Preparation and application background and overview of 2-amino-3-benzyloxypyridine
2-Amino-3-benzyloxypyridine is a pharmaceutical intermediate that can be prepared by the one-step reaction of 2-amino-3-hydroxypyridine and benzyl chloride. 2-Amino-3-benzyloxypyridine can be used to prepare risperidone intermediate 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H- Pyrido[1,2-a]pyrimidin-4-one.
Preparation and application of 2-amino-3-benzyloxypyridine
Control the temperature below 40°C, add 48L purified water to the 300L stainless steel reactor, slowly add 48kg sodium hydroxide under stirring conditions, and stir until dissolved. Add 16kg 2-amino-3-hydroxypyridine, 1.6kg tetrabutylammonium bromide, and 17.92L benzyl chloride to the sodium hydroxide solution in sequence. After the addition is completed, the temperature is raised to 70~75°C and the reaction is continued for 6 hours. Stop stirring and let it stand. Separate the liquids; extract the aqueous phase with toluene (20Lx3); wash with purified water (30Lx2), collect the organic phase, concentrate until a large amount of solid precipitates, control the temperature at 0~5°C, stir and crystallize for 2 hours, centrifuge, use 3.2L for the filter cake Rinse with pre-cooled toluene and vacuum dry at 50-55°C for 3 hours to obtain 22.5kg of intermediate II 2-amino-3-benzyloxypyridine, with a molar yield of 77.3% and a purity of 99.53%.
Preparation and application of 2-amino-3-benzyloxypyridine
Preparation and application of 2-amino-3-benzyloxypyridine Intermediate III: 9-(benzyloxy)-3-(2-hydroxyethyl)-2-methyl-4H-pyridine Preparation of [1,2-a]pyrimidin-4-one
Under stirring conditions, add 13.6L toluene, 8.5kg 2-amino-3-benzyloxypyridine, 8.4kg α-acetyl-γ-butyrolactone, 450g p-toluenesulfonic acid into the 50L glass reaction kettle, add After completion, raise the temperature to reflux, and separate the water generated by the reaction in time. HPLC detects that the remaining 2-amino-3-benzyloxypyridine is less than 2%. Stop heating, distill under reduced pressure until most of the solids are precipitated, stop distillation under reduced pressure, and cool down. to 0-5°C, stirred for crystallization for 2 hours, and filtered with suction to obtain 11.7kg of crude product. Dry with air blast to constant weight, add the crude product into a 50L reaction kettle containing 7.7L methanol, heat to reflux for about 1 hour, then cool to 0~5°C, stir with heat preservation for 1 hour, filter with suction, and dry with air blast to obtain a bright yellow solid in the middle. Body III, bright yellow solid, 9-(benzyloxy)-3-(2-hydroxyethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one 11.5kg, mol The yield is 87.3%, and the purity of 9-hydroxypyridine is 9.62%.
Preparation and application of 2-amino-3-benzyloxypyridine Intermediate IV: 9-(benzyloxy)-3-(2-chloroethyl)-2-methyl-4H-pyridine Preparation of [1,2-a]pyrimidin-4-one
Under stirring conditions at room temperature, add 3600ml of ethylene glycol dimethyl ether and 1800g of 9-(benzyloxy)-3-(2-hydroxyethyl)-2-methyl-4H-pyrido into a 10L three-necked flask. After [1,2-a]pyrimidin-4-one is evenly dispersed, slowly add 1620ml of phosphorus oxychloride dropwise. After the addition is completed, raise the temperature to reflux for 6 hours, stop heating, and cool to room temperature. Slowly add the reaction solution to a 50L glass reaction kettle containing 7.5L cold water at 0-5°C to quench. After addition, a yellow solution is obtained. Use 20% sodium hydroxide solution to adjust the pH to 7-8. The solution turns brick red and has A large amount of solid is produced. Continue stirring for 1 hour and filter with suction. The filter cake is washed three times (1800mlx3) with purified water at 40-50°C. The filter cake is placed in an oven and air-dried at 50°C for 8 hours to obtain Intermediate IV, a pink solid. , 9-(benzyloxy)-3-(2-chloroethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one 1650g, molar yield: 86.5%, purity 99.70%.
Preparation and application of 2-amino-3-benzyloxypyridine Intermediate I: 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9 -Preparation of tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (without adding decolorizing agent)
25~30℃, add 50mL ethanol, 2.5ml concentrated sulfuric acid, and 5.0g 9-(benzyloxy)-3-(2-chloroethyl)-2-methyl-4H- into the 100L hydrogenation reaction bottle. Pyrido[1,2-a]pyrimidin-4-one, start stirring to dissolve, add 0.75g 5% dry palladium carbon to the reaction bottle, replace it with nitrogen three times, replace it with hydrogen three times, control the hydrogen pressure range to 25 psi, react for 23 hours, and filter , concentrate the filtrate by rotary evaporation under reduced pressure; add 30 mL of methylene chloride and 15 mL of purified water to the concentrated residue, stir to dissolve, adjust the pH to 7.00 with 10% NaOH at 0 to 10°C, let stand for liquid separation, use 30 mLx2 for the water phase Extract with dichloromethane, combine the organic phases, and dry over holmium carbonate and anhydrous sodium sulfate. Filtrate with suction, and concentrate the filtrate to obtain a dark green solid residue. Add 30 mL of ethyl acetate to the residue, heat and reflux until the solution is clear, add 30 ml of petroleum ether to the filtrate, cool to 0~5°C, stir and crystallize for 2 hours, and filter. , the filter cake was dried in a blast drying oven at 50-55°C until constant weight and discharged, to obtain key intermediate I, gray solid powder, 3-(2-chloroethyl)-9-hydroxy-2-methyl-6 , 7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one 2.54g, molar yield 68.9%. Purity: 98.54%, chlorine removal by-product compound V: 0.30%.
References
[1][China invention, China invention authorization] CN201710530282.X Preparation method of high-purity paliperidone intermediate
