarbonate; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; ethanol;
A. 4-Amino-3-methylbenzonitrile. To a solution of 3-methyl-4-nitrobenzonitrile (2 g, 12.3 mmol) in 100 mL of EtOH is added SnCl2 (13.9 g, 61.7 mmol). The resulting solution is refluxed. After 2 hours, the solution is cooled to ambient temperatures. The solution is poured into 150 mL of ice water. The pH of the solution is adjusted to >7 with a solution of saturated NaHCO3. The solution is diluted with EtOAc and the resulting mixture is filtered through Celite. The filtered solution is separated. The organic layer is dried over MgSO4, filtered and concentrated to give the title compound (1.57 g, 8.7 mmol) as an off-white solid. 1 H NMR (CDCl3, 300 MHz) delta7.30 (m, 2H), 6.63 (d, 1H), 4.10 (bs, 2H), 2.15 (m, 2H). EI MS, [M]+ =132.
With stannous chloride; sodium hydrogencarbonate; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; ethanol;
A. 4-Amino-3-methyl benzonitrile To a solution of 3-methyl-4-nitrobenzonitrile (2.0 g, 12.3 mmol) in 100 mL of EtOH is added SnCl2 (13.9 g, 61.7 mmol). The resulting solution is heated at reflux. After 2 h, the solution is cooled to ambient temperatures. The solution is poured into 150 mL of ice water. The pH of the solution is adjusted to >7 with a solution of saturated NaHCO3. The solution is diluted with EtOAc and the resulting mixture is filtered through Celite. The filtered solution is separated. The organic layer is dried over MgSO4, filtered and concentrated to give the title compound (1.57 g, 8.7 mmol) as an off-white solid. 1 H NMR (CDCl3, 300 MHz) delta7.30 (m, 2H), 6.63 (d, 1H), 4.10 (bs, 2H), 2.15 (m, 2H). EI MS, [M]+ =132.
12 g (61%)
With ammonium hydroxide; In hydrogenchloride; acetic acid;
C. To a stirred, 25 C. solution of 3-methyl-4-nitrobenzonitrile (24 g, 0.148 mol) in acetic acid (250 mL) under nitrogen was added dropwise a solution of SnCl2.2H2 O (133.57 g., 0.592 mol) in concentrated HCl (250 mL). After stirring for 3 hours, the reaction mixture was added carefully to excess cold ammonium hydroxide. The reaction mixture was extracted several times with ethyl ether. The organic extracts were then combined, dried (Na2 SO4) and evaporated under reduced pressure to afford 12 g (61%) of the title compound, 4-cyano-2-methylaniline, as a white solid; m.p. 64-66 C.
(+/-)-2-{4-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-7-methyl-3H-benzimidazole-5-carboxylic acid methylamide[ No CAS ]
(+/-)-2-{4-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-7-methyl-3H-benzimidazole-5-carboxylic acid dimethylamide[ No CAS ]
(+/-)-2-{4-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-7-methyl-3H-benzimidazole-5-carboxylic acid cyclopropylamide[ No CAS ]
(+/-)-2-{4-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-7-methyl-3H-benzimidazole-5-carboxylic acid cyclopentylamide[ No CAS ]
(+/-)-2-{4-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-7-methyl-3H-benzimidazole-5-carboxylic acid cyclohexylamide[ No CAS ]
(+/-)-4-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-3-[6-(4,4-dimethyl-4,5-dihydro-1H-imidazol-2-yl)-4-methyl-1H-benzimidazol-2yl]-1H-pyridin-2-one[ No CAS ]
4-(4-[5-(<i>N</i>-hydroxycarbamimidoyl)-1-methyl-1<i>H</i>-indol-2-ylmethyl]-methanesulfonyl-amino}-phenoxy)-piperidine-1-carboxylic acid <i>tert</i>-butyl ester[ No CAS ]
With iron; acetic acid; In water; at 90 - 95℃; for 4.5h;
3-METHYL-4-NITROBENZONITRILE (1.0 g, 6 mmol) was dissolved in acetic acid (15 ml). Water (3.75 ml) was added and the mixture was heated between 90-95 C. Iron powder (2.5 g) was added during 1.5 hours and the resulting mixture was heated for 1 hour. Other portion of water (3.75 ml) was added and the heating was continued for additional 2 hours. The solution was allowed to cool to room temperature and the mixture was diluted with water (100 ml) and extracted with ethyl acetate (4 x 40 ml). The organic phase was washed with 5 % NAHCO3 (1 x 50 ml) and water (1 x 50 ml), dried over NA2S04 and evaporated. The crude product was used without further PURIFICATIONS. H NMR (DMSO-d6) : 2. 28 (3H, s), 6.04 (2H, bs), 6.44 (1H, m), 6.48 (1H, m), 7.31 (1H, m).
With N-Bromosuccinimide; Perbenzoic acid; sodium hydrogencarbonate; In ethanol; ethyl acetate; benzene;
Step 1 Synthesis of ethyl (5-cyano-2-nitrobenzyl)aminoacetate: 4.0 g (24.6 mmol) of <strong>[96784-54-2]3-methyl-4-nitrobenzonitrile</strong> was added to a mixture of 100 ml of benzene, 100 ml of perbenzoic acid and 5.3 g (29 mmol) of N-bromosuccinimide, and they were heated under reflux for 2 days. 100 mg of perbenzoic acid and 4.0 g (22.5 mmol) of N-bromosuccinimide were added to the reaction mixture, and they were heated under reflux for 2 days. Thereafter, 100 mg of perbenzoic acid and 4.0 g (22.5 mmol) of N-bromosuccinimide were added to the reaction mixture, and they were heated under reflux for 2 days. After the treatment with ethyl acetate as the extracting solvent by an ordinary method, the obtained crude product was dissolved in 50 ml of ethanol. 6.9 g (49.2 mmol) of ethyl aminoacetate hydrochloride and 6.2 g (73.8 mmol) of sodium hydrogencarbonate were added to the obtained solution, and they were stirred at 70 C. for 6 hours. The solvent was evaporated. After the extraction with ethyl acetate, the extract was washed with 1 N hydrochloric acid. The obtained aqueous layer was made basic with 1 N sodium hydroxide. After the extraction with ethyl acetate, the obtained organic layer was washed with saturated aqueous sodium chloride solution and then dried. The solvent was evaporated to obtain the title compound. Yield: 2.5 g (9.6 mmol) (38%) H-NMR (CDCl3) delta 1.28 (3H, t), 3.42 (2H, s), 4.13 (2H, s), 4.21 (2H, q), 7.72 (1H, dd), 7.99 (1H, d), 8.12 (1H, s)
With hydroxylamine hydrochloride; triethylamine; In ethanol; water;
a) 3-Methyl-4-nitrobenzamide oxime To a solution of <strong>[96784-54-2]3-methyl-4-nitrobenzonitrile</strong> (5 g) in ethanol (100 ml) at room temperature was added hydroxylamine hydrochloride (2.25 g) followed by triethylamine (4.5 ml). The mixture was heated under reflux for 2.5 hours. On cooling the mixture was evaporated to a third of its original volume and poured on to water (200 ml). The mixture was filtered to give the title product as a solid, m.p. 127-9 C.
With pyridine; phosphorus pentachloride; trichlorophosphate; In dichloromethane;
Part A Preparation of the intermediate 4-nitro-3-tolunitrile, represented by the formula: A mixture of PCl5 (200 g, 0.96 mole) and p-toluene sulfonamide (90 g, 0.52 mole) was treated with 3-methyl-4-nitrobenzoic acid (82 g, 0.44 mole). The reaction was stirred at room temperature for 1 hour at which time it was heated to 140C and the POCl3 (150 ml) distilled from the mixture. The reaction was cooled to 5C, pyridine (200 ml) was carefully added and the mixture allowed to stand overnight. The reaction was carefully diluted to 1 L with H2O and the mixture stirred for 3 hours. The brown solid was filtered, washed with H2O and triturated with 5 N aqueous NaOH. The remaining solid was filtered, washed with H2O and dried to afford 60.0 g of a powder. The solid was stirred in 1200 ml CH2Cl2 and filtered. The supernatant was evaporated in vacuo and the residue recrystallized from EtOH to give 35.9 g (23 %) of 4-nitro-3-tolunitrile. MS(FD), m/e 162 (M+).
Step A 4-amino-3-methylbenzonitrile To an ethanol (500 ml)-water (60 ml)-acetic acid (30 ml) mixed solvent were added 3-methyl-4-nitrobenzonitrile (8.40 g, 51.8 mmol) and reduced iron (18 g, 322 mmol), and the mixture was stirred with heating at 85 C. for 3 hr. The reaction mixture was cooled, filtered through celite, and the solution was concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate, washed with diluted aqueous sodium hydroxide solution and saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure to give the title compound (6.37 g, yield 93%) as a pale-yellow solid. 1H-NMR (300 MHz, DMSO-d6); delta(ppm) 2.04 (s, 3H), 5.89 (brs, 2H), 6.64 (d, J=8.1, 1H), 7.26-7.31 (m, 2H).
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