JP4774192B2 - Process for producing crystals of zonisamide free of 1,2-dichloroethane and high-purity crystals of zonisamide - Google Patents
Process for producing crystals of zonisamide free of 1,2-dichloroethane and high-purity crystals of zonisamide Download PDFInfo
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- JP4774192B2 JP4774192B2 JP2003285878A JP2003285878A JP4774192B2 JP 4774192 B2 JP4774192 B2 JP 4774192B2 JP 2003285878 A JP2003285878 A JP 2003285878A JP 2003285878 A JP2003285878 A JP 2003285878A JP 4774192 B2 JP4774192 B2 JP 4774192B2
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- 239000013078 crystal Substances 0.000 title claims description 86
- UBQNRHZMVUUOMG-UHFFFAOYSA-N zonisamide Chemical compound C1=CC=C2C(CS(=O)(=O)N)=NOC2=C1 UBQNRHZMVUUOMG-UHFFFAOYSA-N 0.000 title claims description 79
- 229960002911 zonisamide Drugs 0.000 title claims description 78
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 title claims description 60
- 238000000034 method Methods 0.000 title description 13
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 48
- 238000004519 manufacturing process Methods 0.000 claims description 31
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 31
- 239000000203 mixture Substances 0.000 claims description 24
- 238000004821 distillation Methods 0.000 claims description 20
- 239000002904 solvent Substances 0.000 claims description 18
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 10
- 238000001914 filtration Methods 0.000 claims description 9
- 238000010533 azeotropic distillation Methods 0.000 claims description 8
- ZREYTLWEJMYKRX-UHFFFAOYSA-N 1,2-benzoxazol-3-ylmethanesulfonyl chloride Chemical compound C1=CC=C2C(CS(=O)(=O)Cl)=NOC2=C1 ZREYTLWEJMYKRX-UHFFFAOYSA-N 0.000 claims description 7
- 229910021529 ammonia Inorganic materials 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 4
- 239000011541 reaction mixture Substances 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 27
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 229940088679 drug related substance Drugs 0.000 description 8
- 239000003814 drug Substances 0.000 description 7
- 239000008186 active pharmaceutical agent Substances 0.000 description 6
- 239000013557 residual solvent Substances 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 238000009835 boiling Methods 0.000 description 3
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 238000006114 decarboxylation reaction Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000006277 sulfonation reaction Methods 0.000 description 3
- BVSIAYQIMUUCRW-UHFFFAOYSA-N 2-(1,2-benzoxazol-3-yl)acetic acid Chemical compound C1=CC=C2C(CC(=O)O)=NOC2=C1 BVSIAYQIMUUCRW-UHFFFAOYSA-N 0.000 description 2
- 229930185605 Bisphenol Natural products 0.000 description 2
- 239000001961 anticonvulsive agent Substances 0.000 description 2
- IISBACLAFKSPIT-UHFFFAOYSA-N bisphenol A Chemical compound C=1C=C(O)C=CC=1C(C)(C)C1=CC=C(O)C=C1 IISBACLAFKSPIT-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- -1 that is Chemical compound 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- FJKQPEMPDIUEJU-UHFFFAOYSA-N 1,2-dichloroethane;ethanol;hydrate Chemical compound O.CCO.ClCCCl FJKQPEMPDIUEJU-UHFFFAOYSA-N 0.000 description 1
- LDTICMGSXAIRIW-UHFFFAOYSA-N 1,2-dichloroethane;propan-2-ol;hydrate Chemical compound O.CC(C)O.ClCCCl LDTICMGSXAIRIW-UHFFFAOYSA-N 0.000 description 1
- 238000007605 air drying Methods 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000001291 vacuum drying 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)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は、抗てんかん薬として有用なゾニサミド（化学名：１，２−ベンズイソキサゾール−３−メタンスルホンアミド）の高純度結晶の製造方法、すなわち残留１，２−ジクロロエタンの濃度が５ｐｐｍ以下であるゾニサミドの結晶の製造方法に関する。さらに詳しくは、本発明は残留１，２−ジクロロエタンの濃度が５ｐｐｍ以下であるゾニサミドの結晶を効率的に製造する方法および該方法によって得られる１，２−ジクロロエタンを含まないゾニサミドの結晶に関する。 The present invention relates to a method for producing high-purity crystals of zonisamide (chemical name: 1,2-benzisoxazole-3-methanesulfonamide) useful as an antiepileptic drug, that is, the concentration of residual 1,2-dichloroethane is 5 ppm or less. It is related with the manufacturing method of the crystal | crystallization of zonisamide which is. More specifically, the present invention relates to a method for efficiently producing zonisamide crystals having a residual 1,2-dichloroethane concentration of 5 ppm or less, and a zonisamide crystal containing no 1,2-dichloroethane obtained by the method.
ゾニサミドは日本、米国および韓国において抗てんかん剤として広く臨床で使用されている。ゾニサミドおよびその製造方法は後記特許文献１〜３に開示されている。また、後記非特許文献１には、１，２−ベンズイソキサゾール−３−酢酸のスルホン化および脱炭酸反応によって得られた１，２−ベンズイソキサゾール−３−メタンスルホン酸クロリドを中間体としてゾニサミドが実生産されていることが開示されている。そして、上記スルホン化および脱炭酸反応の溶媒には、後記非特許文献１ではジクロロメタン、後記特許文献１では１，２−ジクロロエタンを用いることが開示されている。 Zonisamide is widely used clinically as an antiepileptic agent in Japan, the United States and South Korea. Zonisamide and its production method are disclosed in Patent Documents 1 to 3 below. Further, Non-Patent Document 1 described later includes 1,2-benzisoxazole-3-methanesulfonic acid chloride obtained by sulfonation and decarboxylation of 1,2-benzisoxazole-3-acetic acid as an intermediate. It is disclosed that zonisamide is actually produced as a body. As the solvent for the sulfonation and decarboxylation reaction, it is disclosed that dichloromethane is used in Non-Patent Document 1 described later and 1,2-dichloroethane is used in Patent Document 1 described later.
原薬の製造工程で使用される溶媒は実生産工程で用いられている通常の技術では完全に除去できない。したがって、複数の工程が最終工程まで連続している原薬の製造においては、それぞれの工程で用いられた溶媒が原薬に残留している可能性がある。そして、通常は原薬に残留する溶媒が治療に役立つことはなく、逆に、残留溶媒の種類と濃度によっては患者の安全に問題が生じる可能性がある。医薬品の安全性を一層高めるとの観点から、日米ＥＵ三極医薬品承認審査ハーモナイゼーション国際会議（ＩＣＨ）において「医薬品の残留溶媒ガイドライン」（後記非特許文献２）が作成された。 Solvents used in the drug substance manufacturing process cannot be completely removed by conventional techniques used in the actual production process. Therefore, in the manufacture of a drug substance in which a plurality of processes are continued up to the final process, the solvent used in each process may remain in the drug substance. In general, the solvent remaining in the drug substance is not useful for treatment, and conversely, depending on the type and concentration of the residual solvent, there may be a problem in patient safety. From the viewpoint of further improving the safety of pharmaceuticals, the “Guidelines for Residual Solvents of Pharmaceuticals” (non-patent document 2 below) was prepared at the International Conference on Harmonization of Trilateral Drug Approval Review (ICH).
溶媒は、収率を向上させたり、結晶形、純度、溶解性といった原薬の物性を決める重要な役割を果たしているため、それが毒性を有することが知られていても、リスク−ベネフィットの観点から原薬の製造においてその使用が避けられない場合がしばしば起こる。このような場合、このガイドラインは原薬の残留溶媒濃度を毒性学的に許容し得る限度値以下にすべきことを規定している。 The solvent plays an important role in determining the physical properties of the drug substance, such as improving yield and crystal form, purity, and solubility, so even if it is known to be toxic, it is a risk-benefit perspective. Often, its use is unavoidable in the manufacture of drug substances. In such cases, the guidelines specify that the drug substance residual solvent concentration should be below the toxicologically acceptable limit.
ゾニサミドの中間体である１，２−ベンズイソキサゾール−３−メタンスルホン酸クロリドの製造に用いる溶媒は、ジクロロメタンよりも１，２−ジクロロエタンが好ましい。なぜならば、１，２−ベンズイソキサゾール−３−酢酸のスルホン化後に行われる脱炭酸反応にはジクロロメタンの沸点より高い温度である約６０℃の加熱が必要だからである。また、１，２−ジクロロエタンは１，２−ベンズイソキサゾール−３−メタンスルホン酸クロリドとアンモニアを反応させてゾニサミドを製造する工程でも使用することができる。しかし、１，２−ジクロロエタンを用いてゾニサミドを製造する場合は、前記の「医薬品の残留溶媒ガイドライン」に従えば、その残留濃度を５ｐｐｍ以下にしなければならない。本ガイドラインはすでに販売されている医薬品には適用されないが、その基準に合致する原薬を製造することは医薬品に対する安全性の観点から極めて重要である。 The solvent used in the production of 1,2-benzisoxazole-3-methanesulfonic acid chloride, which is an intermediate of zonisamide, is preferably 1,2-dichloroethane rather than dichloromethane. This is because the decarboxylation reaction performed after sulfonation of 1,2-benzisoxazole-3-acetic acid requires heating at about 60 ° C., which is higher than the boiling point of dichloromethane. 1,2-dichloroethane can also be used in a process for producing zonisamide by reacting 1,2-benzisoxazole-3-methanesulfonic acid chloride with ammonia. However, when zonisamide is produced using 1,2-dichloroethane, the residual concentration must be 5 ppm or less in accordance with the above-mentioned “Guideline for Residual Solvents for Pharmaceuticals”. Although this guideline does not apply to drugs that are already on the market, it is extremely important to manufacture drug substances that meet the criteria from the viewpoint of safety for drugs.
一般的な残留溶媒の除去は乾燥によって行われる。しかし、実生産工程で通常用いられている乾燥方法では、吸蔵された溶媒を完全に除去することは難しい。後記特許文献４には、水中で溶融させたビスフェノールから遊離する吸蔵された溶媒を蒸留で除去する方法が開示されている。この方法はビスフェノールが水中で加熱されると溶融して吸蔵された溶媒を遊離する特性を利用している。一方、ゾニサミドは水と共に加熱しても溶融しないので、この方法をゾニサミドの結晶中に吸蔵された溶媒の除去に適用することはできない。 Common residual solvent removal is performed by drying. However, it is difficult to completely remove the occluded solvent by a drying method usually used in an actual production process. Patent Document 4 described below discloses a method of removing the occluded solvent released from bisphenol melted in water by distillation. This method utilizes the property that bisphenol melts and releases the occluded solvent when heated in water. On the other hand, since zonisamide does not melt even when heated with water, this method cannot be applied to the removal of the solvent occluded in the crystals of zonisamide.
本発明者らは、上記ガイドラインに沿った安全性の高いゾニサミドの結晶の製造方法について鋭意研究を重ねた結果、高濃度の１，２−ジクロロエタンが残留するゾニサミドの結晶からでも、その結晶に含水Ｃ２−４アルコールを加えて蒸留および結晶化を行うことにより、既存の製造設備に新たな装置を取り付けたり再結晶を繰り返したりすることもなく簡便に、かつ結晶の収量に影響を与えることなく、残留１，２−ジクロロエタンの濃度が意外にも５ｐｐｍ以下であるゾニサミドの結晶が得られることを見出し、本発明の完成に至った。 As a result of intensive studies on a method for producing a highly safe zonisamide crystal in accordance with the above guidelines, the present inventors have found that even from a zonisamide crystal in which a high concentration of 1,2-dichloroethane remains, the water content in the crystal is high. Distillation and crystallization by adding C2-4 alcohol makes it easy to install new equipment in existing production equipment and repeat recrystallization without affecting the yield of crystals. As a result, it was found that zonisamide crystals having a residual 1,2-dichloroethane concentration of 5 ppm or less were obtained, and the present invention was completed.
本発明によれば、ゾニサミドの高純度結晶を製造する方法、殊に残留１，２−ジクロロエタンの濃度が５ｐｐｍ以下であるゾニサミドの結晶を製造する方法が提供される。さらに、本発明によれば、ゾニサミドの高純度結晶、すなわち１，２−ジクロロエタンを含まないゾニサミドの結晶、更に詳しくは残留１，２−ジクロロエタンの濃度が５ｐｐｍ以下であるゾニサミドの結晶が提供される。 According to the present invention, there is provided a method for producing a high purity crystal of zonisamide, particularly a method for producing a crystal of zonisamide having a residual 1,2-dichloroethane concentration of 5 ppm or less. Furthermore, according to the present invention, high-purity crystals of zonisamide, that is, zonisamide crystals that do not contain 1,2-dichloroethane, more specifically, zonisamide crystals in which the concentration of residual 1,2-dichloroethane is 5 ppm or less are provided. .
本発明は以下の態様を含む。 The present invention includes the following aspects.
１．残留１，２−ジクロロエタンの濃度が５ｐｐｍを超える、通常５ｐｐｍを超え２０００００ｐｐｍ以下である、ゾニサミドの結晶に含水Ｃ２−４アルコールを加えた後、この混合物から共沸蒸留により１，２−ジクロロエタンを除去し、共沸蒸留後の残留混合物から残留１，２−ジクロロエタンの濃度が５ｐｐｍ以下である結晶を取得することからなる、残留１，２−ジクロロエタンの濃度が５ｐｐｍ以下であるゾニサミドの結晶を製造する方法。 1. After adding water-containing C 2-4 alcohol to crystals of zonisamide having a residual 1,2-dichloroethane concentration of more than 5 ppm, usually more than 5 ppm and less than or equal to 200000 ppm, 1,2-dichloroethane is obtained from this mixture by azeotropic distillation. Removing and producing crystals of zonisamide having a residual 1,2-dichloroethane concentration of 5 ppm or less from obtaining a crystal having a residual 1,2-dichloroethane concentration of 5 ppm or less from the residual mixture after azeotropic distillation how to.
２．下記工程（ａ）、工程（ｂ）、工程（ｃ）および工程（ｄ）からなる、残留１，２−ジクロロエタンの濃度が５ｐｐｍ以下であるゾニサミドの結晶を製造する方法：
（ａ）残留１，２−ジクロロエタンの濃度が５ｐｐｍを超えるゾニサミドの結晶を含水Ｃ２−４アルコールに溶解した後この混合物の蒸留を開始し；
（ｂ）１，２−ジクロロエタンの共沸終了後に蒸留を中止し；
（ｃ）上記工程（ｂ）で得られる残留混合物を冷却し；
（ｄ）上記工程（ｃ）で析出したゾニサミドの結晶を濾取し、乾燥する。
2. A method for producing crystals of zonisamide comprising the following steps (a), (b), (c) and (d), wherein the concentration of residual 1,2-dichloroethane is 5 ppm or less:
(A) starting the distillation of the mixture after dissolving the crystals of zonisamide with a residual 1,2-dichloroethane concentration above 5 ppm in hydrous C 2-4 alcohol;
(B) discontinuing distillation after the azeotropic distillation of 1,2-dichloroethane;
(C) cooling the residual mixture obtained in step (b) above;
(D) The crystals of zonisamide precipitated in the step (c) are collected by filtration and dried.
３．前記工程（ａ）および工程（ｂ）、並びに下記工程（ｃ１）および工程（ｄ１）からなる、残留１，２−ジクロロエタンの濃度が５ｐｐｍ以下であるゾニサミドの結晶を製造する方法：
（ｃ１）上記工程（ｂ）で得られる残留混合物に工程（ａ）で用いた同じＣ２−４アルコールおよび／または水を加え、この混合物を加熱して蒸留中に析出した結晶を溶解した後冷却する；
（ｄ１）上記工程（ｃ１）で析出したゾニサミドの結晶を濾取し、乾燥する。
3. A method for producing crystals of zonisamide having a concentration of residual 1,2-dichloroethane of 5 ppm or less, comprising the steps (a) and (b) and the following steps (c1) and (d1):
(C1) After adding the same C 2-4 alcohol and / or water used in the step (a) to the residual mixture obtained in the step (b) and heating the mixture to dissolve the crystals precipitated during the distillation. Cooling;
(D1) The crystals of zonisamide precipitated in the step (c1) are collected by filtration and dried.
４．含水Ｃ２−４アルコールが含水イソプロパノールである前記１〜３のいずれか一項に記載の製造方法。 4). The manufacturing method as described in any one of said 1-3 whose hydrous C2-4 alcohol is hydrous isopropanol.
５．含水Ｃ２−４アルコールが３５〜６５ｖｏｌ％含水イソプロパノールである前記１〜３のいずれか一項に記載の製造方法。 5. The manufacturing method as described in any one of said 1-3 whose water-containing C2-4 alcohol is 35-65 vol% water-containing isopropanol.
６．蒸留を中止するときの温度が７８℃〜１００℃である前記２または３に記載の製造方法。 6). 4. The production method according to 2 or 3 above, wherein the temperature when the distillation is stopped is 78 ° C to 100 ° C.
７．残留１，２−ジクロロエタンの濃度が５ｐｐｍ以下であるゾニサミドの結晶。 7). Zonisamide crystals having a concentration of residual 1,2-dichloroethane of 5 ppm or less.
８．残留１，２−ジクロロエタンの濃度が１ｐｐｍ未満であるゾニサミドの結晶。 8). Zonisamide crystals with a residual 1,2-dichloroethane concentration of less than 1 ppm.
９．残留１，２−ジクロロエタンを含有するゾニサミドの結晶であって、残留１，２−ジクロロエタンの濃度が５ｐｐｍ以下であるゾニサミドの結晶。 9. Zonisamide crystals containing residual 1,2-dichloroethane, wherein the concentration of residual 1,2-dichloroethane is 5 ppm or less.
１０．前記１〜６のいずれか一項に記載の製造方法で製造されたゾニサミドの結晶。 10. The crystal | crystallization of zonisamide manufactured with the manufacturing method as described in any one of said 1-6.
本発明で用いられる原料と反応条件および本発明の製造方法の工程を以下に詳しく説明する。 The raw materials and reaction conditions used in the present invention and the steps of the production method of the present invention will be described in detail below.
「残留１，２−ジクロロエタンの濃度が５ｐｐｍを超えるゾニサミドの結晶（以下、「ゾニサミドの原結晶」称することもある）」は、その１，２−ジクロロエタン濃度の上限は特に限定されないが、５ｐｐｍを超え２０００００ｐｐｍ以下の残留１，２−ジクロロエタンを含有するゾニサミドの結晶を意味する。通常、「残留１，２−ジクロロエタンの濃度が５ｐｐｍを超えるゾニサミドの結晶」は、８〜１５００００ｐｐｍの残留１，２−ジクロロエタンを含有するゾニサミドの結晶である。 “The crystals of zonisamide having a residual 1,2-dichloroethane concentration exceeding 5 ppm (hereinafter sometimes referred to as“ original crystals of zonisamide ”) are not particularly limited in the upper limit of the 1,2-dichloroethane concentration, but 5 ppm It means crystals of zonisamide containing residual 1,2-dichloroethane exceeding 200,000 ppm or less. Usually, “crystals of zonisamide having a residual 1,2-dichloroethane concentration exceeding 5 ppm” are crystals of zonisamide containing 8-150,000 ppm of residual 1,2-dichloroethane.
「含水Ｃ２−４アルコール」とは水とＣ２−４アルコールの混合物を意味し、「Ｃ２−４アルコール」の具体例としては、例えば、エタノール、プロパノール、イソプロパノールおよび２−ブタノールが挙げられる。「含水Ｃ２−４アルコール」は含水エタノール、含水プロパノールまたは含水イソプロパノールが好ましく、その中では含水イソプロパノールが最も好ましい。 “Water-containing C 2-4 alcohol” means a mixture of water and C 2-4 alcohol, and specific examples of “C 2-4 alcohol” include, for example, ethanol, propanol, isopropanol and 2-butanol. . The “hydrous C 2-4 alcohol” is preferably hydrous ethanol, hydrous propanol or hydrous isopropanol, and most preferably hydrous isopropanol.
１，２−ジクロロエタンを共沸蒸留により除去する工程は、通常、ゾニサミドの原結晶を含水Ｃ２−４アルコールに溶解する工程から連続して行われる。ゾニサミドの原結晶を溶解する温度は特に限定されないが、通常３０℃以上用いられるＣ２−４アルコールの沸点以下である。 The step of removing 1,2-dichloroethane by azeotropic distillation is usually performed continuously from the step of dissolving the original crystal of zonisamide in water-containing C 2-4 alcohol. Although the temperature which melt | dissolves the zonisamide original crystal | crystallization is not specifically limited, Usually, it is below the boiling point of C2-4 alcohol used 30 degreeC or more.
ゾニサミドの原結晶はゾニサミドの原結晶１重量当り５〜１５倍容量の含水Ｃ２−４アルコールと混合される。言い換えれば、ゾニサミド乾燥重量１ｇと含水Ｃ２−４アルコール５〜１５ｍｌが混合される。好ましくは、ゾニサミドの原結晶はゾニサミドの原結晶１重量当り５．２〜１０．４倍容量の含水Ｃ２−４アルコールと混合される。 The original zonisamide crystals are mixed with 5 to 15 volumes of hydrous C 2-4 alcohol per weight of the original zonisamide crystals. In other words, 1 g of zonisamide dry weight and 5 to 15 ml of water-containing C 2-4 alcohol are mixed. Preferably, the zonisamide raw crystals are mixed with 5.2 to 10.4 times the volume of hydrous C 2-4 alcohol per weight of zonisamide raw crystals.
好ましい含水Ｃ２−４アルコールは、通常、３５〜６５ｖｏｌ％含水Ｃ２−４アルコールであり、更に好ましいものは４０〜６０ｖｏｌ％含水Ｃ２−４アルコールであり、更に一層好ましいものは４５〜５５ｖｏｌ％含水Ｃ２−４アルコールである。この明細書において、例えば、５５ｖｏｌ％含水Ｃ２−４アルコールとは５５容量部の水と４５容量部のＣ２−４アルコールの混合物を意味する。 The preferred hydrous C 2-4 alcohol is usually 35-65 vol% hydrous C 2-4 alcohol, more preferred is 40-60 vol% hydrous C 2-4 alcohol, and even more preferred is 45-55 vol%. It is hydrous C2-4 alcohol. In this specification, for example, 55 vol% water-containing C 2-4 alcohol means a mixture of 55 parts by volume of water and 45 parts by volume of C 2-4 alcohol.
蒸留は常圧または減圧のいずれでも行うことができるが、常圧で行うのが好ましい。蒸留を開始する温度は、通常、１，２−ジクロロエタン−Ｃ２−４アルコール−水の共沸点である。例えば、１，２−ジクロロエタン−エタノール−水の共沸点は６６．７℃であり、１，２−ジクロロエタン−イソプロパノール−水の共沸点は６９．７℃であるが、これらの沸点は、本工程実施時の気圧、モル沸点上昇などの影響を受けて変動する。蒸留を中止するときの温度は含水Ｃ２−４アルコールの種類によって異なるが、通常７８℃〜１００℃であり、好ましくは８５℃〜１００℃であり、さらに好ましくは９０℃〜１００℃である。 The distillation can be carried out at normal pressure or reduced pressure, but is preferably carried out at normal pressure. The temperature at which distillation begins is usually the azeotropic point of 1,2-dichloroethane-C 2-4 alcohol-water. For example, the azeotropic point of 1,2-dichloroethane-ethanol-water is 66.7 ° C, and the azeotropic point of 1,2-dichloroethane-isopropanol-water is 69.7 ° C. Fluctuates under the influence of the rise of atmospheric pressure and molar boiling point. The temperature at which the distillation is stopped varies depending on the type of the hydrous C 2-4 alcohol, but is usually 78 ° C to 100 ° C, preferably 85 ° C to 100 ° C, and more preferably 90 ° C to 100 ° C.
蒸留中止後は残留混合物をそのまま冷却すると残留１，２−ジクロロエタンの濃度が５ｐｐｍ以下であるゾニサミドの結晶が析出する。それに加えて、蒸留の途中で結晶が析出することがある。したがって、蒸留中止後の残留混合物に結晶が析出している場合は、蒸留中止後の残留混合物に蒸留で用いたＣ２−４アルコールおよび／または水を加え、再度加熱して結晶を溶解した後、冷却することによっても残留１，２−ジクロロエタンの濃度が５ｐｐｍ以下であるゾニサミドの結晶が析出する。例えば、蒸留に含水イソプロパノールを用いた場合は、蒸留後の残留混合物の水とイソプロパノールの比率が３５：６５〜６５：３５の範囲、好ましくは４０：６０〜６０：４０の範囲、更に好ましくは４５：５５〜５５：４５の範囲になり、水およびイソプロパノールの総量が乾燥状態のゾニサミドの原結晶重量１当り２〜２０倍容量、好ましくは８〜１４倍容量になるように水および／またはイソプロパノールを加え、得られた混合物を再度加熱した後、冷却する。この工程において活性炭による精製を合わせて行うことは好ましい。 After the distillation is stopped, if the residual mixture is cooled as it is, crystals of zonisamide with a residual 1,2-dichloroethane concentration of 5 ppm or less are deposited. In addition, crystals may precipitate during the distillation. Therefore, when crystals are precipitated in the residual mixture after the distillation is stopped, the C 2-4 alcohol and / or water used in the distillation are added to the residual mixture after the distillation is stopped and the crystals are dissolved again by heating. Even when cooled, crystals of zonisamide with a residual 1,2-dichloroethane concentration of 5 ppm or less are precipitated. For example, when water-containing isopropanol is used for distillation, the ratio of water to isopropanol in the residual mixture after distillation is in the range of 35:65 to 65:35, preferably in the range of 40:60 to 60:40, more preferably 45. Water and / or isopropanol so that the total amount of water and isopropanol is 2 to 20 times by volume, preferably 8 to 14 times by volume, of the original crystal weight of zonisamide in a dry state. In addition, the resulting mixture is heated again and then cooled. In this step, it is preferable to carry out purification with activated carbon.
結晶化したゾニサミドを常法により濾取・乾燥すると、残留１，２−ジクロロエタンの濃度が５ｐｐｍ以下であるゾニサミドの結晶が得られ、多くの場合、残留１，２−ジクロロエタンの濃度が検出限界未満であるゾニサミドの結晶が得られる。濾取したゾニサミドの結晶は６０〜１００℃、好ましくは７０〜９０℃の温度で８〜２４時間、好ましくは１２〜１８時間乾燥する。真空乾燥はさらに好ましい。 When the crystallized zonisamide is filtered and dried by a conventional method, crystals of zonisamide having a residual 1,2-dichloroethane concentration of 5 ppm or less are obtained. In many cases, the concentration of residual 1,2-dichloroethane is below the detection limit. A crystal of zonisamide is obtained. The filtered zonisamide crystals are dried at a temperature of 60 to 100 ° C., preferably 70 to 90 ° C. for 8 to 24 hours, preferably 12 to 18 hours. Vacuum drying is more preferable.
本製法に用いるゾニサミドの原結晶は、前記特許文献１の実施例１で用いられている溶媒を除き、前記特許文献１の参考例３および実施例１に記載の方法に準じて製造できる。すなわち、１，２−ジクロロエタンを溶媒として１，２−ベンズイソキサゾール−３−メタンスルホン酸クロリドとアンモニアを反応させ、反応混合物を濃縮して得られた残留物に水を加えて結晶を濾取すると、含量約８５％の湿ったゾニサミドの結晶が得られる。 The original crystals of zonisamide used in this production method can be produced according to the methods described in Reference Example 3 and Example 1 of Patent Document 1, except for the solvent used in Example 1 of Patent Document 1. That is, 1,2-benzisoxazole-3-methanesulfonic acid chloride and ammonia are reacted with 1,2-dichloroethane as a solvent, and the reaction mixture is concentrated. Water is added to the resulting residue and the crystals are filtered. When taken, wet zonisamide crystals of about 85% content are obtained.
上記方法で得た含量約８５％の湿ったゾニサミドの結晶を５０％含水イソプロパノールから常法に従って再結晶した後、４０〜８０℃で１８時間真空乾燥して得たゾニサミドの結晶は、残留１，２−ジクロロエタンの濃度が８〜１４ｐｐｍであった。 The crystals of moist zonisamide having a content of about 85% obtained by the above method were recrystallized from 50% hydrous isopropanol according to a conventional method and then vacuum-dried at 40 to 80 ° C. for 18 hours. The concentration of 2-dichloroethane was 8-14 ppm.
以下に実施例を挙げて本発明をさらに具体的に説明するが、本発明はこれらに限定されるものではない。ゾニサミドの結晶に残留する１，２−ジクロロエタンの量はガスクロマトグラフ法で測定した。 The present invention will be described more specifically with reference to the following examples. However, the present invention is not limited to these examples. The amount of 1,2-dichloroethane remaining in the zonisamide crystals was measured by gas chromatography.
実施例１−−
前記特許文献１の参考例３および実施例１に記載の方法において１，２−ジクロロエタンを用いて製造された含量約８５％の湿ったゾニサミドの結晶（６０ｇ）に５０％含水イソプロパノール（５００ｍｌ）を加え、撹拌下溶媒を７６〜１００℃で３２０ｍｌ留去した。残留物に水（１０ｍｌ）、イソプロパノール（２００ｍｌ）および活性炭（８ｇ）を加え、加熱溶解した。活性炭を濾去し、５０％含水イソプロパノール（８０ｍｌ）で活性炭を洗浄した。濾液および洗液を合わせて冷却した。析出結晶を濾取し、水（１００ｍｌ）で洗浄後、８０℃で１６時間乾燥して、ゾニサミドの結晶（４８.５ｇ）を得た。この結晶中の１，２−ジクロロエタン濃度は１ｐｐｍ未満（検出限界未満）だった。
Example 1-
In the method described in Reference Example 3 and Example 1 of Patent Document 1, 50% aqueous isopropanol (500 ml) was added to about 85% wet zonisamide crystals (60 g) produced using 1,2-dichloroethane. In addition, 320 ml of the solvent was distilled off at 76-100 ° C. with stirring. Water (10 ml), isopropanol (200 ml) and activated carbon (8 g) were added to the residue and dissolved by heating. The activated carbon was removed by filtration, and the activated carbon was washed with 50% aqueous isopropanol (80 ml). The filtrate and washings were combined and cooled. The precipitated crystals were collected by filtration, washed with water (100 ml), and dried at 80 ° C. for 16 hours to obtain zonisamide crystals (48.5 g). The 1,2-dichloroethane concentration in the crystals was less than 1 ppm (below the detection limit).
実施例２〜３−−
実施例１の製法を含水イソプロパノールの含水濃度および使用量を変更して同様に行った。実験の結果を表１に示す。
Examples 2-3
The production method of Example 1 was similarly carried out by changing the water content concentration and the amount of water-containing isopropanol. The results of the experiment are shown in Table 1.
実施例４−−
含量約８５％の湿ったゾニサミドの結晶（６０ｇ）に５０％含水イソプロパノール（３００ｍｌ）、水（７.５ｍｌ）および１，２−ジクロロエタン（８.８ｇ）を加え、撹拌下溶媒を７９〜１００℃で２１０ｍｌ留去した。残留物を冷却した後に析出した結晶を濾取し、湿ったゾニサミドの結晶（５６.７ｇ）を得た。この湿った結晶中の１，２−ジクロロエタン濃度は１ｐｐｍ未満（検出限界未満）だった。湿った結晶を８０℃で１６時間乾燥し、乾燥したゾニサミドの結晶（４９.９ｇ）を得た。
Example 4-
50% aqueous isopropanol (300 ml), water (7.5 ml) and 1,2-dichloroethane (8.8 g) were added to wet zonisamide crystals (60 g) having a content of about 85%, and the solvent was stirred at 79-100 ° C. 210 ml was distilled off. Crystals deposited after the residue was cooled were collected by filtration to obtain wet zonisamide crystals (56.7 g). The 1,2-dichloroethane concentration in the wet crystals was less than 1 ppm (below the detection limit). The wet crystals were dried at 80 ° C. for 16 hours to obtain dried zonisamide crystals (49.9 g).
実施例５−−
乾燥したゾニサミドの結晶（５０．０ｇ）に５５％含水イソプロパノール（２６０ｍｌ）を加え、さらに１，２−ジクロロエタン（７．５ｇ）と水（７．５ｇ）を加えて、撹拌速度２２０ｒｐｍで撹拌した。その後、混合物の内温が１００℃になるまで加熱して１６０ｍｌの溶媒を留去した。混合物を冷却し、水（１４５ｍｌ）、イソプロパノール（２３０ｍｌ）および活性炭（９．１ｇ）を加えて８０〜８３℃で１時間加熱した。活性炭を濾過し、５０％含水イソプロパノール（１７５ｍｌ）で活性炭を洗浄後、濾液および洗液を合わせて冷却した。約８℃に冷却後、析出した結晶を濾取し、水（１３６ｍｌ）で洗浄した。１００℃で１６時間送風乾燥し、乾燥したゾニサミドの結晶（４７．１ｇ）を得た。
Example 5-
To the dried zonisamide crystals (50.0 g), 55% aqueous isopropanol (260 ml) was added, 1,2-dichloroethane (7.5 g) and water (7.5 g) were further added, and the mixture was stirred at a stirring speed of 220 rpm. Thereafter, the mixture was heated until the internal temperature of the mixture reached 100 ° C., and 160 ml of the solvent was distilled off. The mixture was cooled, water (145 ml), isopropanol (230 ml) and activated carbon (9.1 g) were added and heated at 80-83 ° C. for 1 hour. The activated carbon was filtered, and the activated carbon was washed with 50% aqueous isopropanol (175 ml), and then the filtrate and the washing solution were combined and cooled. After cooling to about 8 ° C., the precipitated crystals were collected by filtration and washed with water (136 ml). By air-drying at 100 ° C. for 16 hours, dried zonisamide crystals (47.1 g) were obtained.
通常の再結晶では１，２−ジクロロエタンを用いて製造したゾニサミドの原結晶から残留１，２−ジクロロエタンの濃度が５ｐｐｍ以下であるゾニサミドの結晶を得ることはできなかった。これに対し、本発明の実施例の製造方法で得られるゾニサミドの結晶の残留１，２−ジクロロエタンの濃度は５ｐｐｍよりも遥かに低い１ｐｐｍ未満（検出限界未満）であった。実施例４に示すとおり、本製造方法はゾニサミドの原結晶に大量の１，２−ジクロロエタンが残留していても有効な方法である。また、実施例５に示すとおり、ゾニサミドの結晶の収率を低下させることもほとんどない。 In ordinary recrystallization, zonisamide crystals having a concentration of residual 1,2-dichloroethane of 5 ppm or less could not be obtained from zonisamide original crystals produced using 1,2-dichloroethane. On the other hand, the concentration of residual 1,2-dichloroethane in the zonisamide crystals obtained by the production method of the example of the present invention was less than 1 ppm (below the detection limit), which is much lower than 5 ppm. As shown in Example 4, this production method is effective even if a large amount of 1,2-dichloroethane remains in the zonisamide original crystal. Further, as shown in Example 5, the yield of zonisamide crystals is hardly reduced.
以上のことより、本製造方法によって、１，２−ジクロロエタンを使用して製造したゾニサミドの原結晶から残留１，２−ジクロロエタンの濃度が５ｐｐｍ以下であるゾニサミドの結晶を効率よく製造することができる。 From the above, according to this production method, crystals of zonisamide having a residual 1,2-dichloroethane concentration of 5 ppm or less can be efficiently produced from zonisamide original crystals produced using 1,2-dichloroethane. .
Claims (5)
（ａ）１，２−ジクロロエタンを溶媒として１，２−ベンズイソキサゾール−３−メタンスルホン酸クロリドとアンモニアを反応させ、反応混合物を濃縮して得られた残留物に水を加えて濾取した、残留１，２−ジクロロエタンの濃度が５ｐｐｍを超えるゾニサミドの結晶を含水イソプロパノールに溶解した後この混合物の蒸留を開始し；
（ｂ）１，２−ジクロロエタンの共沸終了後に蒸留を中止し；
（ｃ）上記工程（ｂ）で得られる残留混合物を冷却し；
（ｄ）上記工程（ｃ）で析出したゾニサミドの結晶を濾取し、乾燥する。 A method for producing crystals of zonisamide comprising the following steps (a), (b), (c) and (d), wherein the concentration of residual 1,2-dichloroethane is 5 ppm or less:
(A) 1,2-Benzisoxazole-3-methanesulfonic acid chloride is reacted with ammonia using 1,2-dichloroethane as a solvent, and the reaction mixture is concentrated. After the zonisamide crystals with a residual 1,2-dichloroethane concentration exceeding 5 ppm were dissolved in hydrous isopropanol , the mixture was started to distill;
(B) discontinuing distillation after the azeotropic distillation of 1,2-dichloroethane;
(C) cooling the residual mixture obtained in step (b) above;
(D) The crystals of zonisamide precipitated in the step (c) are collected by filtration and dried.
（ａ）１，２−ジクロロエタンを溶媒として１，２−ベンズイソキサゾール−３−メタンスルホン酸クロリドとアンモニアを反応させ、反応混合物を濃縮して得られた残留物に水を加えて濾取した、残留１，２−ジクロロエタンの濃度が５ｐｐｍを超えるゾニサミドの結晶を含水イソプロパノールに溶解した後この混合物の蒸留を開始し；
（ｂ）１，２−ジクロロエタンの共沸終了後に蒸留を中止し；
（ｃ１）上記工程（ｂ）で得られる残留混合物にイソプロパノールおよび／または水を加え、この混合物を加熱して蒸留中に析出した結晶を溶解した後冷却する；
（ｄ１）上記工程（ｃ１）で析出したゾニサミドの結晶を濾取し、乾燥する。 A method for producing crystals of zonisamide comprising the following step (a), step (b), step (c1) and step (d1), wherein the concentration of residual 1,2-dichloroethane is 5 ppm or less:
(A) 1,2-Benzisoxazole-3-methanesulfonic acid chloride is reacted with ammonia using 1,2-dichloroethane as a solvent, and the reaction mixture is concentrated. After the zonisamide crystals with a residual 1,2-dichloroethane concentration exceeding 5 ppm were dissolved in hydrous isopropanol , the mixture was started to distill;
(B) discontinuing distillation after the azeotropic distillation of 1,2-dichloroethane;
(C1) Isopropanol and / or water is added to the residual mixture obtained in step (b) above, and the mixture is heated to dissolve crystals precipitated during distillation and then cooled;
(D1) The crystals of zonisamide precipitated in the step (c1) are collected by filtration and dried.
The production method according to claim 2 or 3, wherein the temperature at which the distillation is stopped is 78 ° C to 100 ° C.
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| JP2003285878A Expired - Lifetime JP4774192B2 (en) | 2003-01-22 | 2003-08-04 | Process for producing crystals of zonisamide free of 1,2-dichloroethane and high-purity crystals of zonisamide |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JPS6033114B2 (en) * | 1976-12-16 | 1985-08-01 | 大日本製薬株式会社 | 1,2-benzisoxazole derivative |
| JPS54163823A (en) * | 1978-06-12 | 1979-12-26 | Dainippon Pharmaceutical Co | Antiiepileptic agent based on 33sulphamoylmethyll 1*22benzisoxazole |
| JPS54163570A (en) * | 1978-06-12 | 1979-12-26 | Dainippon Pharmaceutical Co | Benzooxazole derivative |
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