CN112624936A - 一种托芬那酸的水相合成方法 - Google Patents
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- YEZNLOUZAIOMLT-UHFFFAOYSA-N tolfenamic acid Chemical compound CC1=C(Cl)C=CC=C1NC1=CC=CC=C1C(O)=O YEZNLOUZAIOMLT-UHFFFAOYSA-N 0.000 title claims abstract description 49
- 229960002905 tolfenamic acid Drugs 0.000 title claims abstract description 48
- 238000001308 synthesis method Methods 0.000 title claims abstract description 14
- 239000008346 aqueous phase Substances 0.000 title claims description 13
- ZUVPLKVDZNDZCM-UHFFFAOYSA-N 3-chloro-2-methylaniline Chemical compound CC1=C(N)C=CC=C1Cl ZUVPLKVDZNDZCM-UHFFFAOYSA-N 0.000 claims abstract description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 21
- 239000002253 acid Substances 0.000 claims abstract description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 18
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- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims abstract description 11
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- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 12
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 6
- XRXMNWGCKISMOH-UHFFFAOYSA-N 2-bromobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1Br XRXMNWGCKISMOH-UHFFFAOYSA-N 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- IKCLCGXPQILATA-UHFFFAOYSA-N 2-chlorobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1Cl IKCLCGXPQILATA-UHFFFAOYSA-N 0.000 claims description 4
- CJNZAXGUTKBIHP-UHFFFAOYSA-N 2-iodobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1I CJNZAXGUTKBIHP-UHFFFAOYSA-N 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 3
- 239000003153 chemical reaction reagent Substances 0.000 claims description 3
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 2
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- 238000000034 method Methods 0.000 claims 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims 3
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims 2
- 239000012046 mixed solvent Substances 0.000 claims 1
- 229910052757 nitrogen Inorganic materials 0.000 claims 1
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 2
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 description 2
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 description 2
- 229940114079 arachidonic acid Drugs 0.000 description 2
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- 206010006811 Bursitis Diseases 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- AEMOLEFTQBMNLQ-AQKNRBDQSA-N D-glucopyranuronic acid Chemical compound OC1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-AQKNRBDQSA-N 0.000 description 1
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/04—Formation of amino groups in compounds containing carboxyl groups
- C07C227/06—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid
- C07C227/08—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid by reaction of ammonia or amines with acids containing functional groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明公开了一种托芬那酸的水相合成方法。将邻卤苯甲酸和无机碱加入到水中,加热升温至溶解;再向上步所得的混合液中加入3‑氯‑2‑甲基苯胺、碘化亚铜、碱金属碘化物,加热升温反应;冷却,然后加入乙酸乙酯进行萃取,分液,水相用盐酸酸化析晶,过滤,滤饼为托芬那酸粗品,粗品重结晶得到托芬那酸精制产品。本发明制备方法操作步骤简单,起始物料适用性广,使用水作反应溶剂,绿色环保,同时收率也较高,降低了制备成本,适合工业化生产,最终可获得高纯度的托芬那酸产品。
Description
技术领域
本发明涉及化学物质制备技术领域,尤其涉及一种托芬那酸的水相合成方法。
背景技术
托芬那酸是一种应用广泛的非甾体抗炎药物,其主要作用机理是通过抑制环氧化酶(COX)减少花生四烯酸(AA)向炎症介质前列腺素(PGs)转化而起到消炎镇痛的作用,药物在体内几乎完全作为托芬那酸的甘氨酸及葡萄糖醛酸结合物形式通过尿液排泄,没有严重的特异性的毒性反应。目前主要用于关节炎和偏头痛的治疗,也被广泛应用于痛风、滑囊炎和痛经等疾病的治疗。
托芬那酸,英文名称Tolfenamic acid,其化学名称为:2-[(3-氯-2-甲基苯基)氨基]苯甲酸,其结构式如下:
托芬那酸的制备工艺路线在专利CN201310128091、CN201310500878及CN201210291976中均有报道,且专利整体路线没有实质性变化。其整体反应路线如下:
这条路线采用了试剂邻卤苯甲酸和3-氯-2-甲基苯胺作为起始原料,但是专利采用DMF、DMSO、酮作为溶剂,水溶性较强,沸点较高且毒性较大,导致反应完溶剂后处理困难,杂质和产品得不到充分分离,延长了后续产品的精制步骤,降低了产品收率。
发明内容
基于背景技术存在的技术问题,本发明提出了一种盐一种托芬那酸的水相合成方法,本发明制备得到的托芬那酸纯度高,可以为托芬那酸质量研究提供高纯度的对照品。
本发明提供一种托芬那酸的水相合成方法,包括如下步骤:将邻卤苯甲酸和无机碱加入到水中,加热升温至溶解。在惰性气体氛围下,向上步所得的混合液中加入3-氯-2-甲基苯胺、碘化亚铜、碱金属碘化物,加热升温反应;冷却,然后加入乙酸乙酯进行萃取,分液,水相用盐酸酸化析晶,过滤,滤饼为托芬那酸粗品,粗品经重结晶得到托芬那酸精制产品。反应如下所示:
优选的,邻卤苯甲酸与无机碱的摩尔比为1:1.1-1.5。
优选的,无机碱为碳酸钾。
优选的,3-氯-2-甲基苯胺与邻卤苯甲酸的摩尔比1:1。
优选的,碘化亚铜与邻卤苯甲酸的质量比0.05-0.1:1。
优选的,碱金属碘化物与碘化亚铜的摩尔比2:1。
优选的,碱金属碘化物为碘化钾。
优选的,反应温度为90-100℃。
优选的,盐酸酸化pH控制在2-3。
优选的,托芬那酸粗品及精品的烘料温度控制在40-45℃,鼓风干燥。
优选的,重结晶溶剂为无水乙醇。
优选的,邻卤苯甲酸为邻溴苯甲酸
优选的,托芬那酸水相合成所涉及到的单一试剂的纯度均大于95%。
优选的,水溶解邻卤苯甲酸溶液浓度为0.2-0.3g/mL
本发明分别采用邻溴苯甲酸、3-氯-2-甲基苯胺为原料,以水作溶剂,通过铜催化芳基C-N偶联反应,选用简便的后处理及纯化方式得到托芬那酸,且托芬那酸纯度高,高于99.5%,可以为托芬那酸质量研究提供高纯度的对照品。
本发明同样适用于以邻氯苯甲酸、邻碘苯甲酸作为起始物料来制备托芬那酸,但前者收率明显偏低,后者邻碘苯甲酸价格昂贵,不易得。
具体实施方式
下面,通过具体实施例对本发明的技术方案进行详细说明。
实施例1
将100.0g邻溴苯甲酸和82.4g碳酸钾加入到500ml水中,加热升温至55℃,搅拌溶解完全。在惰性气体氛围下,向上步所得的混合液中分别加入70.4g 3-氯-2-甲基苯胺、5.0g碘化亚铜、8.9g碘化钾,加热升温至100℃反应6h;冷却至室温,然后加入乙酸乙酯进行萃取,分液,水相用浓盐酸酸化至pH为2-3,逐渐析出固体,室温搅拌析晶4h,过滤,滤饼45℃鼓风干燥至恒重,得托芬那酸粗品120.0g,粗品经无水乙醇重结晶得到托芬那酸精品108.1g,总收率83.1%;
实施例2
将78.0g邻氯苯甲酸和82.5g碳酸钾加入到300ml水中,加热升温至55℃,搅拌溶解完全。在惰性气体氛围下,向上步所得的混合液中分别加入70.3g 3-氯-2-甲基苯胺、3.9g碘化亚铜、6.8g碘化钾,加热升温至100℃反应12h;冷却至室温,然后加入乙酸乙酯进行萃取,分液,水相用浓盐酸酸化至pH为2-3,逐渐析出固体,室温搅拌析晶4h,过滤,滤饼45℃鼓风干燥至恒重,得托芬那酸粗品88.1g,粗品经无水乙醇重结晶得到托芬那酸精品78.6g,总收率60.0%;
实施例3
将124.0g邻碘苯甲酸和82.8g碳酸钾加入到600ml水中,加热升温至55℃,搅拌溶解完全。在惰性气体氛围下,向上步所得的混合液中分别加入70.6g 3-氯-2-甲基苯胺、6.2g碘化亚铜、10.8g碘化钾,加热升温至100℃反应4h;冷却至室温,然后加入乙酸乙酯进行萃取,分液,水相用浓盐酸酸化至pH为2-3,逐渐析出固体,室温搅拌析晶4h,过滤,滤饼45℃鼓风干燥至恒重,得托芬那酸粗品118.5g,粗品经无水乙醇重结晶得到托芬那酸精品105.2g,总收率82.0%;
实施例4
将100.0g邻溴苯甲酸和83.0g碳酸钾加入到500ml水中,加热升温至55℃,搅拌溶解完全。在惰性气体氛围下,向上步所得的混合液中分别加入70.8g 3-氯-2-甲基苯胺、5.0g碘化亚铜,加热升温至100℃反应8h;冷却至室温,然后加入乙酸乙酯进行萃取,分液,水相用浓盐酸酸化至pH为2-3,逐渐析出固体,室温搅拌析晶4h,过滤,滤饼45℃鼓风干燥至恒重,得托芬那酸粗品101.1g,粗品经无水乙醇重结晶得到托芬那酸精品89.9g,总收率70.0%;
以上所述,仅为本发明较佳的具体实施方式,但本发明的保护范围并不局限于此,任何熟悉本技术领域的技术人员在本发明揭露的技术范围内,根据本发明的技术方案及其发明构思加以等同替换或改变,都应涵盖在本发明的保护范围之内。
Claims (15)
2.根据权利要求1所述一种托芬那酸的水相合成方法,其特征在于,邻卤苯甲酸与无机碱的摩尔比为1:1.1-2.0。
3.根据权利要求1所述一种托芬那酸的水相合成方法,其特征在于,无机碱为碳酸钾、碳酸钠、氢氧化钾或氢氧化钠中的一种。
4.根据权利要求1所述一种托芬那酸的水相合成方法,其特征在于,惰性气体为氮气。
5.根据权利要求1所述一种托芬那酸的水相合成方法,其特征在于,3-氯-2-甲基苯胺与邻卤苯甲酸的摩尔比1:1。
6.根据权利要求1所述一种托芬那酸的水相合成方法,其特征在于,碘化亚铜与邻卤苯甲酸的质量比0.05-0.2:1。
7.根据权利要求1所述一种托芬那酸的水相合成方法,其特征在于,碱金属碘化物与碘化亚铜的摩尔比2:1。
8.根据权利要求1所述一种托芬那酸的水相合成方法,其特征在于,碱金属碘化物为碘化钠、碘化钾的一种。
9.根据权利要求1所述一种托芬那酸的水相合成方法,其特征在于,反应温度为60-100℃。
10.根据权利要求1所述一种托芬那酸的水相合成方法,其特征在于,盐酸酸化pH控制在2-3。
11.根据权利要求1所述一种托芬那酸的水相合成方法,其特征在于,托芬那酸粗品及精品的烘料温度控制在40-50℃,鼓风干燥。
12.根据权利要求1所述一种托芬那酸的水相合成方法,其特征在于,重结晶溶剂为无水乙醇、异丙醇、丙酮、丁酮或及其与水的混合溶剂的一种。
13.根据权利要求1所述一种托芬那酸的水相合成方法,其特征在于,邻卤苯甲酸为邻溴苯甲酸、邻氯苯甲酸或邻碘苯甲酸的一种。
14.根据权利要求1-13任一项所述托芬那酸的水相合成方法,其特征在于,托芬那酸水相合成所涉及到的单一试剂的纯度都大于95%。
15.根据权利要求1-14任一项所述托芬那酸的水相合成方法,其特征在于,水溶解邻卤苯甲酸溶液浓度为0.2-0.5g/mL。
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