* 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.
Stage #1: With sulfuric acid In dichloromethane; water at 0℃; for 3 h; Stage #2: With ammonia In water at 20℃;
A suspension of S-10 (4 g, 21.5 mMol) in 40 mL dichloromethane was slowly added to cold 95percent sulfuric acid (21 g, 215 mMol) while maintaining the batch temperature at 0+/-5° C. After the addition the mixture was agitated at 0+/-5° C. for approximately 3 h. The agitation was stopped and the bottom acid layer was slowly transferred to 40 mL of water while maintaining the temperature at <20° C. To the diluted reaction mixture was slowly added ammonium hydroxide solution at <20° C. until pH was 6-11. The mixture was extracted twice with dichloromethane. The combined organic solution was washed with brine, dried over MgSO4, filtered, and concentrated to give 3.3 g (91percent) of the title compound.Compounds N-2, N-9, N-14/N-15/N-16, N-29/N-30/N-31, N-22/N-23, N-21 were prepared using the same procedure.
80.3%
With sulfuric acid In dichloromethane at 0℃; for 3 h;
Weigh 63g 95percent concentrated sulfuric acid in 500mL three bottles,Cool to 0 ° C.12 g of compound 12,Suspended in 120 mL of dichloromethane,Formulated as a suspension,The suspension was added dropwise to the cold concentrated sulfuric acid,During the dropping process, the control temperature is about 0 ° C,After completion of the drop to maintain this temperature reaction for about 3h,The reaction solution was separated,Take the layer of acid,120mL water to about 0 ,The acid layer slowly added to cold water,The process to keep the temperature does not exceed 20 ,After completion of the dropwise addition, ammonia water was added to the diluted reaction solution until the pH was 6-11,Dripping process temperature does not exceed 20 ,Extracted with 120 mL x 2 DCM,The organic phase was washed with saturated brine and concentrated.To give 8.7 g of a dark brown viscous oil,Yield 80.3percent.
Reference：
[1] Patent: US2007/255057, 2007, A1, . Location in patent: Page/Page column 11
[2] Patent: CN106905245, 2017, A, . Location in patent: Paragraph 0158; 0161; 0162; 0163; 0164
3
[ 50651-39-3 ]
[ 577-72-0 ]
Reference：
[1] Anales de la Real Sociedad Espanola de Fisica y Quimica, 1948, vol. 44, p. 348,352
[2] Promysl.org.Chim., 1939, vol. 6, p. 445,447[3] Chem.Abstr., 1940, p. 2361
[4] Organic and Biomolecular Chemistry, 2010, vol. 8, # 6, p. 1406 - 1414
[5] Patent: CN106278926, 2017, A, . Location in patent: Paragraph 0027; 0028; 0029; 0030; 0031; 0032; 0033-0054
4
[ 119-27-7 ]
[ 577-72-0 ]
Yield
Reaction Conditions
Operation in experiment
98.1%
at 60℃; for 0.583333 h;
The prepared 2,4-dinitroanisole (II) was dissolved in 2 kg of methanol solution, followed by the addition of 60 g of Example 1PdCu / graphene bimetallic catalyst prepared by catalytic hydrogenation reduction reaction,Reaction pressure is 1Mpa,Reaction temperature is 60 ,Reaction time 35min,The reaction is over.After the filter to remove the catalyst,Distillation recovery of methanol,Washed,749.26 g of 4-amino-2-nitroanisole (III) (HPLC purity 99.6percent) was obtained,Yield 98.1percent.
Reference：
[1] Patent: CN107673976, 2018, A, . Location in patent: Paragraph 0059-0060; 0072; 0081
Reference：
[1] Journal of Medicinal Chemistry, 2001, vol. 44, # 22, p. 3599 - 3605
[2] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 5, p. 1247 - 1251
[3] Journal of Labelled Compounds and Radiopharmaceuticals, 2003, vol. 46, p. S113 - S113
[4] Advanced Synthesis and Catalysis, 2008, vol. 350, # 6, p. 863 - 868
[5] Patent: CN104151178, 2016, B, . Location in patent: Paragraph 0055; 0057
7
[ 119-34-6 ]
[ 74-88-4 ]
[ 577-72-0 ]
Yield
Reaction Conditions
Operation in experiment
46%
With caesium carbonate In acetonitrile
REFERENCE EXAMPLE 57 4-Methoxy-3-nitroaniline A solution of 4-amino-2-nitrophenol (10.0 g, 64.9 mmol), cesium carbonate (21 g, 64 mmol), and methyl iodide (9.22 g, 64.9 mmol) in acetonitrile (1500 mL) was heated at reflux for 5 hours. The mixture was cooled to room temperature and subsequently filtered, evaporated, and purified by flash chromatography (chloroform) to give 5.03 g (46percent yield) of a reddish oil. 1H NMR (DMSO-d6) δ 7.09-7.03 (mn, 2H), 6.87 (d, J=3 Hz, 1H), 5.21 (bs, 2H), 3.77 (s, 3H); HRMS (EI) m/z 168.0497 (M+1). Analysis for C7H8 N2O3: Calcd: C, 50.00;H, 4.80; N, 16.66. Found: C, 50.20;H, 5.07; N, 16.60.
Reference：
[1] Patent: US2002/26052, 2002, A1,
8
[ 364-76-1 ]
[ 577-72-0 ]
Yield
Reaction Conditions
Operation in experiment
97%
With hydrogenchloride; sodium methylate In methanol; water
4-Methoxy-3-nitroaniline To a 1M solution of 3-nitro-4-fluoroaniline (16.7 g, 107 mmol, from Aldrich Chemical Co., Milwaukee, Wis. USA) in anhydrous methanol at ambient temperature was added sodium methoxide (23.1 g, 428 mmol) and the resulting solution was refluxed with stirring for 21 hours. The reaction mixture was then cooled to 0° C. and a 12M solution of HCl (13.4 mL) was added dropwise followed by water (250 mL). The crude mixture was extracted three times with Et2 O (200 mL). The organic layers were combined, washed with brine (300 mL), dried over Na2 SO4, and concentrated under vacuum to yield 17.5 g (97percent) of product as a dark brown solid, which was used without further purification. 1 H NMR (400 MHz, DMSO-d6) δ7.09 (d, J=9 Hz, 1H), 7.01 (dd, J=2.8, 1.3 Hz, 1H), 6.85 (ddd, J=9, 2.8, 1.4 Hz, 1H), 5.2 (s, 2H), 3.75 (s, 3H).
97%
With hydrogenchloride; sodium methylate In methanol; water
4-Methoxy-3-nitroaniline To a 1M solution of 3-nitro-4-fluoroaniline (16.7 g, 107 mmol, from Aldrich Chemical Co., Milwaukee, Wis., U.S.A.) in anhydrous methanol at ambient temperature was added sodium methoxide (23.1 g, 428 mmol) and the resulting solution was refluxed with stirring for 21 hours. The reaction mixture was then cooled to 0° C. and a 12M solution of HCl (13.4 mL) was added dropwise followed by water (250 mL). The crude mixture was extracted three times with Et2O (200 mL). The organic layers were combined, washed with brine (300 mL), dried over Na2SO4, and concentrated under vacuum to yield 17.5 g (97percent) of product as a dark brown solid, which was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ7.09 (d, J=9 Hz, 1H), 7.01 (dd, J=2.8, 1.3 Hz, 1H), 6.85 (ddd, J=9, 2.8, 1.4 Hz, 1H), 5.2 (s, 2H), 3.75 (s, 3H).
A suspension of S-10 (4 g, 21.5 mMol) in 40 mL dichloromethane was slowly added to cold 95% sulfuric acid (21 g, 215 mMol) while maintaining the batch temperature at 0+/-5 C. After the addition the mixture was agitated at 0+/-5 C. for approximately 3 h. The agitation was stopped and the bottom acid layer was slowly transferred to 40 mL of water while maintaining the temperature at <20 C. To the diluted reaction mixture was slowly added ammonium hydroxide solution at <20 C. until pH was 6-11. The mixture was extracted twice with dichloromethane. The combined organic solution was washed with brine, dried over MgSO4, filtered, and concentrated to give 3.3 g (91%) of the title compound.Compounds N-2, N-9, N-14/N-15/N-16, N-29/N-30/N-31, N-22/N-23, N-21 were prepared using the same procedure.
80.3%
With sulfuric acid; In dichloromethane; at 0℃; for 3h;
Weigh 63g 95% concentrated sulfuric acid in 500mL three bottles,Cool to 0 C.12 g of compound 12,Suspended in 120 mL of dichloromethane,Formulated as a suspension,The suspension was added dropwise to the cold concentrated sulfuric acid,During the dropping process, the control temperature is about 0 C,After completion of the drop to maintain this temperature reaction for about 3h,The reaction solution was separated,Take the layer of acid,120mL water to about 0 ,The acid layer slowly added to cold water,The process to keep the temperature does not exceed 20 ,After completion of the dropwise addition, ammonia water was added to the diluted reaction solution until the pH was 6-11,Dripping process temperature does not exceed 20 ,Extracted with 120 mL x 2 DCM,The organic phase was washed with saturated brine and concentrated.To give 8.7 g of a dark brown viscous oil,Yield 80.3%.
(E)-N-(4-methoxy-3-nitrophenyl)-3-(3,4,5-trimethoxyphenyl)-2-propenamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
35%
With 1,1-diisopropylethylamine; In 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran; at 20℃; for 24h;
A solution of <strong>[577-72-0]4-methoxy-3-nitroaniline</strong> and 3,4, 5-trimethoxy cinnamic acid was reacted according to General Procedure 3. The title compound, melting point 186-189 C, was thereby obtained in 35 % yield. NMR (DMSO-D6), 8 3.84 (s, 3H), 3.90 (s, 9H), 7.2 (d, 1H vinylic, J=16. 0HZ), 7.37-8. 20 (m, aromatic).
REFERENCE EXAMPLE 57 4-Methoxy-3-nitroaniline A solution of <strong>[119-34-6]4-amino-2-nitrophenol</strong> (10.0 g, 64.9 mmol), cesium carbonate (21 g, 64 mmol), and methyl iodide (9.22 g, 64.9 mmol) in acetonitrile (1500 mL) was heated at reflux for 5 hours. The mixture was cooled to room temperature and subsequently filtered, evaporated, and purified by flash chromatography (chloroform) to give 5.03 g (46% yield) of a reddish oil. 1H NMR (DMSO-d6) delta 7.09-7.03 (mn, 2H), 6.87 (d, J=3 Hz, 1H), 5.21 (bs, 2H), 3.77 (s, 3H); HRMS (EI) m/z 168.0497 (M+1). Analysis for C7H8 N2O3: Calcd: C, 50.00;H, 4.80; N, 16.66. Found: C, 50.20;H, 5.07; N, 16.60.
Example 58 4-Methoxy-3-nitro-1-pentafluorophenylsulfonamidobenzene. The compound was prepared in a manner similar to example 46 by replacing 3-chloroaniline with <strong>[577-72-0]4-methoxy-3-nitroaniline</strong> which was prepared by the method of Norris (Aust. J Chem. 1971, 24, 1449). Orange-yellow solid, mp 95-97 C. 1H NMR (CDCl3): d 7.64 (d, J=2.7; 1H), 7.51 (dd, J=2.7, 9.0; 1H), 7.09 (s, 1H), 7.09 (d, J =9.0; 1H), 3.95 (s, 3H). Anal. Calcd. For C13H7F5N2O5S: C, 39.21; H, 1.77; N, 7.03; S, 8.05. Found: C, 39.19; H, 1.73; N, 6.97; S, 7.95.
STR66 4-Methoxy-3-nitro-1-pentafluorophenylsulfonamidobenzene. The compound was prepared in a manner similar to example 46 by replacing 3-chloroaniline with <strong>[577-72-0]4-methoxy-3-nitroaniline</strong> which was prepared by the method of Norris (Aust. J. Chem. 1971, 24, 1449). Orange-yellow solid, mp 95-97 C. 1 H NMR (CDCl3): d 7.64 (d, J=2.7; 1H), 7.51 (dd, J=2.7, 9.0; 1H), 7.09 (s, 1H), 7.09 (d, J=9.0; 1H), 3.95 (s, 3H). Anal. Calcd. For C13 H7 F5 N2 O5 S: C, 39.21; H, 1.77; N, 7.03; S, 8.05. Found: C, 39.19; H, 1.73; N, 6.97; S, 7.95.
With hydrogenchloride; sodium methylate; In methanol; water;
4-Methoxy-3-nitroaniline To a 1M solution of 3-nitro-4-fluoroaniline (16.7 g, 107 mmol, from Aldrich Chemical Co., Milwaukee, Wis. USA) in anhydrous methanol at ambient temperature was added sodium methoxide (23.1 g, 428 mmol) and the resulting solution was refluxed with stirring for 21 hours. The reaction mixture was then cooled to 0 C. and a 12M solution of HCl (13.4 mL) was added dropwise followed by water (250 mL). The crude mixture was extracted three times with Et2 O (200 mL). The organic layers were combined, washed with brine (300 mL), dried over Na2 SO4, and concentrated under vacuum to yield 17.5 g (97%) of product as a dark brown solid, which was used without further purification. 1 H NMR (400 MHz, DMSO-d6) delta7.09 (d, J=9 Hz, 1H), 7.01 (dd, J=2.8, 1.3 Hz, 1H), 6.85 (ddd, J=9, 2.8, 1.4 Hz, 1H), 5.2 (s, 2H), 3.75 (s, 3H).
17.5 g (97%)
With hydrogenchloride; sodium methylate; In methanol; water;
4-Methoxy-3-nitroaniline To a 1M solution of 3-nitro-4-fluoroaniline (16.7 g, 107 mmol, from Aldrich Chemical Co., Milwaukee, Wis., U.S.A.) in anhydrous methanol at ambient temperature was added sodium methoxide (23.1 g, 428 mmol) and the resulting solution was refluxed with stirring for 21 hours. The reaction mixture was then cooled to 0 C. and a 12M solution of HCl (13.4 mL) was added dropwise followed by water (250 mL). The crude mixture was extracted three times with Et2O (200 mL). The organic layers were combined, washed with brine (300 mL), dried over Na2SO4, and concentrated under vacuum to yield 17.5 g (97%) of product as a dark brown solid, which was used without further purification. 1H NMR (400 MHz, DMSO-d6) delta7.09 (d, J=9 Hz, 1H), 7.01 (dd, J=2.8, 1.3 Hz, 1H), 6.85 (ddd, J=9, 2.8, 1.4 Hz, 1H), 5.2 (s, 2H), 3.75 (s, 3H).
2-Chloroethyl(3-nitro-4-methoxyphenyl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With calcium carbonate; In diethylene glycol dimethyl ether; water;
Stage 1: 2-Chloroethyl(3-nitro-4-methoxyphenyl)carbamate 420.5 g of 4-amino-2-nitroanisole are dissolved in 1275 ml of diethylene glycol dimethyl ether and 150 ml of water, 135 g of calcium carbonate are added and the mixture is heated to 78 C. 375 g of 2-chloroethyl chloroformate are allowed to run into this mixture in the course of 3 hours such that the reaction temperature remains at 78-80 C. The mixture is subsequently stirred for 1.5 hours to bring the reaction to completion and is cooled to 35 C. and water and ice are added. The product which has precipitated is filtered off, washed with water and dried. Yield: 663 g Yield in % of theory, based on 4-amino-2-nitroanisole: 96.5% Melting point: 82-84 C.
A. 2-Nitro-4-methoxyphenol A mixture of 168 g. (0.93 m.) of 3-nitro-p-anisidine, 130 g. of KOH and 1500 ml. of H2 O was refluxed with stirring overnight. The solution was acidified with conc. HCl, keeping the temperature below 20C. The crude product was collected by filtration washed with H2 O and air-dried to give 279 g. m.p. 74-76C. A recrystallization from 2000 ml. of ethanol yields 106 g. m.p.76-78C.
With pyridine; In pyridine; at 100℃; for 0.0833333h;Microwave irradiation;
Example 21 N-(4-Methoxy-3-nitro-phenyl)-isonicotinamide A mixture of <strong>[577-72-0]4-methoxy-3-nitroaniline</strong> (168 mg, 1 mmol) and Isonicotinoyl chloride hydrogen chloride (267 mg, 0.2 M in 1.5 mmol) in pyridine (1 mL) is sealed in a microwave reactor and heated at 100 C. under microwave radiation for 5 mins. Then 1N NaOH aqueous solution is added to the reaction mixture. After stirring at room temperature for several minutes, the mixture is filtered. The solid is washed with H2O and air dried to give 263 mg of the title compound as a yellow solid. MS (ESI) m/z 274 (M+H)+
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 12h;
General procedure: A mixture of 7 (0.02 mol), 8(a-m) or 1-naphthylamine (0.02 mol), EDC (0.08 mol), DMAP (0.002 mol) and DMF (60 ml) was stirred at room temperature for 12 h. Then water (200 ml) was added, and the resulting solid was filtered and washed by water twice. After filtration, the filter cake was recrystallized to yield compounds 9(a-m) and 11 (30-60%).
at 20℃; for 0.0833333h;Inert atmosphere; Neat (no solvent);
General protocol: Aldehyde (1 mmol) and amine (1 mmol) were stirred at room temperature for 5 min under nitrogen atmosphere. 2-(trimethylsilyloxy)furan (1.5 mmol) was added and the reaction mixture was stirred for an additional 15 min. Diastereomeric ratios were determined by 1H NMR spectroscopic analysis of the crude product, and NMR yields were calculated by using methyl tert-butyl ether as internal standard. The crude material was purified by flash chromatography to give the desired product.
at 20℃; for 0.0833333h;Inert atmosphere; Neat (no solvent);
General protocol: Aldehyde (1 mmol) and amine (1 mmol) were stirred at room temperature for 5 min under nitrogen atmosphere. 2-(trimethylsilyloxy)furan (1.5 mmol) was added and the reaction mixture was stirred for an additional 15 min. Diastereomeric ratios were determined by 1H NMR spectroscopic analysis of the crude product, and NMR yields were calculated by using methyl tert-butyl ether as internal standard. The crude material was purified by flash chromatography to give the desired product.
Step 2a: Synthesis of 8 and 3:A suspension of 10 g (59.5 mmol, 1.0 eq) of <strong>[577-72-0]4-methoxy-3-nitroaniline</strong> in 65 mL of dioxane and 65 mL of water was adjusted to pH 12 with 40% NaOH, and then Boc20 (26 g, 1 19.1 mmol, 2.0 eq) was added in 3 portions under ice bath. The reaction was stirred at room temperature overnight. After standing, the mixture was filtered to give a yellow solid, 15 g, in 95% yield.
95%
With sodium hydroxide; In water; at 20℃;Cooling with ice;
A suspension of 10 g (59.5 mmol, 1.0 eq) of <strong>[577-72-0]4-methoxy-3-nitroaniline</strong> in 65 mL of dioxane and 65 mL of water was adjusted to pH 12 with 40% NaOH, and then Boc20 (26 g, 119.1 mmol, 2.0 eq) was added in 3 portions under ice bath. The reaction was stirred at room temperature overnight. After standing, the mixture was filtered to give a yellow solid, 15 g, in 95% yield.
To a solution of 3-nitro-4-methoxyaniline, 37 (107 mmol) in dichloromethane (150 mL) at 10 C, was added triethylamine (161 mmol) drop wise and stirred for 15 min at the same temperature. To this, ethyl 2-(chlorosulfonyl)acetate (22.0 g, 118 mmol) dissolved in dichloromethane (25 mL) was added slowly at the same temperature. Once the addition was over, the reaction mixture was allowed to warm to room temperature and stirred for 3 h. After completion of the reaction, water was added, and the reaction mixture was stirred for 15 min. The organic layer was separated, dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain crude 38. The crude 38 was purified on a silica gel column purification (1:1, ethyl acetate: hexane), resulting in pure 38 as a white crystalline sold, mp 115-119 C. 1H NMR (CDCl3, 300 MHz): delta 1.36 (t, J = 7.2 Hz, 3H, CH3), 3.94 (s, 2H, CH2), 3.99 (s, 3H, OCH3), 4.32 (q, J = 7.2 Hz, 2H, OCH2), 7.07 (br s, 1H, NH), 7.13 (d, J = 9.0 Hz, 1H, Ar-H), 7.62 (dd, J = 2.7, 9.0 Hz, 1H, Ar-H), 7.86 (d, J = 2.7 Hz, 1H, Ar-H).
N-(4-methoxy-3-nitrophenyl)-2-phenyl-1,3-thiazole-5-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
23%
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;
To a solution of 2-phenyl-l,3-thiazole-5-carboxylic acid (502 mg, 2.45 mmol) in diisopropylethylamine (1.25 mL, 7.19 mmol) and DMF (8.2 mL) were added 4-methoxy-3-nitroaniline (403 mg, 2.40 mmol) and 2.10 mL of a 50 % solution of 2,4,6-tripropyl-l,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (T3P) in DMF (3.60 mmol). The mixture was stirred over night at room temperature. Water was added and the mixture was extracted three times with ethyl acetate. The combined organic layers were dried over MgS04 and concentrated in vacuum. After flash-chromatography of the residue the product was suspended in ethyl acetate and stirred with saturated NaHCC>3 solution to remove acidic impurities. The layers were separated, the organic layer was dried over MgS04 and provided after removal of the solvent the desired product (202 mg, 23%). 1H-NMR (400 MHz, DMSO-d6): delta [ppm] = 3.93 (s, 3 H), 7.45 (s, 1 H), 7.52 - 7.61 (m, 3 H), 8.05 (s, 3 H), 8.33 (d, 1 H), 8.67 (s, 1 H), 10.69 (s, 1 H). LC-MS (Method 4): Rt = 1.24 min; MS (ESIpos): m/z = 356 [M+H]+.
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