CN87103879A - 制备苯甲酰基苯基哌啶衍生物的方法 - Google Patents

制备苯甲酰基苯基哌啶衍生物的方法 Download PDF

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CN87103879A
CN87103879A CN198787103879A CN87103879A CN87103879A CN 87103879 A CN87103879 A CN 87103879A CN 198787103879 A CN198787103879 A CN 198787103879A CN 87103879 A CN87103879 A CN 87103879A CN 87103879 A CN87103879 A CN 87103879A
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伯纳德·马耶尔
弗朗索瓦·贝拉米
皮尔·道迪
雅克·罗宾
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RECHERCHES INDUSTRIELLES Ste
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/30—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
    • C07D211/32—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/52—Oxygen atoms attached in position 4 having an aryl radical as the second substituent in position 4

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明介绍了一种制备具有通式(Io)的产物的方法，其中：R1、R2和R3代表氢、卤素、一种较低级的烷基或较低级的烷氧基，R5和R6代表氢、一种较低级的烷基、苯基或苄基。这一方法是将具有通式(Ⅱ)的2-卤-5-硝基-二苯酮(其中X是卤素)与一种具有通式(Ⅲ)的任意取代的哌啶化合物进行反应。这反应是在一种由至少含有20％体积的水以及至多含有80％体积的至少一种芳香烃组成的介质中进行的。

Description

制备苯甲酰基苯基哌啶衍生物的方法
本发明有关于一种制备具有通式(I0)的苯甲酰基苯基哌啶衍生物
Figure A8710387900041
的方法，其中：
——R1、R2和R3可以是相同的或不相同的，各自代表一个氢原子、囟原子、低级的烷基或低级的烷氧基，并且
——R5和R6可以是相同的或不相同的，各自代表一个氢原子、羟基、低级的烷基、苯基或苄基。
在这一定义中，术语“低级的烷基”和“低级的烷氧基”用来指含有1至4个碳原子的基团。
按照本发明，这方法是将具有通式(II)的一种2-囟-5-硝基二苯酮：
Figure A8710387900042
其中X是卤原子，最好是氯或氟，R1、R2和R3的定义如上述，和一种具有通式(III)的任意取代的哌啶：其中R和R的定义如上述，进行反应。所说的反应是在一种由至少含有20％体积的水以及至多含有80％的至少一种芳香烃所组成的含水介质中进行的，这种芳香烃最好是甲苯。
具有通式(I0)的化合物主要用作制备有药物活性的化合物的中间体，(I0)中的硝基可通过还原反应转化为氨基。所说的有药物活性的化合物以前已经叙述过。
通过把具有通式(II)的化合物和具有通式(III)的化合物进行反应，来制备具有通式(I0)化合物的方法，也已经有过叙述，但是在先前采用的工艺中，这个反应是在一种无水的有机中进行的。
本发明的特征在于，所说的反应是在一种至少含有20％体积的水、甚至可以在纯水介质中进行。
对于熟悉本专业的人来说，具有通式(II)的化合物和具有通式(III)的化合物之间的反应能在含水的介质中完成，并不是显而易见的，尤其是因为所用的反应物在所说的含水介质中是不容的；因此按照本发明，这个反应是一个非均相的反应。
但尽管所说的反应具有非均相的性质，本发明的这一方法却有显著的、意料之外的优点，即：
——改进了收率，
——可能节省能量，
——得到的产物容易析离得多。
下面的非限制性的实施例阐述了本发明。
实施例1
在纯水介质中制备2-(4-甲基哌啶-1-基)-5-硝基-4’-氯代二苯酮
将0.024摩尔(0.96克)NaOH、25毫升水、0.02摩尔(5.92克)2，4’-二氯-5-硝基二苯酮和0.022摩尔(2，6毫升)4-甲基哌啶形成的混合物在80℃加热3小时30分钟。冷却到室温后，滤出得到的沉淀，用水洗并干燥，得到6.74克(产率94％)想要的产物，熔点138℃。
实施例2
按照实施例1中的相同实验操作，但用不同的哌啶作反应物，制得了下列产物：
a)用2-甲基哌啶，以91％的收率制得2-(2-甲基哌啶-1-基)-5-硝基-4’-氯代二苯酮，反应时间24小时，获得的产物熔点140℃；
b)用3-甲基哌啶，以97％的收率制得2-(3-甲基哌啶-1-基)-5-硝基-4’-氯代二苯酮，反应时间3小时，获得的产物熔点112℃；
c)用3，5-二甲基哌啶，以95.8％的收率制得2-(3，5-二甲基哌啶-1-基)-5-硝基-4’-氯代二苯酮，反应时间2小时，产物经甲苯重结晶后熔点171℃。
实施例3
按照实施例1中的相同实验操作，但用不同的2-氯-5-硝基二苯酮衍生物和4-甲基哌啶进行反应，制备了下述产物：
a)2-(4-甲基哌啶-1-基)-5-硝基-3’-氯代二苯酮，产率93.4％，反应时间2小时，所说的产物的熔点86℃；
b)2-(4-甲基哌啶-1-基)-5-硝基-4’-甲基二苯酮，产率81％，反应时间1小时30分钟，所说的产物经由异丙醚重结晶后熔点为110℃；
c)2-(4-甲基哌啶-1-基)-5-硝基-4’-甲氧基二苯酮，产率88.4％，反应时间1小时，所说的产物经由异丙醚重结晶后熔点为117℃；
d)2-(4-甲基哌啶-1-基)-5-硝基-3’，4’-二氯二苯酮，产率97％，反应时间9小时，所说的产物熔点114℃；
e)2-(4-甲基哌啶-1-基)-5-硝基-2’，4’-二甲基二苯酮，产率97.5％，反应时间4小时，所说的产物熔点106℃；
F)2-(4-甲基哌啶-1-基)-5-硝基-2’-氯代二苯酮，收率95％，反应时间3小时，所说的产物经异丙醚洗涤后熔点为84℃。
实施例4
在含有水和甲苯的混合物介质中制备2-(4-甲基哌啶-1-基)-5-硝基-4’-氯代二苯酮
将0.024摩尔(0.96克)NaOH，5毫升水，15毫升甲苯，0.02摩尔(5.92克)2，4’-二氯-5-硝基二苯酮和0.022摩尔(2.6毫升)4-甲基哌啶组成的混合物在80℃加热1小时。冷却到室温后，滤出得到的沉淀，用水洗并干燥，得6.51克(产率：90.8％)想要的产物，该产物熔点138℃。
实施例5
按照实施例4中的相同实验操作，但用不同的哌啶衍生物和2，4’二氯-5-硝基二苯酮进行反应，制得了下述产物：
a)2-(3-甲基哌啶-1-基)-5-硝基-4’-氯代二苯酮，产率94.5％，反应时间1小时15分钟，产物熔点111℃；
b)2-(2-甲基哌啶-1-基)-5-硝基-4’-氯代二苯酮，产率70％，反应时间5小时，产物熔点140℃；
c)2-(3，5-二甲基哌啶-1-基)-5-硝基-4’-氯代二苯酮，产率96.2％，反应时间3小时，产物经由甲苯中重结晶后熔点为171℃。
实施例6
按照实施例4中的相同实验操作，但用不同的2-氯-5-硝基-二苯酮衍生物和4-甲基哌啶进行反应，制得了下述产物：
a)2-(4-甲基-哌啶-1-基)-5-硝基-3’-氯代二苯酮，产率83.6％，反应时间1小时30分钟，获得的产物熔点88℃；
b)2-(4-甲基-哌啶-1-基)-5-硝基-4’-甲基二苯酮，产率97％，反应时间2小时，获得的产物熔点110℃；
c)2-(4-甲基-哌啶-1-基)-5-硝基-4’-甲氧基二苯酮，产率68.4％，反应时间1小时，获得的产物经由异丙醚中重结晶后熔点为120℃；
d)2-(4-甲基哌啶-1-基)-5-硝基-3’，4’-二氯二苯酮，产率98.3％，反应时间3小时，获得的产物熔点114℃；
e)2-(4-甲基哌啶-1-基)-5-硝基-2’，4’-二甲基二苯酮，产率88％，反应时间二小时，获得的产物熔点107℃；
f)2-(4-甲基哌啶-1-基)-5-硝基-2’-氯代二苯酮，产率95％，反应时间3小时，获得的产物经戊烷/异丙醚混合物洗涤后熔点为84℃。
实施例7
本例阐明了在含水和甲苯的介质中，用大量反应物进行反应制备2-(4-甲基哌啶-1-基)-5-硝基-4’-氯代二苯酮的操作。
1050毫升甲苯、1公斤2，4’-二氯代-5-硝基二苯酮被加入一个带搅拌器的4立升反应器中，这时反应物部分地溶于介质中。
然后，加入由162克氢氧化钠在500毫升水中制成的溶液；随后借助滴液斗在半小时内加入368克(440毫升)4-甲基哌啶。反应充分放热，可使反应器温度达84℃，因此在开始阶段不必对所说的反应混合物加热。当哌啶加完后，在80℃保持2小时，即直到反应进行完毕。最终产物由介质中结晶出来，约16小时后介质已冷却到室温，滤出得到的晶状产物，用水洗数次(直到洗涤水的PH值为中性)，然后在80℃真空干燥，得1140克(产率：94.08％)想要的产物，熔点138℃。
下列表I总结了按上述实施例制备的产物的结构和熔点，以及用形成本发明主题的方法所制得的一些化合物。
表I
Figure A8710387900101
Figure A8710387900102

Claims (2)

1.一种制备具有下述通式的产物的方法
Figure A8710387900021
，其中：
——R1、R2和R3可以是相同或不相同的基团，各自代表一个氢原子、卤原子、低级的烷基或低级的烷氧基，并且
——R5和R6可以是相同或不相同的基团，各自代表一个氢原子、羟基、低级的烷基、苯基或苄基，这个方法是按照已知的反应，把具有通式(II)的一种2-囟-5-硝基二苯酮
Figure A8710387900022
其中X是卤原子，最好是氯或氟，R1、R2和R3的定义如上述，和一种具有通式(III)的任意取代的哌啶化合物
Figure A8710387900031
其中R5和R6的定义如上述，进行反应。所说的反应是在一种由至少含有20％体积的水以及至多含有80％体积的至少一种芳香烃组成的介绍中完成的，这种芳香烃最好是甲苯。
2.如权利要求1中的一种制备具有通式(I0)的化合物的方法，它是将具有通式(II)的化合物，其中R1和R2代表氢原子，R3代表4位氯原子，X代表氯原子，和一种具有通式(III)的化合物，其中R5代表氢原子，R6代表4位的甲基，进行反应。
CN198787103879A 1986-05-30 1987-05-29 制备苯甲酰基苯基哌啶衍生物的方法 Pending CN87103879A (zh)

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US06/868,443 US4680402A (en) 1981-06-29 1986-05-30 Benzoyl-phenyl-piperidine derivatives
US868443 1986-05-30

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1052228C (zh) * 1996-01-17 2000-05-10 中国科学院大连化学物理研究所 N-甲酰基哌啶及其同系物的制备方法

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FR2508445A1 (fr) * 1981-06-29 1982-12-31 Sori Soc Rech Ind Nouveaux derives de benzoyl-phenyl-piperidine, leur procede de preparation et leur application, notamment en therapeutique

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1052228C (zh) * 1996-01-17 2000-05-10 中国科学院大连化学物理研究所 N-甲酰基哌啶及其同系物的制备方法

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