CN1143077A - 制备卤代乙酰胺衍生物的方法 - Google Patents

制备卤代乙酰胺衍生物的方法 Download PDF

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CN1143077A
CN1143077A CN96106824A CN96106824A CN1143077A CN 1143077 A CN1143077 A CN 1143077A CN 96106824 A CN96106824 A CN 96106824A CN 96106824 A CN96106824 A CN 96106824A CN 1143077 A CN1143077 A CN 1143077A
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神原新治
金内彻
内山景志
寺田达也
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Abstract

卤代乙酰胺的制备方法，包括在碳酸钠存在下，在由含水层和有机溶剂层组成的两相反应体系中与卤代乙酰氯反应。

Description

制备卤代乙酰胺衍生物的方法
本专利申请是CN93109041.5的分案申请。原申请的申请日为1993年6月19日；原申请的发明创造名称为“制备吡咯烷基乙酰胺衍生物的方法”。
本发明涉及用作大脑功能改进剂的吡咯烷基乙酰胺衍生物的制备方法。
正如美国专利USP4,341,-790和JP-A-56-2960(此文中“JP-A”是指未审查的已公开日本专利申请)所述，制备吡咯烷基乙酰胺衍生物的已知方法包括使吡咯烷基乙酸或其活性衍生物在有机溶剂中和二环己基碳二亚胺存在下与胺进行反应。
上述方法不适合于工业规模的生产，因为它有很多缺点，诸如使用了昂贵的二环己基碳二亚胺作缩合剂。要分离和去除由二环己基碳二亚胺的产生的付产物二环己基脲需要复杂的步骤，总产率低。而且，例如2-氧代-1-吡咯烷基乙酸的起始物要由2-吡咯烷酮和溴乙酸甲酯反应和使得到的2-氧代-1-吡咯烷基乙酸甲酯水解制备，并要在高温高压下蒸馏反应混合物进行纯化，这些复杂的操作和低产率对于工业生产是很不利的。
另一方面，由英国专利号1,039,113已知N-取代内酰胺的制备方法。这种已知方法包括先使N-未取代内酰胺与碱金属氢化物反应，然后再使得到的碱金属衍生物与适当的ω-氯代烷基酰胺反应。在此方法中使用的氯代N-乙酰苯胺衍生物可用使Yakugaku Zasshi(药学杂志)，VoL99(2)，PP146-154(1979)中公开的方法制备，该方法包括使二甲代苯胺和-氯乙酰氯在冰乙酸中反应得到2，6-二甲基-氯-N-乙酰苯胺，产率78-80％。但对于工业规模的生产来说这些方法的产率仍然不够令人满意。
本发明的目的是提供一种制备吡咯烷基乙酰胺衍生物的方法，它没有上述已知方法的缺点，而且由经济观点来看也是很好的。
本发明的基础在于卤代乙酰胺衍生物和2-吡咯烷酮的反应，并作了多种改进，例如，改进之一是起始物卤代乙酰胺衍生物是由胺和卤代乙酰氯在二相反应体系中以高产率获得的。
本发明提供了式(I)表示的2-(1-吡咯烷基)乙酰胺衍生物的制备方法。
          R2-CH2CONH-R1    (1)其中R1表示取代或未取代吡啶基或取代苯基；R2表示取代或未取代2-氧代-1-吡咯烷基；该方法包括使式(III)表示的胺：
          NH2-R1    (III)其中R1如上文定义，与卤代乙酰氯在由水层和有机溶剂层组成的二相反应体系中进行反应得到由式(II)表示的卤代乙酰胺衍生物：
       X-CH2CONH-R1    (II)其中R1如上文定义；X表示卤原子，以及再使得到的式(II)卤代乙酰胺衍生物与2-吡咯烷酮或取代的2-吡咯烷酮进行反应。
式(I)的2-(1-吡咯烷基)乙酰胺衍生物是已知化合物，公开于USP4,341,790和JP-A-56-2960。式(I)中所用的符号定义与US4,341,790和JP-A-56-2960相应，这就是说，除上文所述定义外，R1所示吡啶基或苯基上的取代基包括卤原子、三氟甲基、硝基、乙酰基、烷基、烷氧基、烷基巯基、氨基、磺酰基和氨基乙氧羰基，R2所示2-氧代-1-吡咯烷基上的取代基包括羟基。
上述取代基的烷基部分是指有1-5个碳原子的低级烷基；
在式(I)化台物中，最有用的是N-(2，6-二甲苯基)-2-(2-氧代-1-吡咯烷基)乙酰胺。
要形成胺与卤代乙酰氯进行反应的水相/有机相两相体系可以使用的有机溶剂选自在与水或其中溶有无机碱或起始物的水混合时能形成分离相的那些溶剂，优先选用对起始物惰性的溶剂。适当的有机溶剂包括氯仿、二氯甲烷、二氯乙烷、甲苯、二甲苯、乙酸乙酯、叔丁基甲基醚、丙酮和乙腈。从回收、减少空气污染以及反应产率的角度甲苯和二甲苯是最合适的。优选所用溶剂的量为足以溶解起始物。但是，没必要使所用的量足以完全溶解得到的卤代乙酰胺。
本发明中可使用的卤代乙酰氯优选氯代乙酰氯，可以得到式(II)的氯代乙酰胺衍生物。
为使反应顺利进行，优选使水层呈弱碱性至碱性，为此目的，优选加入至少1当量的碱，如碳酸钠、碳酸氢钠、氢氧化钠、氢氧化钾等等。
卤代乙酰氯和胺的摩尔比至少为1，优选1.1至1.5。反应产物(II)可用常规方法，例如(1)冷却反应混合物并过滤收集产物进行分离；或(2)分离和浓缩有机层以及过滤收集产物进行分离。
虽然式(II)中间体可按上文所述分离，但是把有机层用于后面的步骤而不分离出中间体更为有利，因为只有很少的付产物。实际操作中，把分离出的有机层经减压共沸蒸馏至大约1/2至1/3的体积后，有机层中的水含量就达到可允许的限度(约为0.55％V/V)之内。
在使得到的卤代乙酰胺衍生物与取代或未取代的2-吡咯烷酮进行反应之前，必须用碱处理2-吡咯烷酮。可以使用的碱包括强碱，如氢化钾、氢化钠、氨基钠、正丁基锂、叔丁基锂、二乙氨基锂和醇盐。在这些碱之中，优选使用各种醇盐，它们不太贵而且可燃性较小，在100-150℃加热下进行上述处理0.5至5小时的同时可以将付产物醇导出系统之外。特别是优选甲醇钠和乙醇钠，因为便宜并且其付产物甲醇和乙醇容易去除。所用碱的量与吡咯烷酮相比最好不超过等当量。使用过量的碱会导致付反应。
用碱处理通常在不与碱反应的适当溶剂中进行。适宜溶剂的实例有甲苯、二甲苯、氯仿、二氯甲烷、二氯乙烷和叔丁基甲基醚。该处理过程优选在无水体系中进行，因为如果有水存在的话，水会与碱反应或者会干扰处理过程。
把卤代乙酰胺衍生物加入到已经被碱处理过的吡咯烷酮中，使混合物在0-100℃，优选在40-80℃进行反应，得到所需吡咯烷基乙酰胺衍生物。通常所用卤代乙酰胺的量不多于等当量上文所述用碱处理中所用碱的量。在进行反应时，从易于操作的观点，使用与上述用碱处理时所用的同样溶剂更为有利。
在反应混合物中加水冷却使产物结晶很容易分离出反应产物，这种分离步骤也是本发明的发明要点。
下面将用实施例更详尽地说明本发明，当然不能认为本发明仅限于此。
                实施例1
2-氯-N-(2，6-二甲苯基)乙酰胺的制备
在3l甲苯中溶解182g2，6-二甲苯胺，并在1.5l水中溶解159g碳酸钠，把二种溶液合起来，在内温20-35℃下在1.5小时内向其中滴加203g氯代乙酰氯，接着在该温度下搅拌1.5小时。把反应混合物用冰冷却，过滤收集沉淀的晶体，减压后干燥得到282g(95％)标题化合物。M.P.148-148.5℃
1H-NMR(CDCl3)：2.24(6H，S)，4.24(2H，S)，7.16(3H，S)，7.9(1H，brs)
               实施例22-氯-N-(2，6-二甲苯基)乙酰胺的制备
在4l1，2-二氯乙烷中溶解182g2，6-二甲基苯胺，向其中加入1.6l1N氢氧化钠水溶液，接着搅拌。于内温20-35℃，在1.5小时内向混合物中滴加203g氯代乙酰氯，将混合物在同样温度下搅拌1.5小时。反应混合物分离为二层，把有机层减压浓缩，过滤收集沉淀物并减压干燥，得到282g标题化合物(95％)。M.P.148-148.5℃
1H-NMR数据和实施例1一致。
                实施例3N-(2，6-二甲苯基)-2-(2-氧代-1-吡咯烷基)乙酰胺的制备
把9.2g60％氢化钠于氮气流中悬浮于300ml甲苯，将内温控制在40℃或40℃以下，向悬浮液中缓慢滴加21.3g2-吡咯烷酮。把混合物搅拌2小时以后，向其中加入19.7g2-氯-N-(2，6-二甲苯基)乙酰胺，使混合物在60-70℃反应2小时。在反应混合物中加入50ml水，然后搅拌使之冷却。过滤收集沉淀的结晶，减压干燥得到22.2g(90％)标题化合物。M.P.153-153.5℃
1H-NMR(CDCl3)：1.9-2.6(4H，m)，2.18(6H，s)，3.57(2H，t，J＝6.8Hz)，4.07(2H，s)，7.06(3H，s)，7.9(1H，brs)
                 实施例4N-(2，6-二甲苯基)-2-(2-氧代-1-吡咯烷基)乙酰胺的制备。
在氮气流中把897mg氨基钠悬浮于30ml叔丁基甲基醚，向其中缓慢滴加2.13g2-吡咯烷酮，然后回流2小时。冷却后再加入1.97g2-氯-N-(2，6-二甲苯基)乙酰胺，接着回流2小时。在反应混合物加入50ml水，并使混合物搅拌冷却。过滤收集如此形成的晶状沉淀物，减压干燥后得到2.19g(89％)标题化合物。M.P.151-152.5℃
                 实施例5N-(2，6-二甲苯基)-2-(2-氧代-1-吡咯烷基)乙酰胺的制备
在氮气流中把9.0g氨基钠悬浮于300ml甲苯，并在其中缓慢滴加21.3g2-吡咯烷酮。混合物于60-70℃搅拌2小时以后，向其中滴加19.7g2-氯-N-(2，6-二甲苯基)乙酰胺，接着在60-70℃反应2小时。在反应混合物中加50ml水，搅拌混合物使之冷却，过滤回收沉淀的晶体，减压干燥后得到22.4g(91％)标题化合物。M.P.152-152.5℃
                实施例6N-(2，6-二甲苯基)-2-(2-氧代-1-吡咯烷基)乙酰胺的制备
把203g甲醇钠悬浮于5l甲苯中，并在其中加入511g2-吡咯烷酮。把混合物缓慢加热至100-110℃，并使之在此温度下反应3小时。在反应过程中，大约蒸出300ml甲苯。使之冷却，在其中加入296g2-氯-N-(2，6-二甲苯基)乙酰胺，在60-70℃反应2小时。在反应混合物中加入300ml水，接着搅拌冷却。过滤收集形成的晶体，减压干燥后得到332g(90％)标题化合物。M.P.152.5-153℃
                 实施例7N-(2，6-二甲苯基)-2-(2-氧代-1-吡咯烷基)乙酰胺的制备
把182g2，6-二甲苯胺溶解于5l甲苯，并把159g碳酸钠溶于1.5l水，把上述二种溶液合起来，在内温20-35℃用1.5小时向其中滴加203g氯代乙酰氯，接着在此温度下搅拌1.5小时。将反应混合物加热至70℃以溶解沉淀的晶体，然后分离成两层，把有机层减压浓缩至大约500ml，使产生的2-氯代-N-(2，6-二甲苯基)乙酰胺悬浮液冷却。
另外，把203g甲醇钠悬浮于4l甲苯，并在其中加入511g2-吡咯烷酮。把混合物缓慢加热至100-110℃，在此温度下使之反应3小时。反应过程中，大约有300ml甲苯蒸出。冷却后，向其中加入前面制备的2-氯代-N-(2，6-二甲苯基)乙酰胺悬浮液，在60°-70℃反应2小时。在反应混合物中加入300ml水，然后搅拌使之冷却。过滤收集形成的晶体，减压干燥后得到336g(91％)标题化合物。M.P.152-153℃
本文已对本发明进行了详尽的描述并引用具体实施例予以说明。很显然，在不脱离本发明的原理和范围内本专业技术人员可以进行各种改变和改进。

Claims (2)

1.制备式(II)所示的卤代乙酰胺衍生物的方法：
         X-CH2CONH-R1    (II)其中R1表示取代或未取代的吡啶基或取代的苯基；以及X表示卤原子，
该方法包括使式(III)所示的胺：
         NH2-R1         (III)其中R1的定义同上；在碳酸钠存在下，在由含水层和有机溶剂层组成的两相反应体系中与卤代乙酰氯进行反应。
2.根据权利要求1的方法，其中所说的卤代乙酰氯是氯代乙酰氯，所说的卤代乙酰胺衍生物是氯代乙酰衍生物。
CN96106824A 1992-06-19 1996-05-28 制备卤代乙酰胺衍生物的方法 Pending CN1143077A (zh)

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ES2184852T3 (es) * 1995-03-23 2003-04-16 Daiichi Seiyaku Co Cristales anhidros.
US6107330A (en) * 1995-08-07 2000-08-22 Daiichi Pharmaceutical Co., Ltd. Inhibitor for narcotic analgesic dependence/resistance acquisition
US7608636B2 (en) 2000-12-28 2009-10-27 Hamilton Pharmaceuticals, Inc. Medicines for treatment and prevention of neurogenic pain
CN100593538C (zh) * 2007-05-23 2010-03-10 浙江工业大学 一种n-取代丙烯酰基-2,5-吡咯二酮类化合物的制备方法
KR101006734B1 (ko) * 2008-10-14 2011-01-10 차준돈 접 붙이기 수단을 이용한 관상용 영지버섯 제조방법

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US2863752A (en) * 1953-10-30 1958-12-09 Monsanto Chemicals Herbicides
GB1039113A (en) * 1964-08-06 1966-08-17 Ucb Sa New n-substituted lactams
US3647876A (en) * 1969-08-14 1972-03-07 Virginia Chemicals Inc Process in the preparation of n n-di-n-propyl-alpha-chloroacetamid
CH518266A (fr) * 1971-05-21 1972-01-31 Ct D Etudes Pour L Ind Pharma Procédé de préparation d'un nouveau dérivé de la xylidine
FR2216267A1 (en) * 1973-02-01 1974-08-30 Nitrokemia Ipartelepek N-isopropyl chloroacetanilide prodn - by chloroacetylation of N-isopropylaniline
CH582651A5 (zh) * 1973-05-30 1976-12-15 Eszakmagyar Vegyimuevek
DE2835157A1 (de) * 1978-08-10 1980-02-21 Bayer Ag Verfahren zur herstellung von n-substituierten alpha -halogenacetaniliden
IT1141287B (it) * 1979-06-13 1986-10-01 Nattermann A & Cie Ammidi di acidi pirrolidin-(2)-on-(1)-ilalchil-carbossilici,procedimento per la loro preparazione e prodotti medicinali che le contengono
DE3120361A1 (de) * 1981-05-22 1982-12-16 Chemische Werke Hüls AG, 4370 Marl Verfahren zur herstellung von n-benzyl-n-isopropylpivaloylamid

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ES2176192T3 (es) 2002-12-01
NO179903C (no) 1997-01-08
EP0574952B1 (en) 2002-04-10
FI102748B (fi) 1999-02-15
DE69332441D1 (de) 2002-11-28
NO179903B (no) 1996-09-30
EP0574952A1 (en) 1993-12-22
NO932231L (no) 1993-12-20
DE69332441T2 (de) 2003-08-14
PT574952E (pt) 2002-08-30
TW218009B (zh) 1993-12-21
EP0839800A1 (en) 1998-05-06
DE69331792D1 (de) 2002-05-16
CN1085893A (zh) 1994-04-27
PT839800E (pt) 2003-02-28
ATE215931T1 (de) 2002-04-15
EP0839800B1 (en) 2002-10-23
FI102748B1 (fi) 1999-02-15
JPH0665197A (ja) 1994-03-08
DK0839800T3 (da) 2003-02-24
KR940005570A (ko) 1994-03-21
HK1009131A1 (en) 1999-05-28
KR100223387B1 (en) 1999-10-15
FI932813A (fi) 1993-12-20
ATE226570T1 (de) 2002-11-15
DE69331792T2 (de) 2004-11-04
ES2185857T3 (es) 2003-05-01
CA2098663A1 (en) 1993-12-20
DK0574952T3 (da) 2002-06-10
FI932813A0 (fi) 1993-06-17
NO932231D0 (no) 1993-06-17

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