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精细石油化
工
SPECIALITY PETROCHEMICALS
驱虫药五氯柳胺的合成工艺研究
王学成，苏文杰，朱建民，刘祥宜（常州齐晖药业有限公司，江苏常州213127）
第34卷第4期 2017年7月
99 中加人还原性脱色剂精制得五氧柳胺。总收率由54.8%提高至87.5%，纯度达99.7%，单杂均小于0.2%。产物结构经'HNMR、元素分析及MS进行了表征，
关键调：五氧柳胺
催化加氢
2，4-二氯苯酸
中图分类号：TQ453.2*1
文献标识码：A
3,5,6-三氯水杨酸
五氟柳胺又名羟氯柳胺、羟氯柳苯胺和羟氟扎
胺，作为临床抗蜗虫感染的首选药物，具有广谱，低毒，低残留等优良特性"。其化学名为2，3，5-二氯-N-(3,5-二氯-2-羟基苯基)-6-羟基苯甲酰胺，中间体2-氨基-4,6-二氟苯酚采用水合耕还原法[}制备。该法不仅操作步彝复杂，后处理时甲醇蒸馏、氯苯分层等工序，产物极易氧化，面且会产生大量含致癌物水合肼的废水，造成环境污染。Pd/C、 PtO,、Pt/C、RaneyNi催化加氢法选择性差，反应收率低。另外，采用传统活性碳脱色剂精制五氯柳胺，外观较差，不符合EP9.0质量标准要求。
为此，笔者对合成路线进行了优化，并对改进了合成工艺。合成路线优化：以2，4-二氟-6-硝基苯酚(2)为原料，经催化加氢还原，与3，5，6-三氟水杨酸酰氯(5)缩合，并在甲醇/水中加入还原性脱色剂精制得到(1)。工艺改进：1)用催化加氢还原代
驱虫药
替水合肼还原；2)催化加氢还原、氯化、缩合反应采用单一溶剂甲苯，催化加氢制备的2-氨基-4，6-二氯苯酚反应液，不浓缩直接用于粗品的制备；3)精制时采用还原性脱色剂亚硫酸氢钠代替活性炭。
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2，4-二氯-6-硝基苯酚（w≥99%），工业品，连收稿日期；20170109；修改稿收到日期：201704-23。作者第介：王学成(1979-)，硕士，从事就等生虫药物合成研
E-mail:13814760945@139.com 究，
基金项日：十二五"国家科技支律计划项目（2015BAD11B01)，
isovaleraldehyde and ethyl cyanacetate by Knoevenagel condensation, cyano-addition and decarboxyla-tion. For better manufacture, the process of IBSN was studied by investigating solvent,reaction tem-perature and mole ratio, and was successfulscale-up. The most effective synthetic conditions of the in-termediate (3) is: the mole ratio of (Z)-ethyl 2-cyano-5-methylhex-2-enoate, ethyl cyanoacetate, isovaleraldehyde, acetic acidand piperidine is about 1 : 1. 1 : 1. 5 : . 2, keeping the temperature about 20 30 ℃, the yield of intermediate is 96. 3%, and assay by GC is 97. 1%. The optimal synthetic con ditions of IBSN is: the mole proportion of intermediate (3) to sodium cyanide is about 1 : 1. 06, using 95% ethanol solution as solvent, and the reaction temperature is about 7o C.The yield of IBSN is 91. 8%, and assay by GC is 99. 7%. The total yield was increased to 88. 4%. The new process simpli-fied work-up, achieved solvent recycle and was suitable for commercial production.
Key words: pregabalin; isobutylsuccinonitrile; work-up; solvents; scale-up 万方数据