叶酸杂质22

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 8-Oxa-bicyclo[3.2.1]oct-6-en-3-one was synthesized by the known [4+3] cycloaddition of the commercially available furan and the oxyally generated from 1,1,3-trichloroacetone, followed by reduction with zinc (J. Org. Chem. 1999, 64, 3398 and J. Am. Chem. Soc. 2001, 123, 5590). Internal double bond of the cycloadduct was reduced using Pd/C in MeOH to give 8-oxa-bicyclo[3.2.1]octan-3-one. The resulting ketone was subjected to Eadsworth-Horner-Emmons condition to yield the α,β-unsatured ester. Catalytic hydrogenation of the conjugated ester gave rise to an inseparable mixture (˜1:1) of diasteromers with no diastereoselectivity. The mixture of diastereomers carried forward to the next two steps. These steps include reduction of esters with NaBH4/LiCl followed by treatment with TsCl in the presence of NEt3 to furnish the oxabicyclo[3.2.1]octaneethylmethylbenzensolfonate. 1H NMR (CDCl3): δ 7.81-7.78 (m, 2H), 7.37-7.34 (m, 2H), 4.35-4.28 (m, 2H), 4.07-4.02 (m, 2H), 2.46 (s, 3H), 2.07 (m, 1H), 1.95-1.87 (m, 2H), 1.82-1.76 (m, 1H), 1.68-1.63 (m, 2H), 1.55-1.50 (m, 2H), 1.43-1.28 (m, 2H), 1.10 (m, 1H).

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 8-Oxa-bicyclo[3.2.1]oct-6-en-3-one was synthesized by the known [4+3] cycloaddition of the commercially available furan and the oxyally generated from 1,1,3-trichloroacetone, followed by reduction with zinc (J. Org. Chem. 1999, 64, 3398 and J. Am. Chem. Soc. 2001, 123, 5590). Internal double bond of the cycloadduct was reduced using Pd/C in MeOH to give 8-oxa-bicyclo[3.2.1]octan-3-one. The resulting ketone was subjected to Eadsworth-Horner-Emmons condition to yield the α,β-unsatured ester. Catalytic hydrogenation of the conjugated ester gave rise to an inseparable mixture (˜1:1) of diasteromers with no diastereoselectivity. The mixture of diastereomers carried forward to the next two steps. These steps include reduction of esters with NaBH4/LiCl followed by treatment with TsCl in the presence of NEt3 to furnish the oxabicyclo[3.2.1]octaneethylmethylbenzensolfonate. 1H NMR (CDCl3): δ 7.81-7.78 (m, 2H), 7.37-7.34 (m, 2H), 4.35-4.28 (m, 2H), 4.07-4.02 (m, 2H), 2.46 (s, 3H), 2.07 (m, 1H), 1.95-1.87 (m, 2H), 1.82-1.76 (m, 1H), 1.68-1.63 (m, 2H), 1.55-1.50 (m, 2H), 1.43-1.28 (m, 2H), 1.10 (m, 1H).

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 8-Oxa-bicyclo[3.2.1]oct-6-en-3-one was synthesized by the known [4+3]cycloaddition of the commercially available furan and the oxyally generated from 1,1,3-trichloroacetone, followed by reduction with zinc (J. Org. Chem. 1999,64, 3398 and J. Am. Chem. Soc. 2001, 123, 5590). Internal double bond of the cycloadduct was reduced using Pd/C in MeOH to give 8-oxa-bicyclo[3.2.1]octan-3-one. The resulting ketone was subjected to Eadsworth-Horner-Emmons condition to yield the α,β-unsaturated ester. Catalytic hydrogenation of the conjugated ester gave rise to an inseparable mixture (˜1:1) of diasteromers with no diastereoselectivity. The mixture of diastereomers carried forward to the next two steps. These steps include reduction of esters with NaBH4/LiCl followed by treatment with TsCl in the presence of NEt3 to furnish the oxabicyclo[3.2.1]octaneethylmethylbenzensolfonate. 1H NMR (CDCl3): δ 7.81-7.78 (m, 2H), 7.37-7.34 (m, 2H), 4.35-4.28 (m, 2H), 4.07-4.02 (m, 2H), 2.46 (s, 3H), 2.07 (m, 1H), 1.95-1.87 (m, 2H), 1.82-1.76 (m, 1H), 1.68-1.63 (m, 2H), 1.55-1.50 (m, 2H), 1.43-1.28 (m, 2H), 1.10 (m, 1H).

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 8-Oxa-bicyclo[3.2.1]oct-6-en-3-one was synthesized by the known [4+3]cycloaddition of the commercially available furan and the oxyally generated from 1,1,3-trichloroacetone, followed by reduction with zinc (J. Org. Chem. 1999,64, 3398 and J. Am. Chem. Soc. 2001, 123, 5590). Internal double bond of the cycloadduct was reduced using Pd/C in MeOH to give 8-oxa-bicyclo[3.2.1]octan-3-one. The resulting ketone was subjected to Eadsworth-Horner-Emmons condition to yield the α,β-unsaturated ester. Catalytic hydrogenation of the conjugated ester gave rise to an inseparable mixture (˜1:1) of diasteromers with no diastereoselectivity. The mixture of diastereomers carried forward to the next two steps. These steps include reduction of esters with NaBH4/LiCl followed by treatment with TsCl in the presence of NEt3 to furnish the oxabicyclo[3.2.1]octaneethylmethylbenzensolfonate. 1H NMR (CDCl3): δ 7.81-7.78 (m, 2H), 7.37-7.34 (m, 2H), 4.35-4.28 (m, 2H), 4.07-4.02 (m, 2H), 2.46 (s, 3H), 2.07 (m, 1H), 1.95-1.87 (m, 2H), 1.82-1.76 (m, 1H), 1.68-1.63 (m, 2H), 1.55-1.50 (m, 2H), 1.43-1.28 (m, 2H), 1.10 (m, 1H).

实验步骤: 投料: 将SM1（1g，4.18mmol，1.0eq）,1,1,3-三氯丙酮（0.75ml，1.0eq）,L-半胱氨酸（1.52g，3.0eq），物质的量（1：1:3），甲醇：水（1:1）（10ml），加料完毕升至60℃搅拌1h 11：30 送样LCMS监测反应进程（13956-1-2-1h），主峰为产物，停止反应，降温搅拌2h。 将体系过滤，滤饼滤液分别送样LCMS（13956-1-3-LB,13956-1-3-LY)，产物基本在滤液。 将滤液加入氢氧化钠水溶液调节PH至中性，经反向FLASH柱纯化（ACN=25%)冲出F3，送样LCMS（13956-1-F3）确认产物MS无误，浓缩干燥(0.3g褐色固体）。

实验步骤: 投料: 将SM1（1g，4.18mmol，1.0eq）,1,1,3-三氯丙酮（0.75ml，1.0eq）,L-半胱氨酸（1.52g，3.0eq），物质的量（1：1:3），甲醇：水（1:1）（10ml），加料完毕升至60℃搅拌1h 17：30 送样LCMS监测反应进程（13956-1-2-1h），主峰为产物，停止反应。 2026/02/27 将体系过滤，滤饼滤液分别送样LCMS（13956-1-2-LB,13956-1-2-LY)，产物基本在滤液，收集滤液直接用于下一步。

实验步骤: 投料: 取3000ml干燥单口瓶，加入M-C4X-139541-1（23.3g 61.6mmol 1eq）和水（2400ml），室温下搅拌不完全溶解。反应液室温下加入2,4,5-三氨基-6-羟基嘧啶硫酸盐（46.72g 195.3mmol 3.17eq）和三氯丙酮（100g 433.7mmol 7.04eq），室温搅拌下逐滴加入浓盐酸调节反应液PH至1，升温至80℃下搅拌5h 反应液由橙色浑浊液转为棕色浑浊液 后处理：反应液抽滤，得到棕黑色固体，滤液此时PH为1，用氢氧化钠溶液调节PH至5-6，有棕色固体析出，抽滤，棕褐色固体。 待制备

实验步骤: 投料: 取1000ml干燥单口瓶，加入M-C4X-139541-1（5.85g 15.5mmol 1eq）和水（590ml），室温下搅拌不完全溶解。反应液室温下加入2,4,5-三氨基-6-羟基嘧啶硫酸盐（11.75g 49.1mmol 3.17eq）和三氯丙酮（25g 109.1mmol 7.04eq），室温搅拌下逐滴加入浓盐酸调节反应液PH至1，升温至80℃下搅拌5h 反应液由橙色浑浊液转为棕色浑浊液 后处理：反应液抽滤，得到棕黑色固体，送制备待纯化\n纯化

实验步骤: 投料: 取500ml干燥单口瓶，加入M-C4X-139541-1（2.5g 6.6mmol 1eq）和水（250ml），室温下搅拌不完全溶解。反应液室温下加入2,4,5-三氨基-6-羟基嘧啶硫酸盐（5.0g 20.9mmol 3.17eq）和三氯丙酮（12.51g 46.5mmol 7.04eq），室温搅拌下逐滴加入浓盐酸调节反应液PH至1，升温至80℃下搅拌5h 反应液由橙色浑浊液转为棕色浑浊液 后处理：反应液抽滤，得到棕黑色固体，送制备待纯化

实验步骤: 投料: 取3000ml干燥单口瓶，加入M-C4X-139541-1（23.3g 61.6mmol 1eq）和水（2400ml），室温下搅拌不完全溶解。反应液室温下加入2,4,5-三氨基-6-羟基嘧啶硫酸盐（46.72g 195.3mmol 3.17eq）和三氯丙酮（100g 433.7mmol 7.04eq），室温搅拌下逐滴加入浓盐酸调节反应液PH至1，升温至80℃下搅拌5h 反应液由橙色浑浊液转为棕色浑浊液 后处理：反应液抽滤，得到棕黑色固体，滤液此时PH为1，用氢氧化钠溶液调节PH至5-6，有棕色固体析出，抽滤，棕褐色固体。 母液固体均送制备\n纯化: 含量低，难以制备分离

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 5-(Trifluoromethyl)pyridin-2-amine (12.9 g) was dissolved in dimethoxyethane (150 mL) was added 1,1,3-trichloroacetone (12.7 mL) at room temperature, and the mixture was stirred overnight. The precipitated solid was collected, and suspended in ethanol (50 mL), and the mixture was heated under reflux for 3 hr. After allowing to cool to room temperature, the solvent was evaporated under reduced pressure, saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate-tetrahydrofuran (1:1, volume ratio). The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2, volume ratio) to give 2-(dichloromethyl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine (10.3 g) as a white solid. The obtained solid was suspended in a mixed solvent of water (100 mL) and tetrahydrofuran (20 mL), and calcium carbonate (8.0 g) was added to the mixture at room temperature, and the mixture was stirred at 100° C. for 1 hr. The mixture was allowed to cool to room temperature, the insoluble material was filtered off, and the filtrate was extracted with ethyl acetate. The extract was dried over magnesium sulfate, and concentrated under reduced pressure to give a white solid. The residue was washed with diisopropyl ether to give the title object compound (7.3 g, 43%) as white crystals. The precipitated solid was collected the mixture was heated under reflux for 3 hr the solvent was evaporated under reduced pressure, saturated aqueous sodium hydrogen carbonate was added to the residue the mixture was extracted with ethyl acetate-tetrahydrofuran (1:1, volume ratio) The extract was washed with saturated brine dried over magnesium sulfate concentrated under reduced pressure The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2, volume ratio)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: At present, PteGlu of folic acids is industrially produced through chemical synthesis. Briefly, three components of 2,4,5-triamino-6-hydroxypyrimidine, 1,1,3-trichloroacetone and p-aminobenzoylglutamic acid are condensed in the presence of sodium nitrite in a solution of sodium acetate to give a crude product of folic acid, PteGlu, and the product is purified through recrystallization.