JP2006511439A - 医薬上有効な化合物(グラニセトロン)の製造方法 - Google Patents
医薬上有効な化合物(グラニセトロン)の製造方法 Download PDFInfo
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- JP2006511439A JP2006511439A JP2003578360A JP2003578360A JP2006511439A JP 2006511439 A JP2006511439 A JP 2006511439A JP 2003578360 A JP2003578360 A JP 2003578360A JP 2003578360 A JP2003578360 A JP 2003578360A JP 2006511439 A JP2006511439 A JP 2006511439A
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- Prior art keywords
- granisetron
- solvent
- compound
- formula
- methyl
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- 0 C*CC1=CC[C@](C=NNc2c(*(C(N[C@]3CC(CCC4ON4C)CC3)=O)O)cccc2)C=C1 Chemical compound C*CC1=CC[C@](C=NNc2c(*(C(N[C@]3CC(CCC4ON4C)CC3)=O)O)cccc2)C=C1 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
- C07D453/06—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing isoquinuclidine ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/08—Bridged systems
-
- 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
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Life Sciences & Earth Sciences (AREA)
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- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Hospice & Palliative Care (AREA)
- Pharmacology & Pharmacy (AREA)
- Otolaryngology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Description
の化合物を反応させることにより得られる。
a)式(I):
b)式(II)の化合物を、不活性溶媒中、0〜160℃に温度にて、塩基の存在下、アルキル化剤でメチル化し、さらに所望によりその医薬上許容される塩を得る
ことを含む、グラニセトロンまたはその医薬上許容される塩を製造する新規な方法を提供する。
本発明の非限定的な例として以下の実施例を示す。
実施例1:エンド−2−[2−(N’−ベンジリデン−ヒドラジノ)−フェニル]−N−(9−メチル−9−アザ−ビシクロ[3.3.1]ノン−3−イル)−2−オキソ−アセタミド
500mlの丸底フラスコにて250mlのテトラヒドロフラン中に29.22グラム(0.117mol)の1−(ベンジリデン−アミノ)−1H−インドール−2,3−ジオンおよび18グラム(0.117mol)のエンド−9−メチル−9−アザ−ビシクロ[3.3.1]ノン−3−イルアミンを溶かし、不活性雰囲気下で5時間還流した。次に、減圧下で溶媒を蒸発させ、得られたオイルを次の工程に用いた。
実施例1で得られたオイルを総て500mlのメタノールに溶かした後、118mlの2N塩酸(0.234mol)を加えた。この混合物を20℃〜25℃で2時間攪拌した。減圧下で大部分のメタノールを蒸発除去した。250mlの酢酸エチルを加え、生成物を250mlの1N塩酸で抽出した。合併した水相を150mlの酢酸エチルで洗浄した。水相を、10%水酸化ナトリウムを添加してpH10〜11に調整した。生じた固体を濾過し、真空乾燥させ、28.63グラム(82%)の標題生成物を得た。
a)エンド−1−メチル−N−(9−メチル−9−アザバイサイクル[3.3.1]ノン−3−イル)−1H−インダゾール−3−カルボキサミド
2g(6.70mmol)のエンド−N−(9−メチル−9−アザ−ビシクロ[3.3.1]ノン−3−イル)−1H−インダゾール−3−カルボキサミド、38mlの塩化メチレン、1.43mlの50%ソーダ、0.51mlの水および0.1gのTBACを250mlの丸底フラスコに入れた。塩化メチレン8mlに溶かした硫酸ジメチル0.68ml(7.10mmol)の溶液を、温度を18〜22℃に維持しつつ、1時間かけて滴下した。
M.p.: 121-122 ℃
IR(cm-1) : 3420, 2920, 2860, 1670, 1530, 1495, 1285, 1210, 1130, 770, 470.
1H-NMR (CDCl3) (δ, ppm) :
1,05 (m, 2H); 1, 37 (dt, 2H); 1,52 (m, 1H); 1,96 (sc, 3H); 2,51 (s, 3H); 2,53 (m, 2H); 3,09 (d, 2H); 4,06 (s, 3H); 4,57 (m, 1H); 6,78 (d, 1H deut); 7,27 (dt, 1H); 7,39 (sc, 2H); 8,39 (d, 1H);
13C-NMR (CDCl3) (ppm):
14.3, 24.8 (2 C), 33.1 (2 C), 35.9, 40.6, 40.7, 51,2 (2 C), 108.9, 122.4, 122.7, 123.0, 126.7, 137.5, 141.2, 161.8,
残渣を20mlのIPAに溶かし、1.1当量の塩酸を加えた。大部分のIPAを蒸発除去し、20mlのAcOEtを加え、沈殿を分散させ、濾過し、乾燥させた。純度92%のグラニセトロン塩酸塩が収率77%で得られた。
2g(6.7mmol)のエンド−N−(9−メチル−9−アザ−ビシクロ[3.3.1]−ノン−3−イル)−1H−インダゾール−3−カルボキサミド、23mlのトルエン、2mlの50%ソーダ、0.7ml(7.3mmol)の硫酸ジメチルおよび0.1gのTBACを250mlの丸底フラスコに入れた。
2g(6.7mmol)のエンド−N−(9−メチル−9−アザ−ビシクロ[3.3.1]ノン−3−イル)−1H−インダゾール−3−カルボキサミド、38mlのTHF、1.43mlの50%水酸化ナトリウム、0.51mlの水および0.1gのTBACを250mlの丸底フラスコに入れた。THF8mlに溶かした硫酸ジメチル0.68ml(7.1mmol)の溶液を、温度を18〜22℃に維持しつつ、1時間かけて滴下した。
46mlの乾燥DMF、2g(6.70mmol)のエンド−N−(9−メチル−9−アザ−ビシクロ[3.3.1]ノン−3−イル)−1H−インダゾール−3−カルボキサミド、3g(21.7mmol)の炭酸カリウムおよび0.86ml(10.24mmol)の炭酸ジメチルを250mlの丸底フラスコに入れた。
Claims (10)
- 工程a)がプロトン性溶媒またはプロトン性溶媒の混合物中で行われる、請求項1に記載の方法。
- 工程a)が10℃〜40℃の間の温度で行われる、請求項1に記載の方法。
- アルキル化剤が硫酸ジメチルである、請求項1に記載の方法。
- アルキル化剤が炭酸ジメチルである、請求項1に記載の方法。
- 工程b)の溶媒が塩化メチレン、トルエンまたはテトラヒドロフランの中から選択される、請求項1〜4のいずれか1項に記載の方法。
- 塩基が濃水溶液または固形状の水酸化ナトリウムまたはカリウムである、請求項1〜4のいずれか1項に記載の方法。
- 工程b)が相転移触媒の存在下で行われる、請求項1〜4のいずれか1項に記載の方法。
- 工程b)の溶媒がジメチルホルムアミド(DMF)またはN−メチル−2−ピロリドン(NMP)のいずれかから選択される極性非プロトン性溶媒である、請求項1〜5のいずれか1項に記載の方法。
- 塩基がアルカリ金属炭酸塩である、請求項1〜5のいずれか1項に記載の方法。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ES200200713A ES2197001B1 (es) | 2002-03-26 | 2002-03-26 | Procedimiento de obtencion de un compuesto farmaceuticamente activo. |
PCT/IB2003/001058 WO2003080606A1 (en) | 2002-03-26 | 2003-03-21 | Process for preparing a pharmaceutically active compound (granisetron) |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2006511439A true JP2006511439A (ja) | 2006-04-06 |
JP4560293B2 JP4560293B2 (ja) | 2010-10-13 |
Family
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2003578360A Expired - Fee Related JP4560293B2 (ja) | 2002-03-26 | 2003-03-21 | 医薬上有効な化合物(グラニセトロン)の製造方法 |
Country Status (14)
Country | Link |
---|---|
US (1) | US7071209B2 (ja) |
EP (1) | EP1487833B1 (ja) |
JP (1) | JP4560293B2 (ja) |
KR (1) | KR100835553B1 (ja) |
AT (1) | ATE299144T1 (ja) |
AU (1) | AU2003208552A1 (ja) |
CA (1) | CA2481703A1 (ja) |
DE (1) | DE60300986D1 (ja) |
ES (1) | ES2197001B1 (ja) |
IL (1) | IL164742A0 (ja) |
PL (1) | PL211464B1 (ja) |
PT (1) | PT1487833E (ja) |
TW (1) | TWI291959B (ja) |
WO (1) | WO2003080606A1 (ja) |
Families Citing this family (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
MXPA05003317A (es) | 2002-09-25 | 2005-07-05 | Memory Pharm Corp | Indazoles, benzotiazoles y benzoisotiazoles asi como preparacion y usos de los mismos. |
DK1697378T3 (da) | 2003-12-22 | 2008-03-17 | Memory Pharm Corp | Indoler, 1H-indazoler, 1,2-benzisoxazoler og 1,2-benzisothiazoler og fremstilling og anvendelser deraf |
KR101176670B1 (ko) | 2004-03-25 | 2012-08-23 | 메모리 파마슈티칼스 코포레이션 | 인다졸, 벤조티아졸, 벤조이소티아졸, 벤즈이속사졸, 및그의 제조법 및 용도 |
DE602005024677D1 (de) | 2004-04-22 | 2010-12-23 | Memory Pharm Corp | Indole, 1h-indazole, 1,2-benzisoxazole, 1,2-benzoisothiazole, deren herstellung und verwendungen |
JP2007538011A (ja) | 2004-05-07 | 2007-12-27 | メモリー・ファーマシューティカルズ・コーポレイション | 1h−インダゾール、ベンゾチアゾール、1,2−ベンゾイソキサゾール、1,2−ベンゾイソチアゾール、およびクロモン、ならびにそれらの調製および使用 |
MX2007007328A (es) | 2004-12-22 | 2007-07-25 | Memory Pharm Corp | Ligandos del receptor alfa-7 nicotinico y preparacion y sus usos. |
RU2420525C2 (ru) | 2005-07-11 | 2011-06-10 | Мицубиси Танабе Фарма Корпорейшн | Производные оксимов и их получение |
US8911751B2 (en) | 2005-10-11 | 2014-12-16 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Compositions for nasal delivery |
WO2007088557A1 (en) * | 2006-02-01 | 2007-08-09 | Natco Pharma Limited | Process for highly pure crystalline granisetron base |
US20080242696A1 (en) * | 2007-03-27 | 2008-10-02 | Chemagis Ltd. | Crystalline granisetron base and production process therefor |
US8304426B2 (en) | 2007-06-13 | 2012-11-06 | Inke, S.A. | Polymorphic form of Granisetron base, methods for obtaining it and formulation containing it |
CN102131506B (zh) * | 2008-08-19 | 2013-07-24 | 台湾神隆股份有限公司 | 盐酸格拉司琼的多晶型和其制备方法 |
US20120101089A1 (en) * | 2010-10-26 | 2012-04-26 | Ashwani Agarwal | Anti-Emetic Substance |
CN112778203B (zh) * | 2021-01-29 | 2022-02-15 | 兰州交通大学 | 1h-吲唑-3-羧酸衍生物及格拉斯琼和氯尼达明的制备方法 |
CN115372487B (zh) * | 2021-05-18 | 2023-10-10 | 成都倍特得诺药业有限公司 | 盐酸格拉司琼中杂质e的hplc测定方法 |
Citations (1)
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JP2000504715A (ja) * | 1996-02-13 | 2000-04-18 | スミスクライン・ビーチャム・パブリック・リミテッド・カンパニー | グラニセトロンの製造方法 |
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DE3687080T2 (de) | 1985-04-27 | 1993-03-25 | Beecham Group Plc | Azabicyclononyl-indazol-carboxamid mit 5-ht-antagonistischer wirkung. |
GB9404055D0 (en) | 1994-03-03 | 1994-04-20 | Smithkline Beecham Plc | Novel process |
GB9602862D0 (en) * | 1996-02-13 | 1996-04-10 | Smithkline Beecham Plc | Novel process |
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2002
- 2002-03-26 ES ES200200713A patent/ES2197001B1/es not_active Expired - Fee Related
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2003
- 2003-03-21 CA CA002481703A patent/CA2481703A1/en not_active Abandoned
- 2003-03-21 US US10/508,493 patent/US7071209B2/en not_active Expired - Fee Related
- 2003-03-21 JP JP2003578360A patent/JP4560293B2/ja not_active Expired - Fee Related
- 2003-03-21 AT AT03706845T patent/ATE299144T1/de not_active IP Right Cessation
- 2003-03-21 WO PCT/IB2003/001058 patent/WO2003080606A1/en active IP Right Grant
- 2003-03-21 PT PT03706845T patent/PT1487833E/pt unknown
- 2003-03-21 AU AU2003208552A patent/AU2003208552A1/en not_active Abandoned
- 2003-03-21 KR KR1020047015135A patent/KR100835553B1/ko not_active IP Right Cessation
- 2003-03-21 DE DE60300986T patent/DE60300986D1/de not_active Expired - Lifetime
- 2003-03-21 EP EP03706845A patent/EP1487833B1/en not_active Expired - Lifetime
- 2003-03-21 PL PL374447A patent/PL211464B1/pl not_active IP Right Cessation
- 2003-03-26 TW TW092106806A patent/TWI291959B/zh active
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- 2004-10-20 IL IL16474204A patent/IL164742A0/xx unknown
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2000504715A (ja) * | 1996-02-13 | 2000-04-18 | スミスクライン・ビーチャム・パブリック・リミテッド・カンパニー | グラニセトロンの製造方法 |
Also Published As
Publication number | Publication date |
---|---|
WO2003080606A1 (en) | 2003-10-02 |
EP1487833A1 (en) | 2004-12-22 |
WO2003080606A8 (en) | 2005-03-17 |
TW200305572A (en) | 2003-11-01 |
ES2197001A1 (es) | 2003-12-16 |
PL211464B1 (pl) | 2012-05-31 |
PT1487833E (pt) | 2005-11-30 |
DE60300986D1 (de) | 2005-08-11 |
US20050124650A1 (en) | 2005-06-09 |
KR20040099361A (ko) | 2004-11-26 |
JP4560293B2 (ja) | 2010-10-13 |
KR100835553B1 (ko) | 2008-06-09 |
US7071209B2 (en) | 2006-07-04 |
ES2197001B1 (es) | 2004-11-16 |
AU2003208552A1 (en) | 2003-10-08 |
IL164742A0 (en) | 2005-12-18 |
TWI291959B (en) | 2008-01-01 |
PL374447A1 (en) | 2005-10-17 |
EP1487833B1 (en) | 2005-07-06 |
CA2481703A1 (en) | 2003-10-02 |
ATE299144T1 (de) | 2005-07-15 |
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