CN1121070A - 制备嘧啶三酮衍生物的方法 - Google Patents
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
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Abstract
本发明涉及制备式(Ⅱ)化合物的方法,式中各基团定义及该方法描述详见说明书。
Description
本发明涉及制备嘧啶三酮衍生物的方法。本发明坯涉及新的N—二羟基磷酰基嘧啶三酮衍生物,它们可用作某些嘧啶三酮化合物的水溶性前药。
名称为1—(3—正丁氧基—2—氨基甲酰氧基丙基)—5—乙基—5—苯基—(1H,3H,5H)嘧啶—2,4,6—三酮的化合物,在下文中称为febarbamate,这个化合物以前已制备并公开过,参见例如Helvetica Chimica Acta,XLIV,pp.105—113,1960,和英国专利说明书NO.1581834和NO.2137999。这些出版物也公开了相关的化合物及其制备。这些制备方法常常包括通过生成合适的丙二酰脲衍生物的钠盐,并使其与希望制得的化合物相应的烷基化试剂——一般是1—卤—2—氨基甲酰氧基—3—烷氧基丙烷,且通常是氯—化合物——反应,进行5,5—二取代嘧啶三酮的烷基化。这种方法常常会有未转化的起始原料的混合物—N′一单取代5,5—二取代嘧啶三酮衍生物和N,N′—二取代5,5—二取代嘧啶三酮衍生物。
上述衍生物公开在英国专利说明书NO.1193438中。然而,在非均相、高粘度物质中进行的这种反应很难掌握,并且有相当多的原料1—卤—2—氨基甲酰氧基—3—烷氧基丙烷浪费于不可避免地形成不希望的N,N′—二取代衍生物。此原料不易获得,耗时并制备困难,既使进行严格纯化也常含有约2%异构的1—卤—2—烷氧基—3—氨基甲酰氧基丙烷。
现在我们发明了另外一种方法,它能生产基本无杂质的产品。此外,我们的新方法具有显著的经济效益,并且febarbamate及其衍生物的生产易于操作。
此方法包括使式(II)化合物,其中R1和R2和X定义如上文,与异氰酸二卤代氧膦基酯或异氰酸卤代磺酰基酯反应,得到式(III)化合物,其中R1和R2和X定义如上文,Z是式—SO2Y或—POY2基团,其中Y是卤原子,接着水解式(III)化合物。
确信式(III)中间化合物是新的,它包括了本发明的另一特征。式(III)化合物或者可以分离出来,或者就地水解,以提供定义如上的式(I)化合物。优选的Y是氯原子。
式(II)化合物与异氰酸二卤代氧膦基酯或异氰酸卤代磺酰酯可以在溶液中,优选在无水有机溶剂,理想的是在芳烃如甲苯或在卤代烃如二氯甲烷中,使用基本等摩尔量的反应剂,在-10°至50°的温度下进行反应。完成反应一般需要1至5小时,通常是在室温下1小时。
在N—二卤代氧膦基衍生物的情况下,水解反应可以方便地在溶剂混合物,优选的是诸如甲苯或环己烷的有机烃类溶剂和水的混合物中,在pH4至6,温度范围为40℃至110℃,一般为约70℃下进行反应,反应时间在很大程度上依赖所使用的反应条件,从1至24小时不等,但在pH约5.5,温度约70℃时通常需要6小时。
在N—卤代磺酰基衍生物的情况下,水解更快,通常在约40℃下约1小时完成。
我们已发现氯代有机溶剂如二氯甲烷或氯仿的存在阻碍N—P键断裂,并且另一种确信是新的式(IV)中间体可以好的收率分离,其中R1和R2和X定义如上。与式(I)化合物相反,这些物质容易溶于水中,尤其以其盐的形式。式(IV)的这种化合物包含本发明的另一方面。在上述水解N—二卤代氧膦基衍生物的条件下通过加水可使分离出的式(V)化合物转化为式(I)化合物。
按照本发明的化合物可以任何常规的方式制成给药的前药,但特别好是注射和控制释放组合物。此活性组分可以粉状存于安瓿或其它无菌容器中,并在使用之前不久溶于合适的无菌溶剂。
按照本发明的这些化合物的特殊性质也可以部分可溶盐的形式或吸附于树脂上或以任何其它现有技术已知的形式用来制成控制释放组合物。本技术领域的任一熟练技术人员很容易选择使用合适的药学上可接受的稀释剂或赋形剂。
式(II)化合物已被公开,其制备是通过5,5—二取代丙二酰脲钠盐与1—氯—2—羟基—3—烷氧基丙烷反应(HelveticaChimica Acta,XLIV,pp.105—113,1960)。所述的这种方法是很麻烦的并且要工业化生产是很不现实的,原因是需要几次加热并需在减压下数次蒸馏才能得到合适纯度的产品。可以看出,此文献所述的制备方法提供的是产品混合物,且收率低。
现在我们已能设计一种制备式(II)化合物的方法,它可以避免前面方法中的许多问题,并且提供一种能避免在随后的方法中的问题的产品。
按照本发明的另一方面,我们提供一种制备定义如上的式(II)化合物的方法,包括使式(V)化合物其中R1和R2定义如上,与式(VI)或(VIa)化合物反应,其中X定义如上,Hal是卤原子,当使用式(VI)化合物时反应是在大约0.01至0.1摩尔当量有机碱存在下,或当使用式(VIa)化合物时反应是在大约1.0摩尔当量有机碱存在下进行的。
使用的碱最好这样选择,以使水中的pkB高于大约10。此外,通过选择在反应中也起溶剂作用,或至少帮助反应剂溶解的有机碱,在均相介质中反应能进行得更顺利,在大规模工业生产范围内它具有显著的操作上的优点。作为碱,优选的是脂族胺、芳代脂族胺、或芳胺,它们任意地被羟基或另一胺基所取代,三烷基胺,特别三乙胺是最优选的。
希望反应在质子(protic)有机溶剂如低级链烷醇,例如乙醇或正丁醇,或质子惰性的溶剂如酰胺,例如二甲基甲酰胺或二甲基乙酰胺,或包括合适的碱的上述那些溶剂,或其任何合适的混合物中进行。
在此反应中使用的温度一般是在20—150℃范围内,优选70℃,反应时间需2—48小时,优选6小时。
使用英国专利说明书NO.1581834中所述的方法可从反应混合物分离得到的式(II)化合物。
本方法更进一步的优点在于,我们发现通过改变游离巴比土酸起始原料与烷基化剂数量的比例,消耗不希望有的N,N—二取代产物,N—单取代产物的比例可以得到充分改善。优选使用过量的巴比土酸起始原料,巴比土酸起始原料:烷基化剂的摩尔比从至少1∶1至3∶1,优选1∶1至2∶1。
在最优选实施方案中,我们提供了制备上述式(I)化合物的完整方法,它包括使用式(V)和(VI)化合物作为起始原料,并且其中依次使用了经由式(II)和(III)化合物的上述方法的各个步骤。
由于仅使用很经典的操作,如萃取、结晶、过滤和蒸发,因此整个方法特别适用于大规模生产febarbamate(式(I)化合物,其中R1是乙基,R2是苯基,R是3—正丁氧基—2—氨基甲酰氧基丙基)及其衍生物。
现在,将要描述本发明的各个方面及最佳实施方案,并以下面非限制性实施例进一步说明。实施例11—(3—正丁氧基—2—羟丙基)—5—乙基—5—苯基—(1H,3H,5H)—嘧啶—2,4,6—三酮
将含三乙胺(2.02g,0.02mole)的苯巴比妥(69.6g,0.3mole)的乙醇(150ml)溶液与丁基缩水甘油基醚(26.0g,0.2mole)(由Merck&CO.得到)一起于70℃下搅拌6小时。然后将反应混合物倾入水(500ml)中,用甲苯(200ml)于70℃萃取所沉淀的产物。分离甲苯层,用3%硫酸水溶液(200ml)洗涤,并于4℃放置过夜。滤出沉淀的苯巴比妥,滤液用5%碳酸钠水溶液(5×100ml)萃取。然后将有机层用1M氢氧化钠水溶液(2×200ml)萃取,收集水层,用甲苯(100ml)洗涤,用硫酸将pH调至3。用甲苯(150ml)萃取沉淀产物,分离有机层,干燥并减压蒸发,得到标题化合物(40.1g,55%);用HPLC提纯至99%,m.p.92℃。实施例21—(3—正丁氧基—2—羟丙基)—5—乙基—5—苯基—(1H,3H,5H)—嘧啶—2,4,6—三酮
将含三乙胺(20.2g,0.2mole)的苯巴比妥(69.6g,0.3mole)的二甲基甲酰胺(60ml)溶液与1—氯—3—正丁氧基—2—丙醇(33.2g,0.2mole)于70℃下搅拌6小时。然后将反应混合物倾入3%硫酸(500ml),用甲苯于70℃萃取所沉淀的产物。分离甲苯层,用3%硫酸水溶液(200ml)洗涤并于4℃下放置过夜。滤出沉淀的苯巴比妥,用5%碳酸钠水溶液(5×100ml)萃取滤液。然后用1M氢氧化钠水溶液(2×200ml)萃取有机层,收集水层,用甲苯(100ml)洗涤并用硫酸调节pH至3。用甲苯(150ml)萃取沉淀产物,分离有机层,干燥并减压蒸发,得到标题化合物(38.5g,53%);用HPLC提纯至96.5%。实施例3Febarbamate
将1—(3—正丁氧基—2—羟丙基)—5—乙基—5—苯基—(1H,3H,5H)—嘧啶—2,4,6—三酮(10.83g,0.03mole)在20ml二氯甲烷中的溶液在低于30℃的温度下滴加入搅拌的异氰酸氯磺酸酯(4.65g,0.033mole)在20ml二氯乙烷中的溶液中。室温下将反应混合物搅拌1小时,然后加入冰冷却水(100ml)。剧烈反应停止后,于40℃将反应混合物加热1小时。
然后分离有机层,用水(2×100ml)洗涤,干燥并蒸发,得到如玻璃状固体的标题化合物(11.2g,92.4%),含3%起始化合物(由HPLC知)。从乙腈中重结晶此产物,得到febarbamate(8.5g,70.1%),m.p.104℃。纯度至少为99.0%。实施例4Febarbamate
在低于30℃的温度下将1—(3—正丁氧基—2—烃丙基)—5—乙基—5—苯基—(1H,3H,5H)—嘧啶—2,4,6—三酮(10.838,0.03mole)在甲苯(20ml)中的溶液滴加入搅拌的异氰酸二氯氧膦基酯(5.3g,0.033ml)在甲苯(20ml)中的溶液。
室温下将反应混合物搅拌1小时,然后加入冰冷却水(100ml)。剧烈反应停止后,用氢氧化钠溶液将反应溶液的pH调至5。
然后于70℃将反应混合物搅拌6小时,冷却,分离有机相,用水(3×50ml)洗涤,干燥并蒸发,得到玻璃状的标题化合物(10.8g,89%),含有约3%的起始物(通过HPLC)。
从乙腈中重结晶,得到febarbamate(8.1g,66.8%),m.p.104℃。纯度至少为99.0%。实施例51—[3—正丁氧基—2—(N—二羟基磷酰基)—氨基甲酰基氧基丙基]—5—乙基—5—苯基—(1H,3H,5H)—嘧啶—2,4,6—三酮(Ferbarbamate N—磷酸)
将1—(3—正丁氧基—2—羟丙基)—5—乙基—5—苯基—(1H,3H,5H)—嘧啶—2,4,6—三酮(10.83g,0.03mole)在二氯甲烷(20ml)中的溶液滴加到搅拌的异氰酸二氯氧膦基酯(5.3g,0.033mole)在二氯甲烷(20ml)中的溶液。保持温度低于30℃。室温下将反应混合物搅拌1小时,然后加入冰冷却水(100ml)。将此混合物剧烈搅拌1小时并在减压下部分蒸发。用乙醚(2×50ml)萃取沉淀的油,分离有机层,用水(2×200ml)洗涤,干燥,然后蒸发,得到标题化合物(11.3g,85%);由HPLC提纯至纯度95%。IR:3239(宽),2963,2877,1756,1739,1697,1443,1367,1207,1109,1032,950,892,820,776,722,695,557cm-1(kBr disc)。实施例6Febarbamate
将febarbamate N—磷酸(5g,0.0113mole)的水(50ml)溶液用甲苯(25ml)成层,用碳酸钠溶液将pH调至5.5。于70℃将混合物剧烈搅拌6小时。分离有机层,用水(2×25ml)洗涤,干燥并蒸发,得到febarbamate(3.8g,93%);由HPLC纯化至纯度97.5%实施例71—(3—正丁氧基—2—羟丙基)—5,5—二丙基—(1H,3H,5H)—嘧啶—2,4,6—三酮
将含有三乙胺(2.02g,0.2mole)的5,5—二丙基—(1H,3H,5H)—嘧啶—2,4,6—三酮(30.8g,0.15mole)的二甲基甲酰胺(30ml)溶液与丁基缩水甘油基醚(13g,0.1mole)混合。将混合物于60℃加热6小时。此溶液用水(150ml)稀释并用甲苯(2×100ml)萃取。分离有机层,用水(2×100ml)洗涤,干燥并用5%的碳酸钠水溶液(6×100ml)萃取。然后用1M氢氧化钠水溶液(2×100ml)萃取甲苯相。分离出水层,用甲苯(100ml)洗涤并用硫酸将pH调至3。用甲苯(100ml)萃取沉淀的油状产物,分离有机层,用水洗涤,干燥并蒸发,得到标题化合物(16.3g,51.6%);由HPLC纯化至纯度96.5%。实施例81—(3—正丁氧基—2—(N—二羟基磷酰基)氨基甲酰氧基丙基)—5,5—二丙基—(1H,3H,5H)—嘧啶—2,4,6—三酮
在低于30℃的温度下,将1—(3—正丁氧基—2—羟基丙基)—5,5—二丙基—(1H,3H,5H)—嘧啶—2,4,6—三酮(12.52m8,0.04mole)的二氯甲烷(20ml)溶液滴加到搅拌的异氰酸二氯氧膦基酯(7g,0.044mole)的二氯甲烷(20ml)溶液中。室温下将反应混合物搅拌1小时,然后加入冷水(100ml)。然后将此混合物剧烈搅拌1小时,减压下部分蒸发并用乙醚萃取沉淀的油。分离有机层,用水(20ml)洗涤,干燥并蒸发得到玻璃状固体的标题化合物(12.8g,81%);由HPLC纯化至纯度95.5%。IR:3247(宽),2968,2935,2877,1752,1722,1694,1443,1356,1207,1104,1055,1024,950,881,820,776,692,497,cm-1(kBrdisc)。实施例91—(3—正丁氧基—2—氨基甲酰氧基丙基)—5,5—二丙基—(1H,3H,5H)—嘧啶—2,4,6—三酮
将1—(3—正丁氧基—2—(N—二羟基磷酰基)—氨基甲酰氧基丙基)—5,5—二丙基—(1H,3H,5H)—嘧啶—2,4,6—三酮(10g,0.0254mole)的水(75ml)溶液用甲苯(25ml)成层,用碳酸钠溶液将pH调至5.5。然后于70℃将反应混合物剧烈搅拌6小时,分离有机层,用水(2×25ml)洗涤,干燥并蒸发,得到标题化合物(8.2g,90%);纯度94%(通过HPLC)。在甲醇中结晶,得到6.8g(74.6%)产物,m.p.105℃。实施例10
febarbamate N—磷酸二钠盐
使febarbamate N—磷酸(4.4g,0.01mole)和氢氧化钠(0.8g,0.02mole)的甲醇(20ml)溶液减压蒸发(浴温30℃),将残余物用无水甲醇(4ml)结晶给出标题产物(2.2g,47%),m.p.136—138℃。
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