CN1290697A - 酰化作用方法 - Google Patents
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Classifications
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/12—Radicals substituted by oxygen atoms
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明涉及吲哚的酰化作用,更详细地说是3－酰化吲哚的制备,3－酰化吲哚可以被进一步处理产生在3－位具有一个选择性取代基的吲哚。
Description
本发明涉及吲哚的酰化作用，具体地说是关于3-酰化吲哚的制备，可以进一步处理以产生在3-位具有一个可选择的取代基的吲哚。
到目前为止，吲哚的3-酰化作用典型地用例如在国际专利申请PCT／US91／07194中叙述的方法来实现，即通过吲哚的镁盐与酰氯反应：
其中Z是卤素和R是，例如，取代的吡咯烷基、氮杂环丁基或哌啶基。
镁盐是用适当的吲哚与烷基或芳基卤化镁，优选乙基镁溴化物，在一种惰性溶剂，例如，二乙基醚或四氢呋喃中，在-30℃至65℃的温度下，优选大约25℃下进行反应来制备。
酰氯是用相对应的酸与，例如，草酰氯或亚硫酰氯，在一种惰性溶剂，例如，二氯甲烷、二乙基醚或四氢呋喃中，于-10℃至25℃的温度下进行反应来制备。具有含氮杂环部分的酸可以用适当的保护基，例如，羧基苄基(CBZ)进行N-取代使其不与形成的酰氯反应。
然后在-30℃至50℃的温度下，优选约25℃下，将酰氯溶液缓慢加入到搅拌着的镁盐溶液中，得到所需要的3-酰化吲哚。
这种3-酰化吲哚的制备方法需要独立地制备每一种起始物料，是时间和劳动力集中的，因此不适于商业上的扩大。
因此我们开发了一种制备3-酰化吲哚的新方法，这种方法消除了单独制备前述起始物料的需要。根据本发明，通过将酰氯(如果需要，为N-保护的)溶液和烷基或芳基卤化镁溶液分开地或同时地以“同步的”摩尔加入率加入到吲哚的溶液中以优良的产率得到3-酰化吲哚。
因此本发明所着手解决的问题是提供一种快速和成本有效的制备3-酰化吲哚的方法，该方法避免了现有技术的不令人满意的集中合成，尤其是必须制备和分离吲哚的镁盐。
作为一种进一步节省成本的措施，本发明的方法只需要一摩尔当量的昂贵的吲哚起始物料。这与现有技术方法需要二当量形成了对比，按吲哚起始物料计有效地加倍了酰化物料的产率。
根据本发明，提供了一种制备3-酰化吲哚的方法，该方法包括如所述的制备酰氯和然后将(ⅰ)酰氯溶液和(ⅱ)烷基或芳基卤化镁溶液分开地或同时地加入到搅拌着的吲哚溶液中，加入方式为(a)两种进入的试剂流不立即接触，即它们以一定间隔加入以防止它们互相反应而不与吲哚反应，和(b)两种试剂以“同步的”摩尔加入率加入。
更具体地说，本发明提供一种制备式(Ⅰ)的化合物的方法
其中R=C1-C6烷基，C1-C6烷氧基，C3-C7环烷基或选择性地被一个或多个羟基、C1-C4烷基、C1-C4烷氧基、氟、氟(C1-C4)烷基和氟(C1-C4)烷氧基取代的芳基和X是氢或一个或多个独立地选自氰基、卤素、硝基、C1-C6烷基、C1-C6烷氧基、C3-C7环烷基和选择性地被一个或多个氰基、卤素、硝基、C1-C4烷基、C1-C4烷氧基、氟(C1-C4)烷基和氟(C1-C4)烷氧基取代的芳基的取代基；该方法包括分开地和同时地向搅拌着的式(Ⅱ)的吲哚溶液中其中X是如前述所定义的；加入(ⅰ)含有式RCOCl的酰氯的溶液，其中R如前述所定义的；和(ⅱ)含有烷基或芳基卤化镁的溶液加入方式为(a)以足够的间隔加入溶液(ⅰ)和(ⅱ)防止它们互相反应；和(b)溶液(ⅰ)和(ⅱ)以等量摩尔加入率加入。
根据本发明的特别优选的特征，式(Ⅱ)的吲哚是吲哚本身或是5-卤代吲哚和卤化镁是烷基或芳基镁溴化物，优选乙基镁溴化物。
通过下面实施例来说明本发明的方法。
实施例1
3-(N-CBZ-2-吡咯烷基羧基)-5-溴吲哚的制备
向刚干燥过的装有顶置搅拌和保持在氮气层下的容器中加入5-溴吲哚(3．85千克，19．6摩尔)，接着加入二氯甲烷(12．3升)。形成的混合物在室温下搅拌直到得到均匀的溶液，然后冷却至10-12℃。接着将CBZ-脯氨酰氯在二氯甲烷中的溶液(20摩尔，1．02当量)和1M乙基镁溴化物在MTBE(37．7千克，39．2摩尔，2当量)中的溶液从容器的相对两侧用2-3小时同时加入，同时将温度保持在10-15℃。这些加入必须如此实施以使两种物料流不会混合并且每种试剂的摩尔加入率连续地保持同步。
将形成的淤浆用30分钟加入到剧烈搅拌着的浓盐酸(3升)、软化水(28升)和四氢呋喃(29升)的混合物中，同时保持温度低于25℃。将形成的两相混合物搅拌30分钟，使之沉降20分钟，然后相分离，保留上层有机相。有机层用饱和NaHCO3水溶液(28升)在20-25℃下洗20分钟，使之沉降20分钟，然后相分离，保留上层有机相。在减压同时保持温度低于50℃下除去溶剂；在后期阶段观察到结晶化。向形成的淤浆中加入乙酸乙酯(15．5升)和己烷(15．5升)并将形成的混合物冷却至0℃和在此温度下成粒1小时。然后将产物过滤分离，用1∶1的己烷∶乙酸乙酯(10升)洗，然后于35℃下真空干燥过夜以产生6．85千克(82％)的(R)-3-(N-羧基苯甲酰基-2-吡咯烷基羧基)-5-溴-1H-吲哚精细白色晶体。
计算值：C=59．03％，H=4．48％，N=6．56％。
实测值：C=59．01％，H=4．50％，N=6．58％。
实施例2
3-(N-CBZ-2-吡咯烷基羧基)吲哚的制备
向25毫摩尔吲哚在二氯甲烷(25毫升)中的溶液中用1小时同时加入CBZ-脯氨酰氯(25毫摩尔)在25毫升MTBE中的溶液和50毫升的1M乙基镁溴化物在MTBE中的溶液。两个物料流从容器的相对两侧在高效率的搅拌和温度保持在10-15℃下加入。加料一旦完成后，通过加入1．0M盐酸水溶液(50毫升)来终止反应。搅拌后，沉降和相分离，有机相用盐水(50毫升)洗，然后将体积减小75％引起产物结晶化。将产物过滤，用乙酸乙酯(～10毫升)洗并在45℃下真空干燥。产率81％。
实施例3
3-苯甲酰基-5-溴吲哚的制备
用在实施例2中所叙述的步骤以94％的产率得到3-苯甲酰基-5-溴吲哚。
这施例4
3-苯甲酰基吲哚的制备
用在实施例2中所叙述的步骤以91％的产率得到3-苯甲酰基吲哚。
本领域的技术人员将会意识到，根据本发明的方法获得的3-酰化吲哚化合物可以被进一步处理产生在3-位具有选择性取代基的吲哚化合物。
因此本发明的一个具体的实施方案是当R=N-CBZ-2-吡咯烷基和X=溴时，如此获得的式(Ⅰ)的3-(N-CBZ-2-吡咯烷基羧基)-5-溴吲哚：
可以在四氢呋喃中使用例如氢化铝锂进行还原，产生3-(N-甲基-2(R)-吡咯烷基甲基)-5-溴吲哚(Ⅲ)：它又可以用适当的Heck反应被转化成3-(N-甲基-2(R)-吡咯烷基甲基)-5-(2-苯基磺酰基乙烯基)-1H-吲哚(Ⅳ)：
它又可以被催化氢化产生3-(N-甲基-2(R)-吡咯烷基甲基)-5-(2-苯基磺酰基乙基)-1H-吲哚(Ⅴ)：该化合物是一种已知用于治疗周期性偏头痛的5-HT1兴奋剂。
Claims (11)
1．一种制备式(Ⅰ)的化合物的方法其中R=C1-C6烷基，C1-C6烷氧基，C3-C7环烷基或选择性被一个或多个羟基、C1-C4烷基、C1-C4烷氧基、氟、氟(C1-C4)烷基和氟(C1-C4)烷氧基取代的芳基和X是氢或一个或多个独立选自氰基、卤素、硝基、C1-C6烷基、C1-C6烷氧基、C3-C7环烷基和选择性地被一个或多个氰基、卤素、硝基、C1-C4烷基、C1-C4烷氧基、氟(C1-C4)烷基和氟(C1-C4)烷氧基取代的芳基的取代基；该法包括分开地和同时地向搅拌着的式(Ⅱ)的吲哚溶液中
其中X是如在前述中所定义的；加入
(ⅰ)含有式RCOCl的酰氯的溶液其中R如在前述中所定义的；和
(ⅱ)含有烷基或芳基卤化镁的溶液，加入方式为(a)以足够的间隔加入溶液(ⅰ)和(ⅱ)以防止它们互相反应；和(b)溶液(ⅰ)和(ⅱ)以相等的摩尔加入率加入。
2．根据权利要求1的方法，其中式(Ⅱ)的吲哚是吲哚本身或5-卤代吲哚。
3．根据权利要求1或2的方法，其中卤化镁是烷基或芳基镁溴化物。
4．根据权利要求1至3中任一项的方法，其中卤化镁是乙基镁溴化物。
5．根据权利要求1至4任一项的方法，其中R是N-CBZ-2-吡咯烷基和X是溴和如此得到的式(Ⅰ)化合物是
6．根据权利要求5的方法，其中如此获得的式(Ⅰ)化合物接着被还原产生式(Ⅲ)的化合物：
7．根据权利要求6的方法，其中所述的还原是使用氢化铝锂在四氢呋喃中实施的。
8．根据权利要求6和7的方法，其中如此获得的式(Ⅲ)的化合物接着被转化成式(Ⅳ)的化合物：
9．根据权利要求8的方法，其中所述的转化是利用适当的Heck反应来实施的。
10．根据权利要求8和9的方法，其中如此获得的式(Ⅳ)化合物接着被转化成式(Ⅴ)的化合物：
11．根据权利要求10的方法，其中所述的转化是用催化氢化来实施的。
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| GBGB9923314.0A GB9923314D0 (en) | 1999-10-01 | 1999-10-01 | Acylation process |
| GB9923314.0 | 1999-10-01 |
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| CN1142140C CN1142140C (zh) | 2004-03-17 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102414198B (zh) * | 2009-04-22 | 2014-11-12 | 意大利合成制造有限公司 | 3-{[(2r)-1-甲基吡咯烷-2-基]甲基}-5-[2-(苯基磺酰基)乙基]-1h-吲哚的合成 |
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| GB9923314D0 (en) * | 1999-10-01 | 1999-12-08 | Pfizer Ltd | Acylation process |
| US6927296B2 (en) | 2003-07-23 | 2005-08-09 | Pfizer Inc. | Process |
| WO2011024039A1 (en) * | 2009-08-25 | 2011-03-03 | Ramesh Babu Potluri | Synthesis of novel 5-(2-(phenylsulfonyl)ethyl)-1h-indole derivatives |
| US8754239B2 (en) | 2010-01-19 | 2014-06-17 | Sms Pharmaceuticals Limited | Process for preparing eletriptan hydrobromide having α-form |
| JP2023512821A (ja) | 2020-02-04 | 2023-03-29 | マインドセット ファーマ インコーポレイテッド | 中枢神経系障害の治療のためのセロトニン作動性幻覚薬としての３－ピロリジンインドール誘導体 |
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| DK425384A (da) * | 1983-09-28 | 1985-03-29 | Nippon Zoki Pharmaceutical Co | Acylindol-derivater, fremgangsmaade til fremstilling deraf og farmaceutiske praeparater som indeholder dem |
| JPS625012A (ja) * | 1985-06-28 | 1987-01-12 | Chugai Ro Kogyo Kaisha Ltd | 排熱回収バ−ナ |
| US5578612A (en) | 1990-10-15 | 1996-11-26 | Pfizer Inc. | Indole derivatives |
| ES2104733T3 (es) * | 1990-10-15 | 1997-10-16 | Pfizer | Derivados de indol. |
| US5559129A (en) | 1990-10-15 | 1996-09-24 | Pfizer Inc | Indole derivatives |
| US5545644A (en) | 1990-10-15 | 1996-08-13 | Pfizer Inc. | Indole derivatives |
| US5607951A (en) | 1990-10-15 | 1997-03-04 | Pfizer Inc | Indole derivatives |
| US5559246A (en) | 1990-10-15 | 1996-09-24 | Pfizer Inc. | Indole derivatives |
| JPH05154271A (ja) * | 1991-12-05 | 1993-06-22 | Mitsubishi Heavy Ind Ltd | 連続式水洗機 |
| GB9207930D0 (en) * | 1992-04-10 | 1992-05-27 | Pfizer Ltd | Indoles |
| JPH064167A (ja) * | 1992-06-18 | 1994-01-14 | Nec Corp | ディスク媒体障害の復旧方式 |
| GB9417310D0 (en) | 1994-08-27 | 1994-10-19 | Pfizer Ltd | Therapeutic agents |
| FR2735774B1 (fr) * | 1995-06-21 | 1997-09-12 | Sanofi Sa | Utilisation de composes agonistes du recepteur cb2 humain pour la preparation de medicaments immunomodulateurs, nouveaux composes agonistes du recepteur cb2 et les compositions pharmaceutiques les contenant |
| US5998462A (en) * | 1996-12-16 | 1999-12-07 | Allelix Biopharmaceuticals Inc. | 5-alkyl indole compounds |
| JPH10195048A (ja) * | 1997-01-17 | 1998-07-28 | Sumitomo Chem Co Ltd | ３−（ニトロベンゾイル）インドール誘導体の製造法 |
| AU724728B2 (en) | 1997-07-03 | 2000-09-28 | Pfizer Inc. | Pharmaceutical compositions containing eletriptan hemisulphate and caffeine |
| GB9923314D0 (en) * | 1999-10-01 | 1999-12-08 | Pfizer Ltd | Acylation process |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102414198B (zh) * | 2009-04-22 | 2014-11-12 | 意大利合成制造有限公司 | 3-{[(2r)-1-甲基吡咯烷-2-基]甲基}-5-[2-(苯基磺酰基)乙基]-1h-吲哚的合成 |
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