CN105085390B - 一种异烟肼的制备方法 - Google Patents

一种异烟肼的制备方法 Download PDF

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CN105085390B
CN105085390B CN201510537342.1A CN201510537342A CN105085390B CN 105085390 B CN105085390 B CN 105085390B CN 201510537342 A CN201510537342 A CN 201510537342A CN 105085390 B CN105085390 B CN 105085390B
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isoniazid
isonicotinic acid
alcohol
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esterification
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CN105085390A (zh
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杨和军
李洪武
郭拥政
蒋栋
吕士华
朱铁军
李�远
张喜
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ZHEJIANG SECOND PHARMACEUTICAL CO Ltd
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    • 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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    • 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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    • 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
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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

本发明公开了一种异烟肼的制备方法，该方法包括：1)将异烟酸、醇和酰化试剂进行酯化反应，得到异烟酸酯；2)将异烟酸酯与水合肼进行缩合反应，反应液经后处理得到异烟肼成品。该方法通过异烟酸与醇酯化，所得酯化物再与水合肼缩合制得异烟肼，该方法可以很好的控制目标产物异烟肼中杂质的含量，得到高纯度的异烟肼，纯度在99.9％以上，单杂均小于0.10％，且该方法操作简单，易于控制，适于工业化操作。除此之外，本发明利用回收的异烟酸制备异烟肼，可以实现资源的循环利用，减少废物排放，同时降低成本，非常适合工业化生产。

Description

一种异烟肼的制备方法
技术领域
本发明涉及异烟肼药物化学领域，具体涉及一种异烟肼的制备方法。
背景技术
异烟肼(化学名为：4-吡啶甲酰肼，简称INH)对结核杆菌有良好的抗菌作用，疗效较好，用量较小，毒性相对较低，易为病人所接受，异烟肼的结构式如下：
关于异烟肼合成路线的文献并不多，无外乎两种合成路线，一种为异烟酸与水合肼直接缩合制得(李正化.药物化学[M].北京：人民卫生出版社，1993：370.)，该法的缺点在于反应温度较高，能耗较高，且异烟酸有残留；另外一种为以4-氰基吡啶为原料，水解为异烟酰胺，再与水合肼缩合制得(Sycheva TP，Pavlova TN，Shehukina MN.Synthesis ofisoniazid from 4-cyanopyridine[J].Pharma Chem J，1972：6：696—698.)，该法缺点在于4-氰基吡啶的水解不容易控制，易产生副产物异烟酸，同时易产生杂质J。
申请公布号为CN 102391178A(申请号为201110298501.9)的中国发明专利申请公开了一种异烟肼杂质的控制方法，具体反应路线如下：
(1)水解反应：
(2)缩合反应：
在水解反应步骤中，控制反应温度为95℃-105℃，反应时间为1.5小时-3小时；缩合反应步骤中，控制反应温度为90℃-97℃，反应时间为1.5小时-2.5小时；控制4-氰基吡啶与水合肼的摩尔比为1：2-4。该技术方案通过反应条件的控制来尽量避免杂质的产生，其仍然采用以4-氰基吡啶为原料，水解为异烟酰胺，再与水合肼缩合制得异烟肼的方法。
对于异烟肼生产厂家来说，必然会产生大量的异烟肼精制母液，从这些异烟肼精制母液中可以回收异烟酸，如何将回收的异烟酸利用起来，对于异烟肼生产厂家来说有重要意义，为此，我们通过研究开发了一种利用回收的异烟酸制备异烟肼的方法，该法收率高，所得产品质量好，能耗低，优于传统的合成方法。
发明内容
本发明提供了一种异烟肼的制备方法，利用回收的异烟酸制备异烟肼，该法收率高，所得产品质量好，能耗低，优于传统的合成方法。
一种异烟肼的制备方法，包括步骤：
1)将异烟酸、醇和酰化试剂进行酯化反应，得到异烟酸酯；
2)将异烟酸酯与水合肼进行缩合反应，反应液经后处理得到异烟肼成品。
以酰化试剂采用氯化亚砜、醇采用乙醇为例，异烟肼的制备方法制备路线如下：
酯化反应：
缩合反应：
步骤1)中，酰化试剂可以选择氯化亚砜、三光气、草酰氯、三氯氧磷、N,N’-羰基二咪唑中的一种，优选氯化亚砜，如果酰化试剂选择N,N’-羰基二咪唑，反应溶剂选择二氯甲烷，即异烟酸与N,N’-羰基二咪唑在二氯甲烷中反应生成异烟酰咪唑，然后再加入醇生成异烟酸酯。
所述的酯化反应，包括：
a)将异烟酸、醇和催化剂混合，滴加酰化试剂氯化亚砜、三光气、草酰氯、三氯氧磷中的一种进行酯化反应；
或者，b)采用二氯甲烷作为反应溶剂，先将异烟酸和酰化试剂N,N’-羰基二咪唑进行酰化反应，然后与醇进行酯化反应。
所述的醇为甲醇、乙醇、丙醇、丁醇或异丙醇，进一步优选为乙醇。
步骤a)中，所述的催化剂为三乙胺、N,N-二甲基甲酰胺(DMF)或吡啶，优选为三乙胺。
所述的异烟酸与催化剂的投料摩尔比为1：0.05-1，优选1：0.05-0.5。
所述的异烟酸与酰化试剂氯化亚砜、三光气、草酰氯、三氯氧磷中的一种的投料摩尔比为1：1.1-3，优选1：1.1-1.5。
所述的异烟酸与醇的质量比为1：6-15，优选1：6-10。
所述的酯化反应的温度为-5℃～50℃，优选0℃～30℃。所述的酯化反应分为两步，滴加过程和滴加完之后1～3小时的温度0℃～10℃，之后在20℃～30℃保温15～25小时。
步骤b)中，所述的异烟酸与酰化试剂N,N’-羰基二咪唑的投料摩尔比为1：1.1-3，优选1：1.1-1.5。
所述的异烟酸与醇的质量比为1：0.1-2，优选1：0.2-0.8。
所述的异烟酸与二氯甲烷的质量比为1：6-15，优选1：6-10。
所述的酰化反应和酯化反应的温度为-5℃～50℃，优选0℃～30℃。先滴加酰化试剂N,N’-羰基二咪唑进行酰化反应，滴加酰化试剂N,N’-羰基二咪唑过程的温度0℃～10℃，之后在20℃～30℃保温1～3小时，再滴加醇进行酯化反应，滴加完之后在20℃～30℃保温5～15小时。
步骤2)中，缩合反应中，所述的水合肼与步骤1)中的异烟酸的投料摩尔比为1-5：1，优选1.1-1.5：1。
所述的缩合反应的温度为50℃～100℃，优选70℃～80℃，反应时间为5～20小时，优选，8～12小时。
所述的后处理包括：反应液中加入水(稀释液)，升温溶解，加入活性炭，在65℃～80℃保温10min～60min，过滤，滤液冷却，过滤干燥得到异烟肼成品。
通过上述方法制备的异烟肼，产品质量好，单杂均小于0.10％，纯度在99.9％以上，所得产品质量要优于其它方法制备的异烟肼的质量，特别是异烟肼杂质J能做到未检出的水平。
异烟肼杂质J的结构式如下：
该杂质在精制时非常难以去除，所以必须从源头控制，而采用本发明的方法可以将该杂质做到未检出的水平。
按照现有技术(Sycheva TP，Pavlova TN，Shehukina MN.Synthesis ofisoniazid from 4-cyanopyridine[J].Pharma Chem J，1972：6：696—698.)制备所得的异烟肼，杂质J在0.1％以上，影响了异烟肼的质量。
本发明所述的含量、纯度的数据是色谱计算中常用的峰面积归一化法计算的峰面积的百分比。
本发明纯度、有关物质含量的测定方法为现有常规技术，按照2010年《中华人民共和国药典》要求的色谱条件(具体参考2010版中国药典二部295页异烟肼含量测定项色谱条件)，色谱条件如下：
流动相：0.02mol/L磷酸氢二钠溶液(磷酸调pH＝6)：甲醇(85：15，体积比)；
色谱柱：(L1)250×4.6mm；
检测波长：262nm；
流速：1.0ml/min；
柱温：25℃；
进样量：10μl。
与现有技术相比，本发明具有如下优点：
本发明方法可以很好的控制目标产物异烟肼中杂质的含量，得到高纯度的异烟肼，纯度在99.9％以上，单杂均小于0.10％，特别是异烟肼杂质J能做到未检出的水平，且该方法操作简单，易于控制，适于工业化操作。除此之外，本发明中异烟酸可采用回收的异烟酸，可利用回收的异烟酸制备异烟肼，可以实现资源的循环利用，减少废物排放，同时降低成本，非常适合工业化生产。
具体实施方式
以下实施例是为了对本发明进行进一步说明，不应将其视为对本发明的限制。
本发明异烟肼的纯度、有关物质含量的测定方法为现有常规技术，按照2010年《中华人民共和国药典》要求的色谱条件(具体参考2010版中国药典二部295页异烟肼含量测定项色谱条件)，色谱条件如下：
流动相：0.02mol/L磷酸氢二钠溶液(磷酸调pH＝6)：甲醇(85：15，体积比)；
色谱柱：(L1)250×4.6mm；
检测波长：262nm；
流速：1.0ml/min；
柱温：25℃；
进样量：10μl。
实施例1 异烟肼的制备
往2000ml三口瓶中加入200g(1.62mol)异烟酸，1200g乙醇，16.4g(0.162mol)三乙胺，搅拌降温至0℃～5℃，缓慢滴加212g(1.78mol)氯化亚砜，滴加完毕，控温0℃～5℃保温2小时，然后升温至20℃～25℃保温20小时，反应完毕，减压浓缩得油状物，将119g(2.43mol)水合肼加入，升温至70℃～75℃，保温10小时后，加入稀释液(水350g)，适当升温，溶解，得异烟肼粗品的水溶液，加入活性炭10g，70℃～75℃保温半小时后，过滤，滤液先自然冷却6小时，再缓慢冷至0℃，过滤，干燥，得异烟肼成品，纯度99.94％，单杂均小于0.10％，杂质J未检出，总收率86％。
产品结构确证：按上述色谱条件，最后得到的异烟肼成品与异烟肼标准品的出峰位置能完全重合，同时，异烟肼成品的红外图谱与异烟肼标准品的红外图谱完全一致，由此可见，所得异烟肼成品为异烟肼。
实施例2 异烟肼的制备
往3000ml三口瓶中加入200g(1.62mol)异烟酸，1600g乙醇，16.4g(0.162mol)三乙胺，搅拌降温至5℃～10℃，缓慢滴加250g(2.1mol)氯化亚砜，滴加完毕，控温5℃～10℃保温2小时，然后升温至20℃～25℃保温20小时，反应完毕，减压浓缩得油状物，将143g(2.92mol)水合肼加入，升温至73℃～76℃，保温10小时后，加入稀释液(水350g)，适当升温，溶解，得异烟肼粗品的水溶液，加入活性炭10g，70℃～75℃保温半小时后，过滤，滤液先自然冷却6小时，再缓慢冷至0℃，过滤，干燥，得异烟肼成品，纯度99.95％，单杂均小于0.10％，杂质J未检出，总收率89％。
实施例3 异烟肼的制备
往3000ml三口瓶中加入200g(1.62mol)异烟酸，2000g乙醇，16.4g(0.162mol)三乙胺，搅拌降温至5℃～10℃，缓慢滴加289g(2.43mol)氯化亚砜，滴加完毕，控温5℃～10℃保温2小时，然后升温至25℃～30℃保温20小时，反应完毕，减压浓缩得油状物，将158g(3.2mol)水合肼加入，升温至75℃～80℃，保温10小时后，加入稀释液(水350g)，适当升温，溶解，得异烟肼粗品的水溶液，加入活性炭10g，70℃～75℃保温半小时后，过滤，滤液先自然冷却6小时，再缓慢冷至0℃，过滤，干燥，得异烟肼成品，纯度99.93％，单杂均小于0.10％，杂质J未检出，总收率87％。
实施例4 异烟肼的制备
往2000ml三口瓶中加入200g(1.62mol)异烟酸，800g二氯甲烷，搅拌降温至0℃～5℃，将394g(2.43mol)N,N’-羰基二咪唑溶解在800g二氯甲烷中，缓慢滴加该溶液，滴加完毕，控温20℃～25℃保温2小时，然后缓慢滴加100g乙醇，加完后，20℃～25℃保温10小时，反应完毕，减压浓缩得油状物，将87g(1.78mol)水合肼加入，升温至70℃～75℃，保温10小时后，加入稀释液(水350g)，适当升温，溶解，得异烟肼粗品的水溶液，加入活性炭10g，70℃～75℃保温半小时后，过滤，滤液先自然冷却6小时，再缓慢冷至0℃，过滤，干燥，得异烟肼成品，纯度99.92％，单杂均小于0.10％，杂质J未检出，总收率86％。
实施例5 杂质J的制备
将13g(0.1mol)异烟酸加人到250ml烧瓶中，再称取80g(1.6mol)水合肼，逐渐升温至140℃反应24h，最后得到黄色油状液体。待产物冷却凝固后用丙酮重结晶，得到产物4g。
产物结构确证：
核磁数据如表1所示：
表1氢谱(1H-NMR)及归属
编号 δ，ppm 质子(proton)
1，4，5，6 8.075-8.086 4
2，3，7，8 8.803 4
9 6.540 2
红外光谱数据：
3299.10cm-1:νN-H
3173.13cm-1:νN-H
1600.53cm-1:νC＝N
质谱数据：在谱图中准分子离子峰为【M-H】+的质量数为m/z237，样品的相对分子质量为238，与杂质INH-J的分子量一致，表明所得的产物为杂质INH-J。

Claims (5)

1.一种异烟肼的制备方法，其特征在于，包括步骤：
1)将异烟酸、醇和酰化试剂进行酯化反应，得到异烟酸酯；
步骤1)中，所述的酯化反应，包括：
b)采用二氯甲烷作为反应溶剂，先将异烟酸和酰化试剂N,N’-羰基二咪唑进行酰化反应，然后与醇进行酯化反应；
步骤b)中，所述的酰化反应和酯化反应的温度为-5℃～50℃；
步骤b)中，所述的异烟酸与酰化试剂N,N’-羰基二咪唑的投料摩尔比为1：1.1-3；
所述的异烟酸与醇的质量比为1：0.1-2；
所述的异烟酸与二氯甲烷的质量比为1：6-15；
2)将异烟酸酯与水合肼进行缩合反应，反应液经后处理得到异烟肼成品。
2.根据权利要求1所述的异烟肼的制备方法，其特征在于，步骤1)中，所述的醇为甲醇、乙醇、丙醇、丁醇或异丙醇。
3.根据权利要求1所述的异烟肼的制备方法，其特征在于，步骤2)中，所述的水合肼与步骤1)中的异烟酸的投料摩尔比为1-5：1。
4.根据权利要求1所述的异烟肼的制备方法，其特征在于，步骤2)中，所述的缩合反应的温度为50℃～100℃，反应时间为5～20小时。
5.根据权利要求1所述的异烟肼的制备方法，其特征在于，步骤2)中，所述的后处理包括：反应液中加入水，升温溶解，加入活性炭，在65℃～80℃保温10min～60min，过滤，滤液冷却，过滤干燥得到异烟肼成品。
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