CN1699349A - 酰脲n－烷基化的方法及试剂 - Google Patents

酰脲n－烷基化的方法及试剂 Download PDF

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CN1699349A
CN1699349A CNA2005100026661A CN200510002666A CN1699349A CN 1699349 A CN1699349 A CN 1699349A CN A2005100026661 A CNA2005100026661 A CN A2005100026661A CN 200510002666 A CN200510002666 A CN 200510002666A CN 1699349 A CN1699349 A CN 1699349A
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丹尼拉·古特曼
海谢尔·赫佐格
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Abstract

一种酰脲N烷基化的方法，该方法包括在惰性反应介质中，于碱性催化剂的存在下，将结构(I)所示的酰脲与结构(III)所示的烷基化试剂反应。酰脲可为5，5－二取代巴比土酸，或可为苯妥英、苯乙哌啶酮及乙琥胺。烷基化试剂为磺酸酯。碱为氢化物或胺。优选的方法包括在二异丙基乙胺的存在下，用甲磺酸甲氧基甲酯N烷氧基烷基化5，5－二苯基巴比土酸，分离得到的N，Ni－二甲氧基甲基－5，5－二苯基巴比土酸。本发明也提供了新的化合物N－甲氧基甲基乙琥胺、N－甲氧基甲基苯乙哌啶酮及N－甲氧基甲基－5，5－二苯基巴比土酸，以及包括给病人服用这些化合物的方法。

Description

酰脲N-烷基化的方法及试剂
发明背景
本发明涉及一种比迄今所用的技术产率更高、更便利并更安全的用于酰脲N-烷基化的新方法。该方法特别适用于制备N-(烷氧基链烯基)酰脲，其包括N取代的巴比吐酸类抗惊厥剂药物。
所用的术语酰脲在例如Foye.Principles of Medicinal Chemistry，第三版(1990)，164，179页所述，该文献在此引作参考。酰脲为一类通式I所示的酰亚胺：
例子包括安眠药，如醋卡溴脲、烯丙异丙乙酰脲、溴异戊酰脲、卡普脲、卡溴脲和乙巴酰脲；以及抗惊厥剂药物，如乙内酰脲、戊二酰亚胺、唑烷二酮、琥珀酰亚胺和巴比土酸盐如巴比土酸(结构II)。
Figure A20051000266600052
美国专利4,628,056叙述了一种制备1，3-二(甲氧基甲基)-5，5-二苯基巴比土酸(也称为N，N′-二(甲氧基甲基)-5，5-二苯基巴比土酸)的方法，该方法通过将二苯基巴比土酸溶解在冷二甲基甲酰胺中，加入氢化钠，然后加入氯甲基甲醚而进行。氯甲基甲醚广泛用于甲氧基亚甲基官能团的烷基化。但是，它是剧毒的并因致癌物而受到控制。在放热反应条件下，它极易挥发并易燃，因此非常需要其替代物。
大约三十年以前，甲氧基甲基甲磺酸被认为是在自身催化反应中烷基化醇和胺的试剂。Karger等J.A.C.S.91：5663(1969)。胺的反应较复杂，并引起了盐、二聚物和其它副产物的生成。该方法未用于酰脲或酰亚胺的烷基化，因为在氮的给电子能力上存在重大差异。
发明概述
本发明方法避免了使用挥发性的、致癌的氯甲基甲醚，取而代之使用可在原位产生的更活泼，较低挥发性替代的试剂(对操作者没有危险)。
本发明解决了以前未认识到的限制甲氧基甲磺酸酯对醇和胺的烷基化问题。酰脲的碱性比胺弱，所以需要一种不同的氧烷基化的方法。本发明不同于Karger等的方法在于其使用了酰脲、非水碱性催化剂和惰性溶剂、以前未知或没被推荐的改性剂。本发明的方法允许使用各种磺酸盐来制备大量的氧烷基化酰脲，其中一些磺酸盐是以前未知的。本发明的简便得到了以前未曾领会的优点。
本发明的酰脲N烷氧基烷基化的方法包括：在惰性的反应介质中，于碱性催化剂存在下，结构I所示的酰脲与结构III所示的烷基化试剂反应。烷基化试剂III可直接与酰脲结合；或者该方法包括乙酸和磺酸的混合酸酐与二烷氧基甲烷在原位反应得到烷基化试剂III。该方法优选分离得到的N-烷氧基烷基化酰脲。
酰脲优选为5，5-二取代巴比土酸、苯妥英、苯乙哌啶酮或乙琥胺。烷基化试剂为甲氧基甲基甲磺酸、甲氧基甲基苯磺酸或甲氧基甲基对甲苯磺酸。碱选自氢化钠、三乙胺及二异丙基乙胺。
当该方法包括二烷氧基甲烷与混合的乙酸、磺酸的酸酐反应制备磺酸酯时，反应可在与随后的与酰胺的反应(随后进行)相同的容器中进行。
优选的方法包括用选自甲磺酸甲氧基甲酯、苯磺酸甲氧基甲酯及对甲苯磺酸甲氧基甲酯的试剂、于二异丙基乙胺存在下，将5，5-二苯基-巴比土酸N-烷基化，然后分离得到的N，N-二甲氧基甲基-5，5-二苯基-巴比土酸。
本发明也考虑了新型化合物，即N-甲氧基甲基-5，5-二苯基-巴比土酸、N-甲氧基甲基乙琥胺和N-甲氧基甲基苯乙哌啶酮，这些化合物的制备方法，以及包括给病人服用有效量选自N-甲氧基甲基-5，5-二苯基-巴比土酸、N-甲氧基甲基乙琥胺及N-甲氧基甲基苯乙哌啶酮的药剂的方法。
根据说明书和实施例，其它目的和优点将会显而易见。
优选实施方案的详述
在描述附图所述的本发明优选实施方案时，为表达清晰，采用了具体的术语，但是，本发明并不是为了限于所用的具体术语，应理解为每个具体的单元包括所有可以相同方式操作并达到相同目的的技术等同物。
具有所需N-烷基化性质的试剂具有结构III所示的化合物的特征，
其中R基团优选如下：
R3＝H、低级烷基、苯基或取代苯基
R4＝H、低级烷基、苯基或取代苯基
R5＝低级烷基、苯基或取代苯基。
此类结构的具体例子如表1所示：
                        表1
  化合物III   R3   R4   R5
  甲磺酸甲氧基甲酯   H   H   CH3
  甲磺酸乙氧基甲酯   CH3   H   CH3
  甲磺酸苄氧基甲酯   苯基   H   CH3
  乙磺酸甲氧基甲酯   H   H   C2H5
  苯磺酸甲氧基甲酯   H   H   苯基
  对甲苯磺酸甲氧基甲酯   H   H   甲苯基
  甲磺酸甲氧基亚苄酯   H   苯基   CH3
  甲磺酸甲氧基亚乙酯   H   CH3   CH3
特别优选的试剂为甲磺酸甲氧基甲酯。
待烷基化的酰脲属于含有结构I所示的一族化合物：
其可为线性(R1与R2为烷基、芳基或芳基烷基)，或环(R1与R2形成环)。
这些酰脲的例子包括上述所列的物质以及：
苯乙哌啶酮(3-乙基-3-苯基-哌啶-2，6-二酮)
苯妥英(5，5-二苯基-2，4-咪唑烷二酮)
乙琥胺(3-乙基-3-甲基-2，5-吡咯烷二酮)
5，5-二苯基巴比土酸
5-苯基-5-乙基巴比土酸
5，5-二乙基巴比土酸
优选的酰脲试剂在5位上用R基二取代的巴比土酸，如结构IV所示，
其中R基优选为相同或不同的烷基或芳基，最优选两个R基均为苯基。
本发明得到的类似产物，以5，5-二苯基巴比土酸为基质，包括：
用表1的试剂2得到的N，Ni-二乙氧基甲基衍生物，
用表1的试剂7得到的N，Ni-二甲氧基亚苄基衍生物，
用表1的试剂8得到的N，Ni-二甲氧基亚乙基衍生物，
用表1的试剂3得到的N，Ni-苄氧基甲基衍生物。
5，5-二苯基巴比土酸的N-甲氧基甲基衍生物(式IX)可通过本发明的方法制备，
Figure A20051000266600082
用强碱(与氢化物一样强，如NaH)将基质5，5-二苯基巴比土酸转化为其二价阴离子盐，然后加入一当量的表1试剂1，即烷氧基烷基化试剂。通过优化反应以利于单取代，从而得到N-甲氧基甲基-5，5-二苯基巴比土酸。例如加入过量的极强碱NaH，每摩尔酰脲中加入超过二摩尔当量的NaH。用色谱或其它常规方法分离单取代产物，并通过熔点和核磁共振来表征。
烷基化酰脲的药学上有效的盐也在本发明范围之内。
通常使用化学计量的组分，即对于单烷基化，酰脲∶烷基化试剂∶碱的比例约为1∶1∶2，对于二取代，比例约为1∶2∶2，以此类推。根据反应条件，不同的比例是合适的，普通技术人员将认识到通过改变这些比例，反应可进行得较快或较慢，并有较高或较低的产率。例如，如上所讨论的，使用过量的碱利于巴比土酸族酰脲的单取代反应。
为了使反应进行，需要非水碱性催化剂，其碱性可与氢化钠一样强，或与叔胺一样弱。对于双取代产物，碱性催化剂优选不与酰胺基质(或酰亚胺)竞争的胺。因此排除了伯胺与仲胺。优选与烷基化样品反应较慢的叔胺，以便通过位阻(胺取代基的分支)使竞争反应最小。对于这一点特别优选高位阻的胺，比如易于得到的胺，乙基二异丙胺。位阻效应是通过烷基化试剂与酰脲基质竞争，从而抑制了催化剂胺的季胺化，并且没有过多地干扰胺作为碱的能力(接受质子)。可用的碱包括氢化钠、氢化钾、氢化锂、三乙胺、三正丙胺及二异丙基乙胺。
选择溶剂使之不与基质竞争，同时使烷基化速率最大。使用偶极惰性溶剂如二甲基甲酰胺、二甲基亚砜、二甲基乙酰胺、四氢噻吩砜、N-甲基吡咯烷酮等可优化这些特点。否则，普通技术人员可选择任意偶极惰性溶剂，只要该溶剂能让反应物变成溶液。烷基化反应优选的温度范围为在或接近室温(25±5℃)。高温可刺激在烷基化试剂与叔胺催化剂之间的竞争性副反应(当在使用后者处)。
本发明的产率至少与现有工艺的产率一样高。高产率的同时达到了此创造性方法的其它优点，包括更安全、更便利、更经济以及能用于合成新的化合物。创造性的烷基化方法(使用优选的基质和优选的上述试剂)的优选实施方案提供了结构V所示的N，N′双取代巴比土酸，其中R基团为苯基，
Figure A20051000266600091
N，N′-二甲氧基甲基-5，5-二苯基巴比土酸
烷基化优选在偶极惰性溶剂中进行，如N，N-二烷基酰胺，但是其它类型的惰性溶剂也可使用，只要它们与碱相容，这种烷基化技术是特别新的，且是相当便利的，这在于通过使用起始物质可在原位产生活性烷基化样品，而无需分离磺酸盐试剂本身。因此，二甲氧基甲烷(结构VI)可与乙酸和甲磺酸的混合酸酐(结构VII)反应，得到原位生成的磺酸酯，即甲磺酸甲氧基甲酯(结构VIII，其中R3＝H，R4＝H，R5＝CH3的结构III)，其无需分离或纯化就能应用于巴比土酸的N-烷基化。
      VI                      VII                        VIII
下列实施例用于阐述本发明多种实施方案，但不局限于此。
                        实施例1
          N，N i -二甲氧基甲基-5，5-二苯基巴比土酸
A使用有位阻的叔胺催化剂
在0℃，将二甲氧基甲烷(10.85克)加入19.7克乙酰基甲磺酸盐中，在25℃搅拌反应2小时，然后经45分钟将得到的溶液逐渐加入在60毫升干二甲基甲酰胺中的10克5，5-二苯基巴比土酸和13.85克N，N-二异丙基乙胺的混合物中。得到的反应混合物搅拌约15分钟，然后用180毫升2N HCl稀释，再用300毫升乙酸乙酯稀释。分离各相，乙酸乙酯相首先用150毫升饱和氯化钠水溶液洗涤，再用150毫升2N的NaOH水溶液洗涤，无水硫酸钠干燥有机(乙酸乙酯)相，过滤，浓缩干燥得到12.2克N，Ni-二甲氧基甲基-5，5-二苯基巴比土酸，在48毫升甲苯中结晶得到10.5克纯产物(79.6％产率)。
B用三乙胺作为催化剂
按实施例A的步骤，用10.84克三乙胺(代替13.85克二异丙基乙胺)，得到10.62克粗烷基化产物，在40毫升甲苯中结晶得到7.6克(58.5％)N，Ni-二甲氧基甲基5，5-二苯基巴比土酸。
C用氢化钠作为催化剂
按实施例A的步骤，用3.57克氢化钠(60％分散在矿物油中)代替胺催化剂，从甲苯中结晶后得到5.0克(38％)N，Ni-二甲氧基甲基5，5-二苯基巴比土酸。
D用乙酰苯磺酸盐代替乙酰基甲磺酸盐
按实施例A的步骤，用28.55克乙酰苯磺酸盐代替乙酰甲磺酸盐(19.7克)，以75.5％的收率得到纯的烷基化产物。
可用常用的方法，如通过二氧化硅上的TLC(流动相氯仿∶甲醇98∶2)检测反应是否完成。反应混合物用360毫升水稀释，再用480毫升乙酸乙酯萃取，分离有机层，用150毫升水洗两次。减压下蒸馏除去溶剂得到粗产物。在4份甲苯中结晶纯化粗产物，混合物加热至回流以溶解，然后冷却至室温。根据HPLC可测定本发明方法产物的纯度为98-100％，产率约为60-80％。
                          实施例2
            N，N i -二乙氧基甲基-5，5-二苯基巴比土酸
按实施例1A的步骤，用二乙氧基甲烷(15.42克)代替二甲氧基甲烷(10.85克)，可以68％的收率得到纯的N，Ni-二甲氧基甲基-5，5-二苯基巴比土酸。
                          实施例3
                     3-甲氧基甲基苯妥英
按1A的步骤，用苯妥英(18克)代替5，5-二苯基巴比土酸(10克)，可以70％的收率得到3-甲氧基甲基苯妥英。
                          实施例4
                   N-甲氧基甲基苯乙哌啶酮
按1A的步骤，用苯乙哌啶酮(15.5克)代替5，5-二苯基巴比土酸(10克)，可以65％的收率得到N-甲氧基甲基苯乙哌啶酮。
                          实施例5
                     N-甲氧基甲基乙琥胺
按1A的步骤，用乙琥胺(10克)代替5，5-二苯基巴比土酸(10克)，可以60％的收率得到N-甲氧基甲基乙琥胺。
                         实施例6
             N-甲氧基甲基-5，5-二苯基巴比土酸
通过优化实施例1A的步骤以得于单取代反应，即每当量酰脲用过量的NaH和等当量的烷基化试剂，这样能得到单取代的甲氧基甲基衍生物。分离单取代产物并定性。
实施例2-6中的化合物在持续期内具有有益的药学性质。通过给病人服用有效量的以药学可接受的载体形式的化合物，可用于治疗哺乳动物包括人类的惊厥、癫痫发作、肌肉僵硬、神经紧张或焦虑。
本说明书中阐述和讨论的实施方案仅仅是为了指导本领域熟练技术人员按发明者知道的最好方式来使用本发明。这些叙述并不认为限制于本发明的范围中。根据上述启示本领域熟练技术人员可对本发明的上述实施方案进行修改和变化，而不偏离发明，因此，应理解在权利要求书及其等同物的范围内，可以以具体描述之外的方式实现本发明。

Claims (20)

1.一种烷基化酰脲化合物的药用盐，所述烷基化酰脲化合物选自由N-甲氧基甲基乙琥胺、N-甲氧基甲基苯乙哌啶酮及N-甲氧基甲基-5，5-二苯基巴比土酸组成的组。
2.根据权利要求1所述的药用盐，其中所述烷基化酰脲化合物为N-甲氧基甲基乙琥胺。
3.根据权利要求1所述的药用盐，其中所述烷基化酰脲化合物为N-甲氧基甲基苯乙哌啶酮。
4.根据权利要求1所述的药用盐，其中所述烷基化酰脲化合物为N-甲氧基甲基-5，5-二苯基巴比土酸。
5.一种药物组合物，包含有效量的根据权利要求1所述的药用盐和药用载体。
6.根据权利要求5所述的药物组合物，其中所述烷基化酰脲化合物为N-甲氧基甲基乙琥胺。
7.根据权利要求5所述的药物组合物，其中所述烷基化酰脲化合物为N-甲氧基甲基苯乙哌啶酮。
8.根据权利要求5所述的药物组合物，其中所述烷基化酰脲化合物为N-甲氧基甲基-5，5-二苯基巴比土酸。
9.一种酰脲N烷基化的方法，所述方法包括在不含水的碱存在下，将通式X所示的酰脲
与通式III所示的烷基化试剂反应，
其中R5为低级烷基、苯基或甲苯基，
R3为H、CH3、或苯基，以及
R4为H、苯基或CH3。
10.根据权利要求9所述的方法，其中所述不含水的碱为氢化钠和叔胺中的至少一种。
11.根据权利要求9所述的方法，其中所述不含水的碱为选自氢化钠、氢化钾、氢化锂、三乙胺、三正丙胺及二异丙基乙胺中的至少一种。
12.根据权利要求9所述的方法，其中使用选自二甲基甲酰胺、二甲基亚砜、二甲基乙酰胺、四氢噻吩砜、N-甲基吡咯烷酮的溶剂。
13.根据权利要求9所述的方法，其中R4为H。
14.根据权利要求13所述的方法，其中R3为H。
15.分离出的N-甲氧基甲基-5，5-二苯基巴比土酸。
16.根据权利要求15所述的分离出的N-甲氧基甲基-5，5-二苯基巴比土酸，其中所述N-甲氧基甲基-5，5-二苯基巴比土酸是化学合成的。
17.根据权利要求1所述的药用盐在制备用于治疗哺乳动物的惊厥、癫痫发作、肌肉僵硬、神经紧张和焦虑的疾病的药用组合物中的应用。
18.根据权利要求4所述的药用盐在制备用于治疗哺乳动物的惊厥、癫痫发作、肌肉僵硬、神经紧张和焦虑的疾病的药用组合物中的应用。
19.根据权利要求15所述的化合物在制备用于治疗哺乳动物的惊厥、癫痫发作、肌肉僵硬、神经紧张和焦虑的疾病的药用组合物中的应用。
20.根据权利要求16所述的化合物在制备用于治疗哺乳动物的惊厥、癫痫发作、肌肉僵硬、神经紧张和焦虑的疾病的药用组合物中的应用。
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