* 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] Bulletin of the Korean Chemical Society, 2011, vol. 32, # 5, p. 1461 - 1462
2
[ 39106-79-1 ]
[ 27492-84-8 ]
Yield
Reaction Conditions
Operation in experiment
100%
With palladium 10% on activated carbon; hydrogen; sodium sulfate In methanol for 1 h;
The hydrogenation of methyl 2-methoxy-4-nitrobenzoate (700 mg, 3.3 mmol) in methanol (10 mL) catalyzed by 5percent Pd—C (100 mg) and Na2SO4 (100 mg) at 50 psi for 1 h gave methyl 4-amino-2-methoxybenzoate (600 mg, quant.) as a white solid.
99%
With palladium 10% on activated carbon In methanol at 20℃; for 12 h; Inert atmosphere; Autoclave
To a solution of methyl 2-methoxy-4-nitrobenzoate (10.0 g, 0.047 mol) in MeOH (100 mL) was added Pd/C (4.0 g, 10 percent w/w) under a nitrogen atmosphere in anautoclave and the reaction mixture was stirred at 45 psi (hydrogen atm) at room temperature for 12 h. The reaction mixture was passed through a Celite pad and the pad was washed with excess ethyl acetate. The filtrate was evaporated to dryness under reduced pressure to afford methyl 4-amino-2-methoxybenzoate (8.6 g, 0.048 mol, 99 percent yield) as a brown solid. ‘H NMR (400 MHz, DMSO-d6) ö 7.52 (d, J 8.4Hz, 1H), 6.32 (s, 1H), 6.23-6.25 (m, 1H), 5.6 (bs, 2H), 3.72 (s, 3H), 3.67 (s, 3H); LCMS (ESI) m/e 182.2 [(M+H), calcd for C9H12N03, 182.07]; LC/MS retention time (method B): ti = 0.87 mm.
97%
With palladium 10% on activated carbon; hydrogen In methanol at 20℃; for 12 h; Inert atmosphere
To a solution of methyl 2-methoxy-4-nitrobenzoate (12.00 g, 56.86 mmol) in methanol (100 mL) at room temperature under nitrogen was added 10percent palladium on carbon (4.88 g, 4.61 mmol). The resultant mixture was stirred under hydrogen (45 psi) for 12 h at room temperature. After the completion of reaction, the mixture was filtered through a diatomaceous earth (Celite®) pad and the filtrate was concentratedunder reduced pressure to afford methyl 4-amino-2-methoxybenzoate (10 g, 97percent yield) as a yellow solid: LCMS (ESI) m/e 182.2 [(M+H), calcd for C9H12N03, 182.1]; LC/MS retention time (method B): tp. = 0.87 min.
Reference：
[1] Patent: US2015/266828, 2015, A1, . Location in patent: Paragraph 1023
[2] Patent: WO2016/53794, 2016, A1, . Location in patent: Page/Page column 125
[3] Patent: WO2015/6100, 2015, A1, . Location in patent: Page/Page column 176
[4] Proceedings - Indian Academy of Sciences, Section A, 1950, vol. <A> 32, p. 357,362
[5] Journal of the American Chemical Society, 1952, vol. 74, p. 592,595
[6] Journal of the American Chemical Society, 1952, vol. 74, p. 592,595
[7] Archiv der Pharmazie (Weinheim, Germany), 1951, vol. 284, p. 341,346
[8] Patent: EP1021444, 2003, B1, . Location in patent: Page/Page column 24
3
[ 39106-79-1 ]
[ 7440-05-3 ]
[ 27492-84-8 ]
Yield
Reaction Conditions
Operation in experiment
85%
With hydrogen In ethanol
Step b) 4-amino-2-methoxy-benzoic acid methyl ester A mixture of 2-methoxy-4-nitrobenzoic acid methyl ester (12 g, 57 mmol), palladium (10percent on activated carbon), and ethanol (150 ml) was shaken at room temperature under 50 psi of hydrogen for 2 hours. The reaction was filtered through diatomaceous earth, and the diatomaceous earth washed with chloroform. Evaporation of the chloroform washings gave a yellow solid; purification by crystallization gave a light yellow crystalline solid (8.76 g, 85percent) mp 148°-149° C. Analysis for: C9 H11 N O3 Calcd: C, 59.66; H, 6.12; N, 7.73. Found: C, 59.42; H, 6.02; N, 7.69.
85%
With hydrogen In ethanol
Step b) 4-amino-2-methoxy-benzoic acid methyl ester A mixture of 2-methoxy-4-nitrobenzoic acid methyl ester (12 g, 57 mmol), palladium (10percent on activated carbon), and ethanol (150 ml) was shaken at room temperature under 50psi of hydrogen for 2 hours. The reaction was filtered through diatomaceous earth, and the diatomaceous earth washed with chloroform. Evaporation of the chloroform washings gave a yellow solid; purification by crystallization gave a light yellow crystalline solid (8.76 g, 85percent) mp 148°-149° C. Analysis for: C9 H11 N O3 Calcd: C, 59.66; H, 6.12; N, 7.73. Found: C, 59.42; H, 6.02; N, 7.69.
Reference：
[1] Patent: US5700796, 1997, A,
[2] Patent: US5753648, 1998, A,
[3] Patent: US5880122, 1999, A,
With palladium 10% on activated carbon; hydrogen; sodium sulfate In methanol for 1h;
7.3.461 7.3.461 N2,N4-Bis(3-methoxy-4-methoxycarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine (R945065)
The hydrogenation of methyl 2-methoxy-4-nitrobenzoate (700 mg, 3.3 mmol) in methanol (10 mL) catalyzed by 5% Pd-C (100 mg) and Na2SO4 (100 mg) at 50 psi for 1 h gave methyl 4-amino-2-methoxybenzoate (600 mg, quant.) as a white solid.
99%
With palladium 10% on activated carbon In methanol at 20℃; for 12h; Inert atmosphere; Autoclave;
36.A Part A. Methyl 4-amino-2-methoxybenzoate
To a solution of methyl 2-methoxy-4-nitrobenzoate (10.0 g, 0.047 mol) in MeOH (100 mL) was added Pd/C (4.0 g, 10 % w/w) under a nitrogen atmosphere in anautoclave and the reaction mixture was stirred at 45 psi (hydrogen atm) at room temperature for 12 h. The reaction mixture was passed through a Celite pad and the pad was washed with excess ethyl acetate. The filtrate was evaporated to dryness under reduced pressure to afford methyl 4-amino-2-methoxybenzoate (8.6 g, 0.048 mol, 99 % yield) as a brown solid. ‘H NMR (400 MHz, DMSO-d6) ö 7.52 (d, J 8.4Hz, 1H), 6.32 (s, 1H), 6.23-6.25 (m, 1H), 5.6 (bs, 2H), 3.72 (s, 3H), 3.67 (s, 3H); LCMS (ESI) m/e 182.2 [(M+H), calcd for C9H12N03, 182.07]; LC/MS retention time (method B): ti = 0.87 mm.
97%
With palladium 10% on activated carbon; hydrogen In methanol at 20℃; for 12h; Inert atmosphere;
110.A Part A. Methyl 4-amino-2-methoxybenzoate
To a solution of methyl 2-methoxy-4-nitrobenzoate (12.00 g, 56.86 mmol) in methanol (100 mL) at room temperature under nitrogen was added 10% palladium on carbon (4.88 g, 4.61 mmol). The resultant mixture was stirred under hydrogen (45 psi) for 12 h at room temperature. After the completion of reaction, the mixture was filtered through a diatomaceous earth (Celite) pad and the filtrate was concentratedunder reduced pressure to afford methyl 4-amino-2-methoxybenzoate (10 g, 97% yield) as a yellow solid: LCMS (ESI) m/e 182.2 [(M+H), calcd for C9H12N03, 182.1]; LC/MS retention time (method B): tp. = 0.87 min.
With nickel Hydrogenation;
With ethanol; platinum at 50℃; Hydrogenation;
With hydrogenchloride; iron
With hydrogenchloride; tin(ll) chloride
With hydrogen In ethanol at 20℃; for 2h;
16.b
A mixture of 2-methoxy-4-nitrobenzoic acid methyl ester (12 g, 57 mmol), palladium (10% on activated carbon), and ethanol (150 ml) was shaken at room temperature under 50psi of hydrogen for 2 hours. The reaction was filtered through diatomaceous earth, and the diatomaceous earth washed with chloroform. Evaporation of the chloroform washings gave a yellow solid. Purification by crystallization gave a light yellow crystalline solid (8.76 g) mp 148-149°C. Analysis for: C9 H11NO3 Calcd: C, 59.66; H, 6.12; N, 7.73. Found: C, 59.42; H, 6.02; N, 7.69
Stage #1: methyl 2-methoxy-4-nitrobenzoate With sodium hydroxide In methanol; water at 60℃; for 0.5h;
Stage #2: With hydrogenchloride In methanol; water
With sodium carbonate
With water; sodium hydroxide In tetrahydrofuran Reflux;
12
After purification, the methyl ester was cleaved using aqueous sodium hydroxide in tetrahydrofuran heated at reflux.
With Oxone; potassium hydroxide; disodium hydrogenphosphate; tetra(n-butyl)ammonium hydrogensulfate In dichloromethane; water; acetone at 0℃; pH=7.5-8.5;
Stage #1: 2-hydroxy-4-nitro-benzoic acid methyl ester With sodium hydride In DMF (N,N-dimethyl-formamide) at 50℃; for 1h;
Stage #2: methyl iodide at 20 - 80℃; for 4h;
1.b
2-methoxy-4-nitro-benzoic acid methyl ester 788 mg (4 mmol) of 2-hydroxy-4-nitro-benzoic acid methyl ester is mixed in 20 ml of absolute dimethylformamide with 177 mg of sodium hydride (60%; 4.4 mmol), and it is heated for 1 hour to 50 C. After cooling to room temperature, it is mixed with 625 mg (4.4 mmol) of methyl iodide and heated for 4 hours to a bath temperature of 80 C. After concentration by evaporation, it is taken up in 50 ml of water and extracted three times with 25 ml each of ethyl acetate. The ethyl acetate phase is washed with water, dried, filtered and concentrated by evaporation. The residue is chromatographed on 5 g of Isolute SI. (50 ?m) with a gradient from cyclohexane to cyclohexane:ethyl acetate=80:20 as an eluant, and 400 mg (47% of theory) of 2-methoxy-4-nitro-benzoic acid methyl ester is obtained as an oil.
47%
Stage #1: 2-hydroxy-4-nitro-benzoic acid methyl ester With sodium hydride In DMF (N,N-dimethyl-formamide) at 50℃; for 1h;
Stage #2: methyl iodide In DMF (N,N-dimethyl-formamide) at 20 - 80℃; for 4h;
1.b
788 mg (4 mmol) of 2-hydroxy-4-nitro-benzoic acid methyl ester is mixed in 20 ml of absolute dimethylformamide with 177 mg of sodium hydride (60%; 4.4 mmol), and it is heated for 1 hour to 50°C. After cooling to room temperature, it is mixed with 625 mg (4.4 mmol) of methyl iodide and heated for 4 hours to a bath temperature of 80°C. After concentration by evaporation, it is taken up in 50 ml of water and extracted three times with 25 ml each of ethyl acetate. The ethyl acetate phase is washed with water, dried, filtered and concentrated by evaporation. The residue is chromatographed on 5 g of Isolute SI (50 um) with a gradient from cyclohexane to cyclohexane: ethyl acetate = 80: 20 as an eluant, and 400 mg (47% of theory) of 2-methoxy-4-nitro-benzoic acid methyl ester is obtained as an oil.
With trimethylaluminum In toluene at 120℃; for 2.25h;
1.c
c.) 4-Nitro-N-(2-diethylammo-ethyl)-2-methoxy-benzamide 480 mg (2.27 mmol) of 2-methoxy-4-nitro-benzoic acid methyl ester is first mixed in 25 ml of toluene with 264 mg (0.32 ml; 2.27 mmol) of 2-N,N-diethylamino-ethylamine and then mixed quickly with 1.14 ml of trimethyl aluminum (2-molar in toluene). It is then heated for 2.25 hours to a bath temperature of 120° C. After cooling, it is mixed with 30 ml of dilute sodium bicarbonate solution and extracted three times with 25 ml each of ethyl acetate. The ethyl acetate phase is washed with water, dried, filtered and concentrated by evaporation. 300 mg (45% of theory) of 4-nitro-N-(2-diethylamino-ethyl)-2-methoxy-benzamide is obtained. The same compound can also be produced from the commercially available 2-hydroxy-4-nitro-benzoic acid: 5 g (25.4 mmol) of 2-hydroxy-4-nitro-benzoic acid is heated in 12 ml of thionyl chloride for 2 hours to 100° C.
45%
With trimethylaluminum In toluene at 120℃; for 2.25h;
1.c
480 mg (2.27 mmol) of 2-methoxy-4-nitro-benzoic acid methyl ester is first mixed in 25 ml of toluene with 264 mg (0.32 ml; 2.27 mmol) of 2-NN-diethylamino- ethylamine and then mixed quickly with 1.14 ml of trimethyl aluminum (2-molar in toluene). It is then heated for 2.25 hours to a bath temperature of 120°C. After cooling, it is mixed with 30 ml of dilute sodium bicarbonate solution and extracted three times with 25 ml each of ethyl acetate. The ethyl acetate phase is washed with water, dried, filtered and concentrated by evaporation. 300 mg (45% of theory) of 4-nitro-N-(2- diethylamino-ethyl) -2-methoxy-benzamide is obtained.
With thionyl chloride In methanol; dichloromethane
a Step a) 2-methoxy-4-nitrobenzoic acid methyl ester
Step a) 2-methoxy-4-nitrobenzoic acid methyl ester Thionyl chloride (13.9 ml, 190 mmol) was added via syringe to a solution of 2-methoxy-4-nitrobenzoic acid (50 g, 250 mmol) in methanol which was stirred at room temperature for 16 hours. The volatiles were removed in vacuo. The residue dissolved in dichloromethane, washed with (1N) sodium hydroxide, and the organic layer separated and dried (MgSO4). Evaporation in vacuo gave a light yellow solid (50 g, 93%) mp 80°-81° C., which was taken directly to the next step. Analysis for: C9 H9 N O5 Calcd: C, 51.19; H, 4.30; N, 6.63. Found: C, 50.97; H, 4.11; N, 6.51.
93%
With thionyl chloride In methanol; dichloromethane
a Step a) 2-methoxy-4-nitrobenzoic acid methyl ester
Step a) 2-methoxy-4-nitrobenzoic acid methyl ester Thionyl chloride (13.9 ml, 190 mmol) was added via syringe to a solution of 2-methoxy-4-nitrobenzoic acid (50 g, 250 mmol) in methanol which was stirred at room temperature for 16 hours. The volatiles were removed in vacuo. The residue dissolved in dichloromethane, washed with (1N) sodium hydroxide, and the organic layer separated and dried (MgSO4). Evaporation in vacuo gave a light yellow solid (50 g, 93%) mp 80°-81° C., which was taken directly to the next step. Analysis for: C9 H9 N O5 Calcd: C, 51.19; H, 4.30; N, 6.63. Found: C, 50.97; H, 4.11; N, 6.51.
With thionyl chloride In methanol; dichloromethane
16.a Step a) 2-Methoxy-4-nitrobenzoic acid methyl ester
Step a) 2-Methoxy-4-nitrobenzoic acid methyl ester Thionyl chloride (13.9 ml, 190 mrnol) was added, via syringe, to a solution of 4-nitro-2-methoxybenzoic acid (50 g, 250 mmol) and methanol which was stirred at room temperature. The reaction was stirred at room temperature for 16 hours. The volatiles were removed in vacuo. The residue dissolved in dichloromethane, washed with (1) sodium hydroxide, and the organic layer separated and dried (MgSO4). Evaporation in vacuo gave a light yellow solid (50 g) mp 80-81° C., which was taken directly to the next step. Analysis for: C9 H9 NO5 Calcd: C, 51.19; H, 4.30; N, 6.63. Found: C, 50.97; H, 4.11; N, 6.51.
b Step b) 4-amino-2-methoxy-benzoic acid methyl ester
Step b) 4-amino-2-methoxy-benzoic acid methyl ester A mixture of 2-methoxy-4-nitrobenzoic acid methyl ester (12 g, 57 mmol), palladium (10% on activated carbon), and ethanol (150 ml) was shaken at room temperature under 50 psi of hydrogen for 2 hours. The reaction was filtered through diatomaceous earth, and the diatomaceous earth washed with chloroform. Evaporation of the chloroform washings gave a yellow solid; purification by crystallization gave a light yellow crystalline solid (8.76 g, 85%) mp 148°-149° C. Analysis for: C9 H11 N O3 Calcd: C, 59.66; H, 6.12; N, 7.73. Found: C, 59.42; H, 6.02; N, 7.69.
85%
With hydrogen In ethanol
b Step b) 4-amino-2-methoxy-benzoic acid methyl ester
Step b) 4-amino-2-methoxy-benzoic acid methyl ester A mixture of 2-methoxy-4-nitrobenzoic acid methyl ester (12 g, 57 mmol), palladium (10% on activated carbon), and ethanol (150 ml) was shaken at room temperature under 50psi of hydrogen for 2 hours. The reaction was filtered through diatomaceous earth, and the diatomaceous earth washed with chloroform. Evaporation of the chloroform washings gave a yellow solid; purification by crystallization gave a light yellow crystalline solid (8.76 g, 85%) mp 148°-149° C. Analysis for: C9 H11 N O3 Calcd: C, 59.66; H, 6.12; N, 7.73. Found: C, 59.42; H, 6.02; N, 7.69.
With hydrogen In ethanol
16.b Step b) 4-Amino-2-methoxy-benzoic acid methyl ester
Step b) 4-Amino-2-methoxy-benzoic acid methyl ester A mixture of 2-methoxy-4-nitrobenzoic acid methyl ester (12 g, 57 mmol), palladium (10% on activated carbon), and ethanol (150 ml) was shaken at room temperature under 50 psi of hydrogen for 2 hours. The reaction was filtered through diatomaceous earth, and the diatomaceous earth washed with chloroform. Evaporation of the chloroform washings gave a yellow solid. Purification by crystallization gave a light yellow crystalline solid (8.76 g) mp 148-149° C. Analysis for: C9 H11 NO3 Calcd: C, 59.66; H, 6.12; N, 7.73. Found: C, 59.42; H, 6.02; N, 7.69.
16.a
Thionyl chloride (13.9 ml, 190 mmol) was added, via syringe, to a solution of 4-nitro-2-methoxybenzoic acid (50 g, 250 mmol) and methanol which was stirred at room temperature. The reaction was stirred at room temperature for 16 hours. The volatiles were removed in vacuo . The residue dissolved in dichloromethane, washed with (1N) sodium hydroxide, and the organic layer separated and dried (MgSO4). Evaporation in vacuo gave a light yellow solid (50 g) mp 80-81°C, which was taken directly to the next step. Analysis for: C9H9NO5 Calcd: C, 51.19; H, 4.30; N, 6.63. Found: C, 50.97; H, 4.11; N, 6.51
With potassium carbonate In N,N-dimethyl-formamide at 20℃;
7.3.461 7.3.461 N2,N4-Bis(3-methoxy-4-methoxycarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine (R945065)
In a manner analogous to the preparation of N2,N4-bis[4-(2-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine, 2-methoxy-4-nitrobenzoic acid (1 g, 5 mmol), potassium carbonate (1.4 g, 10 mmol) and iodomethane (0.47 mL, 7.5 mmol) gave methyl 2-methoxy-4-nitrobenzoate (820 mg, 77%) as a white solid.
With aluminum (III) chloride In chloroform at -10 - 45℃; for 5.7h;
3.a Example 3
A) 3 kg of trichloromethane, 232 g of methyl 2-methoxy-4-nitrobenzoate was added to the drying reaction flask,Cooling to -10 , into the anhydrous aluminum trichloride 219g, control temperature 0-25 ,164 g of 3-chloroacryloyl chloride was added dropwise to the reaction flask, and the mixture was stirred at room temperature for 1.2 hours,The temperature was raised to 45 ° C for 4.5 hours, cooled to 1 ° C, and the reaction solution was poured into 2000 ml of cold 6N hydrochloric acid,Stirring for 1.2 hours, pumping the product, purified water to neutral, 60 drying compound II 301g,Yield 91.4%.
With ethanol; hydrazine hydrate monohydrate at 80℃; for 2h;
61 Reference Example 61: Preparation of Intermediate I-61
Intermediate I-60 (178 mg, 0.84 mmol) was dissolved in ethanol (2 mL) at room temperature, 80% hydrazine hydrate (10 mL) was added, and the reaction solution was stirred at 80 °C for 2 hours. The reaction solution was concentrated to dryness, separated and purified by silica gel chromatography to obtain intermediate I-61.
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