* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Stage #1: at 0 - 70℃; for 4 h; Heating / reflux Stage #2: With acetic acid In water at 20℃;
770 g (11.665 mol) of KOH pellets (w=85percent) are dissolved in 4000 ml of ice water. 800 g (3.317 mol) methyl-4,5-dimethoxy-2-nitro-benzoate (1) are added to the clear solution and the resulting green suspension is refluxed. During the heating a red solution is formed. The solution is refluxed with stirring for about 4 h while distilling off 850 ml of methanol/water. Once the reaction is complete (monitored by HPLC) the solution is cooled to ambient temperature and adjusted to pH 9 with 337.6 g (5.566 mol) glacial acetic acid. The nitro group reduction and isolation of the product (2) were carried out analogously to Ex. 1.The reaction yielded 558.5 g (3.049 mol, 92percent of theory) in the form of grey crystals.
Reference：
[1] Patent: US2008/319194, 2008, A1, . Location in patent: Page/Page column 5
[2] Journal of the Chemical Society, 1932, p. 1370,1375
[3] ChemMedChem, 2014, vol. 9, # 7, p. 1476 - 1487
[4] Patent: WO2018/119441, 2018, A1, . Location in patent: Paragraph 00556; 00557
2
[ 4998-07-6 ]
[ 31839-20-0 ]
Yield
Reaction Conditions
Operation in experiment
99%
Stage #1: at 100℃; for 3 h; Stage #2: With hydrogenchloride In water at 0℃;
5-hvdroxy-4-methoxy-2-nitrobenzoic acid: A mixture of 4,5- dimethoxy-2-nitrobenzoic acid (15 g, 66 mmol) in aqueous sodium hydroxide (6 M, 60 mL) was heated at 1000C for 3 h, was cooled to room temperature, and was poured into a mixture of concentrated hydrochloric acid and crushed ice (pH <2). The mixture was extracted with ethylacetate, was washed with brine, was dried over magnesium sulfate, was filtered, and was concentrated in vacuo to afford 14 g (99percent yield) of the title compound; 13C NMR (101 MHz, Methanol-D4) d 55.82, 107.46, 114.98, 122.90, 140.33, 149.09, 151.13, 167.96; MS (AP/CI): 212 (M-H)-.
95%
Stage #1: at 100℃; for 12 h; Stage #2: Cooling with ice
Example 1 1; Preparation of 1 -(5-tert-butylisoxazol-3-yl)-3-(3-(6-ethoxy-7-methoxyquinazolin-4- yloxy)phenyl)urea; [00689] Example 1 IA Step 1 : A mixture of 4,5-dimethoxy-2-nitrobenzoic acid(20.6 g, 90.7 mmol) in 20percent KOH solution (136 mL) was heated at 100 °C for 12 hours. After it was cooled with ice, it was acidified with concentrated HCl to pH 2. It was filtered, washed with CH2Cl2 and EtOAc, and dried over vacuum to afford 5- hydroxy-4-methoxy-2-nitrobenzoic acid as solid (18.38 g, 95percent). 1H NMR (300 MHz, DMSO-d6) δ 7.29 (s, 1H), 6.90 (s, 1H), 4.8 (br, 1H), 3.77 (s, 3H).
79%
With hydrogenchloride In water at 100℃; for 3 h;
To 4,5-dimethoxy-2-nitro- benzoic acid was added 6 M HCI (60 mL). The resultant yellow mixture was heated to 100 0C for 3 h, and then cooled to rt. The resultant solid was dissolved in 100 mL of water and poured into a slurry of 9 M HCI and crushed ice. The mixture was extracted twice with ethyl acetate and the combined extracts were washed with brine, dried over magnesium sulfate, and concentrated to give 14.7 g of a pale yellow solid. Recrystallization from ethyl acetate/hexanes provided 10.8 g (79percent) of the title compound.
79%
With sodium hydroxide In water at 100℃; for 3 h;
To 4,5-Dimethoxy-2-nitro-benzoic acid was added 6 M NaOH (60 mL). The resultant yellow mixture was heated to 100° C. for 3 h, and then cooled to rt. The resultant solid was dissolved in 100 mL of water and poured into a slurry of 9 M HCl and crushed ice. The mixture was extracted twice with ethyl acetate and the combined extracts were washed with brine, dried over magnesium sulfate, and concentrated to give 14.7 g of a pale yellow solid. Recrystallization from ethyl acetate/hexanes provided 10.8 g (79percent) of the title compound.
770 g (11.665 mol) of KOH pellets (w=85%) are dissolved in 4000 ml of ice water. 800 g (3.317 mol) methyl-4,5-dimethoxy-2-nitro-benzoate (1) are added to the clear solution and the resulting green suspension is refluxed. During the heating a red solution is formed. The solution is refluxed with stirring for about 4 h while distilling off 850 ml of methanol/water. Once the reaction is complete (monitored by HPLC) the solution is cooled to ambient temperature and adjusted to pH 9 with 337.6 g (5.566 mol) glacial acetic acid. The nitro group reduction and isolation of the product (2) were carried out analogously to Ex. 1.The reaction yielded 558.5 g (3.049 mol, 92% of theory) in the form of grey crystals.
With water; potassium hydroxide; In 1,2-dimethoxyethane; for 24.0h;Reflux;
Into a 3-L round-bottom flask, was placed a solution of methyl 4,5-dimethoxy-2- nitrobenzoate (45 g, 186.57 mmol, 1.00 equiv) in water(800 mL) and DME(200mL), potassium hydroxide (72 g, 1.28 mol, 7.00 equiv). The resulting solution was refluxed for 1 day. The resulting mixture was washed with 2x200 mL of hexane. The pH value of the solution was adjusted to 5 with hydrogen chloride (6 mol/L). The solids were collected by filtration. The resulting mixture was concentrated under vacuum. This resulted in 40 g of 5-hydroxy-4-methoxy- 2-nitrobenzoic acid as a yellow solid. LC-MS: (ES, m/z): 214 [M+H]+ Retention time: 0.217 min
methyl 5-hvdroxy-4-methoxy-2-nitrobenzoate: Preparation 5 (15 g, 70.4 mmol) in methanol (100 mL) was treated with concentrated sulfuric acid (10 mL). The mixture was heated at reflux for 48 h. After cooling to room temperature, the methanol was removed under reduced pressure, the resulting residue was diluted with water and was extracted with ethylacetate. The organic layer was washed with water and then brine, was dried over magnesium sulfate, was filtered, and was concentrated to afford 15.4 g (96% yield) of the title compound; MS (AP/CI): 228 (M+H)+; 226 (M-H)-.
45%
sulfuric acid; at 80℃;
00690] Example 1 IA Step 2: To a suspension of 5-hydroxy-4-methoxy-2- nitrobenzoic acid (8.0 g, 37.5 mmol) in methanol was added concentrated sulfuric acid (3 drops) and it was heated at 80 C overnight. After solvent was removed under reduced pressure, to it was added water and EtOAc. The organic layer was washed with saturated NaHCO3 solution, dried over MgSO4, and concentrated under reduced pressure to afford methyl 5-hydroxy-4-methoxy-2-nitrobenzoate as a solid (3.86 g, 45%). 1H NMR (300 MHz, DMSO-d6) delta 10.96 (s, 1H), 7.63 (s, 1H), 7.08 (s, 1H), 3.91 (s, 3H), 3.81 (s, 3H).
hydrogenchloride; for 15.0h;Reflux;
Example 3: Preparation of <strong>[31839-20-0]5-hydroxy-4-methoxy-2-nitrobenzoic acid</strong> methyl ester; A solution of <strong>[31839-20-0]5-hydroxy-4-methoxy-2-nitrobenzoic acid</strong> (50g) in methanolic hydrochloride (500 ml) was refluxed for 15 hours. After completion of reaction, the solvent was distilled under reduced pressure to give a residue, which was diluted with water and extracted with ethyl acetate. The layers were separated and organic layer was washed with water and distilled to obtain 30 g of title compound.
(a) 5-Hydroxy-4-methoxy-2-nitrobenzoic acid, methyl ester To a solution of <strong>[31839-20-0]5-hydroxy-4-methoxy-2-nitrobenzoic acid</strong> [Sinha J. Ind. Chem. Soc., 47, 925 (1970)] (83.0 g, 0.39 mol) in MeOH (250 ml) was added concentrated H2SO4 (20 ml) and the reaction mixture was heated to reflux for 16 h. On cooling, the reaction mixture was poured into aqueous potassium carbonate solution and acetic acid was added until pH 4 was reached. The mixture was extracted with chloroform, the organic layer washed twice with H2O and dried over MgSO4. Evaporation under reduced pressure afforded the subtitle compound as yellow crystals (77.0 g, 87%). Rf 0.30 (benzene/acetone 4/1, v/v); m.p. 146-9 C.
Example 4: Preparation of <strong>[31839-20-0]5-hydroxy-4-methoxy-2-nitrobenzoic acid</strong> ethyl ester; A mixture of <strong>[31839-20-0]5-hydroxy-4-methoxy-2-nitrobenzoic acid</strong> (83g), sulfuric acid (83g), triethyl orthoformate (166ml) and ethanol (1245ml) was refluxed for 40 hours. After completion of reaction, the solvent was distilled under reduced pressure. The resulting residue was extracted with toluene. The organic layer was washed with water, dried and distilled. Cyclohexane (300ml) was added to the resulting residue and , , g vc oupsilon 1 title compound having purity 99.74% by HPLC.
Example 5: Preparation of <strong>[31839-20-0]5-hydroxy-4-methoxy-2-nitrobenzoic acid</strong> ethyl ester; A mixture of <strong>[31839-20-0]5-hydroxy-4-methoxy-2-nitrobenzoic acid</strong> (1Og), sulfuric acid (5g) and ethanol (100ml) was refluxed for 40 hours. After completion of reaction, the solvent was distilled under reduced pressure. The resulting residue was extracted with toluene (200 ml). The organic layer was washed with water, dried and distilled. Cyclohexane (30ml) was added to the resulting residue and stirred. The reaction mixture was filtered, washed with cyclohexane and dried to give I Og (88.5%) of the title compound having purity 99.77% by HPLC.
With oxalyl dichloride; N,N-dimethyl-formamide; In 2-methyltetrahydrofuran; at 20℃;Inert atmosphere;
<strong>[31839-20-0]5-hydroxy-4-methoxy-2-nitrobenzoic acid</strong> (31.9 g, 0.15 mol, 1.0 eq) and 2-methyltetrahydrofuran (200 mL) are charged into a glass reactor under nitrogen. The solution is stirred and jacket temp is set to 20 C. Oxalyl chloride (24 g, 0.19 mol, 1.25 eq) is added at a rate that the internal temperature is below 25 C. The reaction mixture is stirred for 1-2 hour at 20 C., and cooled to 15 C. Then, anhydrous MeOH (60 ml, 1.5 mol, 10 eq) is added over 15 min, and the reaction temperature is maintained below 25 C. during addition. The reaction mixture is stirred for 2-4 hour at 20 C. until HPLC sample shows complete conversion. Na2CO3 aqueous solution (1 M, 100 ml) is added to the reaction mixture. Layers are separated. The upper organic layer is distilled under vacuum to minimum volume. The dark brown residue is stirred in 100 mL mixed solvent of toluene/hexane (v/v, 2:1) to give a suspension. The slurry is filtered. The solid is dried under vacuum to provide the desired product, methyl 5-hydroxy-4-methoxy-2-nitrobenzoate (31.3 g, 92% yield).
(2S,4R)-1-[(2S)-2-[3-(2-[[5-([4-[(3-chloro-4-fluorophenyl)amino]-7-methoxyquinazolin-6-yl]oxy)pentyl]oxy]ethoxy)propanamido]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide[ No CAS ]
(2S,4R)-4-(tert-butoxy)-1-[(2S)-2-(1-[4-[(3-chloro-4-fluorophenyl)amino]-7-methoxyquinazolin-6-yl]-1,4,7,10,13,16-hexaoxaoctadecan-18-amido)-3,3-dimethylbutanoyl]-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide[ No CAS ]
(2S,4R)-1-[(2S)-2-(1-[4-[(3-chloro-4-fluorophenyl)amino]-7-methoxyquinazolin-6-yl]-1,4,7,10,13,16-hexaoxaoctadecan-18-amido)-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide trifluoroacetate[ No CAS ]
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