CN1974567B - 抗真菌药硝酸舍他康唑的制备方法 - Google Patents
抗真菌药硝酸舍他康唑的制备方法 Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- HAAITRDZHUANGT-UHFFFAOYSA-N 1-[2-[(7-chloro-1-benzothiophen-3-yl)methoxy]-2-(2,4-dichlorophenyl)ethyl]imidazole;nitric acid Chemical compound O[N+]([O-])=O.ClC1=CC(Cl)=CC=C1C(OCC=1C2=CC=CC(Cl)=C2SC=1)CN1C=NC=C1 HAAITRDZHUANGT-UHFFFAOYSA-N 0.000 title claims abstract description 11
- 239000003814 drug Substances 0.000 title claims abstract description 11
- 229960004476 sertaconazole nitrate Drugs 0.000 title claims abstract description 11
- 230000000843 anti-fungal effect Effects 0.000 title claims abstract description 10
- 229940121375 antifungal agent Drugs 0.000 title claims abstract description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Natural products CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 33
- 238000006243 chemical reaction Methods 0.000 claims abstract description 13
- 239000003960 organic solvent Substances 0.000 claims abstract description 8
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims abstract description 7
- 229910017604 nitric acid Inorganic materials 0.000 claims abstract description 7
- 238000010992 reflux Methods 0.000 claims abstract description 5
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 21
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Substances ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 229930192474 thiophene Natural products 0.000 claims description 8
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 235000019441 ethanol Nutrition 0.000 abstract description 13
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 3
- 150000003839 salts Chemical class 0.000 abstract description 2
- -1 1-(2, 4-dichlorophenyl)-2-(1-imidazolyl) ethyl Chemical group 0.000 abstract 1
- OFKWTWJUANJQNU-UHFFFAOYSA-N 3-(bromomethyl)-7-chloro-1-benzothiophene Chemical compound ClC1=CC=CC2=C1SC=C2CBr OFKWTWJUANJQNU-UHFFFAOYSA-N 0.000 abstract 1
- 239000000203 mixture Substances 0.000 abstract 1
- JLGKQTAYUIMGRK-UHFFFAOYSA-N 1-{2-[(7-chloro-1-benzothiophen-3-yl)methoxy]-2-(2,4-dichlorophenyl)ethyl}imidazole Chemical compound ClC1=CC(Cl)=CC=C1C(OCC=1C2=CC=CC(Cl)=C2SC=1)CN1C=NC=C1 JLGKQTAYUIMGRK-UHFFFAOYSA-N 0.000 description 9
- 229960005429 sertaconazole Drugs 0.000 description 9
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 description 4
- 239000000243 solution Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- FRPZMMHWLSIFAZ-UHFFFAOYSA-N 10-undecenoic acid Chemical compound OC(=O)CCCCCCCCC=C FRPZMMHWLSIFAZ-UHFFFAOYSA-N 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 235000001018 Hibiscus sabdariffa Nutrition 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 235000005291 Rumex acetosa Nutrition 0.000 description 1
- 240000007001 Rumex acetosella Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
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Abstract
本发明公开了一种抗真菌药硝酸舍他康唑的制备方法。其特征在于将1-(2，4-二氯苯)-2-(1-咪唑)乙醇首先在醇与有机溶剂的混合溶液中，碱性条件下回流，然后在室温下与3-溴甲基-7-氯苯并[b]噻吩反应，再经硝酸成盐得到。本发明与其他制备方法相比，反应条件温和，产物脱色更容易进行，操作简便，降低了合成成本，使其工艺更适合规模化生产。
Description
【技术领域】
本发明涉及有机合成技术领域，特别是一种抗真菌药硝酸舍他康唑的制备方法。
【背景技术】
局部抗真菌药硝酸舍他康唑(Sertaconazole Nitrate)，分子式：C20H15C13N2S·HNO3，由西班牙Ferrer公司研制开发，并于1992年首次在西班牙上市，现已在中国、美国、德国、阿根廷、秘鲁等多国上市销售，具有疗效高、复发率低、毒性低等特性。在已有技术中，下列专利涉及到硝酸舍他康唑的制备方法，如EP151477，ES529608，ED535656，JP60/181186，US5135943等，上述专利技术是相关的，其合成路线采用以1-(2，4-二氯苯)-2-(1-咪唑)乙醇和3-溴甲基-7-氯苯并[b]噻吩为原料，在惰性气体保下，以六甲基磷酰三胺为溶剂，氢化钠参与反应制得舍他康唑，再与硝酸反应制备硝酸盐。这种合成方法的不足之处在于：
反应需要在惰性气体保护下完成；所用氢化钠为易燃、易爆化学品，危险性大，使用不安全，所以反应必须在无水、无氧条件下操作；所用六甲基磷酰三胺为有毒溶剂，有致癌作用，价格昂贵，回收困难；首先制备舍他康唑，并要用硅胶柱分离纯化，再与硝酸反应制备硝酸舍他康唑，操作繁琐、困难，不适于规模化生产。
此外，中国专利ZL01127506.5涉及硝酸舍他康唑-种新的制备方法，以1-(2，4-二氯苯)-2-(1-咪唑)乙醇和3-溴甲基-7-氯苯并[b]噻吩为原料，以甲苯、水为溶剂、四丁基氯化铵为催化剂，在氢氧化钠参与下进行相转移催化反应，不经分离舍他康唑，直接进行成盐反应制备硝酸舍他康唑，不需要无水、无氧操作，与国外文献方法比较有较大改进，但也存在不足之处：相转移催化反应需要价格较高的四丁基氯化铵做催化剂，由于反应需要在相对较高温度下(80℃)进行，所得产物呈红褐色，产品脱色困难，且不易提纯，损失大，操作繁琐，提高了合成成本。
【发明内容】
本发明的目的旨在为克服现有技术的不足，而提供一种抗真菌药硝酸舍他康唑的制备方法，该方法反应条件温和，操作简便。
本发明为解决上述问题所采用的方案是设计一种抗真菌药硝酸舍他康唑的制备方法。其特征在于将1-(2，4-二氯苯)-2-(1-咪唑)乙醇首先在醇与有机溶剂的混合溶液中，碱性条件下回流，然后在室温下与3-溴甲基-7-氯苯并[b]噻吩反应，再经硝酸成盐得到。
本发明的有益效果是：本发明的制备方法与其他制备方法相比，反应条件温和，产物脱色更容易进行，操作简便，降低了合成成本，使其工艺更适合规模化生产。
【具体实施方式】
本发明将醇与1-(2，4-二氯苯)-2-(1-咪唑)乙醇混合，在氢氧化钠存在下加热回流，冷却，加入3-溴甲基-7-氯苯丙[b]噻吩的甲苯溶液，室温下搅拌反应，加入水及有机溶剂，静置分去水层后，加入硝酸，调节PH1～2，过滤，干燥，重结晶，得硝酸舍他康唑。
所说的每25.6g(0.1mol)的1-(2，4-二氯苯)-2-(1-咪唑)乙醇及26.0g(0.1mol)的3-溴甲基-7-氯苯并[b]噻吩用醇为：120～150ml；有机溶剂为70～100ml。所说的醇为异丙醇。所说的有机溶剂是甲苯、环己烷或四氢呋喃中的一种。所说的回流是3～5小时，然后在室温下反应12～15小时。所说的碱为氢氧化钠或氢氧化钾。
本发明实施例：
在500mL圆底烧瓶中投入氢氧化钠4.0g、1-(2，4-二氯苯)-2-(1-咪唑)乙醇25.6g、异丙醇120mL，加热回流3小时，冷至室温，加入甲苯溶液(甲苯70mL，3-溴甲基-7-氯苯并[b]噻吩26.0g)，搅拌，将混合液置于分液漏斗中，静置，弃去水层，收集甲苯层，并用水洗涤，加入150mL乙醚，搅拌下滴入硝酸8mL，析出固体，过滤，干燥，95％乙醇重结晶，得硝酸舍他康唑成品31.0g，收率61.9％，熔点163-164℃。
Claims (4)
1.一种抗真菌药硝酸舍他康唑的制备方法，其特征在于将1-(2，4-二氯苯)-2-(1-咪唑)乙醇首先在醇与有机溶剂的混合溶液中，在碱存在下于碱性条件下回流，然后在室温下与3-溴甲基-7-氯苯并[b]噻吩反应，再经硝酸成盐得到；所说的醇为异丙醇，所说的有机溶剂是甲苯、环己烷或四氢呋喃中的一种。
2.根据权利要求1所述的抗真菌药硝酸舍他康唑的制备方法，其特征在于所说的每25.6g的1-(2，4-二氯苯)-2-(1-咪唑)乙醇及26.0g的3-溴甲基-7-氯苯并[b]噻吩用醇为：120～150ml；有机溶剂为70～100ml。
3.根据权利要求1所述的抗真菌药硝酸舍他康唑的制备方法，其特征在于所说的回流时间为3～5小时，在室温下反应12～15小时。
4.根据权利要求1所述的抗真菌药硝酸舍他康唑的制备方法，其特征在于所说的碱为氢氧化钠或氢氧化钾。
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0151477A2 (en) * | 1984-02-02 | 1985-08-14 | Ferrer Internacional, S.A. | 1H-Imidazole derivatives, a process for preparing them and pharmaceutical compositions containing them |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0151477A2 (en) * | 1984-02-02 | 1985-08-14 | Ferrer Internacional, S.A. | 1H-Imidazole derivatives, a process for preparing them and pharmaceutical compositions containing them |
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