CN101107230B - 5-氯-2,4-二羟基吡啶的制造方法 - Google Patents
5-氯-2,4-二羟基吡啶的制造方法 Download PDFInfo
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/62—Oxygen or sulfur atoms
- C07D213/69—Two or more oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/62—Oxygen or sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/32—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrane Compounds (AREA)
Abstract
本发明提供一种以温和条件和简短工序，并且废弃产物少地制造作为抗恶性肿瘤剂5-氟尿嘧啶的生物降解酶抑制剂的5-氯-2，4-二羟基吡啶的工业上有利的方法。本发明涉及式(1)表示的5-氯-2，4-二羟基吡啶的制造方法，其特征在于：使式(2)表示的5-氯-1，3-二噁英-4-酮衍生物(2)与式(3)表示的乙烯酮缩二乙醇衍生物(3)反应，得到式(4)表示的吡喃酮衍生物(4)，对其进行酸处理后，与氨反应。，(式中，R1和R2与说明书的定义相同。)，(式中，R3和R4相同或不同，表示碳原子数为1～6的直链或支链的烷基，或者具有碳原子数为1～6的直链或支链的烷基的甲硅烷基。)
，(式中，R3和R4与上述相同。)
Description
技术领域
本发明涉及用作具有优异的抗肿瘤效果的抗恶性肿瘤剂5-氟尿嘧啶的生物降解酶抑制剂的5-氯-2，4-二羟基吡啶的制造方法和作为其制造中间体的吡喃酮衍生物。
背景技术
已知5-氯-2，4-二羟基吡啶(通用名称：吉莫斯特)通过抑制抗恶性肿瘤剂5-氟尿嘧啶的生物降解酶二氢嘧啶脱氢酶而增强该抗肿瘤剂的抗肿瘤活性(参照专利文献1)，而且，作为吉莫斯特、替加氟(tegafur)、氧嗪酸钾(Oteracil potassium)的合剂的5-氟尿嘧啶系抗肿瘤剂(销售名：TS-1)被市售。
目前，作为5-氯-2，4-二羟基吡啶的制造方法，已知有如下方法。此外，在下述记载中，“Ac”表示乙酰基，“Et”表示乙基。
非专利文献1中记载的方法包括在酸性环境下在高压釜中200℃这样过于剧烈的反应条件，因而不言而喻，不适于工业制造方法。
此外，非专利文献2中记载的方法需要非常多的工序，因而在作为工业制造方法的实施上存在问题。
在专利文献2中公开了由丙二酰氯合成α，β-不饱和酮酸酯衍生物，使其与氨进行反应，制造2，4-二羟基-5-卤代吡啶衍生物的方法。由于该方法在中间体α，β-不饱和酮酸酯衍生物的合成原料的操作和反应条件上也存在问题，因此难以作为工业制造方法。
在专利文献3中公开了将3-氰基-2-羟基-3-甲氧基吡啶的5位选择性卤化，并且用强酸进行加热，以水解、脱碳酸除去氰基，制造2，4-二羟基-5-卤代吡啶衍生物的方法。此时，由于使用大量的碱用以中和在水解中使用的大量的酸，结果生成大量作为产业废弃物的盐，因此从环境方面考虑不优选。
专利文献1：日本专利特开昭62-155215号公报
专利文献2：日本专利特开平5-39241号公报
专利文献3：日本专利特开平5-78324号公报
非专利文献1：“Recueil Des Travaux Chemiques Des Pays-Bas”，1954，Vol.73，p.704
非专利文献2：“Recueil Des Travaux Chemiques Des Pays-Bas”，1953，Vol.72，p.285
发明内容
本发明的目的在于提供一种以温和条件和简短工序，并且产业废弃产物少地制造作为抗恶性肿瘤剂5-氟尿嘧啶的生物降解酶抑制剂的5-氯-2，4-二羟基吡啶的工业上有利的方法。
本发明人鉴于上述问题，对5-氯-2，4-二羟基吡啶的工业制造方法进行了深入研究，发现式(4)表示的吡喃酮衍生物作为5-氯-2，4-二羟基吡啶的制造中间体是极为有用的，从而完成本发明。
即，本发明涉及式(1)表示的5-氯-2，4-二羟基吡啶的制造方法，其特征在于：使式(2)表示的5-氯-1，3-二噁英-4-酮衍生物(2)与式(3)表示的乙烯酮缩二乙醇衍生物(3)反应，得到式(4)表示的吡喃酮衍生物(4)，对该吡喃酮衍生物(4)进行酸处理后，与氨反应。
(式中，R1和R2相同或不同，表示碳原子数为1～6的直链或支链的烷基，或者R1和R2也可以与相邻的碳原子一起形成碳原子数为3～6的环烷烃。)
(式中，R3和R4相同或不同，表示碳原子数为1～6的直链或支链的烷基或者具有碳原子数为1～6的直链或支链的烷基的甲硅烷基。)
(式中，R3和R4与上述相同。)
此外，本发明涉及以下式(4)表示的吡喃酮衍生物。
(式中，R3和R4与上述相同。)
发明的效果
采用本发明的制造方法，能够以缓和的条件、简便的方法，并且产业废弃物少地制造5-氯-2，4-二羟基吡啶，适合工业制造。此外，本发明的化合物吡喃酮衍生物能够分离精制，作为医药品制造的中间体是极为有用的。
具体实施方式
式中，作为用R1和R2表示的“碳原子数为1～6的直链或支链的烷基”，可以例举甲基、乙基、丙基、异丙基、丁基、叔丁基、戊基、己基等。此外，作为R1和R2也可以与相邻的碳原子一起形成的“碳原子数为3～6的环烷烃”，可以例举环丙烷、环丁烷、环戊烷、环己烷等。其中，优选碳原子数为3～6的环烷烃，特别优选环己烷。
式中，作为用R3和R4表示的“碳原子数为1～6的直链或支链的烷基”，可以例举甲基、乙基、丙基、异丙基、丁基、叔丁基、戊基、己基等。此外，作为“具有碳原子数为1～6的直链或支链的烷基的甲硅烷基”，可以例举具有1～3个相同或不同的例如甲基、乙基、丙基、异丙基、丁基、叔丁基、戊基、己基等的碳原子数为1～6的直链或支链的烷基的甲硅烷基。其中，优选碳原子数为1～6的烷基，特别优选乙基。
作为本发明的出发物质的5-氯-1，3-二噁英-4-酮衍生物(2)，例如能够根据以下反应式，通过在醋酸存在下以N-氯代琥珀酰亚胺对1，3-二噁英-4-酮衍生物(5)进行处理而得到(J Chem Soc Chem Commun.，699页(1991年))。此外，也能够通过在吡啶的存在下以磺酰氯对1，3-二噁英-4-酮衍生物(5)进行处理而得到。
(式中，R1和R2与上述相同。)
另外，上述1，3-二噁英-4-酮衍生物(5)为公知的化合物，例如能够通过Synthesis，1985，p224-225中记载的方法，使formyl Meldrum′sacid衍生物与酮或醛反应而容易地合成。
本发明的制造方法包括以下所表示的两个工序(a)和(b)。
[工序(a)]
(式中，R1～R4与上述相同。)
本工序为合成本发明的吡喃酮衍生物(4)的工序。
5-氯-1，3-二噁英-4-酮衍生物(2)与乙烯酮缩二乙醇衍生物(3)的反应在溶剂中进行。
作为在反应中使用的溶剂，只要是对反应没有不良影响的溶剂即可，没有特别的限定，可以例举苯、甲苯、二甲苯等芳香族烃类；二乙醚、四氢呋喃、二噁烷等醚类；二氯甲烷、氯仿等卤化烃类等。
乙烯酮缩二乙醇衍生物(3)的使用比率优选为相对于5-氯-1，3-二噁英-4-酮衍生物(2)使用0.7～5当量。
反应温度没有特别限定，通常为50℃～150℃，优选为90℃～140℃。
反应时间没有特别限定，通常为5～120分钟，优选为20～60分钟。此外，式(4)表示的化合物通过通常的分离精制方法例如柱色谱法、蒸馏、提取等，能够容易地分离精制。
[工序(b)]
(式中，R3和R4与上述相同。)
本工序为合成本反应的最终产物5-氯-2，4-二羟基吡啶(1)的工序。
通过对式(4)表示的吡喃酮衍生物进行酸处理，紧接着使其与过剩的氨反应，进行环变换反应。
作为在反应中使用的溶剂，只要是对反应没有不良影响的溶剂即可，没有特别的限定，可以例举甲醇、乙醇等醇类；二乙醚、四氢呋喃、二噁烷等醚类；苯、甲苯、二甲苯等芳香族烃类；二氯甲烷、氯仿等卤化烃类；乙腈、N，N-二甲基甲酰胺、二甲基亚砜等非质子性极性溶剂类；水等。
酸处理可以使用公知的酸，例如盐酸、氢溴酸、硫酸、硝酸等无机酸；甲酸、乙酸、对甲苯磺酸、甲磺酸、三氟乙酸等有机酸；加入质子性溶剂中在原位(in situ)产生酸的氯化乙酰、溴化乙酰等酸性卤化物。
酸处理时的酸的使用比率没有特别限定，相对于吡喃酮衍生物(4)为0.01～10当量，优选为0.1～3当量。
反应温度没有特别限定，通常为0℃～100℃，优选为15℃～60℃。
反应时间没有特别限定，通常为5～120分钟，优选为30～90分钟。
作为在环变换反应中使用的氨，可以例举氨水、液氨、氨气、溶解于在反应体系中导入的溶剂的氨或者在反应体系中原位(in situ)产生的氨。
作为将氨溶解于溶剂中使用时的溶剂，只要是对反应没有不良影响的溶剂即可，没有特别的限定，可以例举苯、甲苯、二甲苯等芳香族烃类；甲醇、乙醇等醇类；二乙醚、四氢呋喃、二噁烷等醚类；二氯甲烷、氯仿等卤化烃类；乙腈、N，N-二甲基甲酰胺、二甲基亚砜等非质子性极性溶剂类；水等。
为了在原位(in situ)产生氨采用现有公知的方法即可，例如，能够通过使用氯化铵等无机铵盐类或乙酸铵等有机铵盐类而进行。而且，也可以添加氢氧化钠或氢氧化钾等碱。
氨的使用比率没有特别限定，优选相对于吡喃酮衍生物(4)为1～30当量。
与氨的反应温度没有特别限定，通常为0℃～100℃，优选为15℃～60℃。
与氨的反应时间没有特别限定，通常为0.5～24分钟，优选为2～16分钟。
根据上述操作得到的5-氯-2，4-二羟基吡啶(1)，能够通过将反应液浓缩，向残渣中加入酸而进行分离。或者，能够在反应结束后加入碱，将析出的5-氯-2，4-二羟基吡啶(1)作为盐进行分离，以酸进行处理，作为5-氯-2，4-二羟基吡啶(1)进行分离。作为盐，可以例举钠盐、钾盐、锂盐等碱金属盐、镁盐、钙盐等碱土类金属的盐等方式。
实施例
通过实施例和参考例对5-氯-2，4-二羟基吡啶(1)的制造方法进行更详细的说明，但本发明并不限于这些实施例。
参考例1
5-氯-2，2-二甲基-1，3-二噁英-4-酮的合成
在冰冷下，向2，2-二甲基-1，3-二噁英-4-酮3.2g(0.025mol)的吡啶(16ml)溶液中滴下2.44ml(0.03mol)的磺酰氯，在相同温度下搅拌30分钟，在室温下搅拌2小时。将反应液冰冷，加入水。以二氯甲烷对反应液进行提取，无水硫酸钠干燥、浓缩二氯甲烷层。通过硅胶柱色谱法(洗脱溶剂正己烷∶乙酸乙酯＝95∶5)精制浓缩残渣，得到油状物质的标记化合物2.08g(收率51.2％)。
1H-NMR(CCl4)δ：1.73(s，6H)，7.23(s，1H)
MS m/z：162(M+)，164(M+2)
参考例2
5-氯-2，2-环己基-1，3-二噁英-4-酮的合成
在冰冷下，向2，2-环己基-1，3-二噁英-4-酮2.52g(0.015mol)的吡啶(13ml)溶液中滴下1.46ml(0.018mol)的磺酰氯，在相同温度下搅拌30分钟，在室温下搅拌2小时。将反应液冰冷，加入水。以二氯甲烷对反应液进行提取，无水硫酸钠干燥、浓缩二氯甲烷层。通过硅胶柱色谱法(洗脱溶剂正己烷∶乙酸乙酯＝95∶5)精制浓缩残渣，通过正己烷将得到的油状物质结晶化，得到标记化合物2.00g(收率65.9％)。
1H-NMR(CDCl3)δ：1.21-2.21(m，10H)，7.28(s，1H)
MS m/z：202(M+)，204(M+2)
实施例1
5-氯-2，2-二乙氧基-2，3-二噁英-4-酮的合成
向参考例2中得到的2，2-环己基-5-氯-1，3-二噁英-4-酮0.91g(0.0045mol)和乙烯酮二乙醚0.63g(0.0054mol)加入二甲苯(10ml)，在128-130℃(内温)下加热搅拌40分钟。将反应液冷却至室温进行浓缩。通过减压蒸馏残渣，得到0.77g标记化合物(收率77.7％)。沸点：113-115℃/0.6kPa
1H-NMR(CDCl3)δ：1.20-1.26(t，6H)，3.01(s，2H)，3.60-3.78(q，4H)，7.48(s，1H)
MS(ESI)：221(M+H)，223((M+2)+H)
实施例2
5-氯-2，4-二羟基吡啶的合成
将参考例1中得到的5-氯-2，2-二甲基-1，3-二噁英-4-酮0.49g(0.003mol)和乙烯酮甲基叔丁基二甲基甲硅烷基醚0.69g(0.0037mol)溶解于干燥甲苯(7ml)中，在氮气氛下回流40分钟。将反应液冷却至室温后进行浓缩，得到5-氯-2-甲氧基-2-叔丁基二甲基硅氧基-2，3-二氢吡喃-4-酮0.94g。以干燥甲醇(25ml)将其溶解，在室温下加入0.5ml(0.007mol)的氯化乙酰，搅拌1小时。浓缩反应液，向残渣中加入甲醇(20ml)溶解，再次浓缩。将残渣溶解于甲醇(25ml)中，在室温下加入浓氨水(28％)(5ml)，搅拌2.5小时。浓缩反应液，向残渣中加入水(5ml)、乙酸(0.5ml)，在室温下搅拌1小时。滤取析出的结晶，水洗后进行减压干燥(40-45℃，18小时)，得到0.16g标记化合物(由5-氯-2，2-二甲基-1，3-二噁英-4-酮的收率为36.5％)。
熔点：262℃(分解)
1H-NMR(DMSO-d6)δ：5.72(s，1H)，7.51(s，1H)，11.31(br，s，2H)
MS m/z：145(M+)
实施例3
5-氯-2，4-二羟基吡啶的合成
将参考例1中得到的5-氯-2，2-二甲基-1，3-二噁英-4-酮0.32g(0.002mol)和乙烯酮二乙醚0.28g(0.0024mol)溶解于干燥甲苯(4ml)中，在氮气氛下回流40分钟。将反应液冷却至室温后进行浓缩，得到5-氯-2，2-二乙氧基-2，3-二氢吡喃-4-酮0.39g(收率89.0％)。将0.23g(0.001mol)该化合物溶解于乙醇(5ml)中，在室温下加入氯化乙酰(0.1ml)，搅拌1小时。浓缩反应液，将残渣溶解于乙醇(5ml)中后，加入浓氨水(28％)(1ml)，在室温下搅拌15小时。浓缩反应液，向残渣中加入水(1.4ml)、乙酸(0.14ml)，在室温下搅拌2小时。滤取析出的结晶，水洗后进行减压干燥(40-45℃，18小时)，得到0.05g标记化合物(由5-氯-2，2-二乙氧基-2，3-二氢吡喃-4-酮的收率为33.0％，由5-氯-2，2-二甲基-1，3-二噁英-4-酮的总计收率为29.4％)。
实施例4
5-氯-2，4-二羟基吡啶的合成
向参考例2中得到的2，2-环己基-5-氯-1，3-二噁英-4-酮0.81g(0.004mol)和乙烯酮二乙醚0.56g(0.0048mol)中加入二甲苯(8ml)，在氮气氛下回流20分钟。将反应液冷却至室温后进行浓缩，得到0.92g的5-氯-2，2-二乙氧基-2，3-二氢吡喃-4-酮作为浓缩残渣。将其溶解于乙醇(20ml)中，加入氯化乙酰(0.5ml)，在室温下搅拌1小时。浓缩反应液，向残渣中加入乙醇(10ml)溶解后，再次浓缩。将残渣溶解于乙醇(1.4ml)中，加入浓氨水(28％)(0.5ml)，在室温下搅拌16小时。滤取析出的结晶，乙醇洗净后，溶解于水(5ml)中。向溶液中加入乙酸(0.5ml)，在室温下搅拌2小时。滤取析出的结晶，水洗后进行减压干燥(40-50℃，18小时)，得到0.31g标记化合物(由2，2-环己基-5-氯-1，3-二噁英-4-酮的收率为53.3％)。
实施例5
5-氯-2，4-二羟基吡啶的合成
向参考例2中得到的2，2-环己基-5-氯-1，3-二噁英-4-酮4.25g(0.021mol)和乙烯酮二乙醚2.91g(0.025mol)中加入二甲苯(40ml)，在128-130℃(内温)下加热搅拌40分钟。将反应液冷却至室温进行浓缩。向残渣中加入乙醇(60ml)溶解，在室温下加入0.17g(0.0022mol)氯化乙酰，搅拌1小时。向反应液中加入浓氨水(28％)(4.2ml)，在室温下搅拌4小时，加入3g(0.0225mol)的30％氢氧化钠水溶液。在室温下搅拌反应液12小时，滤取析出的结晶，用乙醇(10ml，2次)洗净，减压干燥(室温，5小时)后，得到3.04g结晶。将得到的结晶加热溶解于水(30ml)中，冷却至室温后，加入6N盐酸水溶液4.5g，在室温下搅拌5小时。滤取析出的结晶，水洗后进行减压干燥(40-45℃，18小时)，得到2.21g标记化合物(由2，2-环己基-5-氯-1，3-二噁英-4-酮的收率为72.4％)。
Claims (2)
1.一种式(1)表示的5-氯-2，4-二羟基吡啶的制造方法，其特征在于：使式(2)表示的5-氯-1，3-二噁英-4-酮衍生物(2)与式(3)表示的乙烯酮缩二乙醇衍生物(3)反应，得到式(4)表示的吡喃酮衍生物(4)，对该吡喃酮衍生物(4)进行酸处理后，与氨反应，
式中，R1和R2相同或不同，表示碳原子数为1～6的直链或支链的烷基，或者R1和R2也可以与相邻的碳原子一起形成碳原子数为3～6的环烷烃，
式中，R3和R4相同或不同，表示碳原子数为1～6的直链或支链的烷基，或者具有碳原子数为1～6的直链或支链的烷基的甲硅烷基，
式中，R3和R4与上述相同。
2.一种式(4)表示的吡喃酮衍生物，其特征在于：
式中，R3和R4相同或不同，表示碳原子数为1～6的直链或支链的烷基，或者具有碳原子数为1～6的直链或支链的烷基的甲硅烷基。
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101830845A (zh) * | 2010-05-28 | 2010-09-15 | 南京大唐医药科技有限公司 | 5-氯-2,3-二羟基吡啶的合成方法 |
| CN103086962A (zh) * | 2013-01-25 | 2013-05-08 | 苏州昊帆生物科技有限公司 | 5-氯-2,4-二羟基吡啶的合成方法 |
| CN103408487B (zh) * | 2013-08-23 | 2015-07-08 | 北京众和民健医药科技有限公司 | 一种吉莫斯特的精制方法 |
| JP7070938B2 (ja) * | 2020-03-31 | 2022-05-18 | 白鳥製薬株式会社 | ハロヒドロキシ芳香族化合物の製造方法 |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5155113A (en) * | 1984-10-30 | 1992-10-13 | Otsuka Pharmaceutical Co., Ltd. | Composition for increasing the anti-cancer activity of an anti-cancer compound |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5248670A (en) * | 1975-10-17 | 1977-04-18 | Nippon Shinyaku Co Ltd | Preparation of 2,5-disubstituted-pyridine derivatives |
| JPS62155215A (ja) * | 1984-11-30 | 1987-07-10 | Otsuka Pharmaceut Co Ltd | 抗腫瘍活性増強剤 |
| JP2805114B2 (ja) * | 1991-08-05 | 1998-09-30 | 大鵬薬品工業株式会社 | α，β−不飽和ケトエステル誘導体 |
| JP2826646B2 (ja) * | 1991-09-19 | 1998-11-18 | 大鵬薬品工業株式会社 | ３−置換−５−ハロゲノピリジン誘導体 |
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- 2006-01-25 EP EP06712321A patent/EP1842847B1/en not_active Not-in-force
- 2006-01-25 WO PCT/JP2006/301126 patent/WO2006080339A1/ja active Application Filing
- 2006-01-25 KR KR1020077017028A patent/KR101253367B1/ko not_active IP Right Cessation
- 2006-01-25 JP JP2007500539A patent/JP4892472B2/ja not_active Expired - Fee Related
- 2006-01-25 DK DK06712321.6T patent/DK1842847T3/da active
- 2006-01-25 ES ES06712321T patent/ES2381800T3/es active Active
- 2006-01-25 CN CN200680003210XA patent/CN101107230B/zh not_active Expired - Fee Related
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5155113A (en) * | 1984-10-30 | 1992-10-13 | Otsuka Pharmaceutical Co., Ltd. | Composition for increasing the anti-cancer activity of an anti-cancer compound |
Non-Patent Citations (4)
| Title |
|---|
| Masayuki Sato et al.synthesis of 5,6-unsubstituted 1,3-dioxin-4-ones.synthesis 2.1985,(2),224-226. |
| Masayuki Sato et al.synthesis of 5,6-unsubstituted 1,3-dioxin-4-ones.synthesis 2.1985,(2),224-226. * |
| Masayuki Sato et al.Synthesis of 5-Fluoro-1,3-dioxin-4-ones: VersatileBuilding Blocks of Fluorinated Compounds.J. CHEM. SOC., CHEM. COMMUN., 10.1991,(10),699-700. |
| Masayuki Sato et al.Synthesis of 5-Fluoro-1,3-dioxin-4-ones: VersatileBuilding Blocks of Fluorinated Compounds.J.CHEM.SOC.,CHEM. COMMUN.,10.1991,(10),699-700. * |
Also Published As
| Publication number | Publication date |
|---|---|
| EP1842847B1 (en) | 2012-03-07 |
| CA2594702A1 (en) | 2006-08-03 |
| EP1842847A4 (en) | 2011-01-19 |
| KR20070095973A (ko) | 2007-10-01 |
| ES2381800T3 (es) | 2012-05-31 |
| TWI365184B (en) | 2012-06-01 |
| HK1113930A1 (en) | 2008-10-17 |
| US20090043101A1 (en) | 2009-02-12 |
| JP4892472B2 (ja) | 2012-03-07 |
| KR101253367B1 (ko) | 2013-04-11 |
| DK1842847T3 (da) | 2012-04-10 |
| AU2006209556B2 (en) | 2010-12-02 |
| EP1842847A1 (en) | 2007-10-10 |
| TW200637825A (en) | 2006-11-01 |
| US7557216B2 (en) | 2009-07-07 |
| AU2006209556A1 (en) | 2006-08-03 |
| WO2006080339A1 (ja) | 2006-08-03 |
| JPWO2006080339A1 (ja) | 2008-06-19 |
| CA2594702C (en) | 2012-10-02 |
| CN101107230A (zh) | 2008-01-16 |
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