JP2004292364A - Method for producing epinastine hydrochloride - Google Patents
Method for producing epinastine hydrochloride Download PDFInfo
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- JP2004292364A JP2004292364A JP2003086875A JP2003086875A JP2004292364A JP 2004292364 A JP2004292364 A JP 2004292364A JP 2003086875 A JP2003086875 A JP 2003086875A JP 2003086875 A JP2003086875 A JP 2003086875A JP 2004292364 A JP2004292364 A JP 2004292364A
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- JP
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- Prior art keywords
- hydrochloride
- dibenz
- azepine
- dihydro
- imidazo
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- WHWZLSFABNNENI-UHFFFAOYSA-N epinastine Chemical compound C1C2=CC=CC=C2C2CN=C(N)N2C2=CC=CC=C21 WHWZLSFABNNENI-UHFFFAOYSA-N 0.000 title claims abstract description 60
- 229960002548 epinastine hydrochloride Drugs 0.000 title claims abstract description 33
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 41
- 238000000034 method Methods 0.000 claims description 33
- 238000000746 purification Methods 0.000 claims description 16
- 150000001298 alcohols Chemical class 0.000 claims description 6
- OHOWXEDRJQSBEY-UHFFFAOYSA-N 16-chloro-2,4-diazatetracyclo[12.4.0.02,6.07,12]octadeca-1(14),3,7,9,11,15,17-heptaen-3-amine Chemical compound C1C2=CC=CC=C2C2CN=C(N)N2C2=CC=C(Cl)C=C21 OHOWXEDRJQSBEY-UHFFFAOYSA-N 0.000 claims description 4
- 238000001953 recrystallisation Methods 0.000 abstract description 6
- 238000004587 chromatography analysis Methods 0.000 abstract description 2
- VKXSGUIOOQPGAF-UHFFFAOYSA-N epinastine hydrochloride Chemical compound [H+].[Cl-].C1C2=CC=CC=C2C2CN=C(N)N2C2=CC=CC=C21 VKXSGUIOOQPGAF-UHFFFAOYSA-N 0.000 abstract description 2
- 238000000605 extraction Methods 0.000 abstract description 2
- 238000006243 chemical reaction Methods 0.000 abstract 1
- 238000007670 refining Methods 0.000 abstract 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 33
- 239000013078 crystal Substances 0.000 description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 238000001816 cooling Methods 0.000 description 9
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 9
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 9
- 239000005457 ice water Substances 0.000 description 9
- 238000004811 liquid chromatography Methods 0.000 description 9
- 239000002002 slurry Substances 0.000 description 9
- SKQNTLALARIPLX-UHFFFAOYSA-N 7-chloro epinastine hydrochloride Chemical compound Cl.C1C2=CC=CC=C2C2CN=C(N)N2C2=CC=C(Cl)C=C21 SKQNTLALARIPLX-UHFFFAOYSA-N 0.000 description 8
- 239000000356 contaminant Substances 0.000 description 8
- 239000002904 solvent Substances 0.000 description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Substances ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- 229960001701 chloroform Drugs 0.000 description 6
- 239000012535 impurity Substances 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- ATDGTVJJHBUTRL-UHFFFAOYSA-N cyanogen bromide Chemical compound BrC#N ATDGTVJJHBUTRL-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- -1 7-Chloro-9,13b-dihydro-1H-dibenz [c, f] imidazo [1,5-a] azepine Chemical compound 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- BRSZMVHUPSXOTP-UHFFFAOYSA-N 2-(5h-benzo[c][1]benzazepin-6-ylmethyl)isoindole-1,3-dione Chemical compound C=1C2=CC=CC=C2NC(CN2C(C3=CC=CC=C3C2=O)=O)=C2C=CC=CC2=1 BRSZMVHUPSXOTP-UHFFFAOYSA-N 0.000 description 2
- XXHUCKUXFLTXAG-UHFFFAOYSA-N 2-(6,11-dihydro-5h-benzo[c][1]benzazepin-6-ylmethyl)isoindole-1,3-dione Chemical compound N1C2=CC=CC=C2CC2=CC=CC=C2C1CN1C(=O)C2=CC=CC=C2C1=O XXHUCKUXFLTXAG-UHFFFAOYSA-N 0.000 description 2
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 2
- ZNQVEEAIQZEUHB-UHFFFAOYSA-N 2-ethoxyethanol Chemical compound CCOCCO ZNQVEEAIQZEUHB-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000003463 adsorbent Substances 0.000 description 2
- 230000003266 anti-allergic effect Effects 0.000 description 2
- 230000001387 anti-histamine Effects 0.000 description 2
- 239000000739 antihistaminic agent Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 239000003880 polar aprotic solvent Substances 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- AJUMGSLQADLWKL-UHFFFAOYSA-N 1h-azepine;hydrochloride Chemical compound Cl.N1C=CC=CC=C1 AJUMGSLQADLWKL-UHFFFAOYSA-N 0.000 description 1
- BUOFRBIWYSNEEX-UHFFFAOYSA-N 2-(2,5-dihydro-1H-benzo[c][1]benzazepin-6-ylmethyl)isoindole-1,3-dione Chemical compound C1(C=2C(C(N1CC1=C3C(=CC4=C(N1)C=CCC4)C=CC=C3)=O)=CC=CC2)=O BUOFRBIWYSNEEX-UHFFFAOYSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- FPKDBVUHIXYLNP-UHFFFAOYSA-N 6,11-dihydro-5h-benzo[c][1]benzazepin-6-ylmethanamine Chemical compound NCC1NC2=CC=CC=C2CC2=CC=CC=C12 FPKDBVUHIXYLNP-UHFFFAOYSA-N 0.000 description 1
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 229960003449 epinastine Drugs 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- UTCSSFWDNNEEBH-UHFFFAOYSA-N imidazo[1,2-a]pyridine Chemical compound C1=CC=CC2=NC=CN21 UTCSSFWDNNEEBH-UHFFFAOYSA-N 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000013014 purified material Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- HRQDCDQDOPSGBR-UHFFFAOYSA-M sodium;octane-1-sulfonate Chemical compound [Na+].CCCCCCCCS([O-])(=O)=O HRQDCDQDOPSGBR-UHFFFAOYSA-M 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Description
【０００１】
【発明の属する技術分野】
本発明は抗アレルギーおよび抗ヒスタミン作用によって特徴付けられる治療学的に有用な塩酸エピナスチンの製造方法に関するものである。
【０００２】
【従来の技術】
３−アミノ−９，１３ｂ−ジヒドロ−１Ｈ−ジベンズ［ｃ，ｆ］イミダゾ［１，５−ａ］アゼピン・塩酸塩（以下、塩酸エピナスチンと称する）の製造方法としては、６−アミノメチル−６，１１−ジヒドロ−５Ｈ−ジベンズ［ｂ，ｅ］アゼピンを臭化シアン（ブロモシアノーゲン）と反応せしめた後、生成する３−アミノ−９，１３ｂ−ジヒドロ−１Ｈ−ジベンズ［ｃ，ｆ］イミダゾ［１，５−ａ］アゼピン・臭化水素酸塩をフリー化して得られる３−アミノ−９，１３ｂ−ジヒドロ−１Ｈ−ジベンズ［ｃ，ｆ］イミダゾ［１，５−ａ］アゼピンを、塩化水素と反応せしめ塩酸塩とする製造方法が知られている（特許文献１）。
【０００３】
この方法においては塩酸エピナスチンをジメチルホルムアミドから結晶化すると同時に精製を行うという方法が記載されているが、３−アミノ−７−クロロ−９，１３ｂ−ジヒドロ−１Ｈ−ジベンズ［ｃ，ｆ］イミダゾ［１，５−ａ］アゼピン・塩酸塩などの夾雑物が精製されずに結晶中に残存してしまう。また、この方法により得られた塩酸エビナスチン結晶を更に精製する方法では、純度の向上が僅かであり、精製法が限られる上、高品質の塩酸エビナスチンを得ることが出来ない。
【０００４】
【特許文献１】
特開平４−３４６９８８号公報
【０００５】
【発明が解決しようとする課題】
本発明の目的は夾雑物のない高品質の塩酸エピナスチンの製造方法を提供することにある。
【０００６】
【課題を解決する為の手段】
本発明者らは、上記の問題点を解決すべく鋭意検討を行った結果、上記目的は、以下の手段により達成されることを見いだした。
（１）前記式Ｉで表される３−アミノ−９，１３ｂ−ジヒドロ−１Ｈ−ジベンズ［ｃ，ｆ］イミダゾ［１，５−ａ］アゼピンを精製した後、塩酸塩とすることを特徴とする前記式ＩＩで示される塩酸エビナスチンの製造方法。
（２）前記３−アミノ−９，１３ｂ−ジヒドロ−１Ｈ−ジベンズ［ｃ，ｆ］イミダゾ［１，５−ａ］アゼピンを再結晶した後、塩酸塩とすることを特徴とする塩酸エビナスチンの製造方法。
（３）前記３−アミノ−９，１３ｂ−ジヒドロ−１Ｈ−ジベンズ［ｃ，ｆ］イミダゾ［１，５−ａ］アゼピンをアルコール類から再結晶することを特徴とする前記２に記載の塩酸エビナスチンの製造方法。
（４）３−アミノ−７−クロロ−９，１３ｂ−ジヒドロ−１Ｈ−ジベンズ［ｃ，ｆ］イミダゾ［１，５−ａ］アゼピンを除去することを特徴とする前記１〜３のいずれか１項に記載の塩酸エピナスチンの製造方法。
【０００７】以下本発明を詳細に説明する。
３−アミノ−９，１３ｂ−ジヒドロ−１Ｈ−ジベンズ［ｃ，ｆ］イミダゾ［１，５−ａ］アゼピンは特開平４−３４６９８８号公報に記載の方法により製造できる化合物であり、塩酸エピナスチンは前記３−アミノ−９，１３ｂ−ジヒドロ−１Ｈ−ジベンズ［ｃ，ｆ］イミダゾ［１，５−ａ］アゼピンを、やはり前記特開平４−３４６９８８号公報に記載の方法により塩酸塩とすることで製造される。
【０００８】本発明者らは、塩酸エピナスチン結晶を精製することでは除去し難い夾雑物は３−アミノ−９，１３ｂ−ジヒドロ−１Ｈ−ジベンズ［ｃ，ｆ］イミダゾ［１，５−ａ］アゼピン中の不純物が原因であり、３−アミノ−９，１３ｂ−ジヒドロ−１Ｈ−ジベンズ［ｃ，ｆ］イミダゾ［１，５−ａ］アゼピン中に含有される式ＩＩＩで表される３−アミノ−７−クロロ−９，１３ｂ−ジヒドロ−１Ｈ−ジベンズ［ｃ，ｆ］イミダゾ［１，５−ａ］アゼピンが、塩酸エピナスチンの形成過程で、やはり塩酸塩として塩酸エピナスチンに混入してしまうことによることを見いだした。
【０００９】
【化２】
【００１１】３−アミノ−９，１３ｂ−ジヒドロ−１Ｈ−ジベンズ［ｃ，ｆ］イミダゾ［１，５−ａ］アゼピンを一旦、精製した後、塩化水素と反応せしめ塩酸塩とすることで、前記夾雑物が除去された高品質の塩酸エビナスチンが製造できる。
【００１２】３−アミノ−７−クロロ−９，１３ｂ−ジヒドロ−１Ｈ−ジベンズ［ｃ，ｆ］イミダゾ［１，５−ａ］アゼピン（以下７−クロル体と略称する）の混入の原因は、前記特開平４−３４６９８８号公報に記載の塩酸エピナスチン製造における原料物質である、６−フタルイミドメチル−５Ｈ−ジベンズ［ｂ，ｅ］アゼピン（１）の更に源流の原料由来であると推定される。抗アレルギーおよび抗ヒスタミン作用を有する塩酸エピナスチン原体にとってはこれらの夾雑物は少ないことが望ましく、高品質の塩酸エピナスチンが望まれている。
【００１３】前記特開平４−３４６９８８号公報に記載の方法による塩酸エピナスチンにおいては、この夾雑物が、後述するＨＰＬＣを用いた純度測定方法による値で、０．１％以上という比較的高い濃度で含まれる。
前記特開平４−３４６９８８号公報に記載の方法によれば、塩酸エピナスチンの原料である３−アミノ−９，１３ｂ−ジヒドロ−１Ｈ−ジベンズ［ｃ，ｆ］イミダゾ［１，５−ａ］アゼピン（前記式Ｉ）は、具体的には、６−フタルイミドメチル−５Ｈ−ジベンズ［ｂ，ｅ］アゼピン（１）を、接触還元し、６−フタルイミドメチル−６，１１−ジヒドロ−５Ｈ−ジベンズ［ｂ，ｅ］アゼピン（２）を得た後、ヒドラジン分解し、アミノ体（３）を形成した後、連続してブロモシアノーゲンを作用させることで得ている。
【００１４】
【化３】
【００１６】これら６−フタルイミドメチル−ジヒドロ−５Ｈ−ジベンズ［ｂ，ｅ］アゼピン（１）等の共通原料をもちいる方法においては前記の夾雑物は同様に含まれている。
【００１７】塩酸エピナスチンの製造は、具体的には、得られた３−アミノ−９，１３ｂ−ジヒドロ−１Ｈ−ジベンズ［ｃ，ｆ］イミダゾ［１，５−ａ］アゼピンを、塩化水素ガスを溶解したジメチルホルムアミド中に加熱溶解し、溶媒を一部留去、濃縮した後、冷却して、析出する結晶を濾過して得ている。塩酸塩形成、そして精製のための、溶媒としてアルコール等の溶媒を用いると、塩酸エピナスチンの形成過程で、分解がおこることが知られているが、ジメチルホルムアミドは、分解もなく、適度な溶解度を有し、塩酸エピナスチン製造、特にその精製に適した溶媒であり、この方法により高い収率で（例えば９０％程度）で塩酸エピナスチンが得られる。
【００１８】しかしながら、この過程で、原料の３−アミノ−９，１３ｂ−ジヒドロ−１Ｈ−ジベンズ［ｃ，ｆ］イミダゾ［１，５−ａ］アゼピン中に混入した前記７−クロル体が、塩酸エピナスチンの製造過程において、塩酸塩として共析してしまい、前記７−クロル体に関していえば、以後の精製を繰り返しても精製効果があまりなく、純度的によいものが得られない。
【００１９】本発明果による、分解のない、高純度、高品質の塩酸エピナスチンの製造方法は、３−アミノ−９，１３ｂ−ジヒドロ−１Ｈ−ジベンズ［ｃ，ｆ］イミダゾ［１，５−ａ］アゼピンの塩酸塩形成と精製を一度で行わず、３−アミノ−９，１３ｂ−ジヒドロ−１Ｈ−ジベンズ［ｃ，ｆ］イミダゾ［１，５−ａ］アゼピンの精製を一旦行って、（そこで、７−クロル体の含量が著しく低下する）、その後、精製を行った原料を用いて、塩化水素により塩酸塩の形成を行うことにある。この方法によれば著しい純度の上昇がみられる。
【００２０】従って、本発明においては、３−アミノ−９，１３ｂ−ジヒドロ−１Ｈ−ジベンズ［ｃ，ｆ］イミダゾ［１，５−ａ］アゼピンの精製を何らかのかたちで、一旦行えばよく、それにより，塩酸塩ではないフリーの７−クロル体が充分除去されるため、夾雑物としての７−クロル体が少ない３−アミノ−９，１３ｂ−ジヒドロ−１Ｈ−ジベンズ［ｃ，ｆ］イミダゾ［１，５−ａ］アゼピンが得られる。
【００２１】精製法としては再結晶、クロマトグラフィー、抽出などを使用することが出来る。
しかしながら、精製の方法としては、再結晶が好ましく、再結晶溶媒としては炭化水素、ハロゲン化炭化水素、エーテル類、ケトン、アルコール類、エステル類、アミン類、極性非プロトン性溶媒、水、またはその混合溶媒等種々の溶媒が使用できる。
【００２２】なかでも好ましいのはエチレングリコールモノメチルエーテル（メチルセロソルブ）、エチレングリコールモノエチルエーテル（セロソルブ）、イソプロピルエーテル、テトラヒドロフラン、ジオキサン等のエーテル類、アセトン、メチルエチルケトン、シクロヘキサノン、等のケトン類、メタノールの、アルコール、イソプロパノール、等のアルコール類、酢酸メチル、酢酸エチル、酢酸ブチル、等のエステル類、ジメチルホルムアミド、ジメチルアセトアミド等の極性非プロトン性溶媒、水、またはその混合溶媒であり、なかでも特に好ましい溶媒として、メタノール、アルコール、イソプロパノール等アルコール類があげられる。
【００２３】特に、３−アミノ−９，１３ｂ−ジヒドロ−１Ｈ−ジベンズ［ｃ，ｆ］イミダゾ［１，５−ａ］アゼピンの前記塩酸塩形成および精製を同時に行う塩酸エビナスチンの製造において、分解が起こることが知られているメタノールのごときアルコール類を使用することが、精製をおこなう観点から特に好ましいということは意外な効果であった。
【００２４】本発明においては、塩酸エピナスチンの原料である３−アミノ−９，１３ｂ−ジヒドロ−１Ｈ−ジベンズ［ｃ，ｆ］イミダゾ［１，５−ａ］アゼピンの再結晶による精製時に、必要に応じて吸着剤（例えば活性炭等）を添加し、濾過で吸着剤を除いてから結晶化してもよい。
本発明によれば、純度の高い塩酸エピナスチンの製造が、容易に、設備上の大きな負荷なく行え、製造プロセス上、利点が大きい。
【００２５】
【実施例】
以下、実施例によって本発明を具体的に説明するが、本発明はこれらの実施例に限定されるものではない。
【００２６】また、実施例における液体クロマトグラフィー純度は、下記条件にて液体クロマトグラフィー分析を行い、各成分ピークの面積％を用いたものであり純度の指標とした。
装置：ＬＣ−２０００Ｐｌｕｓ ｓｅｒｉｅｓ（日本分光株式会社）
カラム：Ｉｎｅｒｔｓｉｌ ＯＤＳ−３
移動層：２０ｍｍｏｌ−ＫＨ２ＰＯ４（リン酸にてｐＨ＝２．５に調整）水溶液／アセトニトリル＝４０／６０の混合液に、更に２０ｍｍｏｌ濃度となる様にオクタンスルホン酸ナトリウムを加えたもの。
検出波長：２４０ｎｍ
調製例
【００２７】３−アミノ−７−クロロ−９，１３ｂ−ジヒドロ−１Ｈ−ジベンズ［ｃ，ｆ］イミダゾ［１，５−ａ］アゼピン・塩酸塩は下記の一連の工程により合成した。
【００２８】
【化４】
【００３０】また、比較例１の方法で塩酸エピナスチンを得た。
【００３１】前記液体クロマトグラフィー条件で、また、いくつかのカラムで前記の３−アミノ−７−クロロ−９，１３ｂ−ジヒドロ−１Ｈ−ジベンズ［ｃ，ｆ］イミダゾ［１，５−ａ］アゼピン・塩酸塩は塩酸エビナスチンの夾雑物ピークとリテンション・タイムが一致し、夾雑物が３−アミノ−７−クロロ−９，１３ｂ−ジヒドロ−１Ｈ−ジベンズ［ｃ，ｆ］イミダゾ［１，５−ａ］アゼピン・塩酸塩であることを確認した。
【００３２】比較例１
上記方法により得られた３−アミノ−９，１３ｂ−ジヒドロ−１Ｈ−ジベンズ［ｃ，ｆ］イミダゾ［１，５−ａ］アゼピン、１１．５ｇを塩化水素含有のジメチルホルムアミドに溶解させた後、氷水冷却して、スラリー状となった内容物を濾過、乾燥して塩酸エビナスチン１０．１ｇを得た。前記条件での液体クロマトグラフィー純度９９．２１面積％、３−アミノ−７−クロロ−９，１３ｂ−ジヒドロ−１Ｈ−ジベンズ［ｃ，ｆ］イミダゾ［１，５−ａ］アゼピン・塩酸塩は０．１９面積％であった。
また、得られた塩酸エビナスチン１０．１ｇを、更に５．５倍のジメチルホルムアミド（ＤＭＦ）から再結晶した。その結果、７．２ｇの塩酸エビナスチンが得られた。同様に液体クロマトグラフィーにより純度を測定したところ、前記３−アミノ−７−クロロ−９，１３ｂ−ジヒドロ−１Ｈ−ジベンズ［ｃ，ｆ］イミダゾ［１，５−ａ］アゼピン・塩酸塩は０．１５面積％であった。収率が低下したほどには、純度が向上していないことがわかる。
【００３３】実施例１
攪拌機、還流冷却機、温度計の備わった１００ｍｌのフラスコに、３−アミノ−９，１３ｂ−ジヒドロ−１Ｈ−ジベンズ［ｃ，ｆ］イミダゾ［１，５−ａ］アゼピン１１．５ｇ、エタノール５３ｍｌを加えた後、３０分間還流し、結晶を溶解させた。氷水冷却してスラリー状となった内容物を濾過し白色結晶を得た。塩化水素含有のジメチルホルムアミドに白色結晶を溶解させた後、氷水冷却してスラリー状となった内容物を濾過、乾燥し塩酸エビナスチン８．８ｇを得た。液体クロマトグラフィー純度９９．９６面積％、３−アミノ−７−クロロ−９，１３ｂ−ジヒドロ−１Ｈ−ジベンズ［ｃ，ｆ］イミダゾ［１，５−ａ］アゼピン・塩酸塩は０．０１面積％であった。尚、得られた塩酸エビナスチンの融点は２７２℃（日本薬局方 融点測定法；第１法）
【００３４】実施例２
攪拌機、還流冷却機、温度計の備わった１００ｍｌフラスコに３−アミノー９，１３ｂ−ジヒドロー１Ｈ−ジベンズ［ｃ，ｆ］イミダゾ［１，５−ａ］アゼピン１１．５ｇ、メタノール５３ｍＬを加えた後、３０分間還流し結晶を溶解させた。氷水冷却してスラリー状となった内容物を濾過し白色結晶を得た。塩化水素含有のジメチルホルムアミドに白色結晶を溶解させた後、氷水冷却してスラリー状となった内容物を濾過、乾燥し塩酸エピナスチン９．０ｇを得た。液体クロマトグラフィー純度９９．９６面積％、３−アミノ−７−クロロ９，１３ｂ−ジヒドロー１Ｈ−ジベンズ［ｃ，ｆ］イミダゾ［１，５−ａ］アゼピン・塩酸塩は０．０１面積％であった。
【００３５】実施例３
攪拌機、還流冷却機、温度計の備わった１００ｍｌフラスコに３−アミノー９，１３ｂ−ジヒドロー１Ｈ−ジベンズ［ｃ，ｆ］イミダゾ［１，５−ａ］アゼピン１１．５ｇ、メタノール４２ｍＬ、水１１ｍＬを加えた後、３０分間還流し結晶を溶解させた。氷水冷却してスラリー状となった内容物を濾過し白色結晶を得た。塩化水素含有のジメチルホルムアミドに白色結晶を溶解させた後、氷水冷却してスラリー状となった内容物を濾過、乾燥し塩酸エピナスチン９．１ｇを得た。液体クロマトグラフィー純度９９．９５面積％、３−アミノ−７−クロロ９，１３ｂ−ジヒドロー１Ｈ−ジベンズ［ｃ，ｆ］イミダゾ［１，５−ａ］アゼピン・塩酸塩は０．０１面積％
【００３６】実施例４
攪拌機、還流冷却機、温度計の備わった１００ｍｌフラスコに３−アミノー９，１３ｂ−ジヒドロー１Ｈ−ジベンズ［ｃ，ｆ］イミダゾ［１，５−ａ］アゼピン１１．５ｇ、メタノール５３ｍＬ、活性炭１ｇを加えた後、３０分間還流し結晶を溶解させた。溶解後に熱時濾過し活性炭を除去後、氷水冷却してスラリー状となった内容物を濾過し白色結晶を得た。塩化水素含有のジメチルホルムアミドに白色結晶を溶解させた後、氷水冷却してスラリー状となった内容物を濾過、乾燥し塩酸エピナスチン９．０ｇを得た。液体クロマトグラフィー純度９９．９７面積％、３−アミノ−７−クロロ９，１３ｂ−ジヒドロー１Ｈ−ジベンズ［ｃ，ｆ］イミダゾ［１，５−ａ］アゼピン・塩酸塩は０．０１面積％であった。
【００３７】以上、本発明の方法により、飛躍的に（一桁）夾雑物の濃度が低下し、純度が大きく上がることが示された。
【００３８】
【発明の効果】
本発明の方法によれば夾雑物の除去された高品質の塩酸エピナスチンの製造が容易となり、製造プロセス上の価値が大きい。[0001]
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a method for producing therapeutically useful epinastine hydrochloride characterized by its antiallergic and antihistamine actions.
[0002]
[Prior art]
A method for producing 3-amino-9,13b-dihydro-1H-dibenz [c, f] imidazo [1,5-a] azepine hydrochloride (hereinafter referred to as epinastine hydrochloride) includes 6-aminomethyl-6 , 11-Dihydro-5H-dibenz [b, e] azepine is reacted with cyanogen bromide (bromocyanogen), and the resulting 3-amino-9,13b-dihydro-1H-dibenz [c, f] imidazo is produced. 3-amino-9,13b-dihydro-1H-dibenz [c, f] imidazo [1,5-a] azepine obtained by freezing [1,5-a] azepine / hydrobromide is converted into a salt. There is known a production method in which hydrogen chloride is reacted with hydrogen (Patent Document 1).
[0003]
In this method, a method is described in which epinastine hydrochloride is crystallized from dimethylformamide and purified at the same time, but 3-amino-7-chloro-9,13b-dihydro-1H-dibenz [c, f] imidazo [ Impurities such as [1,5-a] azepine / hydrochloride remain in the crystals without being purified. Further, in the method of further purifying the crystal of ebinastine hydrochloride obtained by this method, the purity is slightly improved, the purification method is limited, and high-quality ebinastin hydrochloride cannot be obtained.
[0004]
[Patent Document 1]
JP-A-4-346988 [0005]
[Problems to be solved by the invention]
An object of the present invention is to provide a method for producing high-quality epinastine hydrochloride free of impurities.
[0006]
[Means for solving the problem]
The present inventors have conducted intensive studies to solve the above problems, and as a result, have found that the above object is achieved by the following means.
(1) Purifying the 3-amino-9,13b-dihydro-1H-dibenz [c, f] imidazo [1,5-a] azepine represented by the above formula I and then converting it into a hydrochloride. A method for producing evinastine hydrochloride represented by the above formula II.
(2) A process for producing ebinastine hydrochloride, comprising recrystallizing the 3-amino-9,13b-dihydro-1H-dibenz [c, f] imidazo [1,5-a] azepine to form a hydrochloride. Method.
(3) The evinastine hydrochloride according to the above item 2, wherein the 3-amino-9,13b-dihydro-1H-dibenz [c, f] imidazo [1,5-a] azepine is recrystallized from alcohols. Manufacturing method.
(4) any one of the above-mentioned items 1 to 3, wherein 3-amino-7-chloro-9,13b-dihydro-1H-dibenz [c, f] imidazo [1,5-a] azepine is removed. The method for producing epinastine hydrochloride according to the above item.
Hereinafter, the present invention will be described in detail.
3-Amino-9,13b-dihydro-1H-dibenz [c, f] imidazo [1,5-a] azepine is a compound which can be produced by the method described in JP-A-4-346988, and epinastine hydrochloride is a compound which can be produced by the method described in JP-A-4-346988. Production of 3-amino-9,13b-dihydro-1H-dibenz [c, f] imidazo [1,5-a] azepine by converting it into a hydrochloride by the method described in JP-A-4-346988. Is done.
The present inventors have found that impurities which are difficult to remove by purifying epinastine hydrochloride crystals are 3-amino-9,13b-dihydro-1H-dibenz [c, f] imidazo [1,5-a] azepine. 3-amino-9,13b-dihydro-1H-dibenz [c, f] imidazo [1,5-a] azepine contained in formula III due to impurities in the compound. 7-Chloro-9,13b-dihydro-1H-dibenz [c, f] imidazo [1,5-a] azepine is mixed with epinastine hydrochloride as a hydrochloride in the process of forming epinastine hydrochloride. Was found.
[0009]
Embedded image
[0011] The 3-amino-9,13b-dihydro-1H-dibenz [c, f] imidazo [1,5-a] azepine is purified once, and then reacted with hydrogen chloride to form a hydrochloride. Ebinastine hydrochloride of high quality from which impurities have been removed can be produced.
The cause of contamination of 3-amino-7-chloro-9,13b-dihydro-1H-dibenz [c, f] imidazo [1,5-a] azepine (hereinafter abbreviated as 7-chloro form) is as follows. It is presumed that 6-phthalimidomethyl-5H-dibenz [b, e] azepine (1), which is a raw material in the production of epinastine hydrochloride described in JP-A-4-346988, is further derived from a raw material in the source stream. It is desirable that these contaminants are small in the epinastine hydrochloride drug substance having antiallergic and antihistamine effects, and high quality epinastine hydrochloride is desired.
In epinastine hydrochloride according to the method described in JP-A-4-346988, the impurities are present in a relatively high concentration of 0.1% or more as determined by a purity measurement method using HPLC described later. included.
According to the method described in JP-A-4-346988, 3-amino-9,13b-dihydro-1H-dibenz [c, f] imidazo [1,5-a] azepine which is a raw material of epinastine hydrochloride ( The above formula I) is, for example, a catalytic reduction of 6-phthalimidomethyl-5H-dibenz [b, e] azepine (1) to give 6-phthalimidomethyl-6,11-dihydro-5H-dibenz [b , E] azepine (2) is obtained, hydrazinolyzed to form an amino compound (3), and then continuously treated with bromocyanogen.
[0014]
Embedded image
In the method using common raw materials such as 6-phthalimidomethyl-dihydro-5H-dibenz [b, e] azepine (1), the above-mentioned contaminants are similarly contained.
For the production of epinastine hydrochloride, specifically, the obtained 3-amino-9,13b-dihydro-1H-dibenz [c, f] imidazo [1,5-a] azepine is treated with hydrogen chloride gas. It is obtained by heating and dissolving in dissolved dimethylformamide, partially evaporating the solvent, concentrating, cooling, and filtering the precipitated crystals. It is known that when a solvent such as alcohol is used as a solvent for hydrochloride formation and purification, decomposition occurs during the formation of epinastine hydrochloride, but dimethylformamide does not decompose and has an appropriate solubility. It is a solvent suitable for the production of epinastine hydrochloride, particularly for its purification. This method allows epinastine hydrochloride to be obtained in high yield (for example, about 90%).
However, in this process, the 7-chloro form mixed in the starting material 3-amino-9,13b-dihydro-1H-dibenz [c, f] imidazo [1,5-a] azepine was converted into hydrochloric acid. In the production process of epinastine, it is co-deposited as a hydrochloride, and as for the 7-chloro form, even if the subsequent purification is repeated, the purification effect is not so high, and a product with good purity cannot be obtained.
The process for producing high-purity, high-quality epinastine hydrochloride without decomposition according to the present invention is as follows: 3-amino-9,13b-dihydro-1H-dibenz [c, f] imidazo [1,5-a] The formation and purification of the azepine hydrochloride salt was not performed at once, but the purification of 3-amino-9,13b-dihydro-1H-dibenz [c, f] imidazo [1,5-a] azepine was performed once (where , The content of the 7-chloro form is remarkably reduced), and thereafter, the hydrochloride is formed with hydrogen chloride using the purified material. According to this method, a significant increase in purity is observed.
Therefore, in the present invention, the purification of 3-amino-9,13b-dihydro-1H-dibenz [c, f] imidazo [1,5-a] azepine may be carried out once in any form. , The free 7-chloro form, which is not a hydrochloride, is sufficiently removed, so that 3-amino-9,13b-dihydro-1H-dibenz [c, f] imidazo [1] containing less 7-chloro form as a contaminant , 5-a] azepine is obtained.
As a purification method, recrystallization, chromatography, extraction and the like can be used.
However, as a method of purification, recrystallization is preferable, and as a recrystallization solvent, hydrocarbon, halogenated hydrocarbon, ethers, ketone, alcohols, esters, amines, polar aprotic solvent, water, or the like Various solvents such as a mixed solvent can be used.
Of these, ethers such as ethylene glycol monomethyl ether (methyl cellosolve), ethylene glycol monoethyl ether (cellosolve), isopropyl ether, tetrahydrofuran and dioxane; ketones such as acetone, methyl ethyl ketone and cyclohexanone; Alcohols, such as alcohol, isopropanol, esters such as methyl acetate, ethyl acetate, butyl acetate, etc., polar aprotic solvents such as dimethylformamide, dimethylacetamide, water, or a mixed solvent thereof, and particularly preferred. Examples of the solvent include alcohols such as methanol, alcohol, and isopropanol.
In particular, in the production of ebinastine hydrochloride in which the above-mentioned hydrochloride formation and purification of 3-amino-9,13b-dihydro-1H-dibenz [c, f] imidazo [1,5-a] azepine are carried out at the same time, degradation occurs. It was an unexpected effect that the use of alcohols such as methanol, which is known to occur, is particularly preferable from the viewpoint of purification.
In the present invention, 3-amino-9,13b-dihydro-1H-dibenz [c, f] imidazo [1,5-a] azepine which is a raw material of epinastine hydrochloride is required for purification by recrystallization. If necessary, an adsorbent (for example, activated carbon) may be added, and the adsorbent may be removed by filtration before crystallization.
ADVANTAGE OF THE INVENTION According to this invention, high-purity epinastine hydrochloride can be manufactured easily without a large load on equipment, and there is a great advantage in a manufacturing process.
[0025]
【Example】
Hereinafter, the present invention will be described specifically with reference to Examples, but the present invention is not limited to these Examples.
The purity of the liquid chromatography in the examples was determined by performing liquid chromatography analysis under the following conditions and using the area% of each component peak as an index of the purity.
Apparatus: LC-2000 Plus series (JASCO Corporation)
Column: Inertsil ODS-3
Moving layer: 20 mmol-KH 2 PO 4 (adjusted to pH = 2.5 with phosphoric acid) A mixture of aqueous solution / acetonitrile = 40/60 and sodium octanesulfonate further added to a concentration of 20 mmol.
Detection wavelength: 240 nm
Preparation Example 3-Amino-7-chloro-9,13b-dihydro-1H-dibenz [c, f] imidazo [1,5-a] azepine hydrochloride was synthesized by the following series of steps.
[0028]
Embedded image
Further, epinastine hydrochloride was obtained by the method of Comparative Example 1.
Under the above liquid chromatography conditions and on some columns, the above-mentioned 3-amino-7-chloro-9,13b-dihydro-1H-dibenz [c, f] imidazo [1,5-a] azepine was used. The retention time of the hydrochloride salt coincides with that of the contaminant peak of ebinastine hydrochloride, and the contaminant is 3-amino-7-chloro-9,13b-dihydro-1H-dibenz [c, f] imidazo [1,5-a]. ] It was confirmed to be azepine / hydrochloride.
Comparative Example 1
After dissolving 11.5 g of 3-amino-9,13b-dihydro-1H-dibenz [c, f] imidazo [1,5-a] azepine obtained by the above method in dimethylformamide containing hydrogen chloride, After cooling with ice water, the content in the form of a slurry was filtered and dried to obtain 10.1 g of ebinastine hydrochloride. The purity of liquid chromatography under the above conditions was 99.21 area%, and 3-amino-7-chloro-9,13b-dihydro-1H-dibenz [c, f] imidazo [1,5-a] azepine hydrochloride was 0%. .19 area%.
Further, 10.1 g of the obtained ebinastine hydrochloride was further recrystallized from 5.5-fold dimethylformamide (DMF). As a result, 7.2 g of ebinastine hydrochloride was obtained. When the purity was similarly measured by liquid chromatography, the 3-amino-7-chloro-9,13b-dihydro-1H-dibenz [c, f] imidazo [1,5-a] azepine hydrochloride was 0.1%. It was 15 area%. It can be seen that the purity has not improved as the yield has decreased.
Embodiment 1
In a 100 ml flask equipped with a stirrer, a reflux condenser and a thermometer, 11.5 g of 3-amino-9,13b-dihydro-1H-dibenz [c, f] imidazo [1,5-a] azepine and 53 ml of ethanol were placed. After the addition, the mixture was refluxed for 30 minutes to dissolve the crystals. The contents in the form of a slurry after cooling with ice water were filtered to obtain white crystals. After dissolving the white crystals in dimethylformamide containing hydrogen chloride, the content in a slurry state after cooling with ice water was filtered and dried to obtain 8.8 g of ebinastine hydrochloride. Liquid chromatography purity 99.96 area%, 3-amino-7-chloro-9,13b-dihydro-1H-dibenz [c, f] imidazo [1,5-a] azepine hydrochloride 0.01 area% Met. The melting point of the obtained ebinastine hydrochloride is 272 ° C. (Japanese Pharmacopoeia, melting point method, method 1).
Embodiment 2
11.5 g of 3-amino-9,13b-dihydro-1H-dibenz [c, f] imidazo [1,5-a] azepine and 53 mL of methanol were added to a 100 ml flask equipped with a stirrer, a reflux condenser and a thermometer. The mixture was refluxed for 30 minutes to dissolve the crystals. The contents in the form of a slurry after cooling with ice water were filtered to obtain white crystals. After dissolving the white crystals in dimethylformamide containing hydrogen chloride, the contents in a slurry state after cooling with ice water were filtered and dried to obtain 9.0 g of epinastine hydrochloride. The purity of liquid chromatography was 99.96 area%, and the amount of 3-amino-7-chloro 9,13b-dihydro-1H-dibenz [c, f] imidazo [1,5-a] azepine hydrochloride was 0.01 area%. Was.
Embodiment 3
11.5 g of 3-amino-9,13b-dihydro-1H-dibenz [c, f] imidazo [1,5-a] azepine, 42 mL of methanol and 11 mL of water were added to a 100 ml flask equipped with a stirrer, a reflux condenser and a thermometer. After refluxing for 30 minutes, the crystals were dissolved. The contents in the form of a slurry after cooling with ice water were filtered to obtain white crystals. After dissolving the white crystals in dimethylformamide containing hydrogen chloride, the content in a slurry state after cooling with ice water was filtered and dried to obtain 9.1 g of epinastine hydrochloride. Liquid chromatography purity 99.95 area%, 3-amino-7-chloro 9,13b-dihydro-1H-dibenz [c, f] imidazo [1,5-a] azepine hydrochloride 0.01 area%
Embodiment 4
To a 100 ml flask equipped with a stirrer, reflux condenser and thermometer were added 11.5 g of 3-amino-9,13b-dihydro-1H-dibenz [c, f] imidazo [1,5-a] azepine, 53 mL of methanol and 1 g of activated carbon. After refluxing for 30 minutes, the crystals were dissolved. After the dissolution, the mixture was filtered while hot to remove activated carbon, and then cooled in ice water to form a slurry, which was filtered to obtain white crystals. After dissolving the white crystals in dimethylformamide containing hydrogen chloride, the contents in a slurry state after cooling with ice water were filtered and dried to obtain 9.0 g of epinastine hydrochloride. The purity of liquid chromatography was 99.97 area%, and the amount of 3-amino-7-chloro 9,13b-dihydro-1H-dibenz [c, f] imidazo [1,5-a] azepine hydrochloride was 0.01 area%. Was.
As described above, it has been shown that the concentration of contaminants is drastically reduced (one digit) and the purity is greatly increased by the method of the present invention.
[0038]
【The invention's effect】
According to the method of the present invention, it is easy to produce high-quality epinastine hydrochloride from which contaminants have been removed, and the value in the production process is great.
Claims (4)
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104098575A (en) * | 2013-04-15 | 2014-10-15 | 四川科瑞德凯华制药有限公司 | Epinastine hydrochloride crystal form, and preparation method and application thereof |
| CN115974882A (en) * | 2023-02-08 | 2023-04-18 | 广州艾格生物科技有限公司 | A kind of preparation method of epinastine hydrochloride impurity |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS56139484A (en) * | 1980-03-08 | 1981-10-30 | Boehringer Sohn Ingelheim | Heterocyclic compound |
| JPH04346988A (en) * | 1991-01-25 | 1992-12-02 | Boehringer Ingelheim Kg | Method for manufacturing 3-amino-9,13b-dihydro-1hdibenz (c,f)-imidazo-(1,5-1a)-azepine hydrochloride |
| JP2001064282A (en) * | 1999-08-23 | 2001-03-13 | Sawai Pharmaceutical Co Ltd | Imidazoline compound, its intermediate and production thereof and production of azepine compound and its salt |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS56139484A (en) * | 1980-03-08 | 1981-10-30 | Boehringer Sohn Ingelheim | Heterocyclic compound |
| JPH04346988A (en) * | 1991-01-25 | 1992-12-02 | Boehringer Ingelheim Kg | Method for manufacturing 3-amino-9,13b-dihydro-1hdibenz (c,f)-imidazo-(1,5-1a)-azepine hydrochloride |
| JP2001064282A (en) * | 1999-08-23 | 2001-03-13 | Sawai Pharmaceutical Co Ltd | Imidazoline compound, its intermediate and production thereof and production of azepine compound and its salt |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104098575A (en) * | 2013-04-15 | 2014-10-15 | 四川科瑞德凯华制药有限公司 | Epinastine hydrochloride crystal form, and preparation method and application thereof |
| CN115974882A (en) * | 2023-02-08 | 2023-04-18 | 广州艾格生物科技有限公司 | A kind of preparation method of epinastine hydrochloride impurity |
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