JP5319119B2 - 臭化グリコピロニウムの結晶化および精製 - Google Patents
臭化グリコピロニウムの結晶化および精製 Download PDFInfo
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- JP5319119B2 JP5319119B2 JP2007557594A JP2007557594A JP5319119B2 JP 5319119 B2 JP5319119 B2 JP 5319119B2 JP 2007557594 A JP2007557594 A JP 2007557594A JP 2007557594 A JP2007557594 A JP 2007557594A JP 5319119 B2 JP5319119 B2 JP 5319119B2
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- crystallization
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- glycopyrronium
- glycopyrronium bromide
- mek
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/12—Oxygen or sulfur atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/06—Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/06—Anti-spasmodics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Urology & Nephrology (AREA)
- Epidemiology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicinal Preparation (AREA)
- Silicates, Zeolites, And Molecular Sieves (AREA)
- Pyrrole Compounds (AREA)
Description
本発明は新規な結晶化工程(スキーム1のステージ3)を用いる臭化グリコピロニウムの製造に関する。高純度であることに加えて、溶媒、例えば式R1COR2またはR1COOR2(ここで、R1およびR2はそれぞれ炭素数1から8のアルキルである)で表される溶媒により、均一で微細な粒径に制御される。さらに、好ましくは、この工程は最終結晶化工程を低冷却速度でおこなうことを含む。この方法で得られた臭化グリコピロニウムの粒径により、吸入デリバリーに最適化された薬剤に製剤するのに適した物理的に安定な微粒化薬剤物質が保証される。
本明細書に提示する情報に基づいて、当業者は本発明の使用に好適な溶媒を容易に決定することができる。例としてアセトンが挙げられるが、好適と考えられる他の溶媒としては、たとえば、酢酸エチルのような酢酸エステル類やメチルイソブチルケトン(MEK)のような他のケトン類が挙げられる。上記式中のR1およびR2は好ましくはC1−4アルキルであり、R1は好ましくはメチルである。アセトンより炭素数の多いケトンが再結晶化には好ましい。
粗グリコピロニウム塩基(13.0kg;42.8mol)のアセトン(130L)溶液を臭化メチルガス(4.5kg;47.4mol)で、温度を−5℃と5℃の間に保ちながら30分間処理する。次いで、混合物を15℃と25℃の間に加温し、この温度に2時間保って臭化グリコピロニウムの完全な結晶化を確実にする。生成物を遠心ろ過し、冷アセトン(40−60L)で洗浄し、回収する(15kg)。
この物質(15kg)をメタノール(13.0L)とMEK(90L)との混合物に還流下で溶解する。MEK(135L)をさらに加えて、75〜85℃で30分間還流する。次いで、混合物を−10℃と0℃の間に30℃/時の速度で冷却して精製生成物の制御された結晶化を行った後、遠心ろ過し、冷MEK(30〜50L)で洗浄し、回収する(7kg)。この1次結晶化で得られた生成物の純度は典型的には99%以上であり、ジアステレオマー純度は典型的には94〜95%(HPLCによる)である。
この物質(7kg)をメタノール(10.2L)とMEK(45L)との混合物に還流下で溶解する。MEK(65L)をさらに加えて、75〜85℃で30分間還流する。次いで、混合物を−10℃と0℃の間に30℃/時の速度で冷却して精製生成物の制御された結晶化を行った後、遠心ろ過し、冷MEK(20〜30L)で洗浄し、回収する(5.3kg)。この再結晶化で得られた生成物の純度は典型的には99.9%以上であり、ジアステレオマー純度は典型的には99.5%以上(HPLCによる)である。
この物質(5.3kg)をメタノール(4.2L)とMEK(33)との混合物に還流下で溶解する。MEK(47L)をさらに加えて、75〜85℃で30分間還流する。次いで、混合物を−10℃と0℃の間に30℃/時の速度で冷却して精製生成物の制御された結晶化を行った後、ろ過し、冷MEK(20L)で洗浄し、オーブンで乾燥させる。この薬剤物質は白色微結晶固体(4.9kg)である。この1次再結晶化からの生成物の純度は典型的には99.95%以上であり、ジアステレオマー純度は典型的には99.8%以上(HPLCによる)である。
この方法はWaters社のAlliance 2695型HPLC装置にPDA 996検出器、カラムオーブン、およびWaters社のEmpowerデータシステムを備えたもの、あるいは同等物を使用する。
250mm×4.6mm(内径)
温度: 15℃
注入量: 20μL
検出: UV(230nm)
稼働時間: 20分
移動相: 1.0M酢酸トリエチルアンモニウム緩衝溶液(5.0ml)に
アセトニトリル(750ml)とHPLC水(245ml)を
混合したもの
流速: 1.0ml/分
グラジエント:定組成
(R,S)/(S,R)臭化グリコピロニウム(薬剤物質)および(R,R)/(S,S)不純物についての保持時間(run times)ならびに相対応答時間は次の通り。
Claims (2)
- アセトン中でグリコピロニウム塩基と臭化メチルとを反応させるステップと、
その後、結晶化溶媒としてメチルエチルケトンとメタノールとの混合物を用いる結晶化工程により所望のジアステレオマーを分離するステップ
とを含む、
分離される物質のジアステレオマー比が少なくとも60:40で(R,S)/(S,R)対が(R,R)/(S,S)対より多い、臭化グリコピロニウム結晶の製造方法。 - 生成物(R,S)/(S,R)のジアステレオマー純度が99.8%より高い、請求項1に記載の方法。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB0504463.1 | 2005-03-03 | ||
GBGB0504463.1A GB0504463D0 (en) | 2005-03-03 | 2005-03-03 | Method of crystallisation and purification |
PCT/GB2006/000770 WO2006092617A1 (en) | 2005-03-03 | 2006-03-03 | Crystallisation and purification of glycopyrronium bromide |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2008531674A JP2008531674A (ja) | 2008-08-14 |
JP5319119B2 true JP5319119B2 (ja) | 2013-10-16 |
Family
ID=34451780
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2007557594A Active JP5319119B2 (ja) | 2005-03-03 | 2006-03-03 | 臭化グリコピロニウムの結晶化および精製 |
Country Status (21)
Country | Link |
---|---|
US (1) | US8846954B2 (ja) |
EP (1) | EP1856041B1 (ja) |
JP (1) | JP5319119B2 (ja) |
KR (1) | KR101267108B1 (ja) |
CN (1) | CN101133021B (ja) |
AT (1) | ATE431337T1 (ja) |
AU (1) | AU2006219727B2 (ja) |
BR (1) | BRPI0609057A2 (ja) |
CA (1) | CA2601129C (ja) |
DE (1) | DE602006006808D1 (ja) |
DK (1) | DK1856041T3 (ja) |
ES (1) | ES2326132T3 (ja) |
GB (1) | GB0504463D0 (ja) |
HK (1) | HK1104817A1 (ja) |
IL (1) | IL185576A (ja) |
MX (1) | MX2007010729A (ja) |
NO (1) | NO340220B1 (ja) |
NZ (1) | NZ561293A (ja) |
PT (1) | PT1856041E (ja) |
WO (1) | WO2006092617A1 (ja) |
ZA (1) | ZA200707512B (ja) |
Families Citing this family (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20090005577A1 (en) * | 2007-06-29 | 2009-01-01 | Nikolai Kraiouchkine | Method of producing 1-substituted 3-pyrrolates |
ES2617680T3 (es) * | 2009-04-09 | 2017-06-19 | Novartis Ag | Proceso para la preparación de sales de pirrolidinio |
KR101736529B1 (ko) * | 2010-06-14 | 2017-05-17 | 키에시 파르마슈티시 엣스. 피. 에이. | 글리코피로늄 클로라이드의 결정형 |
CN103159659A (zh) * | 2011-12-19 | 2013-06-19 | 沈阳药科大学 | 一种毒蕈碱受体拮抗剂格隆溴铵的制备方法 |
CN102627595A (zh) * | 2012-03-09 | 2012-08-08 | 徐奎 | 一种制备格隆溴铵的方法 |
KR102377252B1 (ko) | 2013-02-28 | 2022-03-22 | 저니 메디컬 코퍼레이션 | 글리코피롤레이트 염 |
US9006462B2 (en) | 2013-02-28 | 2015-04-14 | Dermira, Inc. | Glycopyrrolate salts |
US8558008B2 (en) | 2013-02-28 | 2013-10-15 | Dermira, Inc. | Crystalline glycopyrrolate tosylate |
CN105175304A (zh) * | 2013-11-13 | 2015-12-23 | 李兴惠 | 抗胆碱药物格隆溴铵及组合物 |
US9926270B2 (en) | 2014-08-20 | 2018-03-27 | Dermira, Inc. | Process for production of glycopyrronium tosylate |
CZ2014680A3 (cs) | 2014-10-06 | 2016-04-13 | Zentiva, K.S. | Způsob přípravy glykopyrronium bromidu |
US9925168B2 (en) * | 2016-01-22 | 2018-03-27 | Chiesi Farmaceutici S.P.A. | Preparation of micronized particles of an antimuscarinic compound by hydrodynamic cavitation |
CN107345945B (zh) * | 2016-05-05 | 2019-12-17 | 辽宁药联制药有限公司 | 一种拆分格隆溴铵对映体及杂质检查的高效液相色谱方法 |
PT109445B (pt) | 2016-06-08 | 2018-11-06 | Hovione Farm Sa | Co-cristais farmacêuticos cristalinos de brometo de glicopirrónio com lactose |
CN107915666A (zh) * | 2016-10-09 | 2018-04-17 | 四川海思科制药有限公司 | 一种格隆溴铵化合物 |
WO2022079194A1 (en) | 2020-10-14 | 2022-04-21 | Pcas | Process for the production of glycopyrronium tosylate |
CN113234003B (zh) * | 2021-04-23 | 2024-02-02 | 广东嘉博制药有限公司 | 一种格隆溴铵及其制备方法 |
CN114428131B (zh) * | 2021-12-27 | 2023-09-15 | 山东泰合医药科技有限公司 | 一种拆分格隆溴铵中间体的非对映异构体的检测方法 |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2956062A (en) * | 1959-02-26 | 1960-10-11 | Robins Co Inc A H | Esters of amino alcohols |
RU2238936C2 (ru) * | 1996-11-11 | 2004-10-27 | Кристиан Р. НОЕ | Энантиомерно чистые основные эфиры арил-циклоалкилгидроксикарбоновых кислот, способ их получения и применение в лекарственных средствах |
AT412088B (de) * | 2002-12-18 | 2004-09-27 | Pharmacon Forschung & Beratung Gmbh | Verfahren zur herstellung der r,r oder s,s konfigurierten glycopyrronium-isomere |
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2005
- 2005-03-03 GB GBGB0504463.1A patent/GB0504463D0/en not_active Ceased
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2006
- 2006-03-03 AT AT06709993T patent/ATE431337T1/de active
- 2006-03-03 BR BRPI0609057-5A patent/BRPI0609057A2/pt not_active Application Discontinuation
- 2006-03-03 ES ES06709993T patent/ES2326132T3/es active Active
- 2006-03-03 US US11/817,166 patent/US8846954B2/en active Active
- 2006-03-03 ZA ZA200707512A patent/ZA200707512B/xx unknown
- 2006-03-03 DK DK06709993T patent/DK1856041T3/da active
- 2006-03-03 EP EP06709993A patent/EP1856041B1/en active Active
- 2006-03-03 WO PCT/GB2006/000770 patent/WO2006092617A1/en active Application Filing
- 2006-03-03 KR KR1020077022077A patent/KR101267108B1/ko active IP Right Grant
- 2006-03-03 DE DE602006006808T patent/DE602006006808D1/de active Active
- 2006-03-03 PT PT06709993T patent/PT1856041E/pt unknown
- 2006-03-03 NZ NZ561293A patent/NZ561293A/en unknown
- 2006-03-03 JP JP2007557594A patent/JP5319119B2/ja active Active
- 2006-03-03 MX MX2007010729A patent/MX2007010729A/es active IP Right Grant
- 2006-03-03 CA CA2601129A patent/CA2601129C/en active Active
- 2006-03-03 AU AU2006219727A patent/AU2006219727B2/en active Active
- 2006-03-03 CN CN2006800069015A patent/CN101133021B/zh active Active
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- 2007-08-29 IL IL185576A patent/IL185576A/en active IP Right Grant
- 2007-09-10 NO NO20074558A patent/NO340220B1/no unknown
- 2007-11-29 HK HK07113058.5A patent/HK1104817A1/xx unknown
Also Published As
Publication number | Publication date |
---|---|
CN101133021A (zh) | 2008-02-27 |
CA2601129A1 (en) | 2006-09-08 |
CN101133021B (zh) | 2011-01-19 |
GB0504463D0 (en) | 2005-04-13 |
ES2326132T3 (es) | 2009-10-01 |
KR20070113263A (ko) | 2007-11-28 |
EP1856041B1 (en) | 2009-05-13 |
KR101267108B1 (ko) | 2013-05-23 |
WO2006092617A1 (en) | 2006-09-08 |
DK1856041T3 (da) | 2009-08-24 |
PT1856041E (pt) | 2009-07-21 |
ATE431337T1 (de) | 2009-05-15 |
DE602006006808D1 (de) | 2009-06-25 |
IL185576A0 (en) | 2008-01-06 |
HK1104817A1 (en) | 2008-01-25 |
US20080227988A1 (en) | 2008-09-18 |
IL185576A (en) | 2011-11-30 |
AU2006219727A1 (en) | 2006-09-08 |
BRPI0609057A2 (pt) | 2010-02-17 |
AU2006219727B2 (en) | 2010-03-04 |
JP2008531674A (ja) | 2008-08-14 |
NZ561293A (en) | 2010-05-28 |
MX2007010729A (es) | 2007-11-08 |
NO340220B1 (no) | 2017-03-20 |
NO20074558L (no) | 2007-09-28 |
US8846954B2 (en) | 2014-09-30 |
CA2601129C (en) | 2013-04-30 |
EP1856041A1 (en) | 2007-11-21 |
ZA200707512B (en) | 2008-11-26 |
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R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |