CN108586327A - 一种氟尼辛的合成方法 - Google Patents
一种氟尼辛的合成方法 Download PDFInfo
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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
- C07D213/80—Acids; Esters in position 3
-
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明属于化学合成技术领域，具体涉及一种氟尼辛的合成方法。该方法包括下述的步骤：2‑氯烟酸和2‑甲基‑3‑三氟甲基苯胺在全氟磺酸树脂催化下反应生成氟尼辛。该方法采用全氟磺酸树脂作为催化剂，反应快，收率高，本步骤收率可达97%。
Description
技术领域
本发明属于化学合成技术领域，具体涉及一种氟尼辛的合成方法。
背景技术
氟尼辛的化学式:C14H13F3N2，化学名为2-[[2-甲基-3-(三氟甲基)苯基]氨基]-3-吡啶甲酸，
结构式：。
氟尼辛是制备氟尼辛葡甲胺的关键原料，使用上主要制备成氟尼辛葡甲胺使用。氟尼辛葡甲胺（flunixin meglumine）是一种新型的、非甾体类动物专用的解热镇痛药物，属于烟酸类衍生物，是环氧化酶的抑制剂。由美国先灵葆雅公司于20世纪90年代开发(商品名为Banamine)，现已在美国、法国、瑞士、德国、英国等许多国家广泛应用。氟尼辛葡甲胺具有解热、消炎和镇痛作用，单独或与抗生素联合用药能够明显改善临床症状，并可以增强抗生素的活性。有人用小白鼠醋酸扭体法、家兔蛋白胨致热法观察氟尼辛葡甲胺的活性，结果都表明氟尼辛葡甲胺具有很好的解热和镇痛作用。兽医临床上常用于缓解马的内脏绞痛、肌肉与骨骼紊乱引起的疼痛及抗炎；牛的各种疾病感染引起的急性炎症的控制，如蹄叶炎、关节炎等，另外也可用于母猪乳房炎、子宫炎及无乳综合征的辅助治疗。在兽医上，氟尼辛葡甲胺也和土霉素联用治疗马的肺炎。据FDA报道，Donald G.Campbell等人用2.2毫克/千克体重剂量注射治疗Hereford后备母牛大肠杆菌内毒素诱导发热，取得了良好效果，且无不良反应；Gerdemann R等人以1.1毫克/千克体重剂量注射治疗马的肠梗阻引起的绞痛，效果很好；Baskett A等人用氟尼辛葡甲胺与己酮可可碱联合使用治疗马的内毒素血症。Mavrogianni等报道，氟尼辛葡甲胺按2.22～2.86毫克/千克体重经肌肉注射给药，对羊乳房炎有良好的辅助治疗效果，患病羊只恢复较快。
目前，文献报道的氟尼辛合成路线主要有以下三种：1、US5248781报道的以2-甲基-3-三氟甲基苯胺和2-氯烟酸乙酯为原料，经200℃加热或二甲苯回流反应、水解得到氟尼辛，收率43.2%-58.5%。该方法使用到高温或毒性大的溶剂二甲苯，反应要求比较高，同时收率低，实际生产中后处理困难。2、US5484931报道的以2-氯烟酸和2-甲基-3-三氟甲基苯胺为原料，对甲苯磺酸催化回流24h以上得到氟尼辛，收率83%，该方法中主要原料2-甲基-3-三氟甲基苯胺过量使用，反应时间长，后处理复杂，收率不高，综合生产成本高，经济性差。3、Heterocycles,38(10),1994,2243-2246报道以2-甲基-3-三氟甲基苯胺和2-氯烟酸乙酯为原料，乙二醇为溶剂，165℃反应6h后经蒸除溶剂，水解得到氟尼辛，总收率77.4%，该方法中反应温度高，蒸馏除去高沸点溶剂乙二醇效率低，水解反应及后续步骤复杂，收率低，经济性差。
专利CN103694167A公开了一种氟尼辛葡甲胺的合成方法，其中包含氟尼辛的合成步骤，具体内容为：2-甲基-3-三氟甲基苯胺和2-氯烟酸为原料，水作溶剂，氧化铜和对甲苯磺酸作催化剂，其中，2-甲基-3-三氟甲基苯胺：2-氯烟酸：对甲苯磺酸：氧化铜的摩尔比为2∶1∶ 0.01～0.1∶0.01～0.1，最优摩尔比为2-甲基-3-三氟甲基苯胺：2-氯烟酸：对甲苯磺酸：氧化铜 =2∶1∶0.05∶0.05，将反应体系加热至回流，维持回流状态反应2～4小时。HPL℃监测体系 中2-氯烟酸含量低于0-5％时，降低温度，当体系温度低于50℃时，加碱，如氢氧化钾或氢 氧化钠的水溶液调pH值至10-0～11-0，过滤滤除过量未反应的原料，滤液用盐酸调pH值至 5-0～6.0，过滤，滤饼经纯化水洗涤，干燥得到氟尼辛。该专利中，以2-氯烟酸和2-甲基-3-三氟甲基苯胺为原料，氧化铜和对甲苯磺酸为催化剂，制备氟尼辛，该方法在采用已有报道的对甲苯磺酸催化的前提下，加入氧化铜，大幅增加了催化效率，缩短了反应时间，提高了收率，所得氟尼辛在乙腈中与葡甲胺成盐，然后重结晶得到氟尼辛葡甲胺，总收率约90%。该方法操作简单，对设备要求不高，适合工业化生产，但是主要原料2-甲基-3-三氟甲基苯胺过量1倍投料，回收利用在实际生产中有很大难度，必然导致生产成本提高。
专利CN102442944A中公开了一种氟尼辛的制备方法，该方法采用2-甲基-3-三氟甲基苯胺和2-氯烟酸乙酯为原料，聚乙二醇或乙二醇为溶剂，碘化亚铜、对甲基苯磺酸为催化剂，在加热至80℃-100℃、搅拌条件下反应，反应完毕后加入碱的水溶液，水解后用酸调pH值小于5，抽滤，滤饼用乙醇洗涤，洗涤后抽滤、减压、干燥后得到氟尼辛。该方法收率90%左右，适合工业化生产，但是该方法中使用的溶剂聚乙二醇或乙二醇的回收会相对提高生产成本，同时产生的含铜废水处理也会增加无水处理成本。
发明内容
为了解决上述的技术问题，本发明提供一种氟尼辛的合成方法，其操作简单，反应时间短，催化剂可反复回收使用，收率高。
本发明是通过下述的技术方案来实现的：
一种的氟尼辛的合成方法，包括下述的步骤：
2-氯烟酸和2-甲基-3-三氟甲基苯胺在全氟磺酸树脂催化下反应生成氟尼辛。
反应式为：
全氟磺酸树脂的结构式为：
。
全氟磺酸树脂是现在已知的最强固体超强酸，具有耐热性能好、化学稳定性和机械强度高等特点。一般是将带有磺酸基的全氟乙烯基醚单体与四氟乙烯进行共聚，得到全氟磺酸树脂。全氟磺酸树脂市面上有售。
上述的氟尼辛的合成方法中，所述反应溶剂为水。
上述的氟尼辛的合成方法中，所述2-氯烟酸和2-甲基-3-三氟甲基苯胺的摩尔比为1.05:1
上述的氟尼辛的合成方法中，所述在全氟磺酸树脂的用量为2-甲基-3-三氟甲基苯胺重量的1%。
上述的氟尼辛的合成方法中，所述反应温度为控制反应温度为65℃-70℃。
上述的氟尼辛的合成方法中，所述时间为2-3小时。
上述的氟尼辛的合成方法中，所述反应还包含后处理步骤，所述后处理步骤为，抽滤，滤液调节pH至4.5，搅拌15-20min，甩滤，水洗，滤饼干燥后得到氟尼辛。所述pH为60%硫酸溶液。
上述的氟尼辛的合成方法，详细步骤为：将2-氯烟酸和2-甲基-3-三氟甲基苯胺加入到水中搅拌，加入全氟磺酸树脂，控制温度至65℃-70℃，反应2.5h后，抽滤，滤液调节pH至4.5，搅拌15-20min，甩滤，水洗，滤饼干燥后得到氟尼辛。所述pH为60%硫酸溶液。
上述的氟尼辛的合成方法中，所述催化剂全氟磺酸树脂可回收使用。
与现有技术相比，本发明的有益效果如下：
（1）本发明的氟尼辛的合成采用全氟磺酸树脂作为催化剂，转化率高，反应快，收率高，本步骤收率可达97%。
（2）本发明反应温度为65℃-70℃，反应时间2.5h，降低了反应温度、缩短了反应时间。
（3）本发明采用的催化剂全氟磺酸树脂可以多次回收使用，可降低生产成本，大幅提高生产的经济性。
（4）工业化生产中，生产成本是决定产品销售生命的重要因素，因此，在保证产品质量的前提下降低生产成本，是工业生产中的重中之重。现有技术中， 2-甲基-3-三氟甲基苯胺一般需要过量使用才能使反应完全，氟尼辛收率比较高，比如专利US5484931中投料比2-甲基-3-三氟甲基苯胺：2-氯烟酸为2.1:1，这种投料方法虽然使得反应比较完，但是大大推高了氟尼辛生产成本，主要原因有三：一是2-甲基-3-三氟甲基苯胺价格高（840元/kg），较之2-氯烟酸（133元/kg）的价格高出许多，因此，大生产中采用2-甲基-3-三氟甲基苯胺过量投料本身就增加生产成本；二是反应中过量的2-甲基-3-三氟甲基苯胺需要从反应母液中进行回收，而2-甲基-3-三氟甲基苯胺水溶性较好，能与水形成共沸物，难以完全回收，回收过程必然带来损失，另外回收2-甲基-3-三氟甲基苯胺本身需要消耗人力物力能源，导致进一步推高生产成本；三是含有2-甲基-3-三氟甲基苯胺的反应废水不能直接排放，需要进行环保处理，增加了后续反应液处理的难度，再次推高了生产成本，且增加了环保压力。本发明的氟尼辛的合成方法中，采用全氟磺酸树脂作为催化剂，解决了原料2-甲基-3-三氟甲基苯胺过量才能使反应完全的问题，大大降低了生产成本和后续反应液处理的难度，减轻了环保压力。
（5）本发明中采用价格低廉的2-氯烟酸过量投料，转化率高，收率可达97%，产品纯度大于99.5%，在保证产品收率和质量的同时，降低了生产成本。
具体实施方式
下面结合具体实施例对本发明作更进一步的说明，以便本领域的技术人员更了解本发明，但并不因此限制本发明。
本发明实施例中，2-氯烟酸购自寿光市金宇化工有限责任公司，2-甲基-3-三氟甲基苯胺购自上海贝合化工有限公司，全氟磺酸树脂购自常州特华商贸有限公司。
实施例1
1000L反应釜中加入300L水，分别投入131.9kg（837.5mol）2-氯烟酸和140kg2-甲基-3-三氟甲基苯胺（800mol），搅拌，加入1.4kg全氟磺酸树脂，升温至65℃-70℃，反应2.5h后，抽滤，滤液用60%硫酸溶液调节pH至4.5，搅拌15-20min，甩滤，30kg水洗涤滤饼，滤饼干燥后得到氟尼辛230.1kg，收率97.1%，纯度99.9%，纯度按照USP38中方法检测，下同。
实施例2
1000L反应釜中加入300L水，分别投入131.9kg（837.5mol）2-氯烟酸和140kg（800mol）2-甲基-3-三氟甲基苯胺，搅拌，加入1.4kg全氟磺酸树脂，升温至70℃，反应2.5h后，抽滤，滤液用60%硫酸溶液调节pH至4.5，搅拌15-20min，甩滤，30kg水洗涤滤饼，滤饼干燥后得到氟尼辛229.8kg，收率97.0%，纯度99.8%。
实施例3
1000L反应釜中加入300L水，分别投入131.9kg（837.5mol）2-氯烟酸和140kg（800mol）2-甲基-3-三氟甲基苯胺，搅拌，加入1.4kg回收全氟磺酸树脂，升温至65℃，反应2.5h后，抽滤，滤液用60%硫酸溶液调节pH至4.5，搅拌15-20min，甩滤，30kg水洗涤滤饼，滤饼干燥后得到氟尼辛229.6kg，收率96.9%，纯度99.9%。
实施例4
1000L反应釜中加入300L水，分别投入131.9kg（837.5mol）2-氯烟酸和140kg（800mol）2-甲基-3-三氟甲基苯胺，搅拌，加入1.4kg回收全氟磺酸树脂，升温至65℃，反应2.5h后，抽滤，滤液用60%硫酸溶液调节pH至4.5，搅拌15-20min，甩滤，30kg水洗涤滤饼，滤饼干燥后得到氟尼辛229.8kg，收率97.0%，纯度99.8%。
Claims (9)
1.一种的氟尼辛的合成方法，包括下述的步骤：
2-氯烟酸和2-甲基-3-三氟甲基苯胺在全氟磺酸树脂催化下反应生成氟尼辛。
2.根据权利要求1所述的氟尼辛的合成方法，其特征在于，所述反应溶剂为水。
3.根据权利要求1所述的氟尼辛的合成方法，其特征在于，所述2-氯烟酸和2-甲基-3-三氟甲基苯胺的摩尔比为1.05:1。
4.根据权利要求1所述的氟尼辛的合成方法，其特征在于，所述在全氟磺酸树脂的用量为2-甲基-3-三氟甲基苯胺重量的1%。
5.根据权利要求1所述的氟尼辛的合成方法，其特征在于，所述反应温度为为65℃-70℃。
6.根据权利要求1所述的氟尼辛的合成方法，其特征在于，所述时间为2-3小时。
7.根据权利要求1所述的氟尼辛的合成方法，其特征在于，所述反应还包含后处理步骤，所述后处理步骤为，抽滤，滤液调节pH至4.5（首选60%硫酸溶液），搅拌15-20min，甩滤，水洗，滤饼干燥后得到氟尼辛。
8.根据权利要求1所述的氟尼辛的合成方法，其特征在于，详细步骤为：将2-氯烟酸和2-甲基-3-三氟甲基苯胺加入到水中搅拌，加入全氟磺酸树脂，控制温度至65℃-70℃，反应2.5h后，抽滤，滤液调节pH至4.5（首选60%硫酸溶液），搅拌15-20min，甩滤，水洗，滤饼干燥后得到氟尼辛。
9.根据权利要求1-9任一所述的氟尼辛的合成方法，其特征在于，所述催化剂全氟磺酸树脂可回收使用。
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