CN100418950C - 制备喹啉衍生物的方法 - Google Patents
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- C07D215/16—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 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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Abstract
制备通式(I)的化合物的方法，通过通式A的喹啉3-甲酸酯衍生物与通式B的苯胺衍生物在选自具有80-200℃沸点的直链或支链烷烃和环烷烃或其混合物的溶剂中进行反应。
Description
发明领域
本发明涉及制备喹啉衍生物的方法.更具体而言，本发明涉及制备喹啉-3-甲酰胺衍生物的改进和简化方法.
发明背景
在美国专利号4,738,971中要求保护作为调节细胞免疫增强剂的N-芳基-1，2-二氢-4-取代-1-烷基-2-氧代-喹啉-3-甲酰胺的一些衍生物.该专利公开了制备该化合物的四种方法.根据与本发明最接近的方法，该化合物通过羧酸或其活性衍生物在作为惰性溶剂的吡啶或喹啉存在下与胺或其活性衍生物反应来制备.美国专利号5,912,349公开了制备上述化合物之一roquinimex(Merck Index 12thEd.，No.8418；
LS2616，N-苯基-N-甲基-1，2-二氢-4-羟基-1-甲基-2-氧代-喹啉-3-甲酰胺)的改进方法.在该专利中，N-甲基靛红酸酐和N-甲基-N-苯基-α-甲酰甲氧基乙酰胺反应得到所要的化合物.美国专利号6,077,851、6,133,285和6,121,287公开了喹啉-3-甲酰胺衍生物的制备.该衍生物可通过多种公知的方法来制备，例如，通过喹啉-3-甲酸酯衍生物在适合的溶剂如甲苯、二甲苯等中与苯胺的反应.在公开的实施例中，其中的甲苯用作溶剂，收率≤80％.
现有技术公开如下
表明用喹啉-3-甲酸酯衍生物进行的N-酰化反应现在已经发现是一个平衡反应，其中的平衡点出乎意料地偏向左边.说明性的实例可通过在100℃，用一当量甲醇的甲苯溶液作溶剂，于密封的容器中加热喹啉-3-甲酰胺衍生物(化合物C)来提供，例如，其中R5＝氯和R6＝H，R ＝乙基和R′＝R″＝氢.不到30分钟结果几乎完全转化为相应的甲基酯(化合物A).
所要化合物的化学稳定性是在反应条件下发生降解.
喹啉-3-甲酰胺衍生物的降解.
上文提供了一个说明性的实例.降解产物(化合物F)是脱羧的喹啉-3-甲酸(化合物E).化合物E由喹啉-3-甲酰胺衍生物与水反应形成.在反应混合物中不可避免地存在少量的水.少量的水一直存在于起始物质和溶剂中，水也可在反应中进入到反应混合物中.当使用例如甲苯时，所要的产物溶解于水中并倾向于与水反应.由喹啉-3-甲酰胺衍生物与水反应形成的喹啉-3-甲酸经过脱羧反应得到脱羧产物(化合物F).喹啉-3-甲酸没有在粗产物中以可探测的量存在.喹啉-3-甲酸酯(化合物A)也与水进行相似的反应，但速度更慢.
发明描述
本发明的主要目的是提供制备喹啉-3-甲酰胺衍生物的改进方法，该衍生物由于其具有高活性和低副作用的药理学性质，在得自病理炎症和自身免疫性疾病的治疗中和多数恶性肿瘤的治疗中被认为是有价值的.更具体而言，为了提高所要产物的收率和化学纯度，本发明涉及由苯胺通过与喹啉-3-甲酸酯衍生物进行N-酰化反应制备喹啉-3-甲酰胺衍生物的大大简化的方法.
现已惊奇地发现，通式(I)的化合物
其中
R选自甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基和烯丙基；
R5选自甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、甲硫基、乙硫基、正丙硫基、甲基亚磺酰基、乙基亚磺酰基、氟、氯、溴、三氟甲基、和OCHxFy；
其中x＝0-2，
y＝1-3，条件是
x+y＝3；
R6是氢；或
R5和R6一起为亚甲基二氧基；
R′选自氢、甲基、甲氧基、氟、氯、溴、三氟甲基、和OCHxFy，
其中x ＝0-2，
y＝1-3，条件是
x+y＝3；
R″选自氢、氟和氯，条件是只有当R′选自氟和氯时R″选自氟和氯；
根据包括通式A的喹啉3-甲酸酯衍生物与通式B的苯胺衍生物
在选自具有80-200℃沸点的直链或支链烷烃和环烷烃或其混合物的溶剂中进行反应的所要求保护的方法以大大改进和简化的方式来制备.
根据优选的实施方案，溶剂是正庚烷、正辛烷或其混合物.
在另一优选的实施方案中，溶剂是顺式，反式-十氢化萘
本发明方法特别优选地利用正庚烷作溶剂来制备N-乙基-N-苯基-5-氯-1，2-二氢-4-羟基-1-甲基-2-氧代-喹啉-3-甲酰胺；利用正庚烷和正辛烷的混合物作溶剂制备N-甲基-N-(4-三氟甲基苯基)-1，2-二氢-4-羟基-5-甲氧基-1-甲基-2-氧代-喹啉-3-甲酰胺；利用顺式，反式-十氢化萘作溶剂来制备N-乙基-N-苯基-1，2-二氢-5-乙基-4-羟基-1-甲基-2-氧代-喹啉-3-甲酰胺.
与使用甲苯、二甲苯等作溶剂相比，现已惊奇地出乎预料地发现，所要产物的收率和纯度性质可大大提高.通过使用所要产物在其中是不溶的，即使在回流温度也不溶的溶剂，结合分出所形成的醇，所要产物的收率几乎是100％，在所要的产物中有非常低浓度的杂质.所要产物的沉淀也更加快了反应速度，并抑制了降解，即避免了所要产物与水的反应.改进该方法的溶剂是具有80-200℃沸点的直链或支链烷烃和环烷烃或其混合物.减压可用于分出所形成的醇.
实施例
不用进一步推敲，可以相信，本领域技术人员利用上文的描述，可对本发明进行最大程度的利用.下面的详细实施例描述了怎样制备多种化合物和/或完成本发明的多种方法，该实施例被认为是简单地说明，无论如何不是以任何方式对上述内容进行限制.
实施例1
1，2-二氢-4-羟基-5-氯-1-甲基-2-氧代-喹啉-3-甲酸甲酯
2-氨基-6-氯苯甲酸(30g)悬浮在1，4-二噁烷(225ml)中，加入氯甲酸乙酯(75ml).混合物在回流温度加热1小时，然后冷却至50℃，加入乙酰氯(75ml).该混合物搅拌10小时，然后过滤出沉淀产物并用甲苯洗涤.真空干燥得到5-氯靛红酸酐(33g，收率97％).5-氯靛红酸酐(30克)溶解于二甲基乙酰胺(300ml)中，通过氮气冷却至5℃.逐份地加入氢化钠(5.8g，70％)，继而加入碘甲烷(11.5ml).反应混合物在室温搅拌18小时，抽真空(40mbar)1小时以分出过量的碘甲烷.加入氢化钠(5.8g，70％)，继而加入丙二酸二甲酯(20ml)，混合物加热至85℃.在85℃3小时后，混合物冷却并用冷水(2.4升)稀释.产物通过加入5MHCL(aq)直到pH ＝1.5-2来沉淀.过滤沉淀产物并由甲醇中重结晶得到题列化合物(29g，收率70％).
利用基本上相同的方法由相应的起始物质获得乙酯.
实施例2
N-乙基-N-苯基-5-氯-1，2-二氢-4-羟基-1-甲基-2-氧代-喹啉-3-甲酰
胺
5-氯-1，2-二氢-4-羟基-1-甲基-2-氧代-喹啉-3-甲酸甲酯(3.0g)、N-乙基苯胺(2当量，2.88ml)、和庚烷(60ml)加热，在6小时35分钟内蒸馏出挥发物，主要是庚烷和形成的甲醇(32ml).冷却至室温后，过滤结晶的悬浮液，结晶用庚烷洗涤并真空干燥得到粗的题列化合物(3.94g，98％)，白色至灰白色结晶.
实施例3
N-乙基-N-苯基-5-氯-1，2-二氢-4-羟基-1-甲基-2-氧代-喹啉-3-甲酰
胺(在甲苯中反应，不属于本发明)
5-氯-1，2-二氢-4-羟基-1-甲基-2-氧代-喹啉-3-甲酸甲酯(3.0g)、N-乙基苯胺(2当量，2.88ml)、和甲苯(60ml)加热，在6小时35分钟内蒸馏出挥发物，主要是甲苯和形成的甲醇(32ml).冷却至室温后，用庚烷(40ml)沉淀产物，结晶过滤并用庚烷洗涤，真空干燥得到粗的题列化合物(3.58g，收率90％)，灰白色结晶.
利用HPLC和参比化合物对粗产物进行分析，见表1.在粗产物中只发现两种副产物.不包括面积％低于0.02％的峰.
表1.粗产物中所要产物和副产物的含量
在庚烷中反应速度的增加是明显的.与庚烷作溶剂相比，使用甲苯时有更多未转化的酯留在粗产物中.速度的差异可能比表1所示的更大，因为在甲苯中的反应在比相应的庚烷中的反应更高的温度发生(甲苯沸点110-112℃，庚烷的沸点98℃).该酯在烷烃中比产物更可溶，事实上正面地影响了平衡并有利于产物的形成.
粗产物的收率使用甲苯(90％)时比使用庚烷(98％)低.这是由于产物和酯在甲苯中比庚烷中有更高的溶解性.当使用庚烷时真正的收率接近100％.脱羧的喹啉甲酸(甲苯0.54％，庚烷0.03％，见表1)是水和所要的产物反应的结果.
Claims (6)
1. 制备通式(I)的化合物的方法
其中
R选自甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基和烯丙基；
R5选自甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、甲硫基、乙硫基、正丙硫基、甲基亚磺酰基、乙基亚磺酰基、氟、氯、溴、三氟甲基和OCHxFy；
其中x＝0-2，
y＝1-3，条件是
x+y＝3；
R6是氢；或
R5和R6一起为亚甲基二氧基；
R′选自氢、甲基、甲氧基、氟、氯、溴、三氟甲基和OCHxFy，
其中x＝0-2，
y＝1-3，条件是
x+y＝3；
R″选自氢、氟和氯，条件是只有当R′选自氟和氯时R″选自氟和氯；
所述方法包括将式A的喹啉-3-甲酸酯衍生物与式B的苯胺衍生物
其中R7选自甲基和乙基；
在选自具有80-200℃沸点的直链或支链烷烃和环烷烃或其混合物的溶剂中进行反应。
2. 根据权利要求1的方法，其中溶剂是正庚烷、正辛烷或其混合物。
3. 根据权利要求1的方法，其中溶剂是顺式，反式-十氢化萘。
4. 根据权利要求1的方法，利用正庚烷作溶剂来制备N-乙基-N-苯基-5-氯-1，2-二氢-4-羟基-1-甲基-2-氧代-喹啉-3-甲酰胺。
5. 根据权利要求1的方法，利用正庚烷和正辛烷的混合物作溶剂来制备N-甲基-N-(4-三氟甲基苯基)-1，2-二氢-4-羟基-5-甲氧基-1-甲基-2-氧代-喹啉-3-甲酰胺。
6. 根据权利要求1的方法，利用顺式，反式-十氢化萘作溶剂来制备N-乙基-N-苯基-1，2-二氢-5-乙基-4-羟基-1-甲基-2-氧代-喹啉-3-甲酰胺。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE0201778A SE0201778D0 (sv) | 2002-06-12 | 2002-06-12 | Process for the manufacture of quinoline derivatives |
| SE0201778-8 | 2002-06-12 | ||
| SE02017788 | 2002-06-12 |
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| Publication Number | Publication Date |
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| CN1659146A CN1659146A (zh) | 2005-08-24 |
| CN100418950C true CN100418950C (zh) | 2008-09-17 |
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| CNB038135310A Expired - Lifetime CN100418950C (zh) | 2002-06-12 | 2003-05-14 | 制备喹啉衍生物的方法 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105051013A (zh) * | 2013-03-14 | 2015-11-11 | 泰华制药工业有限公司 | 拉喹莫德钠晶体及其改进的制造方法 |
| CN111732540A (zh) * | 2020-07-20 | 2020-10-02 | 湖南速博生物技术有限公司 | 一种罗喹美克的制备方法 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE0400235D0 (sv) | 2004-02-06 | 2004-02-06 | Active Biotech Ab | New composition containing quinoline compounds |
| US8314124B2 (en) | 2004-02-06 | 2012-11-20 | Active Biotech Ab | Crystalline salts of quinoline compounds and methods for preparing them |
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| CN111732540B (zh) * | 2020-07-20 | 2020-11-13 | 湖南速博生物技术有限公司 | 一种罗喹美克的制备方法 |
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