CN114105865A - 一种3,4,5-三氯吡啶的合成工艺 - Google Patents
一种3,4,5-三氯吡啶的合成工艺 Download PDFInfo
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- CN114105865A CN114105865A CN202111481935.2A CN202111481935A CN114105865A CN 114105865 A CN114105865 A CN 114105865A CN 202111481935 A CN202111481935 A CN 202111481935A CN 114105865 A CN114105865 A CN 114105865A
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/68—One oxygen atom attached in position 4
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Abstract
本发明涉及一种3,4,5‑三氯吡啶的合成工艺，将4‑吡啶醇100kg在乙腈1500L和水10L中的搅拌溶液加热到40℃，将产物BCHP在烘箱中干燥至恒重；向3，5‑二氯‑4‑吡啶醇（BCHP）170 kg在乙腈850L中搅拌悬浮液中，滴加三氯氧膦（POCl3）317.9kg，将收集的有机相约7000L在40℃或低于40℃下真空浓缩，直达到存在约170L，将混合物冷却到25‑30℃并添加水340L，将混合物在真空下再次浓缩以移除更多的庚烷，当存在不到340L时停止浓缩，添加水850L，并将混合物搅拌2‑3小时，将固体通过过滤分离，并用水340L洗涤滤饼，在40‑45℃下在真空烘箱中干燥直至恒重，收率达到88.8%。优点是提出一种新的工艺路线，操作方便，副产物少，适合大批量生产。
Description
技术领域
本发明涉及吡啶衍生物合成领域，具体涉及一种3,4,5-三氯吡啶的合成工艺。
背景技术
3,4,5-三氯吡啶是一个吡啶衍生物。 在过氧化氢尿素络合物的存在下，它与三氟乙酸酐(TFAA)进行氧化反应。
3,4,5-三氯吡啶可作为核磁共振定量研究的二级标准。 3,4,5-三氯吡啶原有工艺中使用氯气，使用操作不方便，而且副产物比较多，不适合大量生产。
原有的合成路线：通过吡啶合成3,4,5-三氯吡啶：
发明内容
为了解决上述技术问题，本发明提出了一种3,4,5-三氯吡啶的合成工艺，设计合理，工艺完善，操作方便，副产物少，满足大量生产。
本发明的技术方案：
一种3,4,5-三氯吡啶的合成工艺，步骤如下：
步骤Step 1 ：
将4-吡啶醇100kg在乙腈1500L（15倍体积）和水10L（0.1倍体积）中的搅拌溶液加热到40℃，然后在40~55℃下分次添加NCS（308.9kg）,将反应液混合物在45-55℃下搅拌6-8小时,通过HPLC监测反应的进程,反应完毕后，将反应物冷却并搅拌3-4小时,将固体过滤，并用乙腈200L（2倍体积）和水500L（5倍体积）、水200L（2倍体积）洗涤,将产物BCHP在烘箱中干燥至恒重。
步骤Step 2 ：
向3，5-二氯-4-吡啶醇（BCHP）170 kg在乙腈850L（5倍体积）中搅拌悬浮液中，滴加三氯氧膦（POCl3）317.9kg ，将反应混合物加热到50-55℃并搅拌24小时，通过HPLC监测反应的进程，反应完成后将混合物冷却。
然后在2-10℃下将反应混合物缓慢倒入水850L（5倍体积）中。
将混合物搅拌20-30分钟。
用50%NaOH（水溶液）将pH调节到9-10。
将温度升到25-30℃。
并将混合物用正庚烷3060L(18倍体积)和正庚烷1700L×2（2×10倍体积）萃取。
合并有机相用水850L(5倍体积)洗涤。
然后加活性炭25.5kg（0.15倍重量）搅拌1-2小时。
通过硅藻土层过滤有机相。
用庚烷340L（2倍体积）洗涤滤饼。
将收集的有机相约7000L在40℃或低于40℃下真空浓缩，直达到存在约170L（1体积）。
将混合物冷却到25-30℃并添加水340L（2倍体积）。
将混合物在真空下再次浓缩以移除更多的庚烷。
当存在不到340L（2倍体积）时停止浓缩。
添加水850L（5倍体积），并将混合物搅拌2-3小时。
将固体通过过滤分离，并用水340L（2倍体积）洗涤滤饼。
在40-45℃下在真空烘箱中干燥直至恒重，收率达到88.8%。
通过4-羟基吡啶合成3,4,5-三氯吡啶的化学式如下：
本发明的优点是提出一种新的工艺路线，操作方便，副产物少，工艺完善合理，适合大批量生产。
具体实施方式
实施1：
一种3,4,5-三氯吡啶的合成工艺，通过4-羟基吡啶合成3,4,5-三氯吡啶的化学式如下：
步骤Step 1 ：
将4-吡啶醇100kg在乙腈1500L（15倍体积）和水10L（0.1倍体积）中的搅拌溶液加热到40℃，然后在40~55℃下分次添加NCS（308.9kg）,将反应液混合物在45-55℃下搅拌6-8小时,通过HPLC监测反应的进程,反应完毕后，将反应物冷却并搅拌3-4小时,将固体过滤，并用乙腈200L（2倍体积）和水500L（5倍体积）、水200L（2倍体积）洗涤,将产物BCHP在烘箱中干燥至恒重。
步骤Step 2 ：
向3，5-二氯-4-吡啶醇（BCHP）170 kg在乙腈850L（5倍体积）中搅拌悬浮液中，滴加三氯氧膦（POCl3）317.9kg ，将反应混合物加热到50-55℃并搅拌24小时，通过HPLC监测反应的进程，反应完成后将混合物冷却，然后在2-10℃下将反应混合物缓慢倒入水850L（5倍体积）中，将混合物搅拌20-30分钟，用50%NaOH（水溶液）将pH调节到9-10，将温度升到25-30℃，并将混合物用正庚烷3060L(18倍体积)和正庚烷1700L×2（2×10倍体积）萃取，合并有机相用水850L(5倍体积)洗涤，然后加活性炭25.5kg（0.15倍重量）搅拌1-2小时，通过硅藻土层过滤有机相，用庚烷340L(2倍体积)洗涤滤饼，将收集的有机相约7000L在40℃或低于40℃下真空浓缩，直达到存在约170L(1体积)，将混合物冷却到25-30℃并添加水340L(2倍体积)，将混合物在真空下再次浓缩以移除更多的庚烷，当存在不到340L（2倍体积）时停止浓缩，添加水850L(5倍体积)，并将混合物搅拌2-3小时，将固体通过过滤分离，并用水340L（2倍体积）洗涤滤饼，在40-45℃下在真空烘箱中干燥直至恒重，收率达到88.8%。
Claims (2)
1.一种3,4,5-三氯吡啶的合成工艺，其特征在于，步骤如下：
步骤Step 1 ：
将4-吡啶醇100kg在乙腈1500L和水10L中的搅拌溶液加热到40℃，然后在40~55℃下分次添加NCS 308.9kg,将反应液混合物在45-55℃下搅拌6-8小时,通过HPLC监测反应的进程,反应完毕后，将反应物冷却并搅拌3-4小时,将固体过滤，并用乙腈200L和水500L、水200L洗涤,将产物BCHP在烘箱中干燥至恒重；
步骤Step 2 ：
向3，5-二氯-4-吡啶醇（BCHP）170 kg在乙腈850L中搅拌悬浮液中，滴加三氯氧膦（POCl3）317.9kg ，将反应混合物加热到50-55℃并搅拌24小时，通过HPLC监测反应的进程，反应完成后将混合物冷却，
然后在2-10℃下将反应混合物缓慢倒入水850L中，
将混合物搅拌20-30分钟，
用50%NaOH（水溶液）将pH调节到9-10，
将温度升到25-30℃，
并将混合物用正庚烷3060L和正庚烷1700L×2萃取，
合并有机相用水850L洗涤，
然后加活性炭25.5kg搅拌1-2小时，
通过硅藻土层过滤有机相，
用庚烷340L洗涤滤饼，
将收集的有机相7000L在40℃或低于40℃下真空浓缩，直达到存在170L，
将混合物冷却到25-30℃并添加水340L，
将混合物在真空下再次浓缩以移除更多的庚烷，当存在小于等于340L时停止浓缩，
添加水850L，并将混合物搅拌2-3小时，
将固体通过过滤分离，并用水340L洗涤滤饼，
在40-45℃下在真空烘箱中干燥直至恒重，收率达到88.8%。
2.根据权利要求1所述的一种3,4,5-三氯吡啶的合成工艺，其特征在于，通过4-羟基吡啶合成3,4,5-三氯吡啶的化学式如下：
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4379938A (en) * | 1980-05-12 | 1983-04-12 | Ciba-Geigy Corporation | Process for producing 2,3,5-trichloropyridine |
| CN102250016A (zh) * | 2011-05-19 | 2011-11-23 | 绍兴文理学院 | 一种4,5,6-三氯嘧啶的制备方法 |
| CN110741005A (zh) * | 2017-06-20 | 2020-01-31 | 利奥制药有限公司 | 用于制备1,3-苯并二氧杂环戊烯杂环化合物的方法 |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4379938A (en) * | 1980-05-12 | 1983-04-12 | Ciba-Geigy Corporation | Process for producing 2,3,5-trichloropyridine |
| CN102250016A (zh) * | 2011-05-19 | 2011-11-23 | 绍兴文理学院 | 一种4,5,6-三氯嘧啶的制备方法 |
| CN110741005A (zh) * | 2017-06-20 | 2020-01-31 | 利奥制药有限公司 | 用于制备1,3-苯并二氧杂环戊烯杂环化合物的方法 |
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