CN1168375A - 制备取代的嘧啶的方法 - Google Patents

制备取代的嘧啶的方法 Download PDF

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CN1168375A
CN1168375A CN97110515A CN97110515A CN1168375A CN 1168375 A CN1168375 A CN 1168375A CN 97110515 A CN97110515 A CN 97110515A CN 97110515 A CN97110515 A CN 97110515A CN 1168375 A CN1168375 A CN 1168375A
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Y·贝萨德
G·斯塔基
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Abstract

本发明描述了一种新颖的制备通式I取代的嘧啶衍生物的方法，该方法是在亚磺酸盐存在下使卤代嘧啶与选自右述Ⅲa，Ⅲb和Ⅲc的化合物进行反应。通式I的化合物为如具有除草活性的化合物的前体。

Description

制备取代的嘧啶的方法
本发明涉及制备下述通式I的取代的嘧啶衍生物的新颖方法，
Figure A9711051500061
其中R1，R2和R3的定义如下。
通式I的这些化合物是制备如具有除草活性的活性物质(对比EP-A0562510)的重要前体。通式I化合物在与取代基R1的羰基相邻的位置上可含有不对称碳原子。因此，下面说明既包含对映体纯化合物又包含对映体之间的外消旋物和任何混合物。
制备通式I的取代的嘧啶的方法是已知的。这样，如EP-A562510描述了在碳酸钾存在下，将2-苄基磺酰基-4，6-二甲氧基嘧啶与L-α-羟基异戊酸反应制备L-2-(4，6-二甲氧基-2-嘧啶氧基)-3-甲基丁酸甲酯。然而，磺酰基化合物的制备是困难和复杂的，通常它必须分若干步骤从2-硫代-4，6-二甲氧基嘧啶开始制备。
接着试图使2-氯-4，6-二甲氧基嘧啶直接与羟基化合物进行反应。然而，这个反应进行得如此之慢和不完全，以致于需要寻找一种新的方法。
因此，本发明的目的包括寻找一种能在工业上进行的合成通式I化合物的简单路线。用本发明权利要求1的方法可以达到此目的。
在下述通式I-V中指出的各基团具有下述含义。在各种情况下，单独或构成烷氧基，烷羰基，烷氧羰基，烷硫基，烷氨基，二烷氨基，卤代烷氧基，芳烷基等的烷基可为直链或支链并且合适地含1-6个碳原子，较好地1-4个碳原子。字面上所述的这些基团可为甲基，乙基，正或异丙基，正，异，叔丁基，戊基及其异构体或己基及其异构体。
芳基合适地是指任意取代的苯基或萘基，较好地为苯基。因此，芳烷基合适地表示苯基-(C1-C4)-烷基，尤其是苄基，芳氧基较好地表示苯氧基。
烷基和芳基可以含有一个或多个取代基，这些取代基合适地选自(C1-C4)-烷基；卤素，如氟或氯；(C1-C4)-卤代烷基，如三氟甲基；(C1-C4)-烷氧基，如甲氧基或乙氧基；(C1-C4)-卤代烷氧基，硝基或氰基。
合适的卤素为氟，氯和溴或碘，尤其是氟或氯。因此，卤代烷氧基例如可以表示三氟甲氧基或三氯甲氧基。
按本发明，下述通式I的取代的嘧啶衍生物，
其中R1是指：
i)
其中R4是指H，烷基，芳基，芳烷基，羧基，烷羰基或烷氧羰基，R5是指羟基，烷氧基，芳氧基或烷基，
ii)
其中n是1或2
Figure A9711051500081
iii)
其中A是指CH或N，R6和R7相同或不同，代表氢，烷基，烷氧基，芳基，芳氧基或-COOR8基团，其中R8是指氢，烷基或芳基；R2和R3相同或不同，代表H，烷基，烷氧基，烷硫基，卤素，卤代烷氧基，氨基，烷氨基，二烷氨基，
是将通式II的卤代嘧啶与选自IIIa，IIIb和IIIc的羟基化合物，
Figure A9711051500082
其中X代表卤原子，R2和R3如前定义，
Figure A9711051500083
其中R4和R5如前定义，
其中n如前定义，
其中A，R6和R7如前定义，
在通式IV的亚磺酸盐
R9SO2 -M+                       IV
其中R9代表H，烷基，芳基，芳烷基或烷氧芳基，M代表碱金属或碱土金属原子，和无机或有机碱存在下进行反应产生最终产物来制备。
作为本发明方法起始物料的通式II卤代嘧啶可以简单的方式和工业的规模由如EP-A0582288中所述的方法进行制备。
选自通式IIIa，IIIb和IIIc的羟基化合物通常可以商品购得或由常规方法制备。
合适地使用以通式II卤代嘧啶的用量为基准的化学计算量的羟基化合物。
本发明的反应可以两步法或较好地所谓的“一罐式合成法(one potsynthesis)”进行。
在“一罐式合成法”的较好变体中，使用催化量的通式IV的亚磺酸盐，合适地以所用的通式II卤代嘧啶为基准计，其量为1-25mol％，较好地5-10mol％。
适合作为通式IV亚磺酸盐的化合物是那些其中R9为(C1-C4)-烷基，苯基-(C1-C4)-烷基或任选的(C1-C4)-烷基-或(C1-C4)-烷氧基取代的苯基的化合物。R9较好地为甲基，对甲苯基，对甲氧基苯基或苄基。M+合适地为选自钠，钾和锂的碱金属原子，较好地为钠。因此，较好的亚磺酸盐是甲亚磺酸钠，对甲苯亚磺酸钠或苄基亚磺酸钠。
本发明的反应是在无机或有机碱存在下进行的。有机碱的合适的代表性例子为叔胺，如三乙胺或称为Hunig碱的二异丙基乙胺。另一方面，较好地可使用无机碱，如碱金属或碱土金属的碳酸盐，尤其是碱金属碳酸盐，如碳酸钾或碳酸钠。以所用的通式II卤代嘧啶为基准计，所用的碱的量合适地为1mol当量-3mol当量，较好地为1mol当量-1.5mol当量。
反应较好地在对反应试剂是惰性的极性溶剂存在下进行。被证实特别合适的溶剂为N，N-二甲基甲酰胺，四氢噻吩砜，二噁烷，二甲基亚砜或乙二醇醚，如二甘醇二甲醚，但以N，N-二甲基甲酰胺为特别好。
反应较好地在基本上排除水的情况下，在50-150℃，较好地90-110℃的温度下进行。
在约0.5-24小时的反应时间之后，可以如从反应混合物中萃取的适当方式分离出达90％高产率的通式I的最终产物。
两步法反应不同于较好的“一罐式变体”之处在于反应是以通式IV亚磺酸盐的基本上化学计算量进行的。
在此过程中，第一步先在无机或有机碱存在下使通式II卤代嘧啶与通式IV亚磺酸盐反应获得下述通式V的砜，
Figure A9711051500101
其中R2，R3和R9如前定义。此砜可以本领域技术熟练者常用的方式从反应混合物中分离出来或直接用于第二步中。
然后第二步在无机或有机碱存在下与选自通式IIIa，IIIb和IIIc的羟基化合物进行反应，获得最终产物。
对两步法中的碱和反应条件的选择基本上可参照“一罐式合成法”。
实施例
实施例1(两步法)
a1)4，6-二甲氧基-2-(4-甲苯磺酰基)嘧啶的制备
在搅拌下，将4.38g(25.0mol)2-氯-4，6-二甲氧基嘧啶和4.68g(26.3mol)对甲苯亚磺酸钠在25mlN，N-二甲基甲酰胺中加热到100℃。5小时之后，在旋转蒸发器中在60℃/20毫巴除去溶剂。将残留物提取在90ml水和90ml乙酸乙酯中。分出有机相之后，再用75ml乙酸乙酯萃取水相。用水洗涤合并的有机相，用硫酸镁干燥，蒸发。在硅胶柱上(洗脱液，己烷/乙酸乙酯4∶1)经色谱法提纯残留物。从产物部分获得产率为3.79g(理论量的51％)的白色粉末状标题产物。
熔点129.2℃-133.4℃
1H NMR(DMSO，MHz400)δ7.92(2H，d)；
                      7.50(2H，d)；
                      6.48(1H，s)；
                      3.87(6H，s)；
                      2.43(3H，s).
MS：294(MP)，279,261,209.
a2)4，6-二甲氧基-2-甲磺酰基嘧啶的制备
使用甲亚磺酸钠，按实施例a1)制备标题产物。
b1)(+/-)-2-(4，6-二甲氧基-2-嘧啶氧基)-3，3-二甲基丁酸甲酯的制备
在搅拌下，将2.94g(10.0mmol)4，6-二甲氧基-2-(对甲苯磺酰基)嘧啶和1.55g(10.5mmol)(+/-)-2-羟基-3，3-二甲基丁酸甲酯在2.07g(15.0mmol)碳酸钾存在下在20mlN，N-二甲基甲酰胺中加热到100℃。5小时之后，在旋转蒸发器中在60℃/20毫巴除去溶剂。将残留物提取在30ml水和30ml二氯甲烷中。分出有机相之后，再用20ml二氯甲烷萃取水相。用水洗涤合并的有机相，用硫酸镁干燥，蒸发。获得产率为2.30g(理论量的80.9％)的黄色晶体状(GC含量为100％)标题产物。
b2)(+/-)-2-(4，6-二甲氧基-2-嘧啶氧基)-3，3-二甲基丁酸甲酯的制备
在搅拌下，将2.18g(10.0mmol)4，6-二甲氧基-2-甲基磺酰基嘧啶和1.62g(11.0mmol)(+/-)-2-羟基-3，3-二甲基丁酸甲酯在2.07g(15.0mmol)碳酸钾存在下在20ml N，N-二甲基甲酰胺中加热到60℃。3小时之后，在旋转蒸发器中在60℃/20毫巴除去溶剂。将残留物提取在40ml水和40ml乙酸乙酯中。分出有机相之后，再用40ml乙酸乙酯萃取水相。用水洗涤合并的有机相，用硫酸镁干燥，蒸发。获得产率为2.76g(理论量的93.8％)的淡黄色晶体状(GC含量为96.6％)标题产物。
实施例2a(一罐式法)
(+/-)-2-(4，6-二甲氧基-2-嘧啶氧基)-3，3-二甲基丁酸甲酯的制备
在搅拌下，将4.38g(25mmol)2-氯-4，6-二甲氧基嘧啶，3.90g(25mmol)(+/-)-2-羟基-3，3-二甲基丁酸甲酯和0.66g(6.3mmol)甲亚磺酸钠在5.17g(37.5mmol)碳酸钾存在下在25ml N，N-二甲基甲酰胺中加热到120℃。2小时之后，在旋转蒸发器中在70℃/20毫巴除去溶剂。将残留物提取在30ml水和30ml二氯甲烷中。
分出有机相之后，再用20ml二氯甲烷萃取水相。用水洗涤合并的有机相，用硫酸镁干燥，蒸发。获得产率为5.93g(理论量的82.7％)的淡黄色晶体状(GC含量为99.2％)标题产物。
熔点104.4℃-107.0℃
1H NMR(DMSO，MHz 400)δ5.88(1H，d)；
                       4.70(1H，d)；
                       3.85(6H，s)；
                       3.65(3H，s)；
                       1.07(9H，s).
MS：284(MP)，269，228，196，169，157.
实施例2b(一罐式法)
S-(+)-(4，6-二甲氧基-2-嘧啶氧基)-3，3-二甲基丁酸甲酯的制备
在搅拌下，将1.75g(10mmol)2-氯-4，6-二甲氧基嘧啶，1.49g(10mmol)S-(+)-2-羟基-3，3-二甲基丁酸甲酯和0.45g(2.5mmol)对甲苯亚磺酸钠在2.07g(15mmol)碳酸钾存在下在10mlN，N-二甲基甲酰胺中加热到120℃。7小时之后，在旋转蒸发器中在60℃/20毫巴除去溶剂。将残留物提取在30ml水和30ml二氯甲烷中。分出有机相之后，再用20ml二氯甲烷萃取水相。用水洗涤合并的有机相，用硫酸镁干燥，蒸发。在硅胶柱上(洗脱液，己烷/乙酸乙酯4∶1)经色谱法提纯残留物。从产物部分获得产率为1.6g(理论量的56.3％)(GC含量为99％)的淡黄色晶体状标题产物。
熔点111.4℃-114.8℃
S/R对映体之比＝96.7/3.3
1H NMR(DMSO，MHz400)δ5.88(1H，s)；
                      4.70(1H，s)；
                      3.82(6H，s)；
                      3.65(3H，s)；
                      1.04(9H，s).
实施例2c(一罐式法)不加入亚磺酸盐的对比例
(+/-)-2-(4，6-二甲氧基-2-嘧啶氧基)-3，3-二甲基丁酸甲酯的制备
除了不加入亚磺酸钠外，按实施例2a进行反应。
反应24小时之后，前体的转化率达到54％。
实施例3(一罐式法)
(+/-)-3-(4，6-二甲氧基-2-嘧啶氧基)-2-丁酮的制备
在搅拌下，将4.38g(25mmol)2-氯-4，6-二甲氧基嘧啶，2.31g(26.2mmol)3-羟基-2-氧代丁烷和0.66g(6.3mmol)甲亚磺酸钠在5.17g(37.5mmol)碳酸钾存在下在25ml N，N-二甲基甲酰胺中加热到120℃。3小时之后，在旋转蒸发器中在70℃/20毫巴除去溶剂。在硅胶柱上(洗脱液，己烷/乙酸乙酯4∶1)经色谱法提纯残留物。从产物部分获得产率为4.58g(理论量的80.4％)(GC含量为99％)的淡黄色油状标题产物。
1H NMR(DMSO，MHz400)δ5.87(1H，s)；
                      5.70(1H，q)；
                      3.82(6H，s)；
                      2.25(3H，s)；
                      1.44(9H，d).
MS：226；211；183；157；139.
实施例4(一罐式法)
(+/-)-3-(4，6-二甲氧基-2-嘧啶氧基)-2-二氢呋喃酮的制备
在搅拌下，将1.75g(10mmol)2-氯-4，6-二甲氧基嘧啶，1.02g(10mmol)α-羟基-γ-丁内酯和0.26g(2.5mmol)甲亚磺酸钠在2.07g(15.0mmol)碳酸钾存在下在10mlN，N-二甲基甲酰胺中加热到120℃。2小时之后，在旋转蒸发器中在70℃/20毫巴除去溶剂。将残留物提取在30ml水和30ml二氯甲烷中。分出有机相之后，再用20ml二氯甲烷萃取水相。用水洗涤合并的有机相，用硫酸镁干燥，蒸发。获得产率为0.43g(理论量的15.5％)的淡棕色油状(GC含量为94％)标题产物。
MS：240；210；181；157.
实施例5(一罐式法)
2-(4，6-二甲氧基-2-嘧啶氧基)-3-甲基苯甲酸甲酯的制备
在搅拌下，将4.38g(25mmol)2-氯-4，6-二甲氧基嘧啶，4.17g(25.0mmol)2-羟基-3-甲基苯甲酸甲酯和0.66g(6.3mmol)甲亚磺酸钠在5.17g(37.5mmol)碳酸钾存在下在25mlN，N-二甲基甲酰胺中加热到120℃。8小时之后，在旋转蒸发器中在60℃/20毫巴除去溶剂。将残留物提取在30ml水和30ml二氯甲烷中。分出有机相之后，再用20ml二氯甲烷萃取水相。用水洗涤合并的有机相，用硫酸镁干燥，蒸发。在硅胶柱上(洗脱液，己烷/乙酸乙酯4∶1)经色谱法提纯残留物。从产物部分获得产率为5.23g(理论量的65.8％)(GC含量为96％)的标题产物。
熔点73.8℃-79.1℃
1H NMR(DMSO，MHz400)δ7.75(1H，d)；
                      7.58(1H，d)；
                      7.30(1H，t)；
                      5.95(1H，s)；
                      3.75(6H，s)；
                      3.62(3H，s)；
                      2.17(3H，s).
GC/MS：304；273，245
实施例6(一罐式法)
2-(4，6-二甲氧基-2-嘧啶氧基)-苯甲酸甲酯的制备
在搅拌下，将4.38g(25mmol)2-氯-4，6-二甲氧基嘧啶，3.80g(25.0mmol)2-羟基苯甲酸甲酯和0.66g(6.3mmol)甲亚磺酸钠在5.17g(37.5mmol)碳酸钾存在下在25mlN，N-二甲基甲酰胺中加热到120℃。1.5小时之后，在旋转蒸发器中在60℃/20毫巴除去溶剂。将残留物提取在30ml水和30ml二氯甲烷中。分出有机相之后，再用20ml二氯甲烷萃取水相。用水洗涤合并的有机相，用硫酸镁干燥，蒸发。在硅胶柱上(洗脱液，己烷/乙酸乙酯4∶1)经色谱法提纯残留物。从产物部分获得产率为5.76g(理论量的77.0％)(GC含量为97％)的标题产物。
熔点106.7℃-108.3℃
1H NMR(DMSO，MHz400)δ7.92(1H，d)；
                      7.70(1H，t)；
                      7.40(1H，t)；
                      7.32(1H，d)；
                      5.95(1H，s)；
                      3.75(6H，s)；
                      3.62(3H，s).
GC/MS：290；231.
实施例7(一罐式法)
3-(4，6-二甲氧基-2-嘧啶氧基)-2-吡啶羧酸甲酯的制备
在搅拌下，将1.75g(10mmol)2-氯-4，6-二甲氧基嘧啶，1.53g(10mmol)3-羟基-2-吡啶羧酸甲酯和0.104g(1.0mmol)甲亚磺酸钠在2.17g(15mmol)碳酸钾存在下在6mlN，N-二甲基甲酰胺中加热到100℃。5小时之后，在旋转蒸发器中在60℃/20毫巴除去溶剂。在硅胶柱上(洗脱液，己烷/乙酸乙酯4∶1)经色谱法提纯残留物。从产物部分获得产率为1.94g(理论量的61％)(GC含量为92.3％)的黄色油状标题产物。
1H NMR(DMSO，MHz400)δ8.58(1H，d)；
                      7.90(1H，d)；
                      7.74(1H，dd)；
                      6.01(1H，s)；
                      3.75(6H，s)；
                      3.68(3H，s)；

Claims (14)

1.制备通式I取代的嘧啶衍生物的方法，
Figure A9711051500021
其中R1是指：
Figure A9711051500022
i)
其中R4是指H，烷基，芳基，芳烷基，羧基，烷羰基或烷氧羰基，R5是指羟基，烷氧基，芳氧基或烷基，
ii)
其中n是1或2
Figure A9711051500024
iii)
其中A是指CH或N，R6和R7相同或不同，代表氢，烷基，烷氧基，芳基，芳氧基或-COOR8基团，其中R8是指氢，烷基或芳基；R2和R3相同或不同，代表H，烷基，烷氧基，烷硫基，卤素，卤代烷氧基，氨基，烷氨基，二烷氨基，
其特征在于，所述方法是将通式II的卤代嘧啶与选自IIIa，IIIb和IIIc的羟基化合物反应，
Figure A9711051500031
其中X代表卤原子，R2和R3如前定义，
Figure A9711051500032
其中R4和R5如前定义，
Figure A9711051500033
其中n如前定义，
其中A，R6和R7如前定义，该反应是
在通式IV的亚磺酸盐
R9SO2 -M+                   IV
其中R9代表H，烷基，芳基，芳烷基或烷氧芳基，M代表碱金属或碱土金属原子，和无机或有机碱存在下进行的，产生最终产物。
2.如权利要求1所述的方法，其特征在于反应是在催化量的通式IV亚磺酸盐存在下进行的。
3.如权利要求1或2所述的方法，其特征在于以所用的通式II卤代嘧啶为基准计，所用的通式IV亚磺酸盐的量为1-25mol％。
4.如权利要求1-3中任一项权利要求所述的方法，其特征在于通式IV亚磺酸盐中的M+是指选自钠，钾和锂的碱金属原子，R9是指(C1-C4)-烷基，苯基-(C1-C4)-烷基或任选的(C1-C4)-烷基取代的苯基。
5.如权利要求1-4中任一项权利要求所述的方法，其特征在于使用无机碱。
6.如权利要求5所述的方法，其特征在于使用碱金属或碱土金属的碳酸盐作为无机碱。
7.如权利要求1-6中任一项权利要求所述的方法，其特征在于反应是在极性溶剂存在下进行的。
8.如权利要求1-7中任一项权利要求所述的方法，其特征在于反应温度选择为50-150℃。
9.如权利要求1所述的方法，其特征在于反应分两步进行，在这种方法中，第一步先在基本上化学计算量的通式IV亚磺酸盐和无机或有机碱存在下使通式II卤代嘧啶发生反应，获得下述通式V的砜，
其中R2，R3和R9如前定义，第二步在无机或有机碱存在下使通式V的砜与选自通式IIIa，IIIb和IIIc的羟基化合物进行反应，获得通式I的最终产物。
10.如权利要求1或9所述的方法，其特征在于通式IV亚磺酸盐中的M+是指选自钠，钾和锂的碱金属原子，R9是指(C1-C4)-烷基，苯基-(C1-C4)-烷基或任选的(C1-C4)-烷基取代的苯基。
11.如权利要求1，9或10中任一项权利要求所述的方法，其特征在于使用无机碱。
12.如权利要求1和9-11中任一项权利要求所述的方法，其特征在于使用碱金属碳酸盐或碱土金属碳酸盐作为无机碱。
13.如权利要求1和9-12中任一项权利要求所述的方法，其特征在于在第一步和第二步中都存在极性溶剂。
14.如权利要求1和9-13中任一项权利要求所述的方法，其特征在于在第一步和第二步中反应温度都选择为50-150℃。
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