* 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, 1947, p. 890,894
2
[ 38469-83-9 ]
[ 55496-52-1 ]
Reference：
[1] Journal of the Chemical Society, 1947, p. 890,894
3
[ 38469-83-9 ]
[ 62484-31-5 ]
Reference：
[1] Journal of the Chemical Society, 1948, p. 1759,1765
4
[ 38469-83-9 ]
[ 62484-12-2 ]
Reference：
[1] Journal of the Chemical Society, 1948, p. 1759,1765
5
[ 38469-83-9 ]
[ 4294-95-5 ]
Reference：
[1] Journal of the Chemical Society, 1947, p. 1034,1037
6
[ 38469-83-9 ]
[ 33844-21-2 ]
Yield
Reaction Conditions
Operation in experiment
91.8%
With sulfuric acid; acetic acid In water
a. 2-Nitro-4-methoxybenzoic acid A mixture of 2-nitro-4-methoxybenzonitrile (14.0 g, 78.6 mM) in a solution of acetic acid (28 mL), sulfuric acid (28 mL) and water (28 mL) was refluxed for 11 hr, allowed to cool and diluted with water (200 mL). The resulting precipitate which formed was collected, washed with water and dried to give the title benzoic acid (14.2 g, 91.8percent) as a yellow crystalline solid; MS(CI): 198 (M+H).
Reference：
[1] Patent: US5599814, 1997, A,
[2] Journal of the Chemical Society, 1947, p. 1034,1037
[3] Journal of the Chemical Society, 1947, p. 890,894
7
[ 5344-78-5 ]
[ 38469-83-9 ]
Yield
Reaction Conditions
Operation in experiment
75%
at 160℃; for 2 h;
3-Nitro-4-bromoan-isole (5.00 g, 21.54 mmol) was dissolved in anhydrous DMF and CuCN (2.89 g, 32.32 mmol) was added. The mixture was heated at 160 °C for 2 h. After cooling it was poured into crushed ice and a precipitate was formed, which was filtered and dried under vacuum. The greenish solid obtained was dissolved in CHCl3 and the solution was filtered. The solvent removal of the filtrate gave a yellow solid (2.88 g, 75percent); mp 129-130 °C (lit. [9] : 129-131 °C); IR (KBr) νmax (cm-1): 3103, 2230 (CN), 1616, 1529, 1500, 1443, 1348, 1311, 1285, 1248, 1188, 1067, 1020, 899, 840, 808; 1H NMR (300 MHz, CDCl3): δ 7.84-7.79 (m, 2H, H-3 and H-6), 7.28 (dd, 1H, J1 = 2.4 Hz, J2 = 9.0 Hz, H-5), 3.99 (s, 3H, OCH3); 13C NMR (75 MHz, CDCl3): δ 163.2, 150.1, 136.6, 119.9, 115.2, 111.1, 99.4, 56.5; MS (ESI) m/z (percent): 179.1 (100) [M + H]+. Anal. calcd for C8H6N2O3: C, 53.94; H, 3.39; N, 15.73. Found: C, 54.11; H, 3.40; N, 15.75.
Reference：
[1] European Journal of Medicinal Chemistry, 2013, vol. 59, p. 283 - 295
8
[ 5344-78-5 ]
[ 38469-83-9 ]
Reference：
[1] Patent: US5948775, 1999, A,
9
[ 151-50-8 ]
[ 96-96-8 ]
[ 38469-83-9 ]
Reference：
[1] Organic Letters, 2001, vol. 3, # 13, p. 2053 - 2056
[2] Journal of the Chemical Society, 1947, p. 437,44
[3] Journal of the Chemical Society, 1945, p. 861,864
10
[ 33844-21-2 ]
[ 38469-83-9 ]
Reference：
[1] Journal of Organic Chemistry, 2016, vol. 81, # 7, p. 2794 - 2803
Reference：
[1] Journal of Organic Chemistry, 2002, vol. 67, # 26, p. 9276 - 9287
13
[ 4110-33-2 ]
[ 124-41-4 ]
[ 38469-83-9 ]
[ 101084-96-2 ]
Reference：
[1] Journal of Chemical Research, Miniprint, 1992, # 6, p. 1371 - 1382
[2] Patent: US2015/329556, 2015, A1, . Location in patent: Paragraph 1554
14
[ 143-33-9 ]
[ 96-96-8 ]
[ 38469-83-9 ]
Reference：
[1] Journal of the Chemical Society, 1947, p. 1034,1037
15
[ 91-23-6 ]
[ 151-50-8 ]
[ 38469-83-9 ]
Reference：
[1] Canadian Journal of Chemistry, 1989, vol. 67, p. 220 - 226
[2] Canadian Journal of Chemistry, 1989, vol. 67, p. 220 - 226
16
[ 38469-83-9 ]
[ 38487-85-3 ]
Yield
Reaction Conditions
Operation in experiment
99%
With hydrogen In ethanol for 10 h;
Intermediate 3 : 2-Iodo-4-methoxybenzonitrile; To a solution of 4-methoxy-2-nitrobenzonitrle (5.00 g, 22.46 mmol) in EtOH (93 mL) was added 5percent Pd-C (0.500 g) under nitrogen atmosphere. The resulting mixture was hydrogenated at 1 atm. After stirring for 1 O h, the mixture was filtered through celite, washed with EtOAc/MeOH. The combined filtrates were concentrated in vacuo and the residue was purified by column chromatograph on SiO2 using 80 to 100 percent gradient of EtOAc in hexanes to afford 4-methoxy-2-amiobenzonitrle (3.23 g, 99percent). 4-Methoxy-2-aminobenzonitrle (1.0 g, 6.58 mmol) was dissolved in a mixture of H2O (7 niL), acetic acid (7 niL), and cone. HCl at rt, followed by addition of a solution Of NaNO2 (0.513 g, 7.43 mmol) in H2O (2 niL) at 0 0C for 5 min. To the above mixture KI (2.18 g, 13.2 mmol) was added and after stirring for 10 h at rt, the resulting mixture was treated with solid NaHSO3 and diluted with water. The product portion was extracted with CH2Cl2, washed with satd. NaHCO3, brine, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography on SiO2 using 10 to 50percent gradient of EtOAc in hexane to provide the example intermediate (1.0 g, 59percent).
Reference：
[1] Journal of Organic Chemistry, 2002, vol. 67, # 26, p. 9276 - 9287
[2] Patent: WO2009/65035, 2009, A1, . Location in patent: Page/Page column 66-67
[3] Journal of the Chemical Society, 1947, p. 437,44
[4] Journal of the Chemical Society, 1945, p. 861,864
17
[ 38469-83-9 ]
[ 38487-91-1 ]
[ 38487-85-3 ]
Reference：
[1] Journal of the Chemical Society, 1948, p. 1759,1765
To the reaction vessel was placed 470 g of the product of the above step, 2-nitro-4-methoxybenzonitrile, and 2000 g of a 15% sodium hydroxide solution was added thereto, and the reaction temperature was controlled to be 95 Cto 100 C. The reaction is refluxed for a period of time and the GC is followed until the reaction is complete. After the reaction is completed, the mixture is cooled, acid-adjusted, and the mixture is cooled and suction filtered, and washed with water to obtain a white solid 505 g, content 98%.The yield was 97%.
91.8%
With sulfuric acid; acetic acid; In water;
a. 2-Nitro-4-methoxybenzoic acid A mixture of 2-nitro-4-methoxybenzonitrile (14.0 g, 78.6 mM) in a solution of acetic acid (28 mL), sulfuric acid (28 mL) and water (28 mL) was refluxed for 11 hr, allowed to cool and diluted with water (200 mL). The resulting precipitate which formed was collected, washed with water and dried to give the title benzoic acid (14.2 g, 91.8%) as a yellow crystalline solid; MS(CI): 198 (M+H).
With hydrogen;5% palladium over charcoal; In ethanol; under 760.051 Torr; for 10h;
Intermediate 3 : 2-Iodo-4-methoxybenzonitrile; To a solution of 4-methoxy-2-nitrobenzonitrle (5.00 g, 22.46 mmol) in EtOH (93 mL) was added 5% Pd-C (0.500 g) under nitrogen atmosphere. The resulting mixture was hydrogenated at 1 atm. After stirring for 1 O h, the mixture was filtered through celite, washed with EtOAc/MeOH. The combined filtrates were concentrated in vacuo and the residue was purified by column chromatograph on SiO2 using 80 to 100 % gradient of EtOAc in hexanes to afford 4-methoxy-2-amiobenzonitrle (3.23 g, 99%). 4-Methoxy-2-aminobenzonitrle (1.0 g, 6.58 mmol) was dissolved in a mixture of H2O (7 niL), acetic acid (7 niL), and cone. HCl at rt, followed by addition of a solution Of NaNO2 (0.513 g, 7.43 mmol) in H2O (2 niL) at 0 0C for 5 min. To the above mixture KI (2.18 g, 13.2 mmol) was added and after stirring for 10 h at rt, the resulting mixture was treated with solid NaHSO3 and diluted with water. The product portion was extracted with CH2Cl2, washed with satd. NaHCO3, brine, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography on SiO2 using 10 to 50% gradient of EtOAc in hexane to provide the example intermediate (1.0 g, 59%).
Step 1 (1554) To a solution of 2,4-dinitrobenzonitrile (5.00 g, 25.9 mmol) in MeOH (100 mL) was added dropwise a solution (20 mL) of sodium methylate (1.40 g, 25.9 mmol) in MeOH at 0 C., and the mixture was stirred at room temperature for 3 hrs. and heated under reflux for 2 hrs. After allowing to cool to room temperature, insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. MeOH-water (1:1) was added to the concentrated residue to give a suspension and insoluble material was collected by filtration. The solid was washed with MeOH-water (1:1) to give a mixture (2.70 g) of 4-methoxy-2-nitrobenzonitrile and 2-methoxy-4-nitrobenzonitrile as a pale-yellow powder. The obtained pale-yellow powder was suspended in ethanol (80 mL) and hydrazine monohydrate (1.59 g, 31.8 mmol) was added. While heating the mixture to 45 C., Raney Ni (600 mg) was added in several portions, and the mixture was stirred at 60 C. for 1 hr. Raney Ni (600 mg) was added again, and the mixture was heated under reflux for 2 hrs. After allowing to cool to room temperature, insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. Ethyl acetate was added to the obtained concentrated residue, and extracted with 1N hydrochloric acid (×3). The aqueous layer was basified with 1N aqueous sodium hydroxide solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate and concentrated under reduced pressure. The obtained concentrated residue was purified by silica gel column chromatography (67-75% ethyl acetate/hexane) to give 2-amino-4-methoxybenzamide as a pale-yellow powder (1.45 g, 34% for 2 steps).
EXAMPLE 50 2'-Carbamoyl-5'-methoxyoxanilic acid ethyl ester. 91 2-Nitro-4-methoxybenzonitrile (12.8 g) is reduced in a manner similar to example 40, giving 9.0 g of 2-amino-p-anisamide, m.p. 152-156 C. after crystallization from water.
EXAMPLE 50 2'-Carbamoyl-5'-methoxyoxanilic acid ethyl ester. 91 2-Nitro-4-methoxybenzonitrile (12.8 g) is reduced in a manner similar to example 40, giving 9.0 g of 2-amino-p-anisamide, m.p. 152-156 C., after crystallization from water. Elemental Analysis for C8 H10 N2 O2: Calc'd: C, 57.82; H, 6.07; N, 16.86. Found: C, 58.60; H, 5.76; N, 16.65.
EXAMPLE 50 2'-Carbamoyl-5'-methoxyoxanilic acid ethyl ester. 91 2-Nitro-4-methoxybenzonitrile (12.8 g) is reduced in a manner similar to example 40, giving 9.0 g of 2-amino-p-anisamide, m.p. 152-156C., after crystallization from water. Elemental Analysis for C8 H10 N2 O2: Calc'd: C, 57.82; H, 6.07; N, 16.86. Found: C, 58.60; H, 5.76; N, 16.65.
EXAMPLE 2 2-Amino-4-methoxybenzamide To a solution of 37.4 g (0.210 mol) of 4-cyano-3-nitroanisole in 500 mL of ethanol was added 221.6 g (0.982 mol) of tin(II) chloride dihydrate. The reaction mixture was stirred and heated under reflux for 1 hour. After cooling to room temperature, the reaction mixture was poured onto ice. Aqueous sodium bicarbonate was added slowly to the ice mixture until the solution reached pH 7-8. Additional water was added to the mixture, which was then extracted with methylene chloride (2*400 mL) and ethyl acetate (1*300 mL). The separated aqueous layers were filtered between each of the extractions. The off white residue collected on the filters was rinsed with methylene chloride and ethyl acetate several times. The combined organic phases were then dried over magnesium sulfate, filtered and evaporated in the rotary evaporator to obtain 28.5 g crude product (mp 154-155 C.). Elemental analysis for C8 H10 N2 O2: Calc'd: C, 57.82; H, 6.07; N, 16.86; Found: C, 57.95; H, 5.95; N, 16.78.
With potassium iodide;palladium diacetate; In ethyl acetate; N,N-dimethyl-formamide;
EXAMPLE 1 4-Cyano-3-nitroanisole To a solution of 50.0 g (0.261 mol) of 4-bromo-3-nitroanisole (Lancaster Chemicals) in 150 mL of dry N,N-dimethylformamide was added 38.6 g (0.431 mol) of copper(I) cyanide, 0.73 g (0.00325 mol) of palladium(II) acetate, and 3.2 g (0.0193 mol) of potassium iodide, under nitrogen. The reaction mixture was stirred and heated under reflux for 2 hours. After cooling to room temperature, 300 mL of ethyl acetate was added to the reaction mixture. The ethyl acetate was decanted, leaving behind a dark residue on the bottom of the reaction flask. The ethyl acetate solution was extracted with saturated brine (3*150 mL), dried over magnesium sulfate, filtered and evaporated to dryness in a rotary evaporator to yield 24.5 g of orange crystals. An analytical sample (mp 136-138 C.) was obtained by recrystallization from ethyl acetate. Elemental analysis for C8 H6 N2 O3: Calc'd: C, 53.94; H, 3.39; N, 15.73; Found: C, 53.98; H, 3.21; N, 15.67.
With potassium hydroxide; In tetrahydrofuran; N,N-d-methylformamide; dichloromethane; water;
13.1. Methyl 3-amino-6-methoxybenzo[b]thiophene-2-carboxylate A solution of 20.3 g (0.363 mol) of potassium hydroxide in 100 ml of water is added to a mixture of 36.3 g (0.204 mol) of <strong>[38469-83-9]3-nitro-4-cyanoanisole</strong> and 26 g (0.245 mol) of methyl thioglycolate in 400 ml of N,N-d-methylformamide, the temperature being maintained at 0 C. The mixture is left stirring at 0 C. for 20 min and is then poured into a mixture of water and ice. The precipitate is then filtered off, rinsed with water and dried. The product is dissolved in a mixture of dichloromethane and tetrahydrofuran, the organic phase is then dried over sodium sulphate and concentrated under reduced pressure and the residue is triturated in dichloromethane. 26.2 g of product are thus obtained in the form of a light-beige powder. Melting point: 170 C.
7-Methoxy[1]benzothieno[2,3-b]pyrazine-2,3(lH,4H)-dione[ No CAS ]
[ 138993-45-0 ]
Yield
Reaction Conditions
Operation in experiment
6.0 g (24%)
EXAMPLE 11 7-Methoxy[1]benzothieno[2,3-b]pyrazine-2,3(lH,4H)-dione 4-Methoxy-2-nitrobenzonitrile (18 g, 100 mmol) (L. Bradford, et al., J. Chem. Soc., 437 (1947)) was reacted with 3-mercaptopropionitrile and bromonitromethane following the procedure outlined in example 7 (Method K). Yield 6.0 g (24%) of 3-amino-6-methoxy-2-nitrobenzo[b]thiophene. M.p. >250 C. 1 H-NMR (DMSO-d): delta3.85 (s, 3H), 7.05 (d, 1H), 7.45 (s, 1H), 8.21 (d, 1H), 8.80 (br. s, 2H).
4-methoxy-2-[[(1-methylethylidene)amino]oxy]benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran; N,N-dimethyl-formamide;
METHOD B In 20 ml of DMF was dissolved acetone oxime (0.74 g), followed by sodium hydride (0.30 g). After this mixture had stirred for 30 minutes, <strong>[38469-83-9]4-methoxy-2-nitro-benzonitrile</strong> (1.50 g) was added. After an additional 30 minutes the reaction was poured into water (500 ml) and filtered. The solid was collected and dissolved in DCM (250 ml), dried (MgSO4), and concentrated in vacuo. The resulting solid was recrystallized from ethanol to yield 1.5 g of 4-methoxy-2-[[(1-methylethylidene)amino]oxy]benzonitrile, m.p. 78-79 C. ANALYSIS: Calculated for C11 H12 N2 O2: 64.69%C 5.92%H 13.72%N Found: 64.51%C 5.77%H 13.49%N
3-Nitro-4-bromoan-isole (5.00 g, 21.54 mmol) was dissolved in anhydrous DMF and CuCN (2.89 g, 32.32 mmol) was added. The mixture was heated at 160 C for 2 h. After cooling it was poured into crushed ice and a precipitate was formed, which was filtered and dried under vacuum. The greenish solid obtained was dissolved in CHCl3 and the solution was filtered. The solvent removal of the filtrate gave a yellow solid (2.88 g, 75%); mp 129-130 C (lit. [9] : 129-131 C); IR (KBr) numax (cm-1): 3103, 2230 (CN), 1616, 1529, 1500, 1443, 1348, 1311, 1285, 1248, 1188, 1067, 1020, 899, 840, 808; 1H NMR (300 MHz, CDCl3): delta 7.84-7.79 (m, 2H, H-3 and H-6), 7.28 (dd, 1H, J1 = 2.4 Hz, J2 = 9.0 Hz, H-5), 3.99 (s, 3H, OCH3); 13C NMR (75 MHz, CDCl3): delta 163.2, 150.1, 136.6, 119.9, 115.2, 111.1, 99.4, 56.5; MS (ESI) m/z (%): 179.1 (100) [M + H]+. Anal. calcd for C8H6N2O3: C, 53.94; H, 3.39; N, 15.73. Found: C, 54.11; H, 3.40; N, 15.75.
With 2.9-dimethyl-1,10-phenanthroline; oxygen; copper diacetate; silver sulfate; In dimethyl sulfoxide; at 140℃; under 760.051 Torr; for 20h;Schlenk technique; Green chemistry;
General procedure: An oven-dried Schlenk tube equipped with a stir bar was charged with aryl carboxylic acid (0.2 mmol), Ag2SO4 (6.2 mg, 0.02 mmol, 0.1 equiv.), Cu(OAc)2 (36.3 mg, 0.2 mmol, 1 equiv.), K4Fe(CN)6 (13.2 mg, 0.036 mmol, 0.18 equiv.) and 2,9-dimethyl-1,10-phenanthrolinium (12.5 mg, 0.06 mmol, 0.3 equiv.). The tube was fitted with a rubber septum, and then it was evacuated and refilled with dioxygen three times. Under dioxygen, DMSO (4 mL) was added via syringe. The rubber septum was replaced with a Teflon screwcap under dioxygen flow, and the Schlenk tube was pressurized to 1 atm. With stirring, the reaction mixtures were heated at 140 C for the indicated amount of time (unless otherwise specified). After cooling to room temperature, the reaction mixtures were diluted with ether (10 mL) and filtered through a pad of silica gel that was then washed with ether (10 mL *3). The combined organic phase was washed with brine (20 mL *2), dried over Na2SO4, filtered and concentrated in vacuo. The resulting residue was purified using flash column chromatography over silica gel to provide the corresponding product with ethyl acetate/hexane as eluent.
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