* 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, 1921, vol. 119, p. 1431
2
[ 5081-36-7 ]
[ 80410-57-7 ]
Reference：
[1] Angewandte Chemie - International Edition, 2018, vol. 57, # 24, p. 7040 - 7045[2] Angew. Chem., 2018, vol. 130, # 24, p. 7158 - 7163,6
3
[ 5081-36-7 ]
[ 16292-88-9 ]
Reference：
[1] Journal of the American Chemical Society, 1984, vol. 106, # 23, p. 7077 - 7082
4
[ 92241-87-7 ]
[ 16292-88-9 ]
[ 5081-36-7 ]
Reference：
[1] Journal of the American Chemical Society, 1984, vol. 106, # 23, p. 7077 - 7082
5
[ 5081-37-8 ]
[ 5081-36-7 ]
Yield
Reaction Conditions
Operation in experiment
96%
With water In methanol for 2 h; Reflux
3-Methoxy-4-nitrobenzoic acid To a stirred solution of methyl 3-methoxy-4-nitrobenzoate (2.11 g, 10 mmol) in MeOH (30 mL), KOH (1.68 g, 30 mmol) in water (30 mL) was added. The reaction was refluxed for 2 h then MeOH was evaporated by vacuum distillation. The residue was diluted with water (20 mL). The solution was cooled in an ice bath and acidified by KHSO4 (saturated aqueous solution) to pH 3-4. The precipitated solid was collected by filtration, washed with cold water then n-hexane. Yield 96percent (off-white solid), m/z (ESI+) 198 [M+H]+.
Reference：
[1] Patent: US2016/145304, 2016, A1, . Location in patent: Paragraph 0548; 0562; 0563; 0564
[2] ChemMedChem, 2018, vol. 13, # 2, p. 186 - 198
[3] Journal of the American Chemical Society, 1989, vol. 111, # 20, p. 7957 - 7968
[4] eLife, 2017, vol. 6,
[5] Advanced Synthesis and Catalysis, 2018, vol. 360, # 11, p. 2204 - 2210
6
[ 185629-31-6 ]
[ 67-56-1 ]
[ 5081-36-7 ]
Yield
Reaction Conditions
Operation in experiment
82%
Stage #1: With sodium hydride In tetrahydrofuran at 0℃; for 0.25 h; Stage #2: at 0 - 20℃; for 2 h;
Compound 236b: 3-Methoxy-4-nitro-benzoic acid: A solution of methanol (0.18g, 5.5 mmol, 1.1 eq) in THF (10 ml) was added drop- wise to sodium hydride as a 60percent dispersion in mineral oil (0.22 g, 9.2 mmol, 1.8 eq) whilst being cooled to 00C. The reaction stirred for 15 minutes, a solution of 3-fluoro-4-nitro-benzoic acid methyl ester (1.0 g, 5.0 mmol, 1.0 eq) in THF (10 ml) was added and the reaction stirred at room temperature for 1 hour. The reaction had not gone to completion so a solution of methanol (0.18g, 5.5 mmol, 1.1 eq) and sodium hydride as a 60percent dispersion in mineral oil (0.22 g, 9.2 mmol, 1.8 eq) in THF (10 ml) was prepared and added to the reaction mixture. The reaction was stirred for at room temperature for an additional hour. The reaction was diluted with water (20 ml), extracted with ethyl acetate (2 x 20 ml), extracted with DCM (20 ml), the organics combined, dried over sodium sulphate, and the solvent removed in vacuo. The aqueous layer was separated, the solvent removed and the resultant residue purified by column chromatography using 20percent ethyl acetate/cyclohexane as eluent to give the title compound (0.89 g, 4.5 mmol, 82percent). 1H NMR shows product in ca. 95percent purity.
Reference：
[1] Journal of the American Chemical Society, [2] Journal of the American Chemical Society, 2009, vol. 131, p. 5564 - 5572
[3] Journal of Medicinal Chemistry, 2015, vol. 58, # 7, p. 3002 - 3024
8
[ 38512-82-2 ]
[ 5081-36-7 ]
Reference：
[1] Journal of Organic Chemistry, 1980, vol. 45, # 11, p. 2243 - 2246
[2] Organic Process Research and Development, 2000, vol. 4, # 3, p. 162 - 166
[3] European Journal of Inorganic Chemistry, 1998, # 5, p. 613 - 619
[4] Journal of the Chemical Society, 1923, vol. 123, p. 1272
[5] Bulletin de la Societe Chimique de France, 1962, p. 2255 - 2261
9
[ 101420-81-9 ]
[ 124-41-4 ]
[ 5081-36-7 ]
Reference：
[1] Patent: CN105732394, 2016, A, . Location in patent: Paragraph 0016; 0017; 0018
With 2,2'-azobis(isobutyronitrile); oxygen; cobalt(II) diacetate tetrahydrate; acetic acid; sodium bromide; at 130℃; under 9000.9 Torr; for 1.5h;Green chemistry;
<strong>[38512-82-2]3-methoxy-4-nitrotoluene</strong> 25g (149.6mmol, 1.0eq), AIBN 590mg (3.6mmol, 0.024eq),Co(OAc) 2·4H2O 1.8 g (7.3 mmol, 0.049 eq), NaBr 508 mg (4.9 mmol, 0.033 eq), dissolved in HOAc 250 mL (10V).Stir the whole solution, increase the temperature of the outer bath of the reaction coil to 130 C, adjust the coil pressure to 1.2 MPa with oxygen, and start the materialing. The system residence time is 1.5 h and the oxygen is 3 to 5 eq.The system was directly pumped into 375 mL of purified water, and the pH of the system was adjusted to 12-14 with NaOH solids.The aqueous phase was extracted twice with 125 mL MTBE, and the aqueous phase was adjusted to pH 1 with concentrated HCl.A large amount of solid was precipitated, and 16.8 g of the target product was obtained by filtration, yield 57%.
3-Methoxy-4-nitrobenzoic acid
3-Methoxy-4-nitrobenzoic acid To a stirred solution of methyl 3-methoxy-4-nitrobenzoate (2.11 g, 10 mmol) in MeOH (30 mL), KOH (1.68 g, 30 mmol) in water (30 mL) was added. The reaction was refluxed for 2 h then MeOH was evaporated by vacuum distillation. The residue was diluted with water (20 mL). The solution was cooled in an ice bath and acidified by KHSO4 (saturated aqueous solution) to pH 3-4. The precipitated solid was collected by filtration, washed with cold water then n-hexane. Yield 96% (off-white solid), m/z (ESI+) 198 [M+H]+.
86%
With sodium hydroxide In tetrahydrofuran at 20℃; for 15h;
With sodium hydroxide In methanol for 0.5h; Yield given;
5.1 g
With sodium hydroxide In tetrahydrofuran; methanol; water at 20℃; for 12h;
With lithium hydroxide In methanol; water at 20℃; for 20h;
30.2
[0152] Anhydrous HCl was made by addition of thionyl chloride (1.46 mL, 20.4 mmol) and methanol (10 mL) at O0C. To this was added 3-methoxy-4-nitrobenzoic acid 8b (2.00 g, 10.2 mmol). The mixture was stirred at room temperature overnight, concentrated, diluted with aqueous sodium bicarbonate, and extracted with dichloromethane. The organic layer was concentrated in vacuo to afford methyl ester 8c in quantitative yield. H1 NMR (400 MHz, CDCl3) δ 7.82 (d, IH), 7.75 (s, IH), 7.68 (d, IH), 4.02 (s, 3H), 3.99 (s, 3H).
100%
With thionyl chloride at 0 - 20℃;
107.1
3-METHOXY-4-NITROBENZOIC acid (2.00 g, 10.2 mmol) was added to a solution of methanol (10 mL) which had been treated with thionyl chloride (1.46 mL, 20.4 mmol) at 0°C. The mixture was stirred at room temperature overnight, then concentrated, diluted with aqueous sodium bicarbonate and extracted with dichloromethane affording the desired methyl ester in quantitative yield.
95%
With sulfuric acid Reflux; Inert atmosphere;
91%
With boron trifluoride for 12h;
82.1%
With sulfuric acid Reflux; Inert atmosphere;
1.1 Step 1 Synthesis of Compound 2
Go to 50mL with magnetic stirringCompound 1 (0.6 g, 3.0 mmol) was added to a one-neck flaskAnd methanol (15mL),Stir and dissolve,Slowly add concentrated sulfuric acid (1 mL),After the addition is completed, the temperature is raised to reflux.The reaction was stirred under a nitrogen atmosphere for 3 hours.Cool to room temperature,The reaction was quenched by the addition of water (40 mL).Dichloromethane extraction (40mLx2),Combine the organic phase,Washed with saturated saline,Dry over anhydrous sodium sulfate,filter,Concentrated colorless liquid 0.52g,The yield was 82.1%
With sulfuric acid Heating;
With boron trifluoride diethyl etherate for 24h; Reflux;
3.A
Boron trifluoride diethyl etherate (2 mL, 16.3 mmol) was added to a suspension of 3-methoxy-4-nitrobenzoic acid (1.0 g, 5.07 mmol) in anhydrous methanol (15 mL) and the resulting mixture was heated at reflux for 24 hours. The solvent was evaporated under reduced pressure and the residue was partitioned between water and dichloromethane ; the aqueous layer was extracted 3 times with dichloromethane. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified over a silica gel plug (EtOAc /hexane from 40 /60 to 50/50) to give 1.09 g of 3-methoxy-4-nitro-benzoic acid methyl ester as a pale yellow solid.
With sodium tetrahydroborate; boron trifluoride diethyl etherate; In tetrahydrofuran; at 0 - 20℃;
To a suspension of sodium borohydride ( 1 .93 g, 50.7 mmol) in tetrahydrofuran (20 mL) was added slowly a solution of 3 -methoxy-4-nitrobenzoic acid (5.0 g, 25.4 mmol) in tetrahydrofuran (40 mL). Boron trifhioride etherate (10.7 g, 63.4 mmol) was added dropwise at 0C and the mixture was stirred at ambient temperature for 1 6 hours. The mixture was quenched with saturated ammonium chloride (20 mL), diluted with water (50 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give the crude title compound.
With sodium tetrahydroborate; boron trifluoride diethyl etherate; In tetrahydrofuran; at 0 - 20℃; for 16h;
To a suspension of sodium borohydride (1.93 g, 50.7 mmol) in tetrahydrofuran (20 mL) was added slowly a solution of 3-methoxy-4-nitrobenzoic acid (5.0 g, 25.4 mmol) in tetrahydroffiran (40 mL). Boron trifluoride etherate (10.7 g, 63.4 mmol) was added dropwise at 00 C. and the mixture was stirred at ambient temperature for 16 hours. The mixture was quenched with saturated ammonium chloride (20 mL), diluted with water (50 mL) and extracted with ethyl acetate (3x100 mE). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give the crude title compound.
With N-ethyl-N,N-diisopropylamine; HATU In ISOPROPYLAMIDE at 18 - 50℃; for 15h;
To a suspension of 4-nitro-3-methoxybenzoic acid (Aldrich; 5.0 g, 25.3 mmol), N,N-2-tetramethyl-1,3-propanediamine (Aldrich; 4.64 mL, 27.83 mmol) and DIPEA (8.8 mL, 50.60 mmol) in anhydrous DMA (100 mL) under nitrogen at ambient temperature was added HATU (10.6 g, 27.83 mmol) and the resulting reaction mixture was stirred at 50° C. for 3 h and ambient temperature for a further 12 h. Evaporation removed any volatiles and the residue was dissolved in DCM (100 mL) and washed with NaHCO3 (100 mL), brine (100 mL), dried (MgSO4) and the volatiles removed under reduced pressure. Purification by column chromatography (SiO2, eluent gradient: 2-10% MeOH in DCM) afforded the title compound (5.7 g, 73%) as a solid.1H NMR (400 MHz, DMSO-d6): δH 1.06 (s, 6H), 2.42 (s, 2H), 2.82 (s, 6H), 3.30 (s, 2H), 3.98 (s, 3H), 7.57 (dd, 1H), 7.71 (s, 1H), 8.93 (d, 1H); MS m/z 310 [M+H]+.
73%
With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl acetamide at 18 - 50℃; for 15h;
To a suspension of 4-nitro-3-methoxybenzoic acid (Aldrich; 5.0 g, 25.3 mmol), N,N-2- tetramethyl-l,3-propanediamine (Aldrich; 4.64 mL, 27.83 mmol) and DIPEA (8.8 mL, 50.60 mmol) in anhydrous DMA (100 mL) under nitrogen at ambient temperature was added HATU (10.6 g, 27.83 mmol) and the resulting reaction mixture was stirred at 50 0C for 3 h and ambient temperature for a further 12 h. Evaporation removed any volatiles and the residue was dissolved in DCM (100 mL) and washed with NaHCO3 (100 mL), brine (100 mL), dried (MgSO4) and the volatiles removed under reduced pressure. Purification by column chromatography (SiO2, eluent gradient: 2-10% MeOH in DCM) afforded the title compound (5.7 g, 73%) as a solid. 1H NMR (400 MHz5 DMSO-d6): δH 1.06 (s, 6H), 2.42 (s, 2H), 2.82 (s, 6H), 3.30 (s, 2H), 3.98 (s, 3H), 7.57 (dd, IH), 7.71 (s, IH), 8.93 (d, IH); MS m/z 310 [M+H]+.
Stage #1: 3-methoxy-4-nitrobenzoic acid With oxalyl dichloride In tetrahydrofuran at 0 - 20℃; for 1h;
Stage #2: With ammonia In tetrahydrofuran at 0℃; for 0.166667h;
1.a
3-(Methyloxy)-4-nitrobenzonitrile. Following the procedure of Mackman et al. in J. Med. Chem. 2001, 44, 2753-2771 , 3-methoxy-4-nitrobenzoic acid (11.52 g, 58.4 mmol) was dissolved in THF (158 mL) and cooled to 0 DC. Oxalyl chloride (5.6 mL, 64.3 mmol) was added dropwise under a nitrogen atmosphere, followed by a few drops of DMF. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. The mixture was then concentrated to dryness under reduced pressure, and the residue redissolved in THF (158 mL) and cooled to 0 DC. Ammonia gas was bubbled through the solution for 10 min, leading to the formation of a yellow precipitate. The ice bath was removed, and the mixture was sealed and allowed to stir overnight. After the addition of EtOAc (100 mL), the solids were filtered off, washed with water, and dried to provide 3-(methyloxy)-4-nitrobenzamide (10.10 g, 88%) as a yellow solid. Additional product could be recovered from the filtrate by removal of the organic solvent under reduced pressure, then redissolving the residue in EtOAc. The organic layer was washed with 1 N HCI (2 x 100 mL), brine (2 x 100 mL), then dried (Na2SO4), filtered and concentrated to afford an additional 1.07 g (9%). 1 H NMR (d6-DMSO): D 8.25 (bs, 1 H), 7.96 (d, J = 8.0 Hz, 1 H), 7.75 (d, J = 1.6 Hz, 1 H), 7.73 (s, 1 H), 7.57 (dd, J = 1.6, 8.4 Hz, 1 H), 3.98 (s, 3H).
92%
With ammonium chloride; N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 3h;
26.A; 50.A
Step A: To a stirred solution of 3-methoxy-4-nitrobenzoic acid (25.0 g, 126 mmol) in DMF (250 mL) was added NH4Cl (20.0 g, 378 mmol), HATU (72.0 g, 190 mmol), and DIPEA (66 mL, 378 mmol). The mixture was stirred at room temperature for 3 hours, then diluted with water. The resulting precipitate was filtered to afford 3-methoxy-4-nitrobenzamide, Compound 54 (22.8 g, 92% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.24 (s, 1H), 7.95 (d, J=8.3 Hz, 1H), 7.73 (d, J=19.9 Hz, 2H), 7.58 (d, J=8.0 Hz, 1H), 3.98 (s, 3H). ESI-MS: C8H9N2O4 (M+H): calc. 197.05, found: 197.20.
81%
Stage #1: 3-methoxy-4-nitrobenzoic acid With thionyl chloride for 2h; Reflux;
Stage #2: With ammonia In methanol at 20℃; for 72h;
15.a
Example 15Preparation of intermediate 4-amino-3-methoxy-benzonitrile; Step a: A mixture of 3-methoxy-4-nitrobenzoic acid (Acros, 10 g, 51 mmol) in thionyl chloride (36 g) was heated at reflux for 2 h. The mixture was concentrated. To the residue was added a methanolic solution (7 N) of ammonia. The reaction mixture was stirred at room temperature for 72 h. The mixture was concentrated, and the residue was partitioned between ethyl acetate and water. The precipitate between the two layers was filtered and collected to give 3-methoxy-4-nitrobenzamide as a light yellow solid (8 g, 81%).
81%
Stage #1: 3-methoxy-4-nitrobenzoic acid With thionyl chloride for 2h; Reflux;
Stage #2: With ammonia In methanol at 20℃; for 72h;
61.a
Step a: A mixture of 3-methoxy-4-nitrobenzoic acid (Acros, 10 g, 51 mmol) in thionyl chloride (36 g) was heated at reflux for 2 h. The mixture was concentrated. To the residue was added a methanolic solution (7 N) of ammonia. The reaction mixture was stirred at room temperature for 72 h. The mixture was concentrated, and the residue was partitioned between ethyl acetate and water. The precipitate between the two layers was filtered and collected to give 3-methoxy-4-nitrobenzamide as a light yellow solid (8 g, 81%).
Multi-step reaction with 2 steps
1: (COCl)2 / tetrahydrofuran; dimethylformamide / 1 h / 0 °C
2: NH3 / tetrahydrofuran / 0 °C
Multi-step reaction with 2 steps
1: thionyl chloride
Multi-step reaction with 2 steps
1: PCl5
2: NH3
Multi-step reaction with 2 steps
1: thionyl chloride / 2 h / Reflux
2: ammonia / methanol / 72 h / 20 °C
Stage #1: 3-methoxy-4-nitrobenzoic acid With thionyl chloride; sodium hydroxide at 80℃; for 0.5h;
Stage #2: With ammonium hydroxide In tetrahydrofuran; water at 0℃; for 0.5h;
3-Methoxy-4-nitro-benzamide
Intermediate 19: Step a 3-Methoxy-4-nitro-benzamide A round bottom flask fitted with a reflux condenser vented through an aqueous sodium hydroxide solution was charged with 3-methoxy-4-nitro-benzoic acid (3.07 g, 15.6 mmol, Aldrich). Thionyl chloride (10 mL) was added and the resulting suspension was heated in an 80° C. oil bath for 30 min. The mixture was concentrated and the residue was dissolved in THF (10 mL) and added slowly via pipette to an ice-cold solution of concentrated aqueous NH4OH (10 mL). The resulting yellow suspension was stirred at 0° C. for 30 min. The suspension was partially concentrated to remove THF and was filtered to afford the crude title compound as a light yellow solid.
Stage #1: 3-methoxy-4-nitrobenzoic acid With thionyl chloride; sodium hydroxide In water at 80℃; for 0.5h; Reflux;
Stage #2: With ammonium hydroxide In tetrahydrofuran; water at 0℃; for 0.5h; Cooling with ice;
42.a 3-Methoxy-4-nitro-benzamide
Intermediate 42: Step a 3-Methoxy-4-nitro-benzamide A round bottom flask fitted with a reflux condenser vented through an aqueous sodium hydroxide solution was charged with 3-methoxy-4-nitro-benzoic acid (3.07 g, 15.6 mmol, Aldrich). Thionyl chloride (10 mL) was added and the resulting suspension was heated in an 80° C. oil bath for 30 min. The mixture was concentrated and the residue was dissolved in THF (10 mL) and added slowly via pipette to an ice-cold solution of concentrated aqueous NH4OH (10 mL). The resulting yellow suspension was stirred at 0° C. for 30 min. The suspension was partially concentrated to remove THF and was filtered to afford the crude title compound as a light yellow solid.
Multi-step reaction with 2 steps
1: thionyl chloride / 0.5 h / 80 °C
2: ammonium hydroxide / water; tetrahydrofuran / 0.5 h / 0 °C
Multi-step reaction with 2 steps
1: oxalyl dichloride / tetrahydrofuran; N,N-dimethyl-formamide / 2 h / 0 - 20 °C
2: ammonia / tetrahydrofuran / 1 h / 0 - 20 °C
Multi-step reaction with 2 steps
1: oxalyl dichloride; N,N-dimethyl-formamide / tetrahydrofuran / 3 h / 0 °C
2: ammonia / tetrahydrofuran; 1,4-dioxane / 5 h / 0 - 20 °C
With thionyl chloride;palladium on charcoal; In methanol; ethyl acetate;
A solution of 3-fluoro-4-nitrobenzoic acid (1.6 g, 8.65 mmole) in 35 mL methanol at 0 C. was treated dropwise with 1.27 mL of thionyl chloride, stirred at room temperature overnight and volatile material removed in vacuo. The product was purified by flash chromatography (SiO2, 5% methanol/dichloromethane) to provide 1.7 g of a 3:2 mixture consisting of methyl 3-fluoro-4-nitrobenzoate and 3-methoxy-4-nitrobenzoic acid (65). The mixture was used directly in the next step. 150 mg of 10% palladium on charcoal was added to a solution of the above mixture consisting of methyl 3-fluoro-4-nitrobenzoate and 3-methoxy-4-nitrobenzoic acid (1.7 g) in 50 mL ethyl acetate and maintained under H2 (45 psi) for two hours. The reaction mixture was filtered over Celite and concentrated in vacuo. The product was purified by flash chromatography (SiO2, 10% methanol/dichloromethane), giving 0.7 g of methyl 4-amino-3-fluorobenzoate as an off-white solid.
With 1,1'-carbonyldiimidazole; In tetrahydrofuran;
(1) Carbonyldiimidazole (4.5 g, 27.9 mmol) was added to a solution of 3-methoxy-4-nitrobenzoic acid (5 g, 25.4 mmol) in tetrahydrofuran (50 ml) at room temperature. After stirred at room temperature for 6 hours, a magnesium salt of malonic acid monoethyl ester (4.7 g, 27.9 mmol) was added. This mixture was stirred at 60 C. for 1 hour, the reaction solution was diluted with ethyl acetate (100 ml), washed with 1N hydrochloric acid, an aqueous saturated sodium bicarbonate solution and saturated brine, dried with sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography [eluent:hexane-ethyl acetate (3:1)] to obtain ethyl 3-(3-methoxy-4-nitrophenyl)-3-oxopropionate (5.7 g, 21.3 mmol, 84%) as colorless needles. mp.94-95 C. IR numax (KBr) cm-1: 1741, 1693 (C=O). 1H-NMR (CDCl3) delta: 1.269 (1/2*3H, t, J=7.4 Hz), 1.355 (1/2*3H, t, J=7.4 Hz), 4.007 (1/2*2H, s), 4.022 (3H, s), 4.227 (1/2*2H, q, J=7.4 Hz), 4.300 (1/2*2H, q, J=7.4 Hz), 5.727 (1/2*1H, s), 7.35-7.90 (3H, m). Elemental Analysis (C12H13NO6) Cal'd: C, 53.93; H, 4.90; N, 5.24 Found: C, 53.81; H, 4.87; N, 5
21 Methyl 3-methoxy-4-nitrobenzoate
Methyl 3-methoxy-4-nitrobenzoate Thionyl chloride (3.7 g) was added dropwise under ice cooling to a solution of 4.7 g (24 mmol) of 3-methoxy-4-nitrobenzoic acid in 250 ml of methanol. The thus-obtained mixture was stirred at room temperature for 2 hours and then stirred under heating and reflux for 3 hours. After the solvent was distilled out under reduced pressure, the residue was neutralized with aqueous ammonia and then extracted with methylene chloride. The extract was dried over sodium sulfate and then dried up under reduced pressure, whereby 4.9 g of white powder were obtained (yield: 97%). IR(KBr)cm-1: 1732, 1614, 1529, 1306, 1249, 745.
(3-methoxy-4-nitrophenyl)(4-(4-methylpiperazin-1-yl)piperidin-1-yl)methanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
98%
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃;
General procedure: A mixture of acids (1.0 eq), amine (1.0 eq), DIPEA (1.2 eq), and HATU (1.2 eq) in DMF (2 mL) was stirred overnight at room temperature. The reaction mixture was cooled to room temperature and volatile was removed under vacuum. The residue was evaporated twice with DCM, triturated with ether and eventually purified by chromatography on silica gel (PE:EA =1:2) to give the desired products D3-D21.
The 1mol nitrobenzoic acid is dissolved in 20L CS2 added to the reaction vessel, to which 2mol liquid bromine into the control reactor pressure was 0.8MPa, the reaction temperature is maintained at 35C. After the reaction was continued for 2h, remove excess Br2, and thereto is added 3mol CH3ONa, exposed to light conducted at room temperature, with vigorous stirring, the reaction was continued for 2h, evaporated CS2, the resulting solidIt was dissolved in water, filtered and the solid was filtered off, rinsed, and dried, to give methyl 3--4-nitrobenzoic acid.The output of 3-methoxy-4-nitrobenzoic acid had a purity of 80.2%, a yield of 85.7%.
3-methoxy-N-(3-(4-methylpiperazin-1-yl)propyl)-4-nitrobenzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 20℃;
10
To a solution of commercially available 3-methoxy-4-nitrobenzoic acid 21 (100 mg, 0.507 mmol) and 3-(4-methylpiperazin-1-yl)propan-1-amine (159 mg, 1.01 mmol) in DCM (5.00 mL) was added HATU (386 mg, 1.01 mmol) at room temperature and stirred at the same temperature. After confirming the starting material consumption by LC-MS, the reaction mixture was concentrated to give a crude residue. The crude residue was purified by column chromatography utilizing NH silica gel (DCM/methanol) to afford 3-methoxy-N-(3-(4-methylpiperazin-1-yl)propyl)-4-nitrobenzamide (quant).
3-methoxy-N-(4-(4-methoxyphenyl)thiazol-2-yl)-4-nitrobenzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In acetonitrile at 65℃;
The commercially available 3-methoxy-4-nitrobenzoic acid (1.0 eq) was dissolved in acetonitrile (0.25 M) and treated with triethylamine (2.0 eq) and HATU (1.0 eq). To this mixture was then added 4-(4-methoxyphenyl)thiazol-2-amine (1.0 eq). The resulting solution was warmed to 65°C and stirred until the reaction was complete. At this time the solution was cooled to room temperature and diluted with water. The resulting precipitate was collected via filtration, washed with additional water, and dried in vacuo to give 3-methoxy-N-(4-(4-methoxyphenyl)thiazol-2-yl)-4-nitrobenzamide as a pale yellow solid (82% yield). A dry round bottom flask was charged with 10% palladium on carbon (0.05 eq) under an atmosphere of nitrogen. EtOAc (-0.2 M) was then added, followed by 3-methoxy-N-(4-(4-methoxyphenyl)thiazol-2-yl)-4- nitrobenzamide (1.0 eq). A hydrogen-filled balloon was then affixed to the flask and the airspace was evacuated and back-filled with hydrogen. The mixture was vigorously stirred until the reaction was complete, adding additional catalyst as needed and some methanol to ensure solubility. The mixture was then filtered through celite, washing with methanol to give 3-methoxy-N-(4-(4-methoxyphenyl)thiazol-2-yl)-4-nitrobenzamide as a yellow solid. This solid (1.0 eq) was then dissolved in acetonitrile (0.1 M) and treated with excess glyoxylic acid (-15 eq of a 50% aqueous solution). Sodium cyanoborohydride (5.0 eq) was then added and stirred at room temperature until the reaction was complete. The solution was then quenched with acetic acid, and partitioned between EtOAc and IN HC1. The organic portion was then concentrated to a yellow solid that was used without further purification. The crude (2-methoxy-4-((4-(4- methoxyphenyl)thiazol-2-yl)carbamoyl) phenyl)glycine (1.0 eq) was dissolved in DMF and treated with morpholine (10.0 eq). To this room temperature solution was added HATU (3.0 eq) and stirring was continued until the reaction was complete. The solution was then quenched with water which initiated the formation of a white precipitate. This impure solid was collected via filtration and then purified on silica gel (hexane/EtOAc gradient 35%-100%) to give 3-methoxy-N-(4-(4-methoxyphenyl)thiazol-2-yl)-4-((2- mo holino-2-oxoethyl)amino)benzamide as a white solid. ^-NMR (DMSO-d6, 500 MHz): δ 12.33 (s, 1H), 7.88 (d, J = 8.8 Hz, 2H), 7.75 (dd, J = 8.3, 1.9 Hz, 1H), 7.67 (d, J = 2.0 Hz, 1H), 7.44 (s, 1H), 7.00 (d, J = 8.9 Hz, 2H), 6.67 (d, J = 8.5 Hz, 1H), 5.84 (t, J = 4.6 Hz, 1H), 4.05 (d, J = 4.6 Hz, 2H), 3.94 (s, 3H), 3.79 (s, 3H), 3.63 (br, 2H), 3.58 (br, 2H), 3.51 (br, 4H). 1 C-NMR (DMSO-d6, 125 MHz): δ 167.19, 164.61 , 158.90, 158.87, 148.82, 145.38, 141.20, 127.36, 127.05, 123.02, 1 18.38, 1 14.02, 108.83, 108.75, 106.03, 65.98, 65.90, 55.72, 55.12, 44.28, 43.82, 41.87. MS [M+H] : 483.22.
(R)-(3-methoxy-4-nitrophenyl)(3-methylmorpholino)methanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
52.8%
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 3h;
To a solution of 3-methoxy-4-nitrobenzoic acid (200 mg, 1.014 mmol), DIPEA (262 mg, 2.029 mmol) and<strong>[74572-04-6]<strong>[74572-04-6](R)-3-methylmorpholin</strong>e</strong> (113 mg, 1.116 mmol) in THF (5 mL) was added HATU (463mg, 1.217 mmol). The reaction was stirred at 20 C for 3 hours. The mixture wasconcentrated and purified with by column chromatography on silica gel to give the titlecompound 16a (150 mg, 52.8 % yield) as a white solid. LCMS: 281 [M+H]+.
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
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