CN112358442B - 一种2-氟-5-甲酰氯吡啶的制备方法 - Google Patents

一种2-氟-5-甲酰氯吡啶的制备方法 Download PDF

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CN112358442B
CN112358442B CN202011312262.3A CN202011312262A CN112358442B CN 112358442 B CN112358442 B CN 112358442B CN 202011312262 A CN202011312262 A CN 202011312262A CN 112358442 B CN112358442 B CN 112358442B
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柯有胜
张孝朋
刚宏辉
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Inner Mongolia Jiaruimi Fine Chemical Co ltd
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    • 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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    • 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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Abstract

本发明涉及一种2‑氟‑5‑甲酰氯吡啶的制备方法，属于有机化学技术领域。所述的方法步骤为：1)以2‑氟‑5‑甲基吡啶为原料，在高锰酸钾或高锰酸钠存在下反应得到2‑氟‑5‑甲酸吡啶；2)以2‑氟‑5‑甲酸吡啶与氯化亚砜或草酰氯在氯代溶剂中回流反应，反应结束，减压蒸馏溶剂后，加入烷烃溶剂冷冻后过滤得到2‑氟‑5‑甲酰氯吡啶溶液，经过减压精馏得到2‑氟‑5‑甲酰氯吡啶。本发明具有转化率高，得到的产品纯度高达99.0％以上，单杂小于0.5％，生产成本低，适合于工业化生产。

Description

一种2-氟-5-甲酰氯吡啶的制备方法
技术领域
本发明属于有机合成领域，具体涉及一种2-氟-5-甲酰氯吡啶的制备方法。
背景技术
2-氟-5-甲酰氯吡啶(6-氟-3-甲酰氯吡啶)，分子式C6H3ClFNO，CAS：65352-94-5。该产品是一种重要的化工中间体原料，可进一步生成酰肼、酰腙和酰胺，在农药和医药中发挥重要的作用，其应用价值和市场前景十分可观，例如可以用于制备2-(6-氟吡啶-3-基)-4,5-二氢哒唑。
目前国内市场上仅有试剂公司提供小量样品，且纯度通常仅在98％，对于获得高纯产品，尚无十分成熟的工艺技术报道。
发明内容
本发明的目的是提供一种2-氟-5-甲酰氯吡啶的制备方法，本发明转化率高，反应选择性好，产品纯度高，生产成本低，适合于工业化生产。
本发明包括两步反应：氧化反应和酰氯化反应，具体反应采用路线表示如下：
Figure BDA0002790173190000011
具体实施方案包括如下步骤：
1)2-氟-5-甲基吡啶的氧化反应
以2-氟-5-甲基吡啶为原料，在氧化剂存在下加热反应得到2-氟-5-甲酸吡啶。
2)2-氟-5-甲酸吡啶的酰氯化反应
2-氟-5-甲酸吡啶在氯代溶剂中，与草酰氯或氯化亚砜反应，蒸馏除去反应溶剂，然后加入烷烃溶剂降温后过滤，得到2-氟-5-甲酰氯吡啶混合液，减压精馏得到2-氟-5-甲酰氯吡啶。
进一步地，在上述技术方案中，第一步所述氧化剂为KMnO4或NaMnO4。
在氧化实验时，发现原料总是始终明显存在，增加氧化剂当量效果也不明显。经过尝试，当在氧化剂中混入一定量的碱时，反应转化率明显提高。优选方案为1-1.3当量氢氧化钠或氢氧化钾。
进一步地，在上述技术方案中，第一步所述氧化剂与2-氟-5-甲基吡啶摩尔比为2-4：1。碱与2-氟-5-甲基吡啶摩尔比为1-1.3：1。
进一步地，在上述技术方案中，第二步所述氯代溶剂为二氯甲烷、氯仿、1,2-二氯乙烷等。
进一步地，在上述技术方案中，第二步所述烷烃溶剂为正戊烷、正己烷、环己烷或正庚烷等。
进一步地，在上述技术方案中，第二步所述草酰氯或氯化亚砜与2-氟-5-甲酸吡啶当量为1-2.5：1，优选当量为1.3-1.8。
在酰氯反应时，随着反应规模的扩大，收率逐渐降低。通过深入研究发现，在反应过程中可见一定量的固体物，过滤后经分析为2-氟-5-甲酰氯吡啶盐酸盐。通过三种方法来进行解决：1、增加搅拌速度至200-400转/分；2、向反应釜内液面下通入氮气或氩气；3、反应结束后降温密闭过滤后再精馏。
进一步地，在上述技术方案中，减压精馏时收集90～94℃/15mm Hg馏分，得到无色液体产品2-氟-5-甲酰氯吡啶，该产品冷冻后为白色至类白色固体，长时间存放时采用冷冻至固体保存。
发明有益效果
本发明以2-氟-5-甲基吡啶为原料，通过氧化、酰氯化两步反应，合成高纯度的2-氟-5-甲酰氯吡啶。本发明转化率高，生产成本低，适合于工业化生产。
具体实施方式
下面将通过具体实施例对本发明做进一步的具体描述，但不能理解为是对本发明保护范围的限定。
本发明为2-氟-5-甲酰氯吡啶的制备方法，该方法以2-氟-5-甲基吡啶为原料，通过氧化、酰氯化两步反应，合成2-氟-5-甲酰氯吡啶粗品，经过减压精馏有机相，得到高纯度的2-氟-5-甲酰氯吡啶。具体过程如下：
实施例1：
在500mL三口瓶中，加入11.1g(0.1mol)2-氟-5-甲基吡啶，加水250mL，启动机械搅拌，依次加入31.6g(0.2mol)KMnO4和5.6g(0.1mol)KOH，油浴加热至95℃，反应5h，趁热过滤，收集滤液。待滤液降至常温后，用浓盐酸调节pH值至2～4，有固体析出，过滤；滤液用二氯乙烷萃取两遍。将过滤的固体和萃取的油相混合，旋转蒸发，得到类白色固体11.8g，即为2-氟-5-甲酸吡啶(熔点275～278℃)。
将第一步所得的2-氟-5-甲酸吡啶投入500mL三口瓶中，加入200mL二氯甲烷，启动搅拌，滴加二氯亚砜16.0g，回流反应6h后，蒸除溶剂和过量的二氯亚砜。加入正庚烷80mL后，降温密闭过滤，滤液减压精馏，收集90～94℃/15mm Hg馏分，得到无色液体产品2-氟-5-甲酰氯吡啶12.76g，冷冻后为类白色固体，其纯度达99.0％，总收率达到80.1％。
实施例2：
在500mL三口瓶中，加入11.1g(0.1mol)2-氟-5-甲基吡啶，加水250mL，启动机械搅拌，依次加入28.4g(0.2mol)NaMnO4和4.0g(0.1mol)NaOH，油浴加热至95℃，反应5h，趁热过滤，收集滤液。待滤液降至常温后，用浓盐酸调节pH值至2～4，有固体析出，过滤；滤液用二氯乙烷萃取两遍。将过滤的固体和萃取的油相混合，旋转蒸发，得到类白色固体11.5g，即为2-氟-5-甲酸吡啶(熔点275～278℃)。
其他步骤同实施例1，得到无色液体产品2-氟-5-甲酰氯吡啶12.55g，冷冻后为类白色固体，其纯度达99.0％，总收率达到78.7％。
实施例3：
在500mL三口瓶中，加入11.1g(0.1mol)2-氟-5-甲基吡啶，加水250mL，启动机械搅拌，依次加入47.4g(0.3mol)KMnO4和5.6g(0.1mol)KOH，油浴加热至95℃，反应5h，趁热过滤，收集滤液。待滤液降至常温后，用浓盐酸调节pH值至2～4，有固体析出，过滤；滤液用二氯乙烷萃取两遍。将过滤的固体和萃取的油相混合，旋转蒸发，得到类白色固体12.1g，即为2-氟-5-甲酸吡啶(熔点275～278℃)。
将第一步所得的2-氟-5-甲酸吡啶投入500mL三口瓶中，加入200mL二氯甲烷，启动搅拌，滴加二氯亚砜16.0g，回流反应6h后，蒸除溶剂和过量的二氯亚砜。加入正庚烷85mL，降温密闭过滤，滤液减压精馏，收集90～94℃/15mm Hg馏分，得到无色液体产品2-氟-5-甲酰氯吡啶12.85g，冷冻后为类白色固体，其纯度达99.1％，总收率达到80.56％。
实施例4：
在500mL三口瓶中，加入11.1g(0.1mol)2-氟-5-甲基吡啶，加水250mL，启动机械搅拌，依次加入47.4g(0.3mol)KMnO4和5.6g(0.1mol)KOH，油浴加热至95℃，反应5h，趁热过滤，收集滤液。待滤液降至常温后，用浓盐酸调节pH值至2～4，有固体析出，过滤；滤液用二氯乙烷萃取两遍。将过滤的固体和萃取的油相混合，旋转蒸发，得到类白色固体12.1g，即为2-氟-5-甲酸吡啶(熔点275～278℃)。
将第一步所得的2-氟-5-甲酸吡啶投入500mL三口瓶中，加入200mL二氯甲烷，启动搅拌，滴加草酰氯18.0g，回流反应6h后，蒸除溶剂和过量的草酰氯。加入环己烷90mL，降温密闭过滤，滤液减压精馏，收集90～94℃/15mm Hg馏分，得到无色液体产品2-氟-5-甲酰氯吡啶12.2g，冷冻后为白色至类白色固体，其纯度达98.5％，总收率达到76.73％。
实施例5：
在10L反应釜内，加入1.11Kg(10mol)2-氟-5-甲基吡啶，加水4.5L，启动机械搅拌，依次加入4.74Kg(30mol)KMnO4和5.6Kg(10mol)KOH，油浴加热至95℃，反应5h，趁热过滤，收集滤液。待滤液降至常温后，用浓盐酸调节pH值至2～4，有固体析出，过滤；滤液用二氯乙烷萃取两遍。将过滤的固体和萃取的油相混合，旋转蒸发，得到类白色固体1.25Kg，即为2-氟-5-甲酸吡啶。
将第一步所得的2-氟-5-甲酸吡啶投入10L三口瓶中，加入3.5L二氯甲烷，启动搅拌(转速为300转/分)，滴加氯化亚砜2.20Kg，向反应体系中***液面下鼓氮气，保持均匀速度冒泡下回流反应6h后，蒸除溶剂和过量的氯化亚砜，加入8.5L环己烷。降温密闭过滤，滤液减压精馏，收集90～94℃/15mm Hg馏分，得到无色液体产品2-氟-5-甲酰氯吡啶1.26kg，冷冻后为类白色固体，其纯度达98.5％，总收率达到79.2％。
以上所述，仅为本发明较佳的具体实施方式，但本发明的保护范围并不局限于此，任何熟悉本技术领域的技术人员在本发明披露的技术范围内，根据本发明的技术方案及其发明构思加以等同替换或改变，都应涵盖在本发明的保护范围之内。

Claims (6)

1.一种2-氟-5-甲酰氯吡啶的制备方法，其特征在于，该方法包括下述步骤：
1) 氧化反应
以2-氟-5-甲基吡啶为原料，在氧化剂存在下加热反应得到2-氟-5-甲酸吡啶；所述氧化剂为KMnO4或NaMnO4；在氧化剂中混入一定量的碱，碱选自氢氧化钠或氢氧化钾；碱与2-氟-5-甲基吡啶摩尔比为1-1.3：1；
2) 酰氯化反应
2-氟-5-甲酸吡啶在氯代溶剂中，与草酰氯或氯化亚砜反应，蒸馏除去反应溶剂，然后加入烷烃溶剂降温后过滤，得到2-氟-5-甲酰氯吡啶混合液，减压精馏得到2-氟-5-甲酰氯吡啶；本步反应中，采用200-400转/分搅拌速度，并向反应釜内通入氮气或氩气方式进行。
2.根据权利要求1所述2-氟-5-甲酰氯吡啶的制备方法，其特征在于：第一步所述氧化剂与2-氟-5-甲基吡啶摩尔比为2-4：1。
3.根据权利要求1所述2-氟-5-甲酰氯吡啶的制备方法，其特征在于：第二步所述氯代溶剂为二氯甲烷、氯仿或1,2-二氯乙烷。
4.根据权利要求1所述2-氟-5-甲酰氯吡啶的制备方法，其特征在于：第二步所述烷烃溶剂为正戊烷、正己烷、环己烷或正庚烷。
5.根据权利要求1所述2-氟-5-甲酰氯吡啶的制备方法，其特征在于：第二步所述草酰氯或氯化亚砜与2-氟-5-甲酸吡啶当量为1-2.5：1。
6.根据权利要求1所述2-氟-5-甲酰氯吡啶的制备方法，其特征在于：减压精馏时收集90～94℃/15mm Hg馏分，得到无色液体产品2-氟-5-甲酰氯吡啶。
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