摘要：目的：研究甲磺酸沙芬酰胺关键中间体的合成工艺，并对工艺参数进行优化。方法：以对羟基苯甲醛、间氟溴苄为起始原料，经烷基化反应得中间体4-(3-氟苄基)氧苯甲醛，对反应溶剂、投料比、碱种类、碱用量、反应温度、溶剂用量、反应时间、水用量、析晶时间、重结晶溶剂、重结晶溶剂用量、重结晶析晶温度、重结晶析晶时间进行了筛选。结果：最佳工艺参数是反应溶剂N,N-二甲基甲酰胺，投料比对羟基苯甲醛:间氟溴苄比例为1:1，碱种类是碳酸钾，碱用量为碳酸钾1.2当量，反应温度为30~35℃，溶剂用量为10倍，反应时间为5h，水用量为20~25倍，析晶时间为3h~5h，重结晶溶剂为环己烷，重结晶溶剂用量为6~8倍，重结晶析晶温度为0~5℃，重结晶析晶时间为6~12h。结论：优化后的合成工艺条件可控，操作简单，质量可控性好，适合工业化生产。
关键词:甲磺酸沙芬酰胺；中间体；合成；工艺优化
Abstract:Purpose: To study the synthesis process of key
intermediates of safinamide mesylate and optimize the process parameters. Methods: Using p-hydroxybenzaldehyde
and m-fluorobenzyl bromide as starting materials,
4-(3-fluorobenzyl)oxybenzaldehyde (Intermediate 1) was obtained by alkylation
reaction, and the reaction solvent, feed ratio,
alkali type, alkali dosage, reaction temperature, solvent dosage, reaction
time, water dosage, precipitation time, recrystallization solvent,
recrystallization solvent dosage, recrystallization precipitation temperature,
recrystallization precipitation time were investigated. Result: The best process parameters are reaction solvent
N,N-dimethylformamide, feeding ratio of 1:1 for
p-hydroxybenzaldehyde:m-fluorobenzyl bromide, alkali type is potassium carbonate,
alkali dosage is 1.2 times of potassium carbonate, reaction temperature is
30~35 ℃, solvent dosage is 10 times, reaction time is 5h, water dosage is 20~25
times, precipitation time is 3h~5h, recrystallization solvent is cyclohexane,
recrystallization solvent dosage is 6~8 times, the temperature of
recrystallization and precipitation is 0~5℃, and the time of recrystallization
and precipitation is 6~12h. Conclusion: The
optimized synthetic process conditions are controllable, easy to operate, with
good quality control and suitable for industrial production. Key words: Safinamide mesylate;
Intermediates; Synthesis; Process optimization
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