CN1259123A - 用于制备2,6-二氯-5-氟尼克腈的方法和化合物3-氰基-2-羟基-5-氟吡啶-6-酮一钠盐和其互变体 - Google Patents
用于制备2,6-二氯-5-氟尼克腈的方法和化合物3-氰基-2-羟基-5-氟吡啶-6-酮一钠盐和其互变体 Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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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
- C07D213/61—Halogen atoms or nitro radicals
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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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/84—Nitriles
- C07D213/85—Nitriles in position 3
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- Pyridine Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
本发明涉及2,6-二氯-5-氟尼克腈,通过在一种溶剂中,在加入一种碱性催化剂条件下,在30—300℃的温度,使3-氰基-2-羟基-5-氟吡啶-6-酮和/或其互变体和/或其盐和/或它们的互变体与三氯化磷和氯气反应,然后水解产物,可有利地获得。可使用的3-氰基-2-羟基-5-氟吡啶-6-酮∴钠盐化合物是新的化合物,通过3-氰基-2-羟基-5-氟吡啶-6-酮和/或其互变体与醇盐反应,使用适度弱的酸沉淀,可容易地获得。
Description
本发明涉及一种有益的从3-氰基-2-羟基-5-氟吡啶-6-酮和/或其互变体和/或其盐和/或其互变体开始制备制备2,6-二氯-5-氟尼克腈(nicotinonitrile)的方法,还涉及3-氰基-2-羟基-5-氟吡啶-6-酮一钠盐和其互变体(下文称为3-氰基-2-羟基-5-氟吡啶-6-酮一钠盐)。
2,6-二氯-5-氟尼克腈是合成用于从所谓“氮杂”类似的喹诺酮类制备抗生素的重要单元的起始化合物(参考例如DE-OS 35 14076)。这种用途还要求用于中间产物的制备方法能够以高纯度、高产率和高经济效益生产中间产物。
已知一些用于2,6-二氯-5-氟尼克腈的制备方法。这样,从2,6-二氯-5-氟-3-三氯甲基吡啶开始,通过与氯化铵和氧化铜在环丁砜中在180-190℃反应,可制备2,6-二氯-5-氟尼克腈(参考例如WO 95 26 340)。但是,形成的大量盐酸和大量固体需要处理,对于工业实施是一个极大的缺点。
还可以从2,6-二羟基-5-氟尼克腈通过与五氯化磷在磷酰氯中反应获得2,6-二氯-5-氟尼克腈(参考例如EP-A 333 020)。如果使在该文献中还是未知的3-氰基-2-羟基-5-氟吡啶-6-酮一钠盐在EP-A 333 020中所述的条件下反应,仅以67%的产率获得纯度72.6%的所需产物(参考实施例2)。
重复EP-A 333 020所述的方法又表现出一个致命的缺点,即,基于被氯化的羟基官能团,如果使用2.25当量五氯化磷,除了所需的2,6-二氯-5-氟尼克腈以外,还形成了较大量的更高氯化程度的副产物。
使用的五氯化磷是固体,用量大,处理很困难而且在安全方面费用很高,这些也是严重的问题,由于五氯化磷的高残留量和产生较大量的含磷废水造成后处理所需的水解困难。
为了氯化类似的二羟基尼克腈,描述了只使用五氯化磷(参考例如Chem.Pharm.Bull. 35,2280-2285(1987)),由于上述原因在工业上有很大问题。为此目的,还描述了单独使用磷酰氯作为溶剂和氯化剂(参考例如DE-OS 23 07 444)以及加入大量(163摩尔%)三乙基胺(参考例如Angew.Chem.92,390(1980))。
3-氰基-2-羟基-5-氟吡啶-6-酮一钠盐单独与磷酰氯(作为溶剂和氯化剂)反应是不反应的。即使在升高的温度,磷酰氯的反应性也不充分。在分离的产物中仅发现了痕量的2,6-二氯-5-氟尼克腈,而加入三乙基胺也不能导致明显的反应。在磷酰氯/三乙基胺/减量的五氯化磷(被氯化的每当量官能团1.15当量)体系中,再次观察到了低产率和更高比例的不需要的副产物(参考实施例3)。
因此仍然需要一种制备2,6-二氯-5-氟尼克腈的方法,其可以在工业上容易地进行,以好的产率和纯度得到产物,并且在经济上是有利的。
现已发现了用于制备2,6-二氯-5-氟尼克腈的方法,其包括使3-氰基-2-羟基-5-氟吡啶-6-酮和/或其互变体和/或其盐和/或其互变体与三氯化磷和氯气在一种溶剂中在加入一种碱性催化剂条件下在30-300℃反应,然后水解产物。
优选在本发明的方法中使用3-氰基-2-羟基-5-氟吡啶-6-酮的一钠盐(参考式(I))和/或其互变体。
使用碱性催化剂使得在本发明的氯化中使用的氯化剂的量与例如根据EP-A 333 020用于氯化游离二羟基化合物所需的量相比显著降低。另外,水解后高纯度高产率地得到2,6-二氯-5-氟尼克腈,而根据EP-A 333 020提供的条件是不能获得的。
可用于本发明的方法的碱性催化剂是例如有机碱,例如脂族或芳族胺和酰胺;还有无机碱,例如氮和磷的碱性化合物和其盐。优选的碱性催化剂是吡啶、被1-3个C1-C6烷基烷基化的吡啶、哌啶、被1-3个C1-C6烷基烷基化的哌啶、咪唑和吲哚、N-C1-C6烷基氨基吡啶、N-二C1-C6烷基化的苯胺;叔N-C1-C6烷基胺、尿素和尿素衍生物。特别优选的碱性催化剂是三乙基胺、尿素和乙基哌啶。
在此一个特别的优点是,基于被氯化的物质,可以使用少量的催化剂,例如0.1-20摩尔%。该量优选1-15摩尔%,特别优选10-15摩尔%。以化学计算量加入三乙基胺根据本发明是不需要的,而这是根据上述Angew.Chem.的文献从二羟基尼克腈制备二氯尼克腈时所需要的。
使用相对于氯气过量的三氯化磷并进行反应,从而使反应混合物中总是存在至少少量过量的三氯化磷,这样是有利的。例如使用的氯气对三氯化磷的摩尔比可以是0.1∶1-0.99∶1。该比例优选0.5∶1-0.99∶1,特别优选0.9∶1-0.99∶1。
本发明方法的一个特别优点是,基于被氯化的各官能团,只使用1-2当量的氯气,而不是在类似EP-A 333 020的方法中使用2.25当量的五氯化磷。基于被氯化的各官能团,优选使用1.5-2当量的氯气。
可用于进行本发明方法的溶剂是例如磷酰氯和多种惰性有机溶剂,例如芳族或脂族烃类,它们也可被卤化,诸如1,2,3,4-四氢化萘、石油英、石油醚、氯苯、二氯甲烷或氯仿;醚类,诸如***、丁醚、甲丁醚或四氢呋喃;极性非质子性溶剂,诸如环丁砜或N-甲基吡咯烷酮;或希望的它们的任何混合物。优选的溶剂是磷酰氯、氯仿、甲丁醚、N-甲基吡咯烷酮和希望的它们的任何混合物。优选地,磷酰氯是仅有的溶剂。
基于被氯化的物质,使用的溶剂量为例如40-99%重量,优选60-95%重量,特别是80-95%重量。
氯化优选在20-200℃之间的温度进行,特别优选在70-120℃之间。
在本发明方法的一个优选实施方案中,工艺过程如下所述:其中首先在一个搅拌容器中的溶剂或溶剂混合物中引入将被氯化的物质,加入催化剂和三氯化磷,然后将混合物加热到希望的反应温度,随后计量加入氯气,最后将混合物在所述的反应温度范围内的温度保持一定时间。
计量加入氯气的时间可以是例如1-10小时,后反应的时间可以是例如1-20小时。
工艺过程也可如下所述:其中在整个加热到希望的反应温度的时期或在部分时期已经计量加入了氯气。
工艺过程还可如下所述:其中将被氯化的物质作为最后的组分或与催化剂一起计量加入。同时计量加入所有组分也可以。
当反应结束时,溶剂可与形成的磷酰氯和过量的氯化试剂一起蒸出,如果合适可再次使用。
在随后的水解中,例如蒸出溶剂、磷酰氯和过量的氯化试剂后的残留物可如此使用。也可以先将残留物溶解在溶剂中。为此使用不与水混溶或仅稍微混溶于水的溶剂,例如芳族或脂族烃类,它们可以被卤化,诸如苯、甲苯、二甲苯、1,2,3,4-四氢化萘、石油英、石油醚、氯苯、二氯甲烷或氯仿;和醚类,诸如***、丁醚、甲丁醚或四氢呋喃;或希望的它们的任何混合物。残留物优选溶解于甲苯、二甲苯、石油醚、二氯甲烷、氯仿、***、甲丁醚或其混合物,特别优选使用单独的溶剂二氯甲烷溶解残留物。
水解通常用过量水进行。例如每体积份将被水解的物质或其溶液可使用0.5-2体积水。水解期间的温度可以是例如0-100℃。如果存在常压下沸点低于100℃的溶剂,水解在例如0℃到该溶剂沸点(常压下)之间的温度进行。水解优选在0-70℃范围内的温度进行。有利的是,例如,在指出的温度随后再搅拌混合物1-2小时。如果在无溶剂的条件下进行水解,有利的是在水解后加入上述类型的溶剂。
可继续直接加工的2,6-二氯-5-氟尼克腈可通过相分离得到。如果需要,可从溶液中高产率高纯度地分离2,6-二氯-5-氟尼克腈,例如通过蒸发分离。
总之,本发明的方法有许多优点。其以高纯度和好的产率制备2,6-二氯-5-氟尼克腈,不使用固体氯化剂就可以完成,所需的氯化剂的量比根据现有技术的方法少,仅以催化剂量使用碱。另外,实际上没有氯化程度更高的产物形成,以及产生的含磷废水的量降低了。
在现有文献中没有描述过优选作为起始物质的3-氰基-2-羟基-5-氟吡啶-6-酮一钠盐和其互变体。本发明因此也涉及它们。通过,例如,已知的3-氰基-2-羟基-5-氟吡啶-6-酮和/或其互变体与C1-C6烷基醇盐、优选碱金属C1-6烷基醇盐、特别优选甲醇钠在芳族溶剂、优选甲苯,和C1-C6烷基醇、优选甲醇的混合物中反应,使用中强度酸,优选乙酸沉淀出生成的盐和/或其互变体,抽滤,干燥产物,可得到3-氰基-2-羟基-5-氟吡啶-6-酮一钠盐和其互变体。
实施例
每种情况下使用的3-氰基-2-羟基-5-氟吡啶-6-酮是主要包括该互变体的互变体混合物形式。实施例1
首先将240g 3-氰基-2-羟基-5-氟吡啶-6-酮一钠盐(参考实施例8)引入2400g磷酰氯中。然后加入15.8g三乙基胺并随后加入648g三氯化磷,同时小心地进行加热。混合物加热到回流温度(74℃,放出氯化氢),然后在2小时期间通入312g氯气,回流温度缓慢提高到106℃,观察到氯化氢大量放出。为使反应完全,在通入氯气后,混合物在回流下再加热8小时。此后,在底部温度约70℃蒸馏出2794g磷酰氯,压力缓慢降低到120毫巴。冷却混合物,将残余物溶于二氯甲烷中。将形成的悬浮液缓慢加入水中,同时小心放热,其间温度升高到40℃(二氯甲烷的回流温度)。然后继续在40℃搅拌混合物1小时,使其冷却,分出有机相,用新鲜的二氯甲烷萃取水相。合并二氯甲烷相,干燥,在旋转蒸发器上蒸发。在60℃真空中干燥剩下的残余物。得到232.5g棕黄色固体2,6-二氯-5-氟尼克腈(纯度:94.7%,产率:理论的85%)。实施例2
(为了比较,重复EP-A 3 330 020)
先将182g五氯化磷缓慢加入到300g磷酰氯中。然后加入30g 3-氰基-2-羟基-5-氟吡啶-6-酮一钠盐。混合物加热到回流温度(114℃,放出氯化氢),在该温度再搅拌20小时。此后,在真空中蒸馏出磷酰氯。冷却残留物,将残余物溶于二氯甲烷中。将形成的悬浮液缓慢加入冰水中。相分离后,分出有机相,在旋转蒸发器上干燥和蒸发。在60℃真空中干燥剩下的残余物。得到30.3g棕色固体,含有72.6%重量的2,6-二氯-5-氟尼克腈(产率:理论的67%),19.2%重量的含3个氯原子的尼克腈(GC/MS),约8%重量的含4个、有时氯化程度更高的化合物。实施例3
(为比较,与/不与三乙基胺一起使用磷酰氯,并且减少五氯化磷的量)
先将30g 3-氰基-2-羟基-5-氟吡啶-6-酮一钠盐缓慢加入到300g磷酰氯中,混合物加热到回流温度(106℃),在该温度搅拌2小时。直到此时,根本没有观察到氯化氢放出(负转化对照)。
冷却后,小心地加入2.0g三乙基胺(放热)。将混合物再加热到回流温度(106℃),在该温度再搅拌2小时。直到此时,同样根本没有观察到氯化氢放出(负转化对照)。
然后在室温加入81.2g五氯化磷,混合物在回流温度(112℃)加热20小时。在开始,观察到氯化氢的适度释放。随后,在真空中蒸馏出磷酰氯。冷却混合物,将残余物溶于二氯甲烷中。将形成的悬浮液缓慢倾倒入冰水中。分出有机相,水相再用新鲜的二氯甲烷萃取。合并二氯甲烷相,干燥,在旋转蒸发器上蒸发。在60℃真空中干燥剩下的残余物。得到27.0g棕色固体,含有83.1%重量的2,6-二氯-5-氟尼克腈(产率:理论的60%)和约15%重量的其它未知化合物。还发现了痕量的未反应物(0.02%重量)。实施例4
类似于实施例1,使240g 3-氰基-2-羟基-5-氟吡啶-6-酮一钠盐进行反应,但是在室温进行水解。
得到227.6g棕黄色固体2,6-二氯-5-氟尼克腈(纯度:84.7%,产率:理论的74%)。实施例5
类似于实施例1,使48g 3-氰基-2-羟基-5-氟吡啶-6-酮一钠盐进行反应,但是用1.9g尿素作为催化剂代替三乙基胺。
得到48g棕黄色固体2,6-二氯-5-氟尼克腈(纯度:88.5%,产率:理论的81.5%)。实施例6
类似于实施例1,使48g 3-氰基-2-羟基-5-氟吡啶-6-酮一钠盐进行反应,但是用3.5g乙基哌啶作为催化剂代替三乙基胺。
得到46g棕黄色固体2,6-二氯-5-氟尼克腈(纯度:92.2%,产率:理论的81.5%)。实施例7
类似于实施例1,使168g 3-氰基-2-羟基-5-氟吡啶-6-酮一钠盐进行反应,但是计量加入氯气的同时进行加热,在2小时期间从室温上升到73℃。再经4小时后,达到回流温度,混合物在该温度再搅拌6小时。
得到176.5g棕黄色固体2,6-二氯-5-氟尼克腈(纯度:93.9%,产率:理论的90.9%)。实施例8
(合成3-氰基-2-羟基-5-氟吡啶-6-酮一钠盐)
将溶于300ml甲苯的154.1g 3-氰基-2-羟基-5-氟吡啶-6-酮滴加到在250ml甲醇中的77g甲醇钠中,同时在5℃冷却。然后使反应混合物温热至室温,在该温度再搅拌1小时。加入200g冰醋酸,然后加入200ml水,同时在5℃冷却。抽滤出沉淀的固体,用少量冷的甲苯洗涤。干燥后,得到165.5g 3-氰基-2-羟基-5-氟吡啶-6-酮一钠盐(产率:94%)。1H-NMR(D6-DMSO):δ[ppm]=2.5(s,-OH,1H,部分交换的),7.1(d,3JHF≌21Hz,Ar-H,1H),13C-NMR(D6-DMSO):δ[ppm]=67,8(d,3JCF≌7,3Hz,-CH(CN)-),121,2(s,
-CN),125,8(d,2JCF≌18,4Hz,
-CF=CH-C(CN)H-),137,9(d,1JCF≌218,8Hz,
-CF=),157,8(d,2JCF≌25,7Hz,-O-C(=N)-CF),
163,4(s,C=O).元素分析: C H N
计算值: 40.9% 1.15% 15.9%
实验值: 40.3% 1.30% 15.7%氟的原子吸收光谱 计算值 F=10.8%
实验值 F=10.5%熔点: 不均匀,分解颜色: 棕色-米色无定型固
体
光谱学数据表明得到的互变体混合物主要含有3-氰基-2-羟基-5-氟吡啶-6-酮一钠盐。
Claims (10)
1.一种制备2,6-二氯-5-氟尼克腈的方法,其中包括在一种溶剂中,在加入一种碱性催化剂条件下,在30-300℃,使3-氰基-2-羟基-5-氟吡啶-6-酮和/或其互变体和/或其盐和/或其互变体与三氯化磷和氯气反应,然后水解产物。
2. 3-氰基-2-羟基-5-氟吡啶-6-酮一钠盐和其互变体。
3.按权利要求1的方法,其中脂族或芳族胺或酰胺或氮或磷的碱性化合物或其盐用作碱性催化剂。
4.按权利要求1和3的方法,其中基于将被氯化的物质,催化剂的用量为0.1-20摩尔%。
5.按权利要求1、3和4的方法,其中使用的氯气与三氯化磷的摩尔比为0.1∶1-0.99∶1。
6.按权利要求1-5的方法,其中基于将被氯化的各官能团,使用1-2当量的氯气。
7.按权利要求1和3-6的方法,其中使用磷酰氯、芳族或脂族烃类、被卤化的芳族或脂族烃类、醚类、极性非质子性溶剂,或希望的它们的任何混合物作为溶剂。
8.按权利要求1和3-7的方法,其中氯化在20-200℃进行。
9.按权利要求1和3-8的方法,其中当反应结束时,溶剂可与形成的磷酰氯和过量的氯化试剂一起蒸出,如果合适可在剩余的残留物中加入溶剂,并用过量的水在0-100℃进行水解。
10.按权利要求1和3-9的方法,其中水解后,混合物随后在0-100℃再搅拌1-2小时。
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