CN112110853A - 一种合成3-羟基-2-吡啶甲酸及其衍生物的方法 - Google Patents
一种合成3-羟基-2-吡啶甲酸及其衍生物的方法 Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 28
- BRARRAHGNDUELT-UHFFFAOYSA-N 3-hydroxypicolinic acid Chemical compound OC(=O)C1=NC=CC=C1O BRARRAHGNDUELT-UHFFFAOYSA-N 0.000 title abstract description 22
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- 238000006243 chemical reaction Methods 0.000 claims abstract description 63
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 54
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims abstract description 28
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 24
- 238000007333 cyanation reaction Methods 0.000 claims abstract description 24
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Classifications
-
- 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
- C07D213/79—Acids; Esters
-
- 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
- C07D213/79—Acids; Esters
- C07D213/803—Processes of preparation
Abstract
本发明公开了一种3‑羟基‑2‑吡啶甲酸及其衍生物的有效合成方法。该方法包含氧化反应、氰基化反应与水解反应。氧化反应以式I3‑羟基吡啶及其衍生物为底物,在过氧化氢水溶液作氧化剂条件下,在氮气环境下于冰醋酸中60℃进行反应而得到结构通式II所示的氧化产物。氰基化反应,以化合物II与三甲基氰硅烷为底物,冰浴下与二甲氨基甲酰氯混合后,在氮气环境下于二氯甲烷中室温进行反应而得到结构通式III所示的氰基化产物。水解反应,以式III为底物,在氢氧化钠水溶液条件下于乙醇中80℃进行反应而得到结构通式IV所示的3‑羟基‑2‑吡啶甲酸及其衍生物。该方法相对经济,反应普适性较好,易进行克级制备,整个流程可工业化;反应条件绿色。
Description
技术领域
本发明属于精细化工领域,具体涉及一种合成3-羟基-2-吡啶甲酸及其衍生物的方法。
背景技术
吡啶羧酸类配体是含有氮原子和羧基氧原子的一类经典的双齿配体。在不同的pH值下羧基因去质子化程度不同,其氧原子具有多样的配位模式,有着多样的结构与独特的性质(Jiang,H.-L.et al.J.Am.Chem.Soc.2012,36,14690;Ma,J.etal.Cryst.Growth.Des.2011,11,3273;Chen,N.et al.Cryst.Growth.Des.2013,13,2650)。
3-羟基-2-吡啶甲酸类衍生物是常见的一类吡啶羧酸类配体,目前除3-羟基-2-吡啶甲酸(HO-PBA)外,其余3-羟基-2-吡啶甲酸类衍生物价格昂贵。以HO-PBA作配体的金属有机配合物常应用于催化领域,以二水合二[3-羟基-2-吡啶羧酸]钴(II)配合物为例,该配合物在苯甲醛的腈硅化反应,及苯甲酰胺与苯甲醛的反应中均显示了良好的催化性能(CN108840821A)。
此外3-羟基-2-吡啶甲酸的3位引入酚羟基,使得在做双齿配体配位金属的同时,还能在酚羟基位上引入其它官能团,从而实现配合物的各类修饰,有助于有机光电材料多样性合成。以下图含铱配合物的磷光材料为例,通过对3-羟基-2-吡啶甲酸的酚羟基引入强吸电子的2,4-二硝基苯磺酰基,使得铱配合物不发光;而当加入含巯基氨基酸使得2,4-二硝基苯磺酰基离去时,铱配合物发光,故可实现磷光探针的开启式,具有应用于细胞成像领域的前景(CN102786550A)。可以看出该开启式磷光探针配合物的核心功能正是建立在有机配体3-羟基-2-吡啶甲酸之上,三个官能团均发挥作用,氮原子与羧基氧原子对金属螯合配位,酚羟基是做修饰和去修饰的位点。
综上可以发现3-羟基-2-吡啶甲酸及其衍生物拥有良好且独特配位性能,其在催化、光电材料等领域具有广阔的应用前景。然而3-羟基-2-吡啶甲酸虽已商业化生产,但其现有合成方法是以2-吡啶甲酸为初始原料,用重铬酸喹啉(QnDC)作氧化剂溶于浓硫酸,再以醋酸水溶液作溶剂合成3-羟基-2-吡啶甲酸(Suante,H.;Mahanti,M.K.Heterocycl.Commun.2003,9,489)。虽然该合成方法所涉及到的反应物2-吡啶甲酸和重铬酸喹啉均便宜易得,但整个合成步骤涉及对环境极不友好的重铬酸喹啉以及浓硫酸;并且强酸性合成环境存在明显安全隐患;具体步骤中重铬酸喹啉在浓硫酸中质子化过程需冰浴条件,操作繁琐。
因此开发更为绿色、安全、便捷的3-羟基-2-吡啶甲酸及其衍生物的合成方法具有重要的应用前景和经济价值。这其中涉及两个重要的问题:一是如何在合成过程中尽可能地减少对环境不友好的原料的使用和副产物的产生;二是如何改善合成过程中的安全性和便捷性。
发明内容
本发明的目的是提供一种3-羟基-2-吡啶甲酸及其衍生物的方法。
本发明提供的制备所述式IV所示化合物(也即3-羟基-2-吡啶甲酸衍生物)的方法,包括氧化反应、氰基化反应、水解反应;
具体步骤如下:
将所述式I所示化合物3-羟基吡啶衍生物溶于溶剂中,滴加过氧化氢水溶液,惰性气体保护下搅拌,氧化反应完毕后得到所述式II所示化合物;
将所述式II所示化合物溶解在有机溶剂中,加入氰基化试剂,冰浴下滴加二取代氨基甲酰氯类化合物后惰性气体保护下搅拌,氰基化反应完毕得到所述式III所示化合物;
将所述式III所示化合物溶解在有机溶剂中,加入碱的水溶液,后回流至水解反应完毕得到所述式IV所示化合物;
所述式I、式II、式III、式IV中,R选自氢、卤素取代基和供电子基中的任意一种;R的取代位为4位、5位或6位;
上述方法中,所述卤素具体为氟、氯或溴;
所述供电子基为如下基团中的任意一种;C1-C3的烷基、C1-C2的烷氧基;
所述C1-C3的烷基为如下基团中的任意一种:甲基、乙基、正丙基、异丙基;
所述C1-C2的烷氧基为甲氧基、乙氧基;
上述氧化反应方法中,所述惰性气体为氮气和氩气的至少一种。
所述过氧化氢水溶液为过氧化氢的质量浓度为10%至40%的水溶液,优选30%的水溶液,其投料摩尔用量以其中所含过氧化氢的投料摩尔用量计,为所述式I所示化合物的1.0~1.5倍,优选1.1倍。
所述反应在溶剂中进行;所述溶剂为冰醋酸或醋酸水溶液,优选冰醋酸。
所述反应步骤中,温度为50~70℃,优选60℃;时间为8~20小时,优选12小时,该反应时间视不同式I所示反应物不同而变化。反应是否完毕可通过薄层色谱或者气相色谱进行监测。
在反应完毕后,可将反应体系按照常规方法进行简单分离提纯处理,优选的分离方式为:将反应之后的原液转移到圆底烧瓶中,转移时可用一些乙酸乙酯或二氯甲烷冲洗原容器,以减少损失;减压浓缩后,加入石油醚、正己烷或环己烷和少量的乙酸乙酯打浆过滤,烘干得到产物式II所示化合物,后可直接用于下一步氰基化反应。
具体的所述氰基化的反应条件为:将中间产物所述式II所示化合物溶于有机溶剂中,加入氰基化试剂,在零度冰浴下滴加二取代氨基甲酰氯类化合物,惰性气体保护下搅拌,氰基化反应完毕得到所述式III所示化合物;
上述氰基化反应方法中,所述惰性气体为氮气和氩气的至少一种。
所述氰基化试剂为三甲基氰硅烷或叔丁基氰基二甲基硅烷,优选三甲基氰硅烷。
所述二取代氨基甲酰氯类化合物为二甲氨基甲酰氯、二乙氨基甲酰氯或N-乙基-N-甲基甲酰氯,优选二甲氨基甲酰氯。
所述二取代氨基甲酰氯类化合物的投料摩尔用量为所述式II所示化合物的1.0~1.2倍,优选1.02倍。
所述氰基化试剂的投料摩尔用量为所述式II所示化合物的1.0~1.5倍,优选1.25倍。
所述反应在溶剂中进行;所述溶剂为二氯甲烷、1,2-二氯乙烷、氯仿或甲苯,优选二氯甲烷。
所述反应步骤中,温度为20~40℃,优选25℃;时间为10~24小时,优选16小时,该反应时间视不同式II所示反应物不同而变化。反应是否完毕可通过薄层色谱或者气相色谱进行监测。
在反应完毕后,可将反应体系按照常规方法进行简单分离提纯处理,优选的分离方式为:将反应原液往碳酸钾水溶液中滴加,将pH值调至8;用二氯甲烷萃取多次,再向水相加稀盐酸或稀硫酸调节pH值至6,析出大量固体产物;过滤,并用石油醚、正己烷或环己烷冲洗,将滤饼真空烘干,得到所述式III所示化合物粗品,称重并计算产率,后可直接用于下一步水解反应。
具体的所述水解的反应条件为:将所述式III所示化合物溶于有机溶剂中,加入碱的水溶液,后回流加热搅拌至水解反应完毕得到所述式IV所示化合物;
所述碱为氢氧化钠、氢氧化钾或氢氧化锂,优选氢氧化钠。
所述碱的水溶液为碱的质量浓度为15%至25%的水溶液,优选20%的水溶液,其投料摩尔用量以其中所含碱的投料摩尔用量计,为所述式II所示化合物的2.0~3.0倍,优选2.5倍。
所述反应在溶剂中进行;所述溶剂为乙醇、1,4-二氧六环或甲醇,优选乙醇。
所述反应步骤中,温度为60~90℃,优选80℃;时间为8~20小时,优选12小时,该反应时间视不同式III所示反应物不同而变化。反应是否完毕可通过薄层色谱或者气相色谱进行监测。
在反应完毕后,可将反应体系按照常规方法进行分离提纯,优选的分离方式为:将反应之后的原液转移到圆底烧瓶中,转移时可用一些乙酸乙酯或二氯甲烷冲洗原容器,以减少损失;减压浓缩后,加入乙酸乙酯萃取多次,再向水相加稀盐酸或稀硫酸调节pH值至4,析出大量固体产物;过滤,并用水洗滤饼,将滤饼真空烘干,得到所述式IV所示化合物。
本发明提供的合成3-羟基-2-吡啶甲酸及其衍生物的方法,具有以下特点:(1)经济。反应原料3-羟基吡啶是常用的化工原料,其取代基相对简单的衍生物也便宜易得,所使用的氰基化试剂(三烷基氰硅烷)、二取代氨基甲酰氯类化合物、过氧化物、碱和溶剂亦非常的廉价易得。(2)普适。反应对3-羟基吡啶及其衍生物的非2位取代底物,包括各种卤素或给电子基的底物均适用,使得该反应体系能够得到取代基多样化的3-羟基-2-吡啶甲酸类化合物;且该反应体系可承担产物的克级制备,有工业化的潜力。(3)绿色。三步反应的溶剂均为无毒或低毒性溶剂;在相对关键的氰基化步骤用三烷基氰基硅烷引入氰基,避免了使用剧毒的氰化钠和氰化钾;整个反应流程不涉及强酸性条件,克服了旧路线中使用重铬酸喹啉与浓硫酸的缺陷,合成的各个步骤条件对环境相对友好。
附图说明
图1为3-羟基-2-吡啶甲酸的合成路线图
具体实施方式
下面结合具体实施例对本发明作进一步阐述,但本发明并不限于以下实施例。所述方法如无特别说明均为常规方法。下述实施例中所用的材料、试剂等,如无特别说明均能从公开商业途径而得。
实施例1
称取1.000g 3-羟基吡啶(10.5mmol)溶于10.0mL冰醋酸中,滴加1.315g过氧化氢水溶液(30%(w/w),11.6mmol),氮气保护60℃反应12个小时下搅拌。薄层色谱监测反应原料反应完全,将反应液直接旋干,加入石油醚和少量的乙酸乙酯打浆过滤,烘干得到1.210g氧化产物。将上一步氧化产物作原料溶于12.1mL二氯甲烷中,加入1.350g三甲基氰硅烷(13.6mmol),在零度冰浴下滴加1.195g二甲氨基甲酰氯(11.1mmol),氮气保护室温搅拌反应16小时。薄层色谱监测反应原料反应完全,将反应原液往碳酸钾水溶液中滴加,将pH值调至8;用5.0mL二氯甲烷萃取两次,再向水相加稀盐酸或稀硫酸调节pH值至6,析出大量固体产物;过滤,并用5.0mL石油醚冲洗,将滤饼真空烘干,得到0.968g氰基化产物。将上一步氰基化产物作原料溶于10.0mL的乙醇中,然后加入4.033g的氢氧化钠水溶液(20%(w/w),20.2mmol),然后回流12小时,薄层色谱监测反应原料反应完。直接浓酸除去乙醇,然后加入5.0mL乙酸乙酯萃取,然后把水相用稀盐酸调节pH至4,析出固体,然后过滤,滤饼水洗,在烘干得到产物0.968g,目标产物3-羟基-2-吡啶甲酸的分离产率为66%。
实施例2
称取1.146g 3-羟基-6-甲基吡啶(10.5mol)溶于10.0L冰醋酸中,滴加1.315kg化氢水溶液(30%(w/w),11.6mmol),氮气保护60℃反应12个小时下搅拌。薄层色谱监测反应原料反应完全,将反应液直接旋干,加入石油醚和少量的乙酸乙酯打浆过滤,烘干得到1.381g氧化产物。将上一步氧化产物作原料溶于12.1mL二氯甲烷中,加入1.350g三甲基氰硅烷(13.6mmol),在零度冰浴下滴加1.195g二甲氨基甲酰氯(11.1mmol),氮气保护室温搅拌反应16小时。薄层色谱监测反应原料反应完全,将反应原液往碳酸钾水溶液中滴加,将pH值调至8;用5.0mL二氯甲烷萃取两次,再向水相加稀盐酸或稀硫酸调节pH值至6,析出大量固体产物;过滤,并用5.0mL石油醚冲洗,将滤饼真空烘干,得到0.972g氰基化产物。将上一步氰基化产物作原料溶于10.0mL的乙醇中,然后加入3.633g的氢氧化钠水溶液(20%(w/w),18.2mmol),然后回流12小时,薄层色谱监测反应原料反应完。直接浓酸除去乙醇,然后加入5.0mL乙酸乙酯萃取,然后把水相用稀盐酸调节pH至4,析出固体,然后过滤,滤饼水洗,在烘干得到产物0.997g,目标产物3-羟基-6-甲基-2-吡啶甲酸的分离产率为62%。
实施例3
称取1.314g 5-甲氧基吡啶-3-醇(10.5mmol)溶于10.0mL冰醋酸中,滴加1.315g过氧化氢水溶液(30%(w/w),11.6mmol),氮气保护60℃反应12个小时下搅拌。薄层色谱监测反应原料反应完全,将反应液直接旋干,加入石油醚和少量的乙酸乙酯打浆过滤,烘干得到1.417g氧化产物。将上一步氧化产物作原料溶于12.1mL二氯甲烷中,加入1.241g三甲基氰硅烷(12.5mmol),在零度冰浴下滴加1.097g二甲氨基甲酰氯(10.2mmol),氮气保护室温搅拌反应16小时。薄层色谱监测反应原料反应完全,将反应原液往碳酸钾水溶液中滴加,将pH值调至8;用5.0mL二氯甲烷萃取两次,再向水相加稀盐酸或稀硫酸调节pH值至6,析出大量固体产物;过滤,并用5.0mL石油醚冲洗,将滤饼真空烘干,得到0.988g氰基化产物。将上一步氰基化产物作原料溶于10.0mL的乙醇中,然后加入3.294g的氢氧化钠水溶液(20%(w/w),16.5mmol),然后回流12小时,薄层色谱监测反应原料反应完。直接浓酸除去乙醇,然后加入5.0mL乙酸乙酯萃取,然后把水相用稀盐酸调节pH至4,析出固体,然后过滤,滤饼水洗,在烘干得到产物1.011g,目标产物3-羟基-5-甲氧基-2-吡啶甲酸的分离产率为57%。
实施例4
称取1.360g 4-氯-3-羟基吡啶(10.5mmol)溶于10.0mL冰醋酸中,滴加1.315g过氧化氢水溶液(30%(w/w),11.6mmol),氮气保护60℃反应12个小时下搅拌。薄层色谱监测反应原料反应完全,将反应液直接旋干,加入石油醚和少量的乙酸乙酯打浆过滤,烘干得到1.493g氧化产物。将上一步氧化产物作原料溶于12.1mL二氯甲烷中,加入1.278g三甲基氰硅烷(12.9mmol),在零度冰浴下滴加1.130g二甲氨基甲酰氯(10.5mmol),氮气保护室温搅拌反应16小时。薄层色谱监测反应原料反应完全,将反应原液往碳酸钾水溶液中滴加,将pH值调至8;用5.0mL二氯甲烷萃取两次,再向水相加稀盐酸或稀硫酸调节pH值至6,析出大量固体产物;过滤,并用5.0mL石油醚冲洗,将滤饼真空烘干,得到1.251g氰基化产物。将上一步氰基化产物作原料溶于10.0mL的乙醇中,然后加入4.053g的氢氧化钠水溶液(20%(w/w),20.3mmol),然后回流12小时,薄层色谱监测反应原料反应完。直接浓酸除去乙醇,然后加入5.0mL乙酸乙酯萃取,然后把水相用稀盐酸调节pH至4,析出固体,然后过滤,滤饼水洗,在烘干得到产物1.257g,目标产物3-羟基-4-氯-2-吡啶甲酸的分离产率为69%。
Claims (9)
1.一种制备式IV所示化合物的方法,
包括氧化反应、氰基化反应、水解反应,具体步骤如下:
将所述式I所示化合物3-羟基吡啶衍生物溶于溶剂中,滴加过氧化氢水溶液,惰性气体保护下搅拌,氧化反应完毕后得到所述式II所示化合物;
将所述式II所示化合物溶解在有机溶剂中,加入氰基化试剂,冰浴下滴加二取代氨基甲酰氯类化合物后惰性气体保护下搅拌,氰基化反应完毕得到所述式III所示化合物;
将所述式III所示化合物溶解在有机溶剂中,加入碱的水溶液,后回流至水解反应完毕得到所述式IV所示化合物;
所述式I、式II、式III、式IV中,R选自氢、卤素取代基和供电子基中的任意一种;R的取代位为4位、5位或6位;
所述卤素为氟、氯或溴;
所述供电子基为如下基团中的任意一种;C1-C3的烷基、C1-C2的烷氧基;
所述C1-C3的烷基为如下基团中的任意一种:甲基、乙基、正丙基、异丙基;
所述C1-C2的烷氧基为甲氧基、乙氧基;
上述氧化反应方法中,所述惰性气体为氮气和氩气的至少一种;
所述氰基化试剂为三甲基氰硅烷或叔丁基氰基二甲基硅烷的至少一种;
所述二取代氨基甲酰氯类化合物为二甲氨基甲酰氯、二乙氨基甲酰氯或N-乙基-N-甲基甲酰氯的至少一种;
所述碱为氢氧化钠、氢氧化钾或氢氧化锂的至少一种。
2.根据权利要求1所述的方法,其特征在于:所述过氧化氢水溶液投料摩尔用量以其中所含过氧化氢的投料摩尔用量计,为所述式I所示化合物投料摩尔用量的1.0~1.5倍;
所述氰基化试剂的投料摩尔用量为所述式II所示化合物的1.0~1.5倍;
所述二取代氨基甲酰氯类化合物的投料摩尔用量为所述式II所示化合物的1.0~1.2倍;
所述碱的水溶液为碱的投料摩尔用量以其中所含碱的投料摩尔用量计,为所述式II所示化合物的2.0~3.0倍。
3.根据权利要求2所述的方法,其特征在于:所述过氧化氢水溶液为过氧化氢的质量百分浓度为10%~40%的水溶液;
所述碱的水溶液为碱的质量百分浓度为15%~25%的水溶液。
4.根据权利要求1所述的方法,其特征在于:所述氧化反应、氰基化反应和水解反应均在溶剂中进行。
5.根据权利要求4所述的方法,其特征在于:所述氧化反应步骤中,溶剂选自冰醋酸或醋酸水溶液中的至少一种;
所述氰基化反应步骤中,溶剂选自二氯甲烷、1,2-二氯乙烷、氯仿或甲苯中的至少一种;
所述水解反应步骤中,溶剂选自乙醇、1,4-二氧六环或甲醇中的至少一种。
6.根据权利要求1或2所述的方法,其特征在于:所述氧化反应步骤中,温度为50~70℃;时间为8~20小时;
所述氰基化反应步骤中,温度为20~40℃;时间为10~24小时;
所述水解反应步骤中,温度为60~90℃;时间为8~20小时。
7.根据权利要求1所述的方法,其特征在于:所述反应步骤中,反应装置为密闭的反应装置或附加回流装置的反应容器。
8.根据权利要求1所述的方法,其特征在于:还包括对所述氧化反应结束后的反应体系进行分离提纯,得到所述式II所示化合物的步骤;
对氰基化反应结束后的反应体系进行分离提纯,得到所述式III所示化合物的步骤;
对水解反应结束后的反应体系进行分离提纯,得到所述式IV所示化合物的步骤。
9.根据权利要求8所述的方法,其特征在于:
所述氧化反应的分离提纯的步骤为如下:(1)将反应原液转移到圆底烧瓶中,可用一些乙酸乙酯或二氯甲烷冲洗原容器;(2)减压浓缩后,加入10.0mL石油醚打浆过滤,烘干得到产物式II所示化合物;
所述氰基化反应的分离提纯的步骤为如下:(1)将反应原液往碳酸钾水溶液中滴加,将pH值调至8;(2)用5.0mL二氯甲烷萃取两次,再向水相加稀盐酸或稀硫酸调节pH值至6,析出固体产物;(3)过滤,并用5.0mL石油醚冲洗,将滤饼真空烘干,得到所述式III所示化合物;
所述水解反应的分离提纯的步骤为如下:(1)将反应原液转移到圆底烧瓶中,可用一些乙酸乙酯或二氯甲烷冲洗原容器;(2)减压浓缩后,加入5.0mL乙酸乙酯萃取,再向水相加稀盐酸或稀硫酸调节pH值至4,析出固体产物;(3)过滤,水洗滤饼,将滤饼真空烘干,得到所述式IV所示化合物。
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