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With thionyl chloride In <i>N</i>-methyl-acetamide; water
Stage B -- 4-Chloro-5-ethoxycarbonyl-2-methoxy-pyrimidine 99 g (0.5 mol) of 5-ethoxycarbonyl-4-hydroxy-2-methoxy-pyrimidine are suspended in 200 cm3 of dimethylformamide (D.M.F.). 89 g (0.75 mol) of thionyl chloride are added, over a period of about 5 minutes, to the mixture which is stirred. The solid material passes into solution with heating. The homogeneous solution is stirred again for 30 minutes at ambient temperature. The mixture is poured slowly, with stirring, into a mixture of ice (250 g) and water (1 liter). After further stirring (15 minutes), the product of the reaction is extracted with 2 * 400 cm3 of benzene. The combined extracts are washed with a dilute sodium bicarbonate solution and then with water, and dried (MgSO4). By concentration in vacuo, 4-chloro-5-ethoxycarbonyl-2-methoxy-pyrimidine is obtained, in the form of an oil, weighing 101.6 g (yield 94percent). The product is purified by distillation in vacuo, boiling point0.9 =120° C; the distillate crystallises and has a melting point of 26°-28° C. Analysis for C8 H9 ClN2 O3 (molecular weight 216.5): percent calculated: C,44.34; H,4.16; N,12.93. percent found: C,44.18; H,4.33; N,12.88.
With thionyl chloride; In N-methyl-acetamide; water;
Stage B -- 4-Chloro-5-ethoxycarbonyl-2-methoxy-pyrimidine 99 g (0.5 mol) of 5-ethoxycarbonyl-4-hydroxy-2-methoxy-pyrimidine are suspended in 200 cm3 of dimethylformamide (D.M.F.). 89 g (0.75 mol) of thionyl chloride are added, over a period of about 5 minutes, to the mixture which is stirred. The solid material passes into solution with heating. The homogeneous solution is stirred again for 30 minutes at ambient temperature. The mixture is poured slowly, with stirring, into a mixture of ice (250 g) and water (1 liter). After further stirring (15 minutes), the product of the reaction is extracted with 2 * 400 cm3 of benzene. The combined extracts are washed with a dilute sodium bicarbonate solution and then with water, and dried (MgSO4). By concentration in vacuo, 4-chloro-5-ethoxycarbonyl-2-methoxy-pyrimidine is obtained, in the form of an oil, weighing 101.6 g (yield 94%). The product is purified by distillation in vacuo, boiling point0.9 =120 C; the distillate crystallises and has a melting point of 26-28 C. Analysis for C8 H9 ClN2 O3 (molecular weight 216.5): % calculated: C,44.34; H,4.16; N,12.93. % found: C,44.18; H,4.33; N,12.88.
With N-ethyl-N,N-diisopropylamine; In acetonitrile; for 1.5h;Reflux;
Example 15 9-[2-Chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-2-methoxy-7,9-dihydro-8H-purin-8-one A mixture of <strong>[65269-18-3]ethyl 4-chloro-2-methoxypyrimidine-5-carboxylate</strong> (0.22 g), 2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyaniline hydrochloride (0.4 g) and N,N-diisopropylethylamine (0.37 mL) in acetonitrile (3 mL) was heated at reflux for 1.5 hours. The reaction mixture was poured into water. To the mixture was added ethyl acetate, and the insoluble material was collected by filtration. The collected solids were washed with water and ethyl acetate, and dried under reduced pressure to give ethyl 4-[2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenylamino]-2-methoxypyrimidine-5-carboxylate (91 mg). To this material were added methanol (2 mL) and 1 mol/L aqueous sodium hydroxide solution (0.9 mL), and the mixture was stirred at 50C for 1 hour. To the mixture was added tetrahydrofuran (1 mL), and the mixture was stirred at 50C for 1 hour. The reaction mixture was cooled to room temperature. To the mixture was added 1 mol/L hydrochloric acid (1.0 mL), and the mixture was stirred for 30 minutes. The precipitated crystals were collected by filtration. The collected crystals were washed with water and diethyl ether, and dried under reduced pressure to give 4-[2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxy-phenylamino]-2-methoxypyrimidine-5-carboxylic acid (57 mg). To this material were added 1,4-dioxane (1 mL), triethylamine (0.049 mL) and diphenylphosphoryl azide (0.026 mL), and the mixture was stirred at room temperature for 1 hour, and then heated at reflux for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate = 1/1 - 1/5). The product was suspended in a mixed solvent (n-hexane/ethyl acetate = 1/1), and collected by filtration. The collected material was washed with the same solvent, and dried under reduced pressure to give the title compound (20 mg).
(2-chloro-4-methoxypyrimidin-5-yl)methanol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In tetrahydrofuran;
Step 2: (2-chloro-4-methoxypyrimidin-5-yl)methanol To a solution of ethyl 2-chloro-4-methoxypyrimidine-5-carboxylate and <strong>[65269-18-3]ethyl 4-chloro-2-methoxypyrimidine-5-carboxylate</strong> (6 g, 27.8 mmol) in THF (60 mL) was added DIBAL-H (55 mmol, 55 mL, 1.0 M) dropwise at -78 C. under a nitrogen atmosphere, the mixture was stirred at -78 C. for 30 min. The temperature was allowed to rise to room temperature and stirring continued for a further 4 hr. The solution was quenched with aqueous potassium carbonate (150 mL) and extracted with ethyl acetate (300 mL*3). The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether/ethyl acetate (10:1 to 2:1) as eluent) to give (2-chloro-4-methoxypyrimidin-5-yl)methanol (1.8 g). MS (ESI) m/z 175, 177 (M+H)+
A mixture of ethyl 2,4-dichloropyrimidine-5-carboxylate (20 g, 91 mmol) and MeONa (9.8 g, 182 mmol) in methanol (200 mL) was stirred at r.t. for 2 hr. After finished, the mixture was concentrated under reduced pressure and then 200 mL of water was added. The product was extracted with ethyl acetate (100 mL x 3). The combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate (100: 1 to 20: 1) as eluent) to give a 1 : 1 mixture of ethyl 2-chloro-4-methoxypyrimidine-5-carboxylate and ethyl 4-chloro-2- methoxypyrimidine-5-carboxylate (12 g). MS (ESI) m/z 217, 219 (M+H)+
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