Benzoic acid, 3,4-bis(2-methoxyethoxy)-, ethyl ester

(3) 3, 4-Dihydroxy-benzoic acid ethyl ester (compound A') (2.0 g) was dissolved in acetone (20 ml). Potassium carbonate (4.3 g) and 1-bromo-2-methoxy-ethane (compound D) (5 ml) were added to the solution at room temperature, and the mixture was then stirred at 70°C for 24 hr. After the completion of the reaction, the reaction solution was allowed to stand for cooling at room temperature, and the reaction system was concentrated under the reduced pressure. Distilled water was added to the residue, and the mixture was then subjected to separatory extraction with chloroform. The organic layer was washed with saturated brine, was dried over sodium sulfate, and was then concentrated under the reduced pressure. The residue was purified by column chromatography using a hexane-acetone system to give 3, 4-bis-(2-methoxy-ethoxy)-benzoic acid ethyl ester (3.06 g, yield 93percent).To ethyl 3, 4-dihydroxybenzoate (36.4 g, 0.200 mol), K2CO3 (60.8 g, 0.44 mol) and tetrabutylammonium iodide(750 mg) in degassed acetone (400 mL) was added 2-bromoethyl methyl ether (69.5 g, 47 mL). The mixture was stirred under N2 at reflux for 64 hours. Ether (600 mL) was added to the mixture and after stirring 30 minutes at 20 °C theprecipitated salts were removed by filtration. The filtrate was concentrated in vacuo and the residue was triturated withhexane (500 mL) for 30 minutes and the white solid ethyl 3, 4-bis(2-methoxy-ethoxy)benzoate was filtered and dried invacuo (55.5 g; 93percent; M.P. 50-51 °C). A portion of this product (45.7 g, 0.158 mol) in acetic acid (150 mL) was treateddropwise with conc. HNO3 (40 mL) at 5°C and the solution stirred 24 hours before pouring into cold H2O (1.6 L). Themixture was extracted with ethyl acetate (1.1 L), and the organic phase was washed three times with 200 mL H2O, andbrine, dried over Na2SO4, filtered and concentrated in vacuo to afford ethyl 4, 5-bis-(2-methoxy-ethoxy)-2-nitro-benzoate(54.3 g) as a brown oil. This nitro product (52.0 g, 0.15 mol) was dissolved in ethanol (1000 mL) containing 1 equivalentof HCl (generated in the ethanol by prior addition of 11 mL acetyl chloride), PtO2•H2O (1.0 g) was added, and the mixturewas hydrogenated under 45 psi H2 for 6 hours. The catalyst was removed by filtration through Celite, and the filtratewas concentrated in vacuo to a thick slurry which was diluted with ether (400 mL). The solid white hydrochloride salt ofethyl 2-amino-4, 5-bis-(2-methoxy-ethoxy)benzoate was filtered and dried in vacuo (44.7 g; 88percent). A portion of this material(42 g, 0.12 mol) and ammonium formate (7.6 g, 0.12 mol) were disssolved in formamide (63 mL) and the stirred mixturewas heated to 160-165 °C under an atmosphere of N2 for 3 hours. H2O (200 mL) was added and after cooling theprecipitated crude title product was recovered by filtration, washed with cold H2O, and dried in vacuo. The filtrate wasextracted five times with CHCl3, and the pooled organic extracts were washed with brine, dried over Na2SO4, andconcentrated in vacuo. The residue and crude quinazolone precipitate were combined, triturated in hot acetonitrile (250mL) for 30 minutes, cooled to 20 °C and treated with ether (250 mL). After cooling to 4 °C the white solid was filteredand dried in vacuo (30.4 g, 86percent; GC-MS m/z 294 (M+)).In a dry, clean 500ml reaction flask, 36.4 g was added3, 4-dihydroxybenzoate, 82.4 g of potassium carbonate, 6.0 g of 4-methylaminopyridine, 145.6 g of 1-chloro-2-methoxyethane was stirred to a temperature of 90-95 ° C, Reflux insulation, the reaction is completed, cooling down to 20-30 ° C, Add water, stir, place the layer, extract the water layer, combined organic layer, distillation, steaming, cooling cooling. Add isopropyl alcohol and water, filter, filter cake with isopropyl alcohol and water leaching, drying dry product, vacuum drying to obtain 57g products, the yield of 95percent, HPLC purity of 99percent.A solution of ethyl 3, 4-dihydroxybenzoate (1.7 g, 9.3 mmol) was placed in a reaction flask and 8 mL of DMF was added to dissolve it. Potassium tert-butoxide (2.0 g, 17.8 mmol) and potassium iodide (1.0 g, 6.0 mmol), and the temperature was raised to 100 ° C. 2-Chloroethyl methyl ether (3.52 g, 37.2 mmol) was added dropwise and the reaction was continued for 12 h after completion of the dropwise addition. Cooled to room temperature, ice water (200 mL) was added, and extracted three times with ethyl acetate (3 x 200 mL). The organic phase was combined, washed three times with distilled water, three times with saturated brine, dried over anhydrous sodium sulfate overnight, filtered, and the filtrate was evaporated to dryness under reduced pressure to give an oil. The elution system was petroleum ether / ethyl acetate = 1) Ethyl 3, 4-bis (2-methoxyethoxy) benzoate.[Synthesis Example 1]; (Synthesis of ethyl 3, 4-bis(2-methoxyethoxy)benzoate); In a 20 L-volume glass reaction vessel equipped with a stirrer, a thermometer and a reflux condenser, 1, 300 g (7.14 moles) of ethyl 3, 4-dihydroxybenzoate, 2, 324 g (21.4 moles) of 2-chloroethyl methyl ether, 2, 958 g (21.4 moles) of potassium carbonate and 6, 500 mL of N, N-dimethylformamide were placed. The mixture was allowed to react with each other at 90 to 100°C for 9 hours while stirring. After the reaction was complete, the reaction solution was cooled to room temperature. The reaction solution was then filtered, and washed with 6, 500 mL of acetone. The filtrate was concentrated, 3, 900 mL of ethyl acetate and 3, 900 mL of a saturated aqueous sodium carbonate solution were added to the concentrate. The separated organic layer (ethyl acetate layer) was washed twice with 3, 900 mL of a saturated aqueous sodium chloride solution to obtain a solution mixture containing ethyl 3, 4-bis(2-methoxyethoxy)benzoate. The solution mixture was analyzed (according to an absolute quantitative method) by a high performance liquid chromatography. It was confirmed that 2, 023 g of ethyl 3, 4-bis(2-methoxyethoxy)benzoate was produced (reaction yield: 95percent). After 3, 939 mL of acetic acid was added to the solution mixture, the mixture was concentrated under reduced pressure to distill ethyl acetate off. Thus, an acetic acid solution of ethyl 3, 4-bis(2-methoxyethoxy)benzoate was obtained.EXAMPLE 504-chloro-6, 7-bis(2-methoxyethoxy)quinazoline (compound I-1)Ethyl 3, 4-dihydroxybenzoate (36.4 g, 0.2 mol), potassium carbonate (82.8 g, 0.6 mol), and 2-methoxyethyl p-toluenesulfonate (72.0 g, 0.4 mol) were dissolved in acetonitrile (200 ml), heated and refluxed for 6 h. The solvent of the reaction mixture was evaporated under vacuum to obtain a residue. The residue was recrystallized with isopropanol, suction filtered, and dried under vacuum to obtain a white powder 3, 4-bis (2-methoxyethoxy)ethyl benzoate (53.2 g, 89percent).3, 4-bis(2-methoxyethoxy)benzoic acid ethyl ester (15.00 g, 0.05 mol) was added into acetic acid (50 ml) to form a mixture, and while the mixture was stirred in an ice water bath, 65-68percent nitric acid (13 ml) was added to the mixture. The mixture then was stirred for 24 h at room temperature. The reaction mixture was transferred into ice water (500 ml), and extracted with ethyl acetate. The organic phase was combined, washed with saturated sodium bicarbonate solution three times, washed with saturated sodium chloride solution, and then dried by anhydrous sodium sulfate. The organic phase was then filtered to obtain a filtrate. The filtrate was concentrated to obtain a brown oily liquid 2-nitro-4, 5-bis(2-methoxyethoxy)ethyl benzoate (14.10 g, 82.22percent).2-nitro-4, 5-bis(2-methoxyethoxy)benzoic acid ethyl ester (34.3 g, 0.10 mol), ammonium formate (63 g, 1.00 mol), 5percent Pd/C (5.00 g), and formamide (150 ml) were reacted for 7 h at 150° C. The reaction mixture was cooled to room temperature, and a solid precipitated. The precipitate was filtered to obtain a white powder 6, 7-bis-(2-methoxyethoxy)-4(3H)quinazolinone (22.1 g, 75percent).Thionyl chloride (14.9 g) was added dropwise slowly to a solution of 6, 7-bis-(2-methoxyethoxy)-4 (3H) quinazolinone (14.7 g, 0.15 mol), N, N-dimethylformamide (1 ml), and dichloromethane (150 ml). The reaction mixture was stirred at room temperature, and refluxed for 6 h. The reaction mixture was cooled to room temperature, and the pH of the reaction mixture was adjusted to 7-8 with a sodium hydroxide solution. The reaction mixture was then stirred for 30 min at room temperature, and set aside to allow the organic and aqueous layers to separate. The organic layer was collected, and concentrated under vacuum to obtain a white solid 4-chloro-6, 7-bis-(2-methoxyethoxy)-quinazoline (14.1 g, 89.5percent), [MEthyl 3, 4-dihydroxybenzoate (36.4 g, 0.2 mol), potassium carbonate (82.8 g, 0.6 mol), and 2-methoxyethyl p-toluenesulfonate (72.0 g, 0.4 mol) were dissolved in acetonitrile (200 ml), heated and refluxed for 6 h. The compounds (1) (194.28), compounds (1118), potassium carbonate (252.38), toluene (222) and tetrakisbutyl ammonium bromide (5 g), heated to reflux, reacted for 6 hours, HPLC indicated that the reaction was complete, cooled to room temperature, filtered, The filtrate was washed with 1110 mL of water and the aqueous layer was extracted with toluene (555 mL X 2). The toluene layers were combined, washed with 1110 mL ofAnd brine, dried toluene to give the compound (iii) (172.6 g), 95percent yield, purity> 95percent. The NMR of the compound (iii)Identification data are as follows:1.5 Synthesis of ethyl 3, 4-bis(methoxyethoxy)benzoate

Molecular Weight:298.33
XLogP3:2
Hydrogen Bond Acceptor Count:6
Rotatable Bond Count:11
Exact Mass:298.14163842
Monoisotopic Mass:298.14163842
Topological Polar Surface Area:63.2
Heavy Atom Count:21
Complexity:283
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes