CN104003934B - 6-氯-3-氟-2-吡啶甲酸的合成 - Google Patents
6-氯-3-氟-2-吡啶甲酸的合成 Download PDFInfo
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- IRERRSXDWUCFIY-UHFFFAOYSA-N 3-fluoropyridine-2-carboxylic acid Chemical compound OC(=O)C1=NC=CC=C1F IRERRSXDWUCFIY-UHFFFAOYSA-N 0.000 title claims abstract 3
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- ADZJWYULTMTLQZ-UHFFFAOYSA-N tritylphosphane;hydrobromide Chemical compound [Br-].C=1C=CC=CC=1C(C=1C=CC=CC=1)([PH3+])C1=CC=CC=C1 ADZJWYULTMTLQZ-UHFFFAOYSA-N 0.000 claims 1
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- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
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- 108090000430 Phosphatidylinositol 3-kinases Proteins 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
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- FNEPSTUXZLEUCK-UHFFFAOYSA-N benzo-15-crown-5 Chemical compound O1CCOCCOCCOCCOC2=CC=CC=C21 FNEPSTUXZLEUCK-UHFFFAOYSA-N 0.000 description 1
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- IIEWJVIFRVWJOD-UHFFFAOYSA-N ethyl cyclohexane Natural products CCC1CCCCC1 IIEWJVIFRVWJOD-UHFFFAOYSA-N 0.000 description 1
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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
- C07D213/803—Processes of preparation
- C07D213/807—Processes of preparation by oxidation of pyridines or condensed pyridines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/30—Halogen atoms or nitro radicals
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
Abstract
本发明公开了一种6-氯-3-氟-2-吡啶甲酸的合成工艺，所采用的主要起始原料为6-氯-3-氟-2-甲基吡啶。以6-氯-3-氟-2-甲基吡啶为起始原料，稀硫酸为溶剂，重铬酸钾为氧化剂，钨酸钠（Na2WO4·2H2O）及冠醚为组合催化剂，反应完全后，通过常规后处理得到粗品，加热将该粗品溶解于碱性水溶液，用有机溶剂萃取未反应的微量原料及其它杂质，水层用无机酸酸化，冷却结晶，得到6-氯-3-氟-2-吡啶甲酸纯品，收率高，产品品质好。
Description
技术领域
本发明涉及一种6-氯-3-氟-2-吡啶甲酸的合成方法，更准确地说以6-氯-3-氟-2-甲基吡啶为原料氧化反应合成6-氯-3-氟-2-吡啶甲酸的方法。
背景技术
吡啶甲酸是重要精细化工中间体，在医药与农药领域应用广泛。含氟、氯等卤素的吡啶甲酸，更是在医药、农药、精细化学品、功能材料等领域应用非常广泛。最近几年，涌现出大量文献报道了6-氯-3-氟-2-吡啶甲酸的应用，特别是在药物方面的应用。例如：文献(BioorganicandMedicinalChemistryLetters,2013,vol.23,nb3P821–826)报道了采用6-氯-3-氟-2-吡啶甲酸为主要起始原料，合成药物(GABAAreceptor)。专利(EP2098517A1,2009)报道了采用6-氯-3-氟-2-吡啶甲酸为原料，合成药物(GPR120receptor)。专利(US318412A1,2009)报道了采用6-氯-3-氟-2-吡啶甲酸为原料，合成药物(serotnin5-HT2creceptor)。专利(WO2009147190A1,2009)报道了采用6-氯-3-氟-2-吡啶甲酸为原料，合成药物(inhibitorsofPI3-kinase)。
尽管本发明所报道的化合物6-氯-3-氟-2-吡啶甲酸应用非常广泛，但迄今为止还没有任何公开发表的文献报道6-氯-3-氟-2-吡啶甲酸的有效合成方法，也没有类似合成方法可以直接借鉴。
发明内容
本发明的目的在于提供一种反应步骤少、反应试剂便宜的6-氯-3-氟-2-吡啶甲酸合成方法。
为实现上述发明目的，本发明采用的技术方案如下：
一种6-氯-3-氟-2-吡啶甲酸的合成工艺，所采用的主原料为6-氯-3-氟-2-甲基吡啶。
本发明合成6-氯-3-氟-2-吡啶甲酸化学反应过程如下（式1）：
上述6-氯-3-氟-2-吡啶甲酸的合成具体工艺步骤为：
在反应瓶中，依次加入稀硫酸、重铬酸钾、催化剂钨酸钠（Na2WO4·2H2O）、相转移催化剂、6-氯-3-氟-2-甲基吡啶，加热到70～130℃下，反应0.5～20小时，搅拌下，将反应溶液倒入碎冰中，抽滤，滤饼用适量冰水洗涤，烘干水分，得到灰色固体，加热将该固体溶解于碱性水溶液，冷却后用有机溶剂萃取未反应的原料及其它杂质，水层用无机酸酸化，析出固体，抽滤，烘干，得到6-氯-3-氟-2-吡啶甲酸白色固体。
所述催化剂为钨酸钠（Na2WO4·2H2O），其用量为原料6-氯-3-氟-2-甲基吡啶质量的2～20%。
所述相转移催化剂为冠醚18冠6、冠醚苯并18冠6、冠醚二苯并18冠6、冠醚15冠5、冠醚苯并15冠5、冠醚二苯并15冠5中的一种或者几种，其用量为原料6-氯-3-氟-2-甲基吡啶质量的0.1～5%；
所述稀硫酸浓度为5～60%。
所述碱性水溶液为氢氧化钠水溶液、氢氧化钾水溶液、氢氧化锂水溶液、碳酸钠水溶液、碳酸钾水溶液中的一种，其水溶液浓度为2～70%。
所述酸化过程中所用无机酸为盐酸、硫酸、硝酸、氢溴酸中的一种，其浓度为5～30%。
所述原料6-氯-3-氟-2-甲基吡啶，可以从试剂商(asymchem)购买，也可以按照下述方法进行合成。6-氯-3-硝基-2-甲基吡啶为初始原料，经过硝基还原为氨基，重氮化反应得到6-氯-3-氟-2-甲基吡啶（式2），详细实验操作步骤见实施例1～2。
与现有公开技术相比，本发明具有如下优点：
1、现有技术没有对6-氯-3-氟-2-吡啶甲酸的合成方法进行充分公开，而本发明对6-氯-3-氟-2-吡啶甲酸的合成方法进行完整、详细、充分地进行了公开。
2、从原料6-氯-3-氟-2-甲基吡啶出发，一步合成6-氯-3-氟-2-吡啶甲酸，工序少，操作简单。
3、反应选择性好，收率高，终产品品质好。
4、所有反应都是常温、常压反应，易于实现工业化生产。
因此，综上所述本发明具有良好的经济效益和社会效益。
以下通过实施例的具体实施方式再对本发明的上述内容作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下实例。在不脱离本发明上述技术思想情况下，根据本领域普通技术知识和惯用手段做出的各种替换或变更，均应包括在本发明的范围内。
具体实施方式：
实施例1：6-氯-3-氨基-2-甲基吡啶的合成
在1升高压加氢反应釜中依次加入300毫升乙醇、6-氯-3-硝基-2-甲基吡啶86.3g（0.5mol）、5%钯炭催化剂8.6g，开启搅拌，加热到40～45℃，通入高纯氢气，维持氢气压力0.3～0.5MPa，反应6～8小时，取样中控取样分析原料6-氯-3-氨基-2-甲基吡啶含量低于0.3%，停止反应，降到室温，滤出催化剂，所得滤液，减压蒸尽乙醇得到灰色固体，用乙酸乙酯与环己烷混合溶液重结晶，烘干后得到产品56.1g，液相相对含量98%以上，该固体可以直接用于下述实施例2的进一步反应。
实施例2：6-氯-3-氟-2-甲基吡啶的合成
在配有机械搅拌的2000毫升三颈瓶中加入20%盐酸460毫升，再加入按照实施例1的方法制备的6-氯-3-氨基-2-甲基吡啶71.3g（0.5mol），充分搅拌，采用冰盐浴将反应体系温度控制在0～3℃，缓慢滴加亚硝酸钠水溶液（含亚硝酸钠38.0g、水38.0毫升），滴加用时1小时，滴加完后，维持该温度搅拌0.5小时，滴加48%氟硼酸水溶液270毫升，滴加过程温度不超过5℃，滴加完后，缓慢升到室温反应2小时。将反应液倒入冰水中，充分搅拌，用10%氢氧化钠水溶液中和到pH=7，加入萃取剂三氯甲烷，萃取两次，分液，合并后的萃取液再用饱和食盐水洗涤一次，分液，所得有机层用无水硫酸钠干燥，过滤，旋蒸除掉溶剂三氯甲烷，用正己烷重结晶，得到6-氯-3-氟-2-甲基吡啶43.6g，液相相对含量96%。该产品可以直接用于下述实施例中的进一步反应。
实施例3：6-氯-3-氟-2-吡啶甲酸的合成
在反应瓶中，依次加入40%稀硫酸400ml、重铬酸钾176g、二水钨酸钠（Na2WO4·2H2O）4.4g、相转移催化剂（冠醚18冠6）0.8g、按照实施例2的方法制备的6-氯-3-氟-2-甲基吡啶43.6g（0.3mol），加热到105℃下，反应6小时，将反应溶液倒入3kg碎冰中，抽滤，滤饼用适量冰水洗涤，加热将该滤饼溶解于碳酸钾水溶液中，冷却后用三氯甲烷萃取未反应的原料及其它杂质，水层用20%盐酸酸化，冷却，析出的固体抽滤，烘干，得到6-氯-3-氟-2-吡啶甲酸白色固体48.5g，收率92.0%，液相含量98.7%。6-氯-3-氟-2-吡啶甲酸熔点：161～164℃；MS(ES):m/z=176.0[M+H]+。1HNMR(400MHz,CDCl3)δppm10.45(s,br,1H)；8.87-8.85(d,1H，J=7.9Hz),8.66-8.63(d,1H，J=7.9Hz)。
实施例4：6-氯-3-氟-2-吡啶甲酸的合成
二水钨酸钠（Na2WO4·2H2O）0.4g、相转移催化剂（冠醚18冠6）0.4g，其他操作同实施例3。按照实施例3进行操作，得到白色6-氯-3-氟-2-吡啶甲酸纯品38.0克，含量97.8%，收率72.1%。
实施例5：6-氯-3-氟-2-吡啶甲酸的合成
二水钨酸钠（Na2WO4·2H2O）0g，其他操作同实施例3。按照实施例3进行操作，得到白色6-氯-3-氟-2-吡啶甲酸纯品38.0克，含量95.7%，收率42.3%。
实施例6：6-氯-3-氟-2-吡啶甲酸的合成
重铬酸钾220g，其他操作同实施例3。按照实施例3进行操作，得到白色6-氯-3-氟-2-吡啶甲酸纯品49.3克，含量98.0%，收率93.5%。
Claims (5)
1.一种6-氯-3-氟-2-吡啶甲酸的合成工艺，其特征是所采用的起始原料为6-氯-3-氟-2-甲基吡啶，其合成6-氯-3-氟-2-吡啶甲酸化学反应过程如式1：
上述6-氯-3-氟-2-吡啶甲酸的合成具体工艺步骤为：
在反应瓶中，依次加入稀硫酸、重铬酸钾、分子式为Na2WO4·2H2O的钨酸钠催化剂、相转移催化剂、6-氯-3-氟-2-甲基吡啶，加热到70～130℃下，反应0.5～20小时，搅拌下，将反应溶液倒入碎冰中，抽滤，滤饼用适量冰水洗涤，烘干水分，得到灰色固体，加热将该固体溶解于碱性水溶液，冷却后用有机溶剂萃取未反应的原料及其它杂质，水层用无机酸酸化，析出固体，抽滤，烘干，得到6-氯-3-氟-2-吡啶甲酸白色固体；钨酸钠催化剂用量为原料6-氯-3-氟-2-甲基吡啶质量的5～10%。
2.根据权利要求1所述反应，其特征是相转移催化剂为冠醚18冠6、冠醚苯并18冠6、冠醚二苯并18冠6、冠醚15冠5、冠醚苯并15冠5、冠醚二苯并15冠5中的一种或者几种，其用量为原料6-氯-3-氟-2-甲基吡啶质量的0.1～5%；或者相转移催化剂为四苯基氯化鏻、四苯基溴化鏻、三苯基甲基溴化鏻、三苯基乙基溴化鏻、三苯基乙基碘化鏻、三苯基丙基溴化鏻、三苯基丁基溴化鏻、苄基三苯基氯化鏻、苄基三苯基溴化鏻、四丁基溴化铵、四丁基氯化铵、苄基三乙基氯化铵中的一种或者几种，其用量为原料6-氯-3-氟-2-甲基吡啶质量的0.5～2%。
3.根据权利要求1所述反应，其特征是稀硫酸浓度为30～50%。
4.根据权利要求1所述反应，其特征是所述碱性水溶液为氢氧化钠水溶液、氢氧化钾水溶液、氢氧化锂水溶液、碳酸钠水溶液、碳酸钾水溶液中的一种，其水溶液浓度为10～20%。
5.根据权利要求1所述反应，其特征是酸化过程中所用无机酸为盐酸、硫酸、硝酸、氢溴酸中的一种，其浓度为10～20%。
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