* 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.
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
2
[ 65-49-6 ]
[ 77-78-1 ]
[ 27492-84-8 ]
Yield
Reaction Conditions
Operation in experiment
92.1%
With potassium hydroxide In acetone at 25℃; for 5.5 h; Large scale
(1) the bottle in the four port by adding 2 kg (13.06mol) P-amino-salicylic acid and 2.3 kg (40.10mol) grind garrulous potassium hydroxide, then adding 6 liter acetone solution, and strongly stirring. The temperature dropped to 25 °C, began to gradually dropwise 3 + (31.68mol) of sulfuric acid dimethyl ester. After dropping, to continue reaction 5.5 hours. Reaction-end splines, in addition to evaporating the solvent, and by adding 8 liters of water to dissolve, then using 25 liter of ethyl acetate extracted three times, the final combined ethyl acetate, drying the spin vaporization 2.18 kg of 4-amino-2-methoxy-benzoic acid methyl ester, in the yield of 92.1percent.
92.82%
With sodium hydroxide In acetone at 20℃; for 6 h;
1.1) After adding acetone (118.2 g, 20.37 mol) to a 500 mL three-necked flask,Further adding p-aminosalicylic acid (15.3 g, 0.1 mol) and sodium hydroxide (15.12 g, 0.27 mol), and stirring uniformly to obtain a mixture A;1.2) dimethyl sulfate (32.35g, 0.257mol) was added dropwise to the mixture A obtained in the step 1.1), after the completion of the dropwise addition, the mixture B was obtained;1.3) The mixture B is placed under room temperature conditions, after 6h to obtain a mixture C;1.4) The mixture C obtained in step 1.3) is filtered, the solid obtained after filtration is washed and dried to obtain compound II (yield 92.82percent);The washing process is: first washing with a 5percent sodium hydrogen carbonate solution,Use water again for washing
72%
With tetrabutylammomium bromide; potassium hydroxide In acetone at 25 - 35℃; for 1 h; Industry scale
4-Amino salicylic acid (VI) (2 kg) was added in acetone (12 lit) under stirring. Tetrabutyl ammonium bromide (2.09 kg) was added followed by addition of potassium hydroxide (2.18 kg) and the reaction mass was stirred. To the reaction mass dimethyl sulphate (3.89 kg) was added dropwise at 25-35°C. Stirring was continued at 25-35°C for 60 min. Reaction mass was quenched in prechilled water (30 Lit) at 0-5°C. Reaction mass was stirred and solid obtained by filtration under suction. Solid was washed with water and dried under suction. The wet solid was leached with methanol (2 Lit) at 60-65°C. The reaction mass was cooled to 0-5°C and solid was obtained by filtration, dried under vacuum.Yield : 72percentPurity: 98percent
63.4%
With potassium hydroxide In acetone at 20℃;
[0541| To a stirred solution of 269-1 (20.0 g, 130.68 mmol) in acetone (400 mL) was added KOH (18.4 g, 15 mmol) and (CH3)2S04 (29.4 mL, 318.9 mmol). The mixture was stirred at r.t. overnight. The solvent was evaporated at low pressure, and the residue was dissolved in hot water. The pH was adjusted to 9 with 1 N NaOH solution. After cooling to r.t., the precipitate was filtered off and thoroughly washed with cold EtOAc to give 269-2 as a light yellow powder (23.66 g, 63.4percent). +ESl-MS:m/z 181.8 [M+H]+.
Reference：
[1] Patent: CN105237422, 2016, A, . Location in patent: Paragraph 0018; 0019; 0020
[2] Patent: CN107629001, 2018, A, . Location in patent: Paragraph 0112; 0114-0118; 0148-0154; 0185-0190; 0221-0226
[3] Heterocycles, 2003, vol. 60, # 7, p. 1653 - 1672
[4] Patent: WO2011/158084, 2011, A1, . Location in patent: Page/Page column 10
[5] Patent: WO2015/26792, 2015, A1, . Location in patent: Paragraph 0541
[6] Chemical and Pharmaceutical Bulletin, 1997, vol. 45, # 12, p. 2079 - 2084
[7] Archiv der Pharmazie, 1995, vol. 328, # 7-8, p. 585 - 594
[8] Journal of Labelled Compounds and Radiopharmaceuticals, 2001, vol. 44, p. S225 - S227
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,
4
[ 67-56-1 ]
[ 2486-80-8 ]
[ 27492-84-8 ]
Yield
Reaction Conditions
Operation in experiment
86%
at 0℃; Heating / reflux
2.9 g of 4-amino-2-methoxy-benzoic acid (77.17 mmol) was dissolved in 200 mL MeOH. At 0° C., to this solution was added 2 eq SOCl2 (12.5 mL, 154.24 mmol) The reaction mixture was heated to reflux temperature overnight. After solvent and excess of SOCl2 were removed under reduced pressure, the residue was suspended in 10percent Na2CO3. The precipitate that formed was solution was filtered and filter cake was washed with cold water until the washing became neutral. The product was then dried under vacuum at 50° C. About 12.04 g product was obtained after drying (86percent). M+H+(182).
Reference：
[1] Journal of the Indian Chemical Society, 1994, vol. 71, # 6-8, p. 345 - 354
[2] Chemistry - A European Journal, 2012, vol. 18, # 24, p. 7377 - 7381
9
[ 6935-15-5 ]
[ 27492-84-8 ]
Reference：
[1] Chemistry - A European Journal, 2012, vol. 18, # 24, p. 7377 - 7381
10
[ 619-19-2 ]
[ 27492-84-8 ]
Reference：
[1] Archiv der Pharmazie (Weinheim, Germany), 1951, vol. 284, p. 341,346
11
[ 13684-28-1 ]
[ 27492-84-8 ]
Reference：
[1] Archiv der Pharmazie (Weinheim, Germany), 1951, vol. 284, p. 341,346
12
[ 186581-53-3 ]
[ 2486-80-8 ]
[ 27492-84-8 ]
Reference：
[1] Archiv der Pharmazie (Weinheim, Germany), 1951, vol. 284, p. 341,346
13
[ 77-78-1 ]
[ 4136-97-4 ]
[ 27492-84-8 ]
[ 106868-33-1 ]
Reference：
[1] Journal of the Indian Chemical Society, 1994, vol. 71, # 6-8, p. 345 - 354
14
[ 27492-84-8 ]
[ 7206-70-4 ]
Reference：
[1] Organic Preparations and Procedures International, 1992, vol. 24, # 1, p. 64 - 66
15
[ 27492-84-8 ]
[ 364-62-5 ]
Reference：
[1] Archiv der Pharmazie, 1980, vol. 313, # 4, p. 297 - 300
16
[ 27492-84-8 ]
[ 108-24-7 ]
[ 4093-29-2 ]
Yield
Reaction Conditions
Operation in experiment
88%
Stage #1: at 60 - 65℃; for 2 h; Stage #2: With sodium hydrogencarbonate In water
To a solution of methyl 4-amino-2^methoxybenzoate (501 mg, 2.77 mmol) in ethanol (8 ml) was added acetic anhydride (0.42 ml, 4.44 mmol, 1.6 eq) and the clear solution heated at 60-65 °C for 2 h. After cooling to room temperature the solvent was removed by rotary evaporator and the residue treated with water (10 ml) and saturated sodium bicarbonate solution (10 ml) before extracting with ethyl acetate (20 ml, 2 x 10 ml). The combined ethyl acetate extract was washed with water, then brine, dried (MgSC>4) and evaporated to give methyl 4-acetamido-2-methoxybenzoate (545 mg, 88percent) as a white solid. 'H nmr1 (400 MHz, c1/4-dmso) δ 2.07, s, 3H, 4-AcNH; 3.74, s, 3H, 2-OMe or COOMe; 3.77, s, 3H, COOMe or 2-OMe; 7.19, br d (J = 8.8 Hz), IH, H5; 10.22, s, IH, NH.Ref. 17: J. Med. Chem. 2007, 50(15), 3561-3572.
84.1%
at 50℃; for 2 h;
[0542] To a solution of 269-2 (14.4 g, 8 mmol) in EtOH (120 mL) was added acetic anhydride (9.0 g, 88 mmol). The mixture was allowed to stir at 50 °C for 2 h. The mixture was cooled to r.t., and neutralized with aqueous NaHC03 solution. The mixture was extracted with EA (3 x 60 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated at low pressure. The residue was purified by flash column chromatography on silica gel (PE:EA 1 : 1 ) to give 269-3 (15.0 g. 84.1 percent). +ESI-MS:m/z 223.9 [M+H]+.
Reference：
[1] Journal of Medicinal Chemistry, 2007, vol. 50, # 15, p. 3561 - 3572
[2] Patent: WO2011/123890, 2011, A1, . Location in patent: Page/Page column 118-119
[3] Patent: WO2015/26792, 2015, A1, . Location in patent: Paragraph 0542
[4] Archiv der Pharmazie, 1980, vol. 313, # 4, p. 297 - 300
[5] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 7, p. 2311 - 2315
17
[ 27492-84-8 ]
[ 75-36-5 ]
[ 4093-29-2 ]
Yield
Reaction Conditions
Operation in experiment
100%
Stage #1: With triethylamine In dichloromethane at 0℃; for 0.25 h; Stage #2: at 20℃;
To a stirred solution of methyl 4-amino-2-methoxybenzoate (10 g, 55 mmol) in dichloromethane (100 mL) was added triethylamine (15.4 mL, 110 mmol) at 0 °C and the mixture was stirred for 15 mm. To this mixture, acetyl chloride (5.68 g, 71 mmol) was added drop wise and the mixture was stirred at room temperature overnight. The reaction was quenched by addition of water (75 mL). The organiclayer was separated, washed with brine solution (100 mL), dried over sodium sulfate and concentrated under reduced pressure to afford methyl 4-acetamido-2- methoxybenzoate (13.0 g, 58.2 mmol, quantitative yield) as a yellow solid: LCMS (ESI) m/e 224.2 [(M+H), calcd for C11H14N04, 224.1]; LC/MS retention time (method B): tR = 1.21 mm.
91%
Stage #1: With triethylamine In dichloromethane at 0℃; for 0.166667 h; Stage #2: for 3 h;
To a solution of methyl 4-amino-2-methoxybenzoate (2.0 g, 0.0 11 mol) in DCM (50 mL) cooled to 0 °C was added triethylamine (3.0 mL, 0.022 mol) and the reaction mixture was stirred for 10 minutes. Acetyl chloride (1.3 g, 0.0 165 mol) was addeddropwise and the reaction was stirred for 3 h. Water (50 mL) was added and the aqueous layer was extracted with DCM (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and volatiles were evaporated to dryness under reduced pressure to give methyl 4-acetamido-2-methoxybenzoate (2.3 g, 0.01 mol, 91percent yield) as a light brown solid. ‘H NMR (400 MHz, DMSO-d6) ö 10.22 (s,1H), 7.66 (d, J= 8.8 Hz, 1H), 7.47 (d, J= 1.6 Hz, 1H), 7.20 (dd, J 8.4, 2.0 Hz, 1H),3.74-3.79 (m, 6H), 2.07 (s, 3H); LCMS (ESI) m/e 224.2 [(M+H), calcd for C11H14NO4, 224.08]; LC/MS retention time (method B): ti = 1.20 mm.
The starting material was prepared as follows: 3-Methoxy-4-methoxycarbonylaniline (14.15 g, 78 mmol) was suspended in isopropanol and heated at 50° C. 2,2-Dimethyl-5-methoxymethylene-1,3-dioxane-4,6-dione (14.8 g, 80 mmol), (Montatsh. Chem. 1967, 98, 564), was then added in portions over 10 minutes and the mixture was heated at reflux for 30 minutes.. The mixture was left to cool to ambient temperature overnight.. The precipitate formed was collected by filtration, washed with isopropanol and dried under vacuum to give 5-((3-methoxy-4-methoxycarbonylanilino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (25.2 g, 96percent).
95%
at 70℃; for 1 h;
Methyl 4-amino-2-methoxy-benzoate (1.07 g) and 5-methoxymethylene-2,2-dimethyl-[1,3]dioxan-4,6-dione (1.0 g) were dissolved in 2-propanol (20 ml), and the mixture was stirred at 70°C for one hr. The solvent was removed by distillation under the reduced pressure, and the residue was washed with ether to give methyl 4-[(2,2-dimethyl-4,6-dioxo-[1,3]dioxan-5-ylidenemethyl)-amino]-2-methoxy-benzoate (1.71 g, yield 95percent). Methyl 4-[(2,2-dimethyl-4,6-dioxo-[1,3]dioxan-5-ylidenemethyl)-amino ]-2-methoxy-benzoate (1.70 g) and biphenyl (4.76 g) were suspended in diphenyl ether (15 ml), and the suspension was stirred at 240°C for one hr. The suspension was cooled to room temperature, and the precipitated crystal was collected by filtration and was washed with ether. The crystal thus obtained as such was used in the next reaction without further purification. N,N-Dimethylformamide (2 drops) was added to the crystal thus obtained. Further, phosphorus oxychloride (2.5 ml) was added thereto, and the mixture was stirred at 100°C for 2 hr. The solvent was removed by distillation under the reduced pressure, and water was added to the residue under ice cooling. The aqueous layer was neutralized with an aqueous sodium hydrogencarbonate solution, and the organic layer was extracted with ethyl acetate. The ethyl acetate layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography with a methanol-chloroform system to give methyl 4-chloro-7-methoxy-quinoline-6-carboxylate (707 mg, yield 55percent) (2 steps).
Reference：
[1] Patent: US6809097, 2004, B1, . Location in patent: Page column 67
[2] Patent: EP1724268, 2006, A1, . Location in patent: Page/Page column 48
[3] Journal of Medicinal Chemistry, 2008, vol. 51, # 6, p. 1649 - 1667
[4] Journal of Medicinal Chemistry, 2008, vol. 51, # 6, p. 1668 - 1680
25
[ 2033-24-1 ]
[ 27492-84-8 ]
[ 149-73-5 ]
[ 205448-64-2 ]
Yield
Reaction Conditions
Operation in experiment
89.62%
at 90℃; for 1 h;
Methyl 2-methoxy-4-amino-benzoate (500.00 g, 2.76 mol), 2,2-dimethyl-1,3-dioxane-4,6-dione (397.73 g, 2.76 mol) and trimethyl orthoformate (292.84 g, 2.76 mol) were added to isopropanol (5.00 L). The reaction solution was heated up to an outer temperature of 90 °C and kept refluxing for 1 hour. The completion of the reaction was detected by TLC. The reaction solution was cooled to an outer temperature of 20 °C in an ice bath and then filtered. The solid was washed with MTBE (300 ml * 2) and then concentrated to dryness in a water bath. Compound 1A (873.00 g, 2.47 mol, the yield was 89.62percent and the purity was 95percent) was obtained as a light red powder. NMR (DMSO) demonstrated that the product was correct. 1H NMR (400 MHz, DMSO-d6) ppm 1.67 (s, 6 H) 3.76 (s, 3 H) 3.86 (s, 3 H) 7.19 (dd, J=8.41, 1.63 Hz, 1 H) 7.43 (d, J=1.25 Hz, 1 H) 7.71 (d, J=8.28 Hz, 1 H) 8.69 (d, J=10.04 Hz, 1 H) 11.25 (d, J=9.03 Hz, 1 H)
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
With Oxone; potassium hydroxide; disodium hydrogenphosphate; tetra(n-butyl)ammonium hydrogensulfate In dichloromethane; water; acetone at 0℃; pH=7.5-8.5;
To a solution of methyl 4-amino-2^methoxybenzoate (501 mg, 2.77 mmol) in ethanol (8 ml) was added acetic anhydride (0.42 ml, 4.44 mmol, 1.6 eq) and the clear solution heated at 60-65 C for 2 h. After cooling to room temperature the solvent was removed by rotary evaporator and the residue treated with water (10 ml) and saturated sodium bicarbonate solution (10 ml) before extracting with ethyl acetate (20 ml, 2 x 10 ml). The combined ethyl acetate extract was washed with water, then brine, dried (MgSC>4) and evaporated to give methyl 4-acetamido-2-methoxybenzoate (545 mg, 88%) as a white solid. 'H nmr1 (400 MHz, c¼-dmso) delta 2.07, s, 3H, 4-AcNH; 3.74, s, 3H, 2-OMe or COOMe; 3.77, s, 3H, COOMe or 2-OMe; 7.19, br d (J = 8.8 Hz), IH, H5; 10.22, s, IH, NH.Ref. 17: J. Med. Chem. 2007, 50(15), 3561-3572.
84.1%
In ethanol; at 50℃; for 2h;
[0542] To a solution of 269-2 (14.4 g, 8 mmol) in EtOH (120 mL) was added acetic anhydride (9.0 g, 88 mmol). The mixture was allowed to stir at 50 C for 2 h. The mixture was cooled to r.t., and neutralized with aqueous NaHC03 solution. The mixture was extracted with EA (3 x 60 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated at low pressure. The residue was purified by flash column chromatography on silica gel (PE:EA 1 : 1 ) to give 269-3 (15.0 g. 84.1 %). +ESI-MS:m/z 223.9 [M+H]+.
With N-iodo-succinimide In acetonitrile at 0 - 20℃; for 3h; Inert atmosphere;
90%
With Iodine monochloride In methanol for 1h;
68 Preparation of methyl 4-amino-5-iodo-2-methoxybenzoate (Compound 68D)
Iodine monochloride (0.54mL, 10.5mmol)Add to methyl 4-amino-2-methoxybenzoate (1.8 g, 10 mmol)Stirring was continued for 1 hour in the methanol solution. The reaction solution is poured into water,Extracted with ethyl acetate (3×50 mL), washed with saturated brineFilter, spin dry petroleum ether / ethyl acetate (3/1)The compound 68D (2.7 g, 90% yield) was isolated and purified.
73%
With water; sodium bisulfate hydrate; sodium iodide In acetonitrile for 51h; Irradiation;
25 Synthesis of Compound 3c
In a 25mL reaction tube, add methyl 4-amino-2-methoxybenzoate (33.8mg, 0.2mmol), sodium iodide (89.9mg, 0.6mmol), sodium bisulfate hydrate (82.8mg, 0.6 mmol), water (72mg, 4mmol) and acetonitrile (2mL), stirred under the irradiation of three 2-watt LED lamps for 51 hours. After the reaction was completed, extracted, dried, filtered, concentrated, and separated by column chromatography to obtain a white solid 3c ( 45 mg, 73%);
73%
With sodium hydrogensulfate monohydrate; water; sodium iodide In acetonitrile at 20℃; for 51h; Schlenk technique; Irradiation; Green chemistry;
With Iodine monochloride In acetic acid
With N-iodo-succinimide In acetonitrile at 0 - 20℃; for 2h;
Methyl 4-amino-5-iodo-2-methoxybenzoate (22)
To a 0°C solution of methyl 4-amino-2-methoxybenzoate 5 (3.0 g, 16.6 mmol, 1.0 eq.) in MeCN (100 mL) was added N-iodosuccinimide (3.91 g, 17.4 mmol, 1.05 eq.). The resulting mixture was then stirred at rt for 2h. The mixture was then concentrated and partitioned between AcOEt and sat. aq. NaHCO3. The organic phase was washed with sat. aq. NaHCO3 (2x) and brine (1x), dried (MgSO4) and concentrated under reduced pressure. The product (5.05 g, quant.) was used for the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 3.81 (s, 3H), 3.82 (s, 3H), 4.52 (br. s, 2H), 6.27 (s, 1H), 8.16 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 51.6, 55.9, 71.5, 97.1, 111.1, 142.8, 151.6, 161.7, 164.8; HRMS (ESI+) m/z calcd for C9H11INO3 [M + H]+ 307.9778, found: 307.9794.
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0℃; for 2.25h;
To a cooled (0C) solution of phosgene (20% solution in toluene, 2.76 ml, 5.52 MMOL) in dry DICHLOROMETHANE (75 ml) was added, under an argon atmosphere, methyl 4-amino-2- methoxybenzoate (1 G, 5.52 MMOL) in one portion, followed by a dropwise addition of diisopropylethylamine (1.92 ML, 11.04 MMOL). The mixture was stirred for 15 minutes at 0C prior to the addition of 2-bromo-4 (trifluoromethoxy) aniline (0.83 ML, 5.52 MMOL). The reaction mixture was stirred at 0C for a further 2 hours and then was allowed to stir at room temperature overnight. The organic phase was washed with 1 N aq. HCI (2x), sat. aq. NAHCO3, dried over MGS04 and concentrated in vacuo to give a solid residue which was recrystallized in hot acetonitrile. The fine crystalline solid was filtered off, washed with cold acetonitrile and dried in vacuo to give the title compound Ex 106 as a pale-orange solid (1. 64G, 3.54 mmol, 64%). 'H-NMR (DMSO-d6) : 6 3.74 (s, 3H), 3.80 (s, 3H), 7.02 (d, 1H), 7.38 (s, 1H), 7.42 (d, 1H), 7.69 (d, 1H), 7.74 (s, 1H), 8.17 (d, 1H), 8.36 (s, 1H), 9.85 (s, 1H)
With potassium iodide; iodine; sodium nitrite In hydrogenchloride; water; ethyl acetate
110 2-Chloro-4-iodo-benzoic Acid, Methyl Ester
EXAMPLE 110 2-Chloro-4-iodo-benzoic Acid, Methyl Ester 4-Amino-2-methoxy-benzoic acid methyl ester (22.97 g) was cooled to an internal temperature of -10° C. in concentrated hydrochloric acid (110 ml) and stirred as a suspension. A precooled solution of sodium nitrite (98.71 g) in water (45 ml) was added to this mixture, at such a rate so as to maintain a reaction temperature of less than 0° C. After stirring for 25 minutes at 0° C. the reaction was treated with a solution of potassium iodide (24.44 g) and iodine (18.37 g) in water (50 ml) at such a rate so as to maintain a reaction temperature of less than -4° C. Ethyl acetate (100 ml) was added during the addition and the dark mixture was stirred at 0° C. for one hour. The organic layer was diluted with ethyl acetate and washed well with saturated sodium thiosulfate solution. The resulting orange solution was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo to yield an oil which was purified by suction filtration through silica gel eluding with hexane/ethyl acetate (50/1). The resulting purified oil solidified on cooling to give 33.71 g of the title compound. MS, m/z: 296 (M)+.
Stage #1: Methyl 4-amino-2-methoxybenzoate With hydrogenchloride; sodium nitrite In water at 0℃; for 0.416667h;
Stage #2: With iodine; potassium iodide In water; ethyl acetate at -4 - 0℃; for 1h;
110 REFERENCE EXAMPLE 110; 2-Chloro-4-iodo-benzoic acid, methyl ester
REFERENCE EXAMPLE 110 2-Chloro-4-iodo-benzoic acid, methyl ester 4-Amino-2-methoxy-benzoic acid methyl ester (22.97 g) was cooled to an internal temperature of -10°C in concentrated hydrochloric acid (110 ml) and stirred as a suspension.. A precooled solution of sodium nitrite (98.71 g) in water (45 ml) was added to this mixture, at such a rate so as to maintain a reaction temperature of less than 0°C. After stirring for 25 minutes at 0 °C the reaction was treated with a solution of potassium iodide (24.44 g) and iodine (18.37 g) in water (50 ml) at such a rate so as to maintain a reaction temperature of less than -4°C. ethyl acetate (100 ml) was added during the addition and the dark mixture was stirred at 0 °C for one hour.. The organic layer was diluted with ethyl acetate and washed well with saturated sodium thiosulfate solution.. The resulting orange solution was washed with brine and dried over anhydrous magnesium sulfate.. The solvent was evaporated invacuo to yield an oil which was purified by suction filtration through silica gel eluding with hexane/ethyl acetate (50/1).. The resulting purified oil solidified on cooling to give 33.71 g of the title compound. MS, m/z: 296 (M)+.
In isopropyl alcohol; at 50 - 80℃; for 2.5h;Cooling with ice;
To a mixture of Compound 1 (20 g, 110.38 mmol, 1 eq) in IPA (200 mL) was added Compound 2 (21 g, 112.80 mmol, 1.02 eq) in portions at 50 C. The mixture was stirred at 80 C for 2 h, then cooled down in an ice-water bath for 0.5 h. The resulting mixture was filtered, and the solid was washed with z-PrOH (5 mL) and dried under vacuum to give Compound 3 as a white solid (36 g, 97.3% yield). 1H NMR (400 MHz, DMSO-d6) 11.26 (br s, 1H), 8.71 (br s, 1H), 7.73 (d, 1H), 7.44 (d, 1H), 7.20 (dd, 1H), 3.87 (s, 3H), 3.77 (s, 3H), 1.68 (s, 6H).
96%
In isopropyl alcohol; at 50℃; for 0.666667h;Heating / reflux;
The starting material was prepared as follows: 3-Methoxy-4-methoxycarbonylaniline (14.15 g, 78 mmol) was suspended in isopropanol and heated at 50 C. 2,2-Dimethyl-5-methoxymethylene-1,3-dioxane-4,6-dione (14.8 g, 80 mmol), (Montatsh. Chem. 1967, 98, 564), was then added in portions over 10 minutes and the mixture was heated at reflux for 30 minutes.. The mixture was left to cool to ambient temperature overnight.. The precipitate formed was collected by filtration, washed with isopropanol and dried under vacuum to give 5-((3-methoxy-4-methoxycarbonylanilino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (25.2 g, 96%).
95%
In isopropyl alcohol; at 70℃; for 1h;
Methyl 4-amino-2-methoxy-benzoate (1.07 g) and 5-methoxymethylene-2,2-dimethyl-[1,3]dioxan-4,6-dione (1.0 g) were dissolved in 2-propanol (20 ml), and the mixture was stirred at 70C for one hr. The solvent was removed by distillation under the reduced pressure, and the residue was washed with ether to give methyl 4-[(2,2-dimethyl-4,6-dioxo-[1,3]dioxan-5-ylidenemethyl)-amino]-2-methoxy-benzoate (1.71 g, yield 95%). Methyl 4-[(2,2-dimethyl-4,6-dioxo-[1,3]dioxan-5-ylidenemethyl)-amino ]-2-methoxy-benzoate (1.70 g) and biphenyl (4.76 g) were suspended in diphenyl ether (15 ml), and the suspension was stirred at 240C for one hr. The suspension was cooled to room temperature, and the precipitated crystal was collected by filtration and was washed with ether. The crystal thus obtained as such was used in the next reaction without further purification. N,N-Dimethylformamide (2 drops) was added to the crystal thus obtained. Further, phosphorus oxychloride (2.5 ml) was added thereto, and the mixture was stirred at 100C for 2 hr. The solvent was removed by distillation under the reduced pressure, and water was added to the residue under ice cooling. The aqueous layer was neutralized with an aqueous sodium hydrogencarbonate solution, and the organic layer was extracted with ethyl acetate. The ethyl acetate layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography with a methanol-chloroform system to give methyl 4-chloro-7-methoxy-quinoline-6-carboxylate (707 mg, yield 55%) (2 steps).
49.B
2.9 g of 4-amino-2-methoxy-benzoic acid (77.17 mmol) was dissolved in 200 mL MeOH. At 0° C., to this solution was added 2 eq SOCl2 (12.5 mL, 154.24 mmol) The reaction mixture was heated to reflux temperature overnight. After solvent and excess of SOCl2 were removed under reduced pressure, the residue was suspended in 10% Na2CO3. The precipitate that formed was solution was filtered and filter cake was washed with cold water until the washing became neutral. The product was then dried under vacuum at 50° C. About 12.04 g product was obtained after drying (86%). M+H+(182).
Example 15A; 2-Methoxy-4-[(thiazol-5-ylmethyl)-amino]-benzoic acid methyl ester; To a solution of methyl 4-amino-2-methoxybenzoate (1.50 g, 8.3 mmol) in dichloroethane (30 mL) was added to <strong>[1003-32-3]thiazole-5-carboxaldehyde</strong> (0.98 g, 8. 7 mmol) and followed by a few drops of acetic acid. The reaction was stirred at room temperature for 1 h and followed by addition of sodium triacetoxyborohydride (3.76 g, 17.7 mmol) in portions. The resulting reaction mixture was stirred at room temperature overnight. The reaction was quenched with water and 1N aq. NaOH solution and extracted with dichloromethane (3x). The combined organic extracts were dried (Na2S04) and concentrated. The crude was purified by flash column chromatography on silica gel to give 2-methoxy-4-[(thiazol-5-ylmethyl)-amino]-benzoic acid methyl ester as a tan colored oil in 90% yield (2.04 g).'H NMR (300 MHz, CDC13) 3.83 (s, 3H), 3.84 (s, 3H), 4.64 (d, J=1. OHz, 2H), 6.16 (d, J= 2.2Hz, 1H), 6.23 (dd, J=2.2, 8.6Hz, 1H), 7.78 (d, J=8.6Hz, 1H), 7.83 (d, J=0. 8Hz, 1H), 8.75 (d, J=0.7Hz, 1H).
With potassium iodide; sulfuric acid; iodine; sodium nitrite In water
27.A Step A.
Step A. 4-Iodo-2-methoxybenzoic Acid Methyl Ester 4-Amino-2-methoxybenzoic acid methyl ester (3.0 g, 16.6 mmol) was suspended in water (40 mL) and concentrated sulfuric acid (10 mL). The suspension was cooled in an ice/salt water bath, and an aqueous solution (10 mL) of sodium nitrite (1.26 g, 18.3 mmol) was added dropwise so that the temperature remained close to 0° C. After the addition, a homogeneous, yellow-green solution was obtained. An aqueous solution (60 mL) of potassium iodide (3.02 g, 18.2 mmol) and iodine (2.31 g, 9.1 mmol) was then added dropwise, and the reaction stirred for an additional 1 hour. The reaction mixture was then extracted with ethyl acetate, the organic extracts were combined and washed with 1 N sodium thiosulfate, 1 N sodium hydroxide and brine. After drying over anhydrous sodium sulfate the solution was filtered and concentrated in vacuo to give 2.7 g of the title product as an orange oil which was used in the next step. 1H NMR (DMSO-d6, 400 MHz): δ 2.76 (s, 3H), 3.82 (s, 3H), 7.39 (s, 2H), 7.48 (s, 1H). MS [El, m/z]: 292 [M]+.
With potassium iodide; sulfuric acid; iodine; sodium nitrite In water
13.A Step A.
Step A. 4-Iodo-2-methoxybenzoic acid methyl ester 4-Amino-2-methoxybenzoic acid methyl ester (3.0 g, 16.6 mmol) was suspended in water (40 mL) and concentrated sulfuric acid (10 mL). The suspension was cooled in an ice/salt water bath, and an aqueous solution (10 mL) of sodium nitrite (1.26 g, 18.3 mmol) was added dropwise so that the temperature remained close to 0° C. After the addition, a homogeneous, yellow-green solution was obtained. An aqueous solution (60 mL) of potassium iodide (3.02 g, 18.2 mmol) and iodine (2.31 g, 9.1 mmol) was then added dropwise, and the reaction stirred for an additional 1 hour. The reaction mixture was then extracted with ethyl acetate, the organic extracts were combined and washed with 1 N sodium thiosulfate, 1 N sodium hydroxide and brine. After drying over anhydrous sodium sulfate the solution was filtered and concentrated in vacuo to give 2.7 g of the title product as an orange oil which was used in the next step. 1H NMR (DMSO-d6, 400 MHz): δ2.76 (s, 3H), 3.82 (s, 3H), 7.39 (s, 2H), 7.48 (s, 1H). MS [El, m/z]: 292 [M]+.
The 4-(4-chloro-2-fluorophenoxy)-7-methoxyquinoline-6-carboxylic acid used as a starting material was prepared as follows: A suspension of methyl 4-amino-2-methoxybenzoate (26.5 g) in isopropanol (500 ml) was stirred and heated to 50 C. for 10 minutes. 2,2-Dimethyl-5-methoxymethylene-1,3-dioxane-4,6-dione (methoxymethylene Meldrum's Acid, 25.6 g) was added and the resultant suspension was warmed to 80 C. and stirred for 40 minutes. The reaction mixture was allowed cool to ambient temperature and the white precipitate was isolated and washed with diethyl ether. There was thus obtained 2,2-dimethyl-5-(3-methoxy-4-methoxycarbonyl-anilinomethylene)-1,3-dioxane-4,6-dione (40.5 g); NMR Spectrum: (CDCl3) 1.77 (s, 6H), 3.88 (s, 3H), 3.96 (s, 3H), 6.75 (s, 1H), 6.87 (d, 1H), 7.92 (d, 1H), 8.67 (d, 1H), 11.29 (d, 1H); Mass Spectrum: M+H+ 279.
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.
With thiophene; hydrogen;palladium 10% on activated carbon; In methanol; at 100℃; under 75007.5 Torr;
A mixture of 4-amino-2-methoxybenzoic acid methyl ester (0.138 mol) and l-acetyl-4- piperidinone (0.14 mol) in methanol (300 ml) was hydrogenated at 1000C (100 bar) for 32 hours with palladium-on-carbon (10%) (3 g) as a catalyst in the presence of a thiophene solution (1 ml). After uptake of hydrogen (1 equivalent), the catalyst was filtered off over dicalite and the filtrate's solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: first ethyl acetate 100% and then CH2Cl2ZCH3OH 95/5). The product fractions were collected and the solvent was evaporated, yielding 41.5 g of intermediate (38).
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 38h;
Step 1 Methyl 2-methoxy-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamido)benzoate Procedure: A mixture of <strong>[269409-73-6]3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid</strong> (600 mg, 2.4 mmol), methyl 4-amino-2-methoxybenzoate (362 mg, 2 mmol), EDCI (764 mg, 4 mmol) and DMAP (488 mg, 4 mmol) in 10 mL of DMF was stirred at room temperature for 38 hours. The mixture was poured into water and extracted with EtOAc (3*15 mL). The organic layer was washed with brine and dried over Na2SO4. After filtration and concentration, the residue was purified by column chromatography on silica gel eluting with (petroleum ether:EtOAc=4:1) to give methyl 2-methoxy-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamido)benzoate (180 mg, 22%) as solid. 1H NMR (300 MHz, CD3OD): delta 8.31 (s, 1H), 8.05-8.01 (m, 1H), 7.97-7.94 (m, 1H), 7.81 (d, 1H, J=8.7 Hz), 7.71 (d, 1H, J=1.8 Hz), 7.53 (d, 1H, J=7.5 Hz), 7.37 (dd, 1H, J1=8.7 Hz, J2=2.1 Hz), 3.91 (s, 3H), 3.85 (s, 3H).
22%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 38h;
A mixture of 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzoic acid (600 mg, 2.4 mmol), methyl 4-amino-2-methoxybenzoate (362 mg, 2 mmol), EDCI (764 mg, 4 mmol) and DMAP (488 mg, 4 mmol) in 10 mL of DMF was stirred at room temperature for 38 hours. The mixture was poured into water and extracted with EtOAc (3x15 mL). The organic layer was washed with brine and dried over Na2S04. After filtration and concentration, the residue was purified by column chromatography on silica gel eluting with (petroleum ether : EtOAc = 4: 1) to give methyl 2-methoxy-4-(3-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)benzamido)benzoate (180 mg, 22 %) as solid. 1H NMR (300 MHz, CD3OD): delta 8.31 (s, 1H), 8.05 - 8.01 (m, 1H), 7.97 - 7.94 (m, 1H), 7.81 (d, 1H, = 8.7 Hz), 7.71 (d, 1H, = 1.8 Hz), 7.53 (d, 1H, = 7.5 Hz), 7.37 (dd, 1H, ; = 8.7 Hz, J2 = 2.1 Hz), 3.91 (s, 3H), 3.85 (s, 3H).
18.5%
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride;dmap; In N,N-dimethyl-formamide; at 20℃; for 36h;
Step 1Methyl-2-methoxy-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamido)benzoate Procedure:A mixture of methyl 4-amino-2-methoxybenzoate (453 mg, 2.5 mmol), <strong>[269409-73-6]3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid</strong> (1.24 g, 5 mmol), EDCI (0.96 g, 5 mmol) and DMAP (0.61 g, 5 mmol) in 10 mL of DMF was stirred at room temperature for 36 h. The mixture was poured into water and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine and dried over Na2SO4. After filtration and concentration, the residue was purified by column chromatography (silica gel, 200-300 mesh, petroleum ether/EtOAc 5:1, v/v) to give methyl 2-methoxy-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamido)benzoate (240 mg, 18.5%). 1H NMR (300 MHz, CD3OD): delta 8.31 (s, 1H), 8.05-8.02 (m, 1H), 7.97-7.94 (m, 1H), 7.82 (d, 1H, J=6.7 Hz), 7.72 (d, 1H, J=2.1 Hz), 7.54 (t, 1H, J=7.7 Hz), 7.37 (dd, 1H, J1=8.7 Hz, J2=2.1 Hz), 3.32 (s, 3H), 3.31 (s, 3H), 1.38 (s, 12H). LC/MS: 412 [M+H]+, 844.9 [2M+Na]+.
18.5%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 36h;Product distribution / selectivity;
A mixture of methyl 4-amino-2-methoxybenzoate (453 mg, 2.5 mmol), 3-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)benzoic acid (1.24 g, 5 mmol), EDCI (0.96 g, 5 mmol) and DMAP (0.61 g, 5 mmol) in 10 mL of DMF was stirred at room temperature for 36 h. The mixture was poured into water and extracted with EtOAc (3 10 mL). The combined organic layers were washed with brine and dried over Na2S04. After filtration and concentration, the residue was purified by column chromatography (silica gel, 200 - 300 mesh, petroleum ether / EtOAc 5: 1, v/v) to give methyl 2-methoxy-4-(3-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)benzamido)benzoate (240 mg, 18.5 %). 1H NMR (300 MHz, CD3OD): delta 8.31 (s, 1H), 8.05 - 8.02 (m, 1H), 7.97 - 7.94 (m, 1H), 7.82 (d, 1H, J = 6.1 Hz), 7.72 (d, 1H, J = 2.1 Hz), 7.54 (i, 1H, J = 7.7 Hz), 7.37 (dd, 1H, Jl = 8.7 Hz, J2 = 2.1 Hz), 3.32 (s, 3H), 3.31 (s, 3H), 1.38 (s, 12H). LC/MS: 412 [M + H]+, 844.9 [2M + Na]+
To a stirred solution of methyl 4-amino-2-methoxybenzoate (10 g, 55 mmol) in dichloromethane (100 mL) was added triethylamine (15.4 mL, 110 mmol) at 0 C and the mixture was stirred for 15 mm. To this mixture, acetyl chloride (5.68 g, 71 mmol) was added drop wise and the mixture was stirred at room temperature overnight. The reaction was quenched by addition of water (75 mL). The organiclayer was separated, washed with brine solution (100 mL), dried over sodium sulfate and concentrated under reduced pressure to afford methyl 4-acetamido-2- methoxybenzoate (13.0 g, 58.2 mmol, quantitative yield) as a yellow solid: LCMS (ESI) m/e 224.2 [(M+H), calcd for C11H14N04, 224.1]; LC/MS retention time (method B): tR = 1.21 mm.
91%
To a solution of methyl 4-amino-2-methoxybenzoate (2.0 g, 0.0 11 mol) in DCM (50 mL) cooled to 0 C was added triethylamine (3.0 mL, 0.022 mol) and the reaction mixture was stirred for 10 minutes. Acetyl chloride (1.3 g, 0.0 165 mol) was addeddropwise and the reaction was stirred for 3 h. Water (50 mL) was added and the aqueous layer was extracted with DCM (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and volatiles were evaporated to dryness under reduced pressure to give methyl 4-acetamido-2-methoxybenzoate (2.3 g, 0.01 mol, 91% yield) as a light brown solid. ?H NMR (400 MHz, DMSO-d6) oe 10.22 (s,1H), 7.66 (d, J= 8.8 Hz, 1H), 7.47 (d, J= 1.6 Hz, 1H), 7.20 (dd, J 8.4, 2.0 Hz, 1H),3.74-3.79 (m, 6H), 2.07 (s, 3H); LCMS (ESI) m/e 224.2 [(M+H), calcd for C11H14NO4, 224.08]; LC/MS retention time (method B): ti = 1.20 mm.
90%
With triethylamine; In dichloromethane; at 20℃; for 12h;
Methyl 4-amino-2-methoxybenzoate (10 g, 55 mmol) at room temperatureAnd triethylamine (8.4 g, 83 mmol) was dissolved in dry dichloromethane.Acetyl chloride (5.8 mL, 66 mmol) was slowly added dropwise, and the mixture was stirred at room temperature for 12 h.At the end of the reaction, the reaction was quenched with saturated sodium bicarbonate solution.The reaction solution was washed with water and brine, and the organic layer was dried.Concentrated under reduced pressure,The solid product compound 64A (11 g, 90% yield)It was used in the next reaction without further purification.
With N-chloro-succinimide In acetonitrile for 3h; Reflux;
63 Preparation of methyl 4-amino-5-chloro-2-methoxybenzoic acid methyl ester (Compound 63A)
Methyl 4-amino-2-methoxybenzoate (5 g, 27.6 mmol) at room temperatureAnd N-chlorosuccinimide (4.05 g, 30.36 mmol) dissolved in dry acetonitrile,The temperature was slowly raised to reflux for 3 hours. Thin chromatographic detection,When the reaction material completely disappeared, it was cooled to room temperature and concentrated under reduced pressure.A crude product solid product recrystallized from petroleum ether/ethyl acetate (1:20)White solid compound 63A (5.3 g, 90% yield).
88.3%
With N-chloro-succinimide; N,N-dimethyl-formamide at 70℃; for 3h; Large scale;
2.2
(2) the above-mentioned the resulting 4-amino-2-methoxybenzoic acid methyl ester and N-chloro succinimide the mole ratio is that 1:1 in 70 °C stirring in DMF solution of 3 hours later, is poured into the ice water is separated out in solid, filtering and drying to obtain 1.70 kg of 4-amino-5-chloro-2-methoxybenzoic acid methyl ester, in the yield of 88.3%.
82.4%
With N-chloro-succinimide In N,N-dimethyl-formamide at 70℃; for 12h;
30.1 Step 1: 4-amino-5-chloro-2-methoxybenzoate
To a stirred solution of methyl 4-amino-2-methoxybenzoate (5.00 g, 27.595 mmol, 1.00 equiv) in DMF (50.00 mL) was added NCS (3.70 g, 27.709 mmol, 1.00 equiv) at room temperature. The resulting mixture was stirred for 12 h at 70°C in an oil bath and then quenched with water at room temperature. The resulting mixture was extracted with EtOAc and the combined organic layers were washed with brine, and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with PE/EtOAc (30:70) to afford methyl 4-amino-5- chloro-2-methoxybenzoate (4.9 g, 82.4% yield) as a yellow green solid.
Methyl 2-methoxy-4-amino-benzoate (500.00 g, 2.76 mol), 2,2-dimethyl-1,3-dioxane-4,6-dione (397.73 g, 2.76 mol) and trimethyl orthoformate (292.84 g, 2.76 mol) were added to isopropanol (5.00 L). The reaction solution was heated up to an outer temperature of 90 C and kept refluxing for 1 hour. The completion of the reaction was detected by TLC. The reaction solution was cooled to an outer temperature of 20 C in an ice bath and then filtered. The solid was washed with MTBE (300 ml * 2) and then concentrated to dryness in a water bath. Compound 1A (873.00 g, 2.47 mol, the yield was 89.62% and the purity was 95%) was obtained as a light red powder. NMR (DMSO) demonstrated that the product was correct. 1H NMR (400 MHz, DMSO-d6) ppm 1.67 (s, 6 H) 3.76 (s, 3 H) 3.86 (s, 3 H) 7.19 (dd, J=8.41, 1.63 Hz, 1 H) 7.43 (d, J=1.25 Hz, 1 H) 7.71 (d, J=8.28 Hz, 1 H) 8.69 (d, J=10.04 Hz, 1 H) 11.25 (d, J=9.03 Hz, 1 H)
Weigh15 grams of Meldrum's acid (104 mmol),Add to 50 mL (300 mmol) of triethyl orthoformate and stir at 90 C for 3 h. Further, 50 mL of isopropyl alcohol and 21.92 g (0.121 mmol) of methyl 4-amino-2-methoxybenzoate (3) were added, and the mixture was refluxed for 1 hour. After completion of the reaction, a large amount of a yellow precipitate was obtained, which was cooled to room temperature, filtered, and the filter cake was washed thoroughly with diethyl ether and dried to give a pale yellow solid (4) 29.76 g, yield 85%.
methyl 2-methoxy 4-(4,6-dichloropyridin-2-yl)methylaminobenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
66%
Compound 42B (640 mg, 3.6 mmol),Methyl 2-methoxy-4-aminobenzoate (781 mg, 4.3 mmol)Dissolved in 50 mL of dichloromethane, and added anhydrous magnesium sulfate (4.3 mg, 36 mmol).After stirring at room temperature for 12 hours, it was filtered, dried and dissolved in methanol (20 mL).And sodium cyanoborohydride (600 mg, 10 mmol) was added.Stir at room temperature for 6 hours, spin dry,Purification of the compound 42C (817 mg, 66% yield).
methyl 4-((5,7-dichlorobenzofuran-3-yl)amino)-2-methoxybenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50%
With toluene-4-sulfonic acid In water; toluene for 4h; Reflux;
59 Preparation of methyl 4-((5,7-dichlorobenzofuran-3-yl)amino)-2-methoxybenzoate (Compound 59C)
Compound 59B (204 mg, 1 mmol),Methyl 4-amino-2-methoxybenzoate (217 mg, 1.2 mmol),P-toluenesulfonic acid (19 mg, 0.1 mmol) was dissolved in toluene.The water was refluxed for 4 hours. Cool to room temperature and dilute with ethyl acetate.Washed with saturated NaHCO3, brine, dried over anhydrous sodium sulfate.Filter and spin dry,Separation and purification of petroleum ether/ethyl acetate (6/1) gave Compound 59C (179 mg, 50% yield).
Heated the mixture triethylorthoformate (306.7 g), methyl 4-amino-2-methoxybenzoate compound of formula-3a (250 g), Meldrum?s acid compound of formula-2 (238.64 g) and isopropanol (1750 ml) to 65-70C and stirred for 2 hours at the same temperature. The reaction mixture was cooled to 25-30C and stirred it for 1 hour at the same temperature. Filtered the precipitated solid, washed with isopropanol and dried to get the title compound. Yield: 449 g, Purity by HPLC: 99.88%, MR: l94-200C.
With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 65℃;
19 Synthesis of compound 2-A
Lithium aluminum hydride (228mg) was added to 15mL tetrahydrofuran,Dissolve methyl 2-methoxy-4-aminobenzoate (725 mg) in 5 mL of tetrahydrofuran at 0°C and slowly drop it into the reaction solution.After the dropwise addition is complete, move to 65°C and reflux and stir to react. Overnight TLC monitors the completion of the reaction,Add 1mL water dropwise at 0, quench with 1mL 0.5N sodium hydroxide solution, filter out the insoluble matter with Celite, The filtrate was purified by concentrated column chromatography (petroleum ether: ethyl acetate=1:1) to obtain compound 2-A (420 mg).
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