CN101602744B - 一种硝唑尼特的制备方法 - Google Patents
一种硝唑尼特的制备方法 Download PDFInfo
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- CN101602744B CN101602744B CN200910016459XA CN200910016459A CN101602744B CN 101602744 B CN101602744 B CN 101602744B CN 200910016459X A CN200910016459X A CN 200910016459XA CN 200910016459 A CN200910016459 A CN 200910016459A CN 101602744 B CN101602744 B CN 101602744B
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- nitazoxanide
- anhydrous
- nitrothiazole
- amino
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- YQNQNVDNTFHQSW-UHFFFAOYSA-N acetic acid [2-[[(5-nitro-2-thiazolyl)amino]-oxomethyl]phenyl] ester Chemical compound CC(=O)OC1=CC=CC=C1C(=O)NC1=NC=C([N+]([O-])=O)S1 YQNQNVDNTFHQSW-UHFFFAOYSA-N 0.000 title claims abstract description 19
- 229960002480 nitazoxanide Drugs 0.000 title claims abstract description 18
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 30
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 28
- 238000006243 chemical reaction Methods 0.000 claims abstract description 17
- MIHADVKEHAFNPG-UHFFFAOYSA-N 2-Amino-5-nitrothiazole Chemical compound NC1=NC=C([N+]([O-])=O)S1 MIHADVKEHAFNPG-UHFFFAOYSA-N 0.000 claims abstract description 14
- 229940018167 2-amino-5-nitrothiazole Drugs 0.000 claims abstract description 14
- 239000000243 solution Substances 0.000 claims abstract description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000003756 stirring Methods 0.000 claims abstract description 10
- 239000011259 mixed solution Substances 0.000 claims abstract description 7
- 238000001953 recrystallisation Methods 0.000 claims description 2
- 240000000203 Salix gracilistyla Species 0.000 claims 3
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims 3
- 150000001263 acyl chlorides Chemical class 0.000 claims 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims 2
- 238000013019 agitation Methods 0.000 claims 1
- 238000001035 drying Methods 0.000 claims 1
- 235000019441 ethanol Nutrition 0.000 claims 1
- DSGKWFGEUBCEIE-UHFFFAOYSA-N (2-carbonochloridoylphenyl) acetate Chemical compound CC(=O)OC1=CC=CC=C1C(Cl)=O DSGKWFGEUBCEIE-UHFFFAOYSA-N 0.000 abstract description 8
- 238000000034 method Methods 0.000 abstract description 5
- 239000012467 final product Substances 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 239000005457 ice water Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 208000030852 Parasitic disease Diseases 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 208000035143 Bacterial infection Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 241000223935 Cryptosporidium Species 0.000 description 1
- 206010017533 Fungal infection Diseases 0.000 description 1
- 241000224466 Giardia Species 0.000 description 1
- 208000031888 Mycoses Diseases 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229960005130 niridazole Drugs 0.000 description 1
- -1 nitrothiazole amide compound Chemical class 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 230000003071 parasitic effect Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Abstract
一种硝唑尼特的制备方法，其特征在于将2-氨基-5-硝基噻唑与无水丙酮混合均匀，向所得的混合液中加入由无水丙酮与邻乙酰水杨酰氯组成的溶液，然后在搅拌下缓慢滴加无水三乙胺，恒温反应，滴加无水三乙胺后，保持反应温度继续搅拌，边搅拌边将所得反应液倒入冰水中，静置，过滤，干燥，用乙醇重结晶，得到硝唑尼特。本发明方法简单可行，终产物收率在75％左右，且反应步骤得以简化，提高了生产效率。
Description
技术领域
本发明涉及一种治疗动物与人体寄生虫病的硝唑尼特的制备方法。
背景技术
近年来，硝唑尼特作为一种高效、广谱抗动物与人体寄生虫、细菌和真菌感染的药物被广泛关注，它是美国药品和食品监督管理局(FDA)批准的第一个和唯一的用于治疗隐孢子虫属的药物，也是40多年来批准用于治疗贾第虫属的第一种新药，目前在澳大利亚、新西兰、美国、加拿大、墨西哥等国家上市，我国农业部还没有该产品注册。
硝唑尼特为硝基噻唑酰胺化合物，化学名是2-乙酰氧基-N-(5-硝基-2-噻唑)苯甲酰胺[2-(acetolyloxy)-N-(5-nitro-2-thiazolyl)benzamide]。在硝唑尼特的制备中，文献方法是先将水杨酸乙酰化，再制成酰卤，最后与2-氨基-5-硝基噻唑缩合，产率70％。该法(见反应式)的缺陷是产物在后续的反应中会脱掉乙酰基，影响了硝唑尼特的收率。
发明内容
本发明的目的是提供一种更简单有效的硝唑尼特的制备方法，它能克服现有合成方法反应步骤较多，反应较繁琐的缺点。
一种硝唑尼特的制备方法，其特征在于将2-氨基-5-硝基噻唑与无水丙酮混合均匀，向所得的混合液中加入由无水丙酮与邻乙酰水杨酰氯组成的溶液，然后在搅拌下缓慢滴加无水三乙胺，恒温反应，滴加无水三乙胺后，保持反应温度继续搅拌，边搅拌边将所得反应液倒入冰水中，静置，过滤，干燥，用乙醇重结晶，得到硝唑尼特。
本发明方法简单可行，终产物收率在75％左右，且反应步骤得以简化，提高了生产效率。
具体实施方式
将2-氨基-5-硝基噻唑与无水丙酮混合均匀，向所得的混合液中加入由无水丙酮与邻乙酰水杨酰氯组成的溶液，在搅拌下再缓慢滴加催化剂无水三乙胺，使两种反应物2-氨基-5-硝基噻唑和乙酰水杨酰氯恒温反应，无水三乙胺滴加完毕后，保持反应温度继续搅拌，然后边搅拌边将所得反应液倒入冰水中，静置，过滤，干燥，用乙醇重结晶，即得硝唑尼特。
本发明的反应式如下式所示：
实施例
在装有搅拌棒、回流冷凝管、恒压滴液漏斗和温度计的干燥四口烧瓶中，加入12g 2-氨基-5-硝基噻唑和36g脱水处理得到的无水丙酮，混合均匀得到混合液，另将37.8g无水丙酮溶解在25.2g邻乙酰水杨酰氯中制成溶液，在搅拌下缓慢向该溶液滴加无水三乙胺10.0g，温度保持在25℃。滴加完毕后保持25℃温度继续搅拌60min，然后将所得溶液加入上述混合液中；2-氨基-5-硝基噻唑和邻乙酰水杨酰氯反应，边搅拌边将所得的反应液倒入285g冰水中，静置，过滤，干燥，用乙醇重结晶，即得硝唑尼特。
所述混合液中的2-氨基-5-硝基噻唑与无水丙酮的质量比为1∶3～3.5；所述的溶液中邻乙酰水杨酰氯与无水丙酮的质量比为1∶1.5～1.8；2-氨基-5-硝基噻唑与邻乙酰水杨酰氯的质量比为：1∶2.0～2.5；无水三乙胺与2-氨基-5-硝基噻唑的质量比为：1∶1.2～1.5。恒温反应温度为24-26℃；无水三乙胺滴加完毕后搅拌时间为58-62min。倒入冰水的体积为所得反应液的2-3倍；重结晶用的溶剂为乙醇。
Claims (4)
1.一种硝唑尼特的制备方法，其特征在于将2-氨基-5-硝基噻唑与无水丙酮混合均匀，向所得的混合液中加入由无水丙酮与邻乙酰水杨酰氯组成的溶液，然后在搅拌下缓慢滴加无水三乙胺，恒温反应，滴加无水三乙胺后，保持反应温度继续搅拌，边搅拌边将所得反应液倒入冰水中，静置，过滤，干燥，用乙醇重结晶，得到硝唑尼特；其中，所述的混合液中的2-氨基-5-硝基噻唑与无水丙酮的质量比为1∶3～3.5；所述的溶液中邻乙酰水杨酰氯与无水丙酮的质量比为1∶1.5～1.8；所述的2-氨基-5-硝基噻唑与邻乙酰水杨酰氯的质量比为：1∶2.0～2.5；所述的无水三乙胺与2-氨基-5-硝基噻唑的质量比为：1∶1.2～1.5。
2.如权利要求1所述的硝唑尼特的制备方法，其特征在于所述恒温反应温度为 24-26℃。
3.如权利要求1所述的硝唑尼特的制备方法，其特征在于所述无水三乙胺滴加完毕后搅拌时间为 58-62min。
4.如权利要求1所述的硝唑尼特的制备方法，其特征在于所述倒入冰水的体积为所得反应液的 2-3倍。
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| CN105175352A (zh) * | 2015-10-27 | 2015-12-23 | 杭州澳医保灵药业有限公司 | 一种硝唑尼特的制备方法 |
| GB2625684A (en) * | 2021-10-05 | 2024-06-26 | Council Of Scient And Industrial Research An Indian Registered Body Incorporated Under The Regn Of S | An improved process for the preparation of nitazoxanide and intermediates thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3950351A (en) * | 1973-08-08 | 1976-04-13 | S.P.R.L. Phavic | New derivatives of 2-benzamido-5-nitro thiazoles |
| CN1935796A (zh) * | 2006-08-02 | 2007-03-28 | 杭州欣阳三友精细化工有限公司 | 硝唑尼特的制备方法 |
| CN101007792A (zh) * | 2007-01-31 | 2007-08-01 | 浙江大学 | 一种合成硝基噻唑苯酰胺化合物的方法 |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3950351A (en) * | 1973-08-08 | 1976-04-13 | S.P.R.L. Phavic | New derivatives of 2-benzamido-5-nitro thiazoles |
| CN1935796A (zh) * | 2006-08-02 | 2007-03-28 | 杭州欣阳三友精细化工有限公司 | 硝唑尼特的制备方法 |
| CN101007792A (zh) * | 2007-01-31 | 2007-08-01 | 浙江大学 | 一种合成硝基噻唑苯酰胺化合物的方法 |
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