CN1310711A - 喹啉衍生物的制备方法及中间体 - Google Patents
喹啉衍生物的制备方法及中间体 Download PDFInfo
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- CN1310711A CN1310711A CN99809003A CN99809003A CN1310711A CN 1310711 A CN1310711 A CN 1310711A CN 99809003 A CN99809003 A CN 99809003A CN 99809003 A CN99809003 A CN 99809003A CN 1310711 A CN1310711 A CN 1310711A
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- quinoline
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D215/14—Radicals substituted by oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Quinoline Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
本发明涉及经氰基甲基膦酸二乙酯与式(2)所示醛化合物反应所得的腈化合物(1)得到喹啉衍生物(3)的制备方法及其中间体(1)。
Description
技术领域
本发明涉及可作为降胆固醇药物(HMG-CoA还原酶抑制剂)有用中间体的式(3)所示喹啉衍生物的制备方法。
背景技术
式(4)所示喹啉化合物是特开平1-279866号公报、欧洲专利公开304063号公报、美国专利5011930号公报中记载的作为降胆固醇药物(HMG-CoA还原酶抑制剂)有用的化合物。
上述专利中记载的喹啉化合物(4)的制备方法如下所示，将醛化合物(2)转化为α,β-不饱和羧酸酯化合物(5)，再还原成醇化合物(6)后，氧化成目的喹啉衍生物(3)。将α,β-不饱和羧酸酯化合物还原，直接合成目的喹啉衍生物(3)虽然效率高，但其控制有困难。
发明的揭示
为了解决上述问题，本发明者进行了锐意研究，发现经氰基甲基膦酸二乙酯与式(2)所示醛化合物反应得到的腈化合物(1)可一步得到目的喹啉衍生物(3)。
即，本发明涉及经氰基甲基膦酸二乙酯与式(2)所示醛化合物反应所得的腈化合物(1)得到喹啉衍生物(3)的制备方法及其中间体(1)。
经氰基甲基膦酸二乙酯与式(2)所示醛化合物反应得到的腈化合物(式(1))可一步得到目的喹啉衍生物(3)。
实施发明的最佳状态
以下，对本发明化合物的制备方法加以说明。
腈化合物(1)的合成
反应中使用的溶剂可列举甲苯、二甲苯等芳族烃、四氢呋喃、二噁烷等醚溶剂、二氯乙烷、邻二氯苯等卤系溶剂。
氰基甲基膦酸二乙酯的用量在0.5-5倍摩尔范围内，较佳为0.9-1.5倍范围。
碱的种类可使用氢化钠、氢氧化钠、氢氧化钾、甲醇钠、乙醇钠、叔丁醇钾、碳酸钾等。使用量随使用的溶剂和碱的种类而异，但在0.5-10倍摩尔范围内。例如，溶剂为甲苯、碱为氢氧化钠(水溶液)的组合情况下，必要时也可使用Aliquat 336等相转移催化剂。
反应温度在-20-80℃范围内，较佳为20-40℃范围。
喹啉衍生物(3)的合成
用氢化二异丁基铝作为还原剂，甲苯、二甲苯等芳族烃作为溶剂，进行反应，得到良好结果。氢化二异丁基铝的用量为0.5-5倍摩尔的范围，较佳为0.9-1.5倍摩尔的范围；反应温度在-50-50℃范围内，较佳为-30-5℃范围。也可考虑以甲酸为溶剂，用阮内镍进行还原反应。
实施例
以下，列举实施例对本发明作详细描述，但本发明并不限于这些实施例。
腈化合物(1)的合成
将2-环丙基-4-(4-氟苯基)喹啉-3-甲醛199g(683mmol)溶于960g甲苯中，加入氰基甲基膦酸二乙酯136g(765mmol,1.1当量)、Aliquat 3365.5g(13.6mmol,0.02当量)。
搅拌下，内温维持25-35℃，经0.5-1小时滴加20％氢氧化钠水溶液400g，在同样温度下搅拌1小时。
反应结束后，加水200g，搅拌30分钟后分层。所得有机层用10％氢氧化钠水溶液400ml洗涤，加入400ml饱和食盐水，加1N盐酸水溶液调节为pH7，分层。在所得有机层中加入硫酸钠50g，搅拌1小时后，加活性炭5g、硅胶20g，再搅拌30分钟后，用铺有celite的漏斗过滤。
所得滤液减压蒸去溶剂至残量为400g，将析出的结晶原地加热溶解，加入己烷580g，加热回流30分钟后，冷却至5℃，在同一温度下搅拌2小时，将析出的结晶过滤，用甲苯一己烷(1∶5,w/w)和己烷洗涤后，干燥，得到3-{2-环丙基-4-(4-氟苯基)-3-喹啉基}丙-2-烯腈189g，收率88％，熔点176-178℃。
喹啉衍生物(3)的合成
将3-{2-环丙基-4-(4-氟苯基)-3-喹啉基}丙-2-烯腈181g(576mmol)溶于1812ml甲苯中，冷却至内温-10℃。维持内温-10℃至-5℃的情况下，经1小时向其中滴加1.02摩尔氢化二异丁基铝甲苯溶液650ml(663mmol,1.15当量)，在同样温度下搅拌1小时。
反应后，于维持-10℃至-5℃的情况下滴加乙醇30.5g，在同样温度下搅拌30分钟。维持10℃以下，滴加1N盐酸155ml，在同样温度下搅拌1小时后，在维持同样温度下再滴加35％盐酸9.06ml，于内温25-30℃搅拌1小时。将其用铺有celite的漏斗过滤。
在所得滤液中加入1N盐酸725ml，搅拌30分钟后分层，有机层用1N盐酸360ml、饱和食盐水545ml洗涤。水层全部合并后，用乙酸乙酯725ml再萃取，用饱和食盐水360ml洗涤，与前述有机层合并。在其中加水1090ml，用饱和碳酸氢钠水溶液调节为pH7，用水1090ml、饱和食盐水1090ml洗涤。
所得溶液减压蒸去溶剂，加入环己烷360g、正己烷720g。将其加热回流30分钟后，冷却至0-5℃，在同样温度下搅拌2小时，将析出的结晶过滤，用环己烷-正己烷(1∶2,w/w)、正己烷洗涤后，干燥，得到3-(2-环丙基-4-(4-氟苯基)-3-喹啉基)丙-2-烯醛170g，收率93％。
熔点：146-147℃。
Claims (2)
1．式(1)所示腈化合物。
2．喹啉衍生物(3)的制备方法，其特征在于：经氰基甲基膦酸二乙酯与式(2)所示醛化合物反应所得的腈化合物(1)制得。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP20791198 | 1998-07-23 | ||
| JP207911/1998 | 1998-07-23 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1310711A true CN1310711A (zh) | 2001-08-29 |
| CN1107670C CN1107670C (zh) | 2003-05-07 |
Family
ID=16547618
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN99809003A Expired - Fee Related CN1107670C (zh) | 1998-07-23 | 1999-07-22 | 喹啉衍生物的制备方法及中间体 |
Country Status (21)
| Country | Link |
|---|---|
| US (1) | US6335449B1 (zh) |
| EP (1) | EP1099694B1 (zh) |
| JP (1) | JP4281248B2 (zh) |
| KR (1) | KR100529201B1 (zh) |
| CN (1) | CN1107670C (zh) |
| AT (1) | ATE302190T1 (zh) |
| AU (1) | AU746722C (zh) |
| CA (1) | CA2338334C (zh) |
| CZ (1) | CZ299881B6 (zh) |
| DE (1) | DE69926760T2 (zh) |
| DK (1) | DK1099694T3 (zh) |
| ES (1) | ES2247813T3 (zh) |
| IL (2) | IL140924A0 (zh) |
| MX (1) | MXPA01000890A (zh) |
| NO (1) | NO317787B1 (zh) |
| NZ (1) | NZ509401A (zh) |
| PT (1) | PT1099694E (zh) |
| RU (1) | RU2214402C2 (zh) |
| SK (1) | SK285675B6 (zh) |
| WO (1) | WO2000005213A1 (zh) |
| ZA (1) | ZA200100525B (zh) |
Families Citing this family (20)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP4496585B2 (ja) * | 2000-01-24 | 2010-07-07 | 日産化学工業株式会社 | キノリルプロペナールの製造方法 |
| JP4496586B2 (ja) * | 2000-01-24 | 2010-07-07 | 日産化学工業株式会社 | キノリルアクリロニトリルの製造法及びその中間体 |
| JP4496584B2 (ja) * | 2000-01-24 | 2010-07-07 | 日産化学工業株式会社 | キノリルプロペナールの製造法 |
| ATE366239T1 (de) * | 2000-01-24 | 2007-07-15 | Nissan Chemical Ind Ltd | Verfahren zur herstellung von quinolylpropenal |
| JP4867071B2 (ja) * | 2000-02-21 | 2012-02-01 | 日産化学工業株式会社 | キノリン誘導体の製造方法 |
| AU2001232342A1 (en) | 2000-02-21 | 2001-08-27 | Kuraray Co. Ltd. | Processes for preparing quinoline derivatives and intermediates thereof |
| JPWO2002030425A1 (ja) * | 2000-10-12 | 2004-02-19 | 日産化学工業株式会社 | 糖尿病合併症予防・治療剤 |
| JP2002155056A (ja) * | 2000-11-17 | 2002-05-28 | Ube Ind Ltd | キノリルアクリロニトリル誘導体の製法 |
| TWI309644B (zh) | 2001-02-14 | 2009-05-11 | Nissan Chemical Ind Ltd | |
| JP4590749B2 (ja) * | 2001-02-14 | 2010-12-01 | 宇部興産株式会社 | キノリンカルボキシアルデヒド誘導体の製法 |
| KR20040026705A (ko) * | 2001-08-16 | 2004-03-31 | 테바 파마슈티컬 인더스트리즈 리미티드 | 스타틴의 칼슘 염 형태의 제조 방법 |
| CA2513837A1 (en) * | 2003-02-12 | 2004-08-26 | Paul Adriaan Van Der Schaaf | Crystalline forms of pitavastatin calcium |
| WO2007125547A2 (en) | 2006-05-03 | 2007-11-08 | Manne Satyanarayana Reddy | Novel process for statins and its pharmaceutically acceptable salts thereof |
| US8404841B2 (en) | 2006-10-09 | 2013-03-26 | Msn Laboratories Limited | Process for the preparation of statins and their pharmaceutically acceptable salts thereof |
| WO2010089770A2 (en) | 2009-01-19 | 2010-08-12 | Msn Laboratories Limited | Improved process for the preparation of highly pure (3r,5s)-7-[2-cyclopropyl-4-(4-fluorophenyl) quinolin-3-yl]-3,5-dihydroxy-6(e)-heptenoic acid and pharmaceutically acceptable salts thereof |
| EP2526099B1 (en) | 2010-01-18 | 2016-03-30 | MSN Laboratories Limited | Improved process for the preparation of amide intermediates and their use thereof |
| JP2013516459A (ja) | 2010-01-20 | 2013-05-13 | カディラ・ヘルスケア・リミテッド | ピタバスタチン及び医薬として許容可能なそれらの塩の製造方法 |
| US9034901B2 (en) | 2010-08-25 | 2015-05-19 | Cadila Healthcare Limited | Pitavastatin calcium and process for its preparation |
| CN103508949B (zh) * | 2013-10-22 | 2015-12-09 | 黄河三角洲京博化工研究院有限公司 | 一种（e）-3-[2-环丙基-4-（4-氟-苯基）-3-喹啉基]丙烯醛的合成方法 |
| EP3166929A1 (en) | 2014-07-09 | 2017-05-17 | Lupin Limited | Polymorphic forms of pitavastatin sodium |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5815836A (ja) * | 1981-07-17 | 1983-01-29 | オリンパス光学工業株式会社 | 内視鏡管路の洗浄装置 |
| US5854259A (en) | 1987-08-20 | 1998-12-29 | Nissan Chemical Industries Ltd. | Quinoline type mevalonolactones |
| JP2569746B2 (ja) | 1987-08-20 | 1997-01-08 | 日産化学工業株式会社 | キノリン系メバロノラクトン類 |
| US5185328A (en) | 1987-08-20 | 1993-02-09 | Nissan Chemical Industries Ltd. | Quinoline type mevalonolactones useful for treating hyperlipidemia, hyperlipoproteinemia or atherosclerosis |
| DE3905908A1 (de) * | 1989-02-25 | 1990-09-06 | Bayer Ag | Substituierte chinoline, verfahren zu ihrer herstellung und ihre verwendung in arzneimitteln |
| JP3528186B2 (ja) | 1991-06-24 | 2004-05-17 | 日産化学工業株式会社 | 光学活性キノリンメバロン酸のジアステレオマー塩 |
| JP3130342B2 (ja) | 1991-10-04 | 2001-01-31 | 日産化学工業株式会社 | 動脈硬化性血管内膜肥厚抑制薬 |
| WO1995023125A1 (fr) | 1994-02-25 | 1995-08-31 | Daicel Chemical Industries, Ltd. | Procede de production de compose de mevalonolactone optiquement actif |
-
1999
- 1999-07-22 ES ES99931484T patent/ES2247813T3/es not_active Expired - Lifetime
- 1999-07-22 AU AU47992/99A patent/AU746722C/en not_active Ceased
- 1999-07-22 EP EP99931484A patent/EP1099694B1/en not_active Expired - Lifetime
- 1999-07-22 PT PT99931484T patent/PT1099694E/pt unknown
- 1999-07-22 DE DE69926760T patent/DE69926760T2/de not_active Expired - Lifetime
- 1999-07-22 CA CA002338334A patent/CA2338334C/en not_active Expired - Fee Related
- 1999-07-22 WO PCT/JP1999/003923 patent/WO2000005213A1/ja active IP Right Grant
- 1999-07-22 RU RU2001105200/04A patent/RU2214402C2/ru not_active IP Right Cessation
- 1999-07-22 SK SK62-2001A patent/SK285675B6/sk not_active IP Right Cessation
- 1999-07-22 CN CN99809003A patent/CN1107670C/zh not_active Expired - Fee Related
- 1999-07-22 JP JP2000561169A patent/JP4281248B2/ja not_active Expired - Fee Related
- 1999-07-22 KR KR10-2001-7000778A patent/KR100529201B1/ko not_active IP Right Cessation
- 1999-07-22 DK DK99931484T patent/DK1099694T3/da active
- 1999-07-22 AT AT99931484T patent/ATE302190T1/de active
- 1999-07-22 IL IL14092499A patent/IL140924A0/xx active IP Right Grant
- 1999-07-22 US US09/764,994 patent/US6335449B1/en not_active Expired - Lifetime
- 1999-07-22 NZ NZ509401A patent/NZ509401A/xx not_active IP Right Cessation
- 1999-07-22 MX MXPA01000890A patent/MXPA01000890A/es not_active IP Right Cessation
- 1999-07-22 CZ CZ20010062A patent/CZ299881B6/cs not_active IP Right Cessation
-
2001
- 2001-01-16 IL IL140924A patent/IL140924A/en not_active IP Right Cessation
- 2001-01-18 ZA ZA200100525A patent/ZA200100525B/en unknown
- 2001-01-22 NO NO20010357A patent/NO317787B1/no not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| EP1099694A1 (en) | 2001-05-16 |
| CA2338334A1 (en) | 2000-02-03 |
| AU4799299A (en) | 2000-02-14 |
| ZA200100525B (en) | 2001-08-01 |
| CN1107670C (zh) | 2003-05-07 |
| SK285675B6 (sk) | 2007-06-07 |
| NO20010357D0 (no) | 2001-01-22 |
| EP1099694A4 (en) | 2002-08-14 |
| DE69926760D1 (de) | 2005-09-22 |
| SK622001A3 (en) | 2001-08-06 |
| NO20010357L (no) | 2001-01-22 |
| US6335449B1 (en) | 2002-01-01 |
| WO2000005213A1 (fr) | 2000-02-03 |
| JP4281248B2 (ja) | 2009-06-17 |
| KR100529201B1 (ko) | 2005-11-17 |
| ATE302190T1 (de) | 2005-09-15 |
| CZ200162A3 (en) | 2001-06-13 |
| RU2214402C2 (ru) | 2003-10-20 |
| AU746722B2 (en) | 2002-05-02 |
| DK1099694T3 (da) | 2005-09-19 |
| EP1099694B1 (en) | 2005-08-17 |
| DE69926760T2 (de) | 2006-01-19 |
| NZ509401A (en) | 2002-08-28 |
| PT1099694E (pt) | 2005-10-31 |
| KR20010070987A (ko) | 2001-07-28 |
| IL140924A0 (en) | 2002-02-10 |
| CA2338334C (en) | 2008-07-15 |
| AU746722C (en) | 2003-03-27 |
| IL140924A (en) | 2006-06-11 |
| ES2247813T3 (es) | 2006-03-01 |
| NO317787B1 (no) | 2004-12-13 |
| MXPA01000890A (es) | 2002-06-04 |
| CZ299881B6 (cs) | 2008-12-17 |
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