WO2023004914A1 - Purification method for sertaconazole nitrate - Google Patents
Purification method for sertaconazole nitrate Download PDFInfo
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- WO2023004914A1 WO2023004914A1 PCT/CN2021/114842 CN2021114842W WO2023004914A1 WO 2023004914 A1 WO2023004914 A1 WO 2023004914A1 CN 2021114842 W CN2021114842 W CN 2021114842W WO 2023004914 A1 WO2023004914 A1 WO 2023004914A1
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- reflux
- sertaconazole nitrate
- purification method
- ethanol
- sertaconazole
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- 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 48
- 229960004476 sertaconazole nitrate Drugs 0.000 title claims abstract description 48
- 238000000034 method Methods 0.000 title claims abstract description 26
- 238000000746 purification Methods 0.000 title claims abstract description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 52
- 239000013078 crystal Substances 0.000 claims abstract description 32
- 238000010992 reflux Methods 0.000 claims abstract description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 25
- 238000002844 melting Methods 0.000 claims abstract description 21
- 230000008018 melting Effects 0.000 claims abstract description 21
- 238000003756 stirring Methods 0.000 claims abstract description 18
- 239000000706 filtrate Substances 0.000 claims abstract description 15
- 239000012043 crude product Substances 0.000 claims abstract description 6
- 238000002156 mixing Methods 0.000 claims abstract description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 abstract description 14
- 229940079593 drug Drugs 0.000 abstract description 5
- 239000003814 drug Substances 0.000 abstract description 5
- 238000001914 filtration Methods 0.000 abstract description 4
- 238000001035 drying Methods 0.000 abstract description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
- 239000010410 layer Substances 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- 230000000052 comparative effect Effects 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 4
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- PIURQZBTTSWWOY-UHFFFAOYSA-N 7-chloro-3-methyl-1-benzothiophene Chemical compound C1=CC=C2C(C)=CSC2=C1Cl PIURQZBTTSWWOY-UHFFFAOYSA-N 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- -1 o-chlorophenylthioacetone Chemical compound 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- PWOBDMNCYMQTCE-UHFFFAOYSA-N 2-chlorobenzenethiol Chemical compound SC1=CC=CC=C1Cl PWOBDMNCYMQTCE-UHFFFAOYSA-N 0.000 description 1
- OFKWTWJUANJQNU-UHFFFAOYSA-N 3-(bromomethyl)-7-chloro-1-benzothiophene Chemical compound ClC1=CC=CC2=C1SC=C2CBr OFKWTWJUANJQNU-UHFFFAOYSA-N 0.000 description 1
- 239000004342 Benzoyl peroxide Substances 0.000 description 1
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 1
- 239000003390 Chinese drug Substances 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 235000019400 benzoyl peroxide Nutrition 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- BULLHNJGPPOUOX-UHFFFAOYSA-N chloroacetone Chemical compound CC(=O)CCl BULLHNJGPPOUOX-UHFFFAOYSA-N 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 229920000137 polyphosphoric acid Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000013517 stratification Methods 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Definitions
- the application relates to the technical field of preparation of raw materials, in particular to a purification method of sertaconazole nitrate.
- Sertaconazole nitrate is a synthetic imidazole antifungal drug.
- the prior art For the purification of sertaconazole nitrate crude drug, the prior art generally adopts 95% ethanol to heat and dissolve the crude sertaconazole nitrate, and then recrystallize it by cooling down and standing for crystallization.
- the inventors found that by adopting this recrystallization method, the melting point of the obtained sertaconazole nitrate is 163-167° C., which meets the requirements of the National Drug Standards of the State Food and Drug Administration of China.
- the melting point of sertaconazole nitrate recorded in the European Pharmacopoeia or the British Pharmacopoeia is 156-161°C, which is obviously different from the melting point recorded in the Chinese drug standards.
- the present application provides a new purification method of sertaconazole nitrate to prepare the crystal form of sertaconazole nitrate with a melting point of 156-161°C.
- the present application firstly provides a purification method of sertaconazole nitrate, which is used to prepare sertaconazole nitrate crystal form with a melting point of 156-161°C.
- the purification method includes:
- step (1) the mass ratio of the crude sertaconazole nitrate to 95% ethanol is 1: (1-5).
- step (1) the mass ratio of the crude sertaconazole nitrate to 95% is 1:(2-3).
- step (1) reflux for 0.5-3 hours.
- step (1) reflux for 1-2 hours.
- step (2) after adding activated carbon, the reflux is continued for 10-30 minutes.
- step (4) the mass ratio of the water added dropwise to 95% ethanol is (0.5-2):1.
- step (4) the mass ratio of the water added dropwise to 95% ethanol is 1:1.
- step (5) after the dropwise addition is completed, the stirring is continued for 10-50 minutes, and then the crystals are filtered and dried.
- the present application also provides a purification method of sertaconazole nitrate, which is used to prepare sertaconazole nitrate crystal form with a melting point of 156-161°C, which comprises the following steps:
- 95% ethanol refers to a mixture of ethanol and water with an ethanol mass fraction of 95%.
- the purification method of sertaconazole nitrate uses 95% ethanol to heat and dissolve the crude product of sertaconazole nitrate, and then adds water dropwise for dissolution and crystallization. It is unexpectedly found that sertaconazole nitrate with a melting point of 156-161°C can be obtained Conazole crystal form.
- the melting point of this crystal form meets the requirements of the European Pharmacopoeia or the British Pharmacopoeia, providing technical support for the export of drugs to these countries and regions.
- the filtrate was pumped back into the reactor for stratification.
- the organic layer was collected and 3.50 kg of concentrated nitric acid was added dropwise therein to precipitate a solid.
- the filter cake was washed with water and ether successively. After drying, 23.04 kg of crude sertaconazole nitrate was obtained.
- the melting point of the sertaconazole nitrate crystals prepared in Examples 1-3 and Comparative Example 1 was determined according to the first method of melting point determination method 0612 of the 2015 edition of the "Chinese Pharmacopoeia" general rule (A temperature transfer liquid heating method). The results are shown in the table below.
- Example 2 158.8-159.6°C
- Example 3 159.0-159.8°C Comparative example 1 163.4-163.8°C
Abstract
A purification method for sertaconazole nitrate, which is used for preparing a sertaconazole nitrate crystal form with a melting point of 156-161°C. The purification method comprises: (1) mixing a crude product of sertaconazole nitrate with 95% ethanol, then raising the temperature to reflux; (2) adding activated carbon, then continuing to reflux; (3) after reflux finishes, filtering to remove the activated carbon so as to obtain a filtrate; (4) adding water dropwise to the obtained filtrate while stirring to precipitate a crystal; and (5) after dropwise addition is complete, filtering the crystal and then drying. After using 95% ethanol to heat and dissolve the crude product of sertaconazole nitrate, water is added dropwise to dissolve and crystallize same; it was unexpectedly found that a crystal form of sertaconazole nitrate with a melting point of 156-161°C can be obtained. The melting point of the crystal form meets requirements of the European Pharmacopoeia or the British Pharmacopoeia, which provides technical support for exporting the drug to these countries and regions.
Description
本申请涉及原料药制备技术领域，特别涉及一种硝酸舍他康唑的纯化方法。The application relates to the technical field of preparation of raw materials, in particular to a purification method of sertaconazole nitrate.
硝酸舍他康唑是人工合成的咪唑类广普抗真菌药。Sertaconazole nitrate is a synthetic imidazole antifungal drug.
对于硝酸舍他康唑原料药的纯化，现有技术普遍采用95％乙醇加热溶解硝酸舍他康唑粗品，然后降温并静置析晶的方式对其重结晶。本发明人发现，采用这种重结晶方式，所得到的硝酸舍他康唑的熔点为163-167℃，符合中国的国家食品药品监督管理局国家药品标准的规定。For the purification of sertaconazole nitrate crude drug, the prior art generally adopts 95% ethanol to heat and dissolve the crude sertaconazole nitrate, and then recrystallize it by cooling down and standing for crystallization. The inventors found that by adopting this recrystallization method, the melting point of the obtained sertaconazole nitrate is 163-167° C., which meets the requirements of the National Drug Standards of the State Food and Drug Administration of China.
但是，在欧盟药典或英国药典中记载的硝酸舍他康唑的熔点为156-161℃，明显与中国药品标准中记载的熔点不同。However, the melting point of sertaconazole nitrate recorded in the European Pharmacopoeia or the British Pharmacopoeia is 156-161°C, which is obviously different from the melting point recorded in the Chinese drug standards.
为了能够将硝酸舍他康唑原料药出口至英国、欧盟等国家、地区，需要研发新的硝酸舍他康唑的纯化方法，以制备出熔点为156-161℃的硝酸舍他康唑晶型。In order to be able to export sertaconazole nitrate raw materials to countries and regions such as the United Kingdom and the European Union, it is necessary to develop a new purification method for sertaconazole nitrate in order to prepare sertaconazole nitrate crystalline form with a melting point of 156-161°C .
发明内容Contents of the invention
本申请提供了一种新的硝酸舍他康唑的纯化方法，以制备出熔点为156-161℃的硝酸舍他康唑晶型。The present application provides a new purification method of sertaconazole nitrate to prepare the crystal form of sertaconazole nitrate with a melting point of 156-161°C.
具体技术方案如下。The specific technical scheme is as follows.
本申请首先提供了一种硝酸舍他康唑的纯化方法，用于制备熔点为156-161℃的硝酸舍他康唑晶型，所述纯化方法包括：The present application firstly provides a purification method of sertaconazole nitrate, which is used to prepare sertaconazole nitrate crystal form with a melting point of 156-161°C. The purification method includes:
(1)将硝酸舍他康唑粗品与95％乙醇混合后，升温至回流；(1) After mixing the sertaconazole nitrate crude product with 95% ethanol, the temperature is raised to reflux;
(2)加入活性炭，然后继续回流；(2) add gac, then continue to reflux;
(3)回流结束后，过滤去除活性炭，得滤液；(3) after reflux finishes, filter and remove gac, obtain filtrate;
(4)在搅拌下向所得滤液中滴加水，以析出晶体；(4) Add water dropwise to the obtained filtrate under stirring to precipitate crystals;
(5)滴加完毕后，将晶体过滤并干燥。(5) After completion of the dropwise addition, the crystals were filtered and dried.
在一些实施方式中，步骤(1)中，硝酸舍他康唑粗品与95％乙醇的质量比为1：(1-5)。In some embodiments, in step (1), the mass ratio of the crude sertaconazole nitrate to 95% ethanol is 1: (1-5).
在一些实施方式中，步骤(1)中，硝酸舍他康唑粗品与95％的质量比为1：(2-3)。In some embodiments, in step (1), the mass ratio of the crude sertaconazole nitrate to 95% is 1:(2-3).
在一些实施方式中，步骤(1)中，回流0.5-3小时。In some embodiments, in step (1), reflux for 0.5-3 hours.
在一些实施方式中，步骤(1)中，回流1-2小时。In some embodiments, in step (1), reflux for 1-2 hours.
在一些实施方式中，步骤(2)中，加入活性炭后，继续回流10-30分钟。In some embodiments, in step (2), after adding activated carbon, the reflux is continued for 10-30 minutes.
在一些实施方式中，步骤(4)中，所滴加的水与95％乙醇的质量比为(0.5-2)：1。In some embodiments, in step (4), the mass ratio of the water added dropwise to 95% ethanol is (0.5-2):1.
在一些实施方式中，步骤(4)中，所滴加的水与95％乙醇的质量比为1：1。In some embodiments, in step (4), the mass ratio of the water added dropwise to 95% ethanol is 1:1.
在一些实施方式中，步骤(5)中，滴加完毕后，继续搅拌10-50分钟，然后将晶体过滤并干燥。In some embodiments, in step (5), after the dropwise addition is completed, the stirring is continued for 10-50 minutes, and then the crystals are filtered and dried.
本申请还提供了一种硝酸舍他康唑的纯化方法，用于制备熔点为156-161℃的硝酸舍他康唑晶型，其包括以下步骤：The present application also provides a purification method of sertaconazole nitrate, which is used to prepare sertaconazole nitrate crystal form with a melting point of 156-161°C, which comprises the following steps:
(1)将硝酸舍他康唑粗品与95％乙醇混合后，升温至回流，并保持回流1小时，其中硝酸舍他康唑粗品与95％乙醇的质量比为1：(2-3)；(1) After mixing the crude sertaconazole nitrate with 95% ethanol, the temperature was raised to reflux and kept under reflux for 1 hour, wherein the mass ratio of the crude sertaconazole nitrate to 95% ethanol was 1: (2-3);
(2)加入活性炭，然后继续回流30分钟；(2) Add gac, then continue to reflux for 30 minutes;
(3)回流结束后，过滤去除活性炭，得滤液；(3) after reflux finishes, filter and remove gac, obtain filtrate;
(4)在搅拌下向所得滤液中滴加水，以析出晶体，其中所滴加的水与95％乙醇的质量比为1：1；(4) Add water dropwise to the obtained filtrate under stirring to precipitate crystals, wherein the mass ratio of the water added dropwise to 95% ethanol is 1:1;
(5)滴加完毕后，继续搅拌30分钟，将晶体过滤并干燥。(5) After the dropwise addition, the stirring was continued for 30 minutes, and the crystals were filtered and dried.
在本申请中，95％乙醇是指乙醇质量分数为95％的乙醇和水的混合物。In this application, 95% ethanol refers to a mixture of ethanol and water with an ethanol mass fraction of 95%.
本申请提供的硝酸舍他康唑的纯化方法，使用95％乙醇加热溶解硝酸舍他康唑粗品，然后滴加水进行溶析结晶，意外地发现，可以获得熔点为156-161℃的硝酸舍他康唑晶型。该晶型的熔点符合欧盟药典或英国药典的要求，为将药物出口到这些国家地区提供了技术支持。The purification method of sertaconazole nitrate provided by this application uses 95% ethanol to heat and dissolve the crude product of sertaconazole nitrate, and then adds water dropwise for dissolution and crystallization. It is unexpectedly found that sertaconazole nitrate with a melting point of 156-161°C can be obtained Conazole crystal form. The melting point of this crystal form meets the requirements of the European Pharmacopoeia or the British Pharmacopoeia, providing technical support for the export of drugs to these countries and regions.
为使本申请的目的、技术方案和优点更加清楚，下面通过具体实施例将对本申请的技术方案进行清楚、完整地描述。In order to make the purpose, technical solution and advantages of the present application clearer, the technical solution of the present application will be clearly and completely described through specific examples below.
需要说明的是，以下实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市售购买获得的常规产品。It should be noted that, in the following examples, those without specific conditions were carried out according to conventional conditions or conditions suggested by the manufacturer. The reagents or instruments used were not indicated by the manufacturer, and they were all conventional products that could be purchased from the market.
硝酸舍他康唑粗品的制备例The preparation example of sertaconazole nitrate crude product
(1)将80kg纯化水加入至反应釜中，边搅拌边加入2.92kg氢氧化钠，使之完全溶解，得到3.6wt％的氢氧化钠溶液，再加入10.4kg邻氯硫酚，室温搅拌30min；搅拌下加入6.66kg氯丙酮，加完再搅拌反应60min，反应完毕后静置，分层为水层和油层。然后加21.36kg乙醚萃取水层，得乙醚层。将乙醚层水洗三次后与油层合并，减压蒸馏，得邻氯苯硫代丙酮12.14kg。(1) 80kg of purified water is added to the reactor, while stirring, 2.92kg of sodium hydroxide is added to dissolve it completely to obtain a 3.6wt% sodium hydroxide solution, then 10.4kg of o-chlorothiophenol is added, and stirred at room temperature for 30min Add 6.66kg of chloroacetone under stirring, and then stir and react for 60 minutes after adding, leave it to stand after the reaction is completed, and layer into a water layer and an oil layer. Then add 21.36kg of diethyl ether to extract the water layer to obtain the diethyl ether layer. The ether layer was washed three times with water, combined with the oil layer, and distilled under reduced pressure to obtain 12.14 kg of o-chlorophenylthioacetone.
(2)在反应釜A中加入121.4kg多聚磷酸，搅拌，再加入12.14kg邻氯苯硫代丙酮。将反应混合物升温至120℃后保温5小时，控制温度在120～140℃。在另一反应釜B中加入水，降温备用。放出反应釜A中的反应液，缓慢加入至反应釜B中进行稀释。向反应釜B中加入86.20kg乙醚进行萃取，静置分层，取乙醚层。乙醚层水洗后浓缩，减压蒸馏；收集135～137℃/10mmHg馏分，得3-甲基-7-氯苯并[b]噻吩16.72kg。(2) Add 121.4kg polyphosphoric acid in reactor A, stir, then add 12.14kg o-chlorophenylthioacetone. The temperature of the reaction mixture was raised to 120° C. and then kept for 5 hours, and the temperature was controlled at 120 to 140° C. Add water in another reaction kettle B, and cool down for later use. Release the reaction liquid in reactor A, slowly add it to reactor B for dilution. Add 86.20kg ether to the reaction kettle B for extraction, let stand to separate the layers, and take the ether layer. The ether layer was washed with water, concentrated, and distilled under reduced pressure; the 135-137°C/10mmHg fraction was collected to obtain 16.72kg of 3-methyl-7-chlorobenzo[b]thiophene.
(3)往反应釜中加入265.84kg四氯化碳，16.72kg 3-甲基-7-氯苯并[b]噻吩，采用200W灯泡照射，搅拌下投入1kg过氧化苯甲酰，将混合物加热至沸腾，分批加入17.06kg N-溴代丁二酰亚胺，保持沸腾状态继续搅拌5小时。将反应混合物冷却，过滤，浓缩滤液至析出沉淀。过滤后滤饼用12.54kg石油醚洗涤，干燥后得黄色3-溴甲基-7-氯苯并[b]噻吩粉末12.96kg。(3) Add 265.84kg carbon tetrachloride, 16.72kg 3-methyl-7-chlorobenzo[b]thiophene in the reactor, adopt 200W light bulb to irradiate, drop into 1kg benzoyl peroxide under stirring, the mixture is heated To boiling, add 17.06kg N-bromosuccinimide in batches, keep boiling and continue to stir for 5 hours. The reaction mixture was cooled, filtered, and the filtrate was concentrated until a precipitate precipitated out. After filtration, the filter cake was washed with 12.54 kg of petroleum ether, and dried to obtain 12.96 kg of yellow 3-bromomethyl-7-chlorobenzo[b]thiophene powder.
(4)往反应釜中加入16.58kg水、2.98kg氢氧化钠、甲苯43.28kg；再加入50质量％的四丁基氯化铵水溶液3.36kg、3-溴甲基-7-氯苯并[b]噻吩12.96kg、1-(2，4-二氯苯)-2-(1-咪唑)乙醇10.76kg，升温至80℃，恒温搅拌4小时。然后将反应混合物冷却并静置分层，收集甲苯层，加入36.42kg乙醚、98.76kg水，搅拌，放置至沉淀完全，过滤。滤液抽回反应釜中分层。收集有机层并向其中滴加浓硝酸3.50kg，析出固体，过滤后将滤饼先后用水和乙醚洗涤。干燥后得硝酸舍他康唑粗品23.04kg。(4) Add 16.58 kg of water, 2.98 kg of sodium hydroxide, and 43.28 kg of toluene into the reactor; then add 3.36 kg of 50 mass % tetrabutylammonium chloride aqueous solution, 3-bromomethyl-7-chlorobenzo[ b] 12.96kg of thiophene, 10.76kg of 1-(2,4-dichlorobenzene)-2-(1-imidazole)ethanol, heated to 80°C, and stirred at constant temperature for 4 hours. Then the reaction mixture was cooled and allowed to stand to separate layers, the toluene layer was collected, 36.42 kg of ether and 98.76 kg of water were added, stirred, placed until the precipitation was complete, and filtered. The filtrate was pumped back into the reactor for stratification. The organic layer was collected and 3.50 kg of concentrated nitric acid was added dropwise therein to precipitate a solid. After filtration, the filter cake was washed with water and ether successively. After drying, 23.04 kg of crude sertaconazole nitrate was obtained.
硝酸舍他康唑粗品的纯化Purification of Crude Sertaconazole Nitrate
实施例1Example 1
反应瓶内加入95％乙醇60.63g，升温至60℃，边搅拌边加入硝酸舍他康唑粗品23.04g，将混合物升温并回流1小时。加入活性炭，保持回流15分钟，趁热过滤掉活性炭，得滤液。在搅拌下向滤液中滴加纯化水60.63g，以析出晶体，滴加完毕后再搅拌30分钟，然后过滤得到晶体。将过滤所得晶体在真空干燥箱干燥，得硝酸舍他康唑晶体19.06g。Add 60.63 g of 95% ethanol into the reaction bottle, raise the temperature to 60° C., add 23.04 g of crude sertaconazole nitrate while stirring, and raise the temperature of the mixture and reflux for 1 hour. Add activated carbon, maintain reflux for 15 minutes, filter the activated carbon while it is hot, and obtain the filtrate. 60.63 g of purified water was added dropwise to the filtrate under stirring to precipitate crystals. After the dropwise addition was completed, the mixture was stirred for another 30 minutes, and then filtered to obtain crystals. The filtered crystals were dried in a vacuum oven to obtain 19.06 g of sertaconazole nitrate crystals.
实施例2Example 2
实施例2与实施例1的区别在于95％乙醇的用量为100g。The difference between embodiment 2 and embodiment 1 is that the consumption of 95% ethanol is 100g.
实施例3Example 3
实施例3与实施例1的区别在于滴加的水量为100g。The difference between embodiment 3 and embodiment 1 is that the amount of water added dropwise is 100g.
对比例1Comparative example 1
在反应瓶内加入95％乙醇60.63g，升温至60℃，边搅拌边加入硝酸舍他康唑粗品23.04g，将混合物升温并回流1小时。加入活性炭，保持回流15分钟，趁热过滤掉活性炭。滤液降温，静置析出结晶并过滤。将过滤所得晶体在真空干燥箱中干燥，得硝酸舍他康唑晶体20.18g。Add 60.63 g of 95% ethanol into the reaction flask, raise the temperature to 60° C., add 23.04 g of crude sertaconazole nitrate while stirring, and raise the temperature of the mixture and reflux for 1 hour. Add activated carbon, maintain reflux for 15 minutes, and filter the activated carbon while hot. The filtrate was cooled, allowed to stand still to precipitate crystals and filtered. The filtered crystals were dried in a vacuum oven to obtain 20.18 g of sertaconazole nitrate crystals.
熔点的测定Determination of melting point
按照《中国药典》2015版通则0612熔点测定法第一法(A传温液加热法)测定实施例1-3以及对比例1制备的硝酸舍他康唑晶体的熔点。结果见下表。The melting point of the sertaconazole nitrate crystals prepared in Examples 1-3 and Comparative Example 1 was determined according to the first method of melting point determination method 0612 of the 2015 edition of the "Chinese Pharmacopoeia" general rule (A temperature transfer liquid heating method). The results are shown in the table below.
| 实施例/对比例Example/Comparative example | 熔点melting point |
| 实施例1Example 1 | 158.2-159.0℃158.2-159.0℃ |
| 实施例2Example 2 | 158.8-159.6℃158.8-159.6℃ |
| 实施例3Example 3 | 159.0-159.8℃159.0-159.8℃ |
| 对比例1Comparative example 1 | 163.4-163.8℃163.4-163.8℃ |
从上表中的熔点数据可以看出，实施例1-3采用溶析结晶方法对硝酸舍他康唑进行重结晶时，晶型对应的熔点在156-161℃范围内，满足英国、欧盟等国家、地区的出口要求。对比例1使用95％乙醇进行降温析晶的方法制备的硝酸舍他康唑晶型，其熔点在163℃以上。From the melting point data in the above table, it can be seen that when recrystallization of sertaconazole nitrate is carried out in Examples 1-3 by the dissolution crystallization method, the melting point corresponding to the crystal form is in the range of 156-161°C, which meets the requirements of the United Kingdom, the European Union, etc. Export requirements of countries and regions. In Comparative Example 1, the crystal form of sertaconazole nitrate prepared by using 95% ethanol for crystallization at lower temperature has a melting point above 163°C.
以上所述实施例仅表达了本申请的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对本申请专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本申请构思的前提下，还可以做出若干变形和改进，这些都属于本申请的保护范围。The above-mentioned embodiments only express several implementation modes of the present application, and the description thereof is relatively specific and detailed, but should not be construed as limiting the patent scope of the present application. It should be noted that those skilled in the art can make several modifications and improvements without departing from the concept of the present application, and these all belong to the protection scope of the present application.
Claims (10)
- 一种硝酸舍他康唑的纯化方法，其特征在于，用于制备熔点为156-161℃的硝酸舍他康唑晶型，所述纯化方法包括：A method for purifying sertaconazole nitrate, characterized in that it is used to prepare crystal forms of sertaconazole nitrate with a melting point of 156-161°C, the purification method comprising:(1)将硝酸舍他康唑粗品与95％乙醇混合后，升温至回流；(1) After mixing the sertaconazole nitrate crude product with 95% ethanol, the temperature is raised to reflux;(2)加入活性炭，然后继续回流；(2) add gac, then continue to reflux;(3)回流结束后，过滤去除活性炭，得滤液；(3) after reflux finishes, filter and remove gac, obtain filtrate;(4)在搅拌下向所得滤液中滴加水，以析出晶体；(4) Add water dropwise to the obtained filtrate under stirring to precipitate crystals;(5)滴加完毕后，将晶体过滤并干燥。(5) After completion of the dropwise addition, the crystals were filtered and dried.
- 根据权利要求1所述的纯化方法，其特征在于，步骤(1)中，硝酸舍他康唑粗品与95％乙醇的质量比为1：(1-5)。The purification method according to claim 1, characterized in that, in step (1), the mass ratio of the crude sertaconazole nitrate to 95% ethanol is 1: (1-5).
- 根据权利要求2所述的纯化方法，其特征在于，步骤(1)中，硝酸舍他康唑粗品与95％的质量比为1：(2-3)。The purification method according to claim 2, characterized in that, in step (1), the mass ratio of the crude sertaconazole nitrate to 95% is 1: (2-3).
- 根据权利要求1所述的纯化方法，其特征在于，步骤(1)中，回流0.5-3小时。The purification method according to claim 1, characterized in that, in step (1), reflux for 0.5-3 hours.
- 根据权利要求4所述的纯化方法，其特征在于，步骤(1)中，回流1-2小时。Purification method according to claim 4, is characterized in that, in step (1), reflux 1-2 hour.
- 根据权利要求1所述的纯化方法，其特征在于，步骤(2)中，加入活性炭后，继续回流10-30分钟。Purification method according to claim 1, is characterized in that, in step (2), after adding gac, continue to reflux for 10-30 minutes.
- 根据权利要求1所述的纯化方法，其特征在于，步骤(4)中，所滴加的水与95％乙醇的质量比为(0.5-2)：1。The purification method according to claim 1, characterized in that, in step (4), the mass ratio of the water added dropwise to 95% ethanol is (0.5-2):1.
- 根据权利要求7所述的纯化方法，其特征在于，步骤(4)中，所滴加的水与95％乙醇的质量比为1：1。The purification method according to claim 7, characterized in that, in step (4), the mass ratio of the water added dropwise to 95% ethanol is 1:1.
- 根据权利要求1所述的纯化方法，其特征在于，步骤(5)中，滴加完毕后，继续搅拌10-50分钟，然后将晶体过滤并干燥。The purification method according to claim 1, characterized in that, in step (5), after the dropwise addition is completed, the stirring is continued for 10-50 minutes, and then the crystals are filtered and dried.
- 一种硝酸舍他康唑的纯化方法，其特征在于，用于制备熔点为156-161℃的硝酸舍他康唑晶型，其包括以下步骤：A method for purifying sertaconazole nitrate, characterized in that it is used to prepare sertaconazole nitrate crystal form with a melting point of 156-161°C, comprising the following steps:(1)将硝酸舍他康唑粗品与95％乙醇混合后，升温至回流，并保持回流1小时，其中硝酸舍他康唑粗品与95％乙醇的质量比为1：(2-3)；(1) After mixing the crude sertaconazole nitrate with 95% ethanol, the temperature was raised to reflux and kept under reflux for 1 hour, wherein the mass ratio of the crude sertaconazole nitrate to 95% ethanol was 1: (2-3);(2)加入活性炭，然后继续回流30分钟；(2) Add gac, then continue to reflux for 30 minutes;(3)回流结束后，过滤去除活性炭，得滤液；(3) after reflux finishes, filter and remove gac, obtain filtrate;(4)在搅拌下向所得滤液中滴加水，以析出晶体，其中所滴加的水与95％乙醇的质量比为1：1；(4) Add water dropwise to the obtained filtrate under stirring to precipitate crystals, wherein the mass ratio of the water added dropwise to 95% ethanol is 1:1;(5)滴加完毕后，继续搅拌30分钟，将晶体过滤并干燥。(5) After the dropwise addition, the stirring was continued for 30 minutes, and the crystals were filtered and dried.
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|---|---|---|---|---|
| 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 |
| CN1358719A (en) * | 2001-09-26 | 2002-07-17 | 河北省药物研究所 | Process for synthesizing sertaconazole |
| CN101022727A (en) * | 2004-09-13 | 2007-08-22 | 菲尔若国际公司 | Method for manufacturing imidazole compounds and salts and pseudopolymorphs thereof |
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| ES2249992B1 (en) * | 2004-09-13 | 2007-03-01 | Ferrer Internacional, S.A. | A PROCEDURE FOR MANUFACTURING ENANTIOMERIC COMPOUNDS OF IMIDAZOL. |
| CN112694470B (en) * | 2020-12-30 | 2022-11-18 | 海南海神同洲制药有限公司 | Preparation process of sertaconazole nitrate |
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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 |
| CN1358719A (en) * | 2001-09-26 | 2002-07-17 | 河北省药物研究所 | Process for synthesizing sertaconazole |
| CN101022727A (en) * | 2004-09-13 | 2007-08-22 | 菲尔若国际公司 | Method for manufacturing imidazole compounds and salts and pseudopolymorphs thereof |
Non-Patent Citations (1)
| Title |
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| VENKATESWARLU RAYUDU S.; KUMAR P.: "An Easy, Efficient and Improved Synthesis of Sertaconazole Nitrate", RUSSIAN JOURNAL OF ORGANIC CHEMISTRY, M A I K NAUKA - INTERPERIODICA, RU, vol. 55, no. 8, 1 August 2019 (2019-08-01), RU , pages 1212 - 1216, XP036901417, ISSN: 1070-4280, DOI: 10.1134/S1070428019080219 * |
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