CN101337930B - 脲衍生物的制备方法 - Google Patents
脲衍生物的制备方法 Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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
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- C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C275/32—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms
- C07C275/34—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms having nitrogen atoms of urea groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
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Abstract
Description
本申请是申请日为2004年11月8日、申请号为200480033071.6(国际申请号为PCT/JP2004/016526)、发明名称为“脲衍生物及其制备方法”的申请的分案申请。
技术领域
本发明涉及有效预防或治疗伴随血管新生异常增殖的各种疾病的脲衍生物及其制备方法。
背景技术
已知以通式(C)表示的脲衍生物具有优异的血管新生抑制作用(专利文献1)。另外,还已知以通式(C)表示的脲衍生物具有强的c-Kit激酶抑制作用(专利文献2、非专利文献1)。
[式中,R1表示氢原子、C1-6烷基或C3-8环烷基;R2表示氢原子或甲氧基。]
专利文献1所述的制备方法作为脲衍生物的制备方法是有用的,但从总收率等方面考虑,还有进一步改善的余地。所以,期待开发出总收率更高的脲衍生物的工业化制法以及该制备方法中有用的中间体。
另外,在专利文献1中完全没有公开以本发明中所述通式(C)表示的脲化合物的有效制备方法以及以通式(A-1)及(A-2)表示的有用中间体。
专利文献1:国际公开第02/32872号说明书
专利文献2:国际公开第2004/080462号说明书
非专利文献1:95th Annual Meeting Proceedings,AACR(AmericanAssociation for Cancer Research),Volume 45,Page 1070-1071,2004
发明内容
本发明的目的是提供有效预防或治疗伴随血管新生异常增殖的各种疾病的脲衍生物的新制备中间体及其制备方法。
鉴于上述情况,本发明人等进行了深入研究,结果发现了有效预防或治疗伴随血管新生异常增殖的各种疾病的脲衍生物的新制备中间体及其制备方法,从而完成了本发明。即,本发明提供
[1]下式表示的化合物(A-1)或其盐或它们的水合物;
[式中,R1表示氢原子、C1-6烷基或C3-8环烷基。]
[2]如[1]所述的化合物或其盐或它们的水合物,其中,R1为氢原子、甲基、乙基、正丙基或环丙基;
[3]如[1]所述的化合物或其盐或它们的水合物,其中,R1为环丙基;
[4]下式表示的化合物(A-1)的制备方法,
[式中,R1表示与上述相同的含义。]
其特征在于,利用下式表示的化合物(A-3)和下式表示的化合物(A-4)反应生成下式表示的化合物(A-2),然后,使化合物(A-2)与式R1-NH2[式中,R1表示与上述相同的含义]表示的化合物反应;
[式中,Ar表示可以具有选自卤原子、甲基、甲氧基以及硝基中的1个或2个取代基的C6-10芳基。]
[式中,Ar表示与上述相同的含义。]
[5]如[4]所述的制备方法,其中,R1为氢原子、甲基、乙基、正丙基或环丙基;
[6]如[4]所述的制备方法,其中,R1为环丙基;
[7]如[4]~[6]任一项所述的制备方法,其中,Ar为苯基;
[8]下式表示的化合物(A-2)或其盐或它们的水合物;
[式中,Ar表示与上述相同的含义。]
[9]如[8]所述的化合物或其盐或它们的水合物,其中,Ar为苯基;
[10]下式表示的化合物(C)或其盐的制备方法,
[式中,R1和R2表示与上述相同的含义。]
其特征在于,使下式表示的化合物(A-1)和下式表示的化合物(B)反应;
[式中,R1表示与上述相同的含义。]
[式中,R2表示氢原子或甲氧基;L表示离去基团。]
[11]如[10]所述的制备方法,其特征在于,该方法使用碱;
[12]如[11]所述的制备方法,其中,碱是碱金属的碳酸盐或碱金属的醇盐;
[13]如[11]所述的制备方法,其中,碱是碳酸铯、碳酸钾或叔丁醇钾;
[14]如[10]~[13]任一项所述的制备方法,其中,R1为氢原子、甲基、乙基、正丙基或环丙基;
[15]如[10]~[13]任一项所述的制备方法,其中,R1为环丙基;
[16]如[10]~[15]任一项所述的制备方法,其中,R2为氢原子;
[17]如[10]~[16]任一项所述的制备方法,其中,L是氯原子。
具体实施方式
下面,对本说明书中记载的用语、符号等的含义进行说明,并对本发明进行详细说明。
本发明中的化合物或其盐是无水物、水合物、溶剂合物中的任一种。
本说明书中使用的“C1-6烷基”是作为从碳原子数为1~6的脂肪族烃中任意除去1个氢原子后衍生的一价基团的碳原子数为1~6的直链或支链烷基,具体可以举出甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、仲戊基、新戊基、1-甲基丁基、2-甲基丁基、1,1-二甲基丙基、1,2-二甲基丙基、正己基、异己基、1-甲基戊基、2-甲基戊基、3-甲基戊基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2,3-二甲基丁基、3,3-二甲基丁基、1-乙基丁基、2-乙基丁基、1,1,2-三甲基丙基、1,2,2-三甲基丙基、1-乙基-1-甲基丙基、1-乙基-2-甲基丙基等,优选为甲基、乙基、正丙基等。
本说明书中使用的“C3-8环烷基”表示碳原子数为3~8的环状脂肪族烃基,具体可以举出环丙基、环丁基、环戊基、环己基、环庚基、环辛基等,优选为环丙基。
本说明书中使用的“C6-10芳基”表示碳原子数为6~10的芳香族烃环基,具体可以举出苯基、1-萘基、2-萘基等,优选为苯基。
本说明书中使用“卤原子”是指氟原子、氯原子、溴原子或碘原子,优选氯原子。
本说明书中使用的“碱”表示有机碱(例如吡啶、2,6-二甲基吡啶、三甲基吡啶、三乙胺、二异丙基乙基胺、二氮杂双环[5.4.0]十一碳-7烯等)或无机碱(碱金属的碳酸盐(例如,碳酸铯、碳酸钾、碳酸钠等)、碱金属的醇盐(例如,叔丁醇钾、乙醇钠等)、碱金属的氢化物(例如,氢化钾、氢化钠等)、碱金属的氢氧化物(例如,氢氧化钾、氢氧化钠等))。作为使化合物(A-1)与化合物(B)作用得到化合物(C)的步骤中使用的碱,优选碱金属的碳酸盐或碱金属的醇盐,较优选碳酸铯、碳酸钾或叔丁醇钾。
本说明书中使用的“盐”,例如可以举出与无机酸成的盐、与有机酸成的盐、与无机碱成的盐、与有机碱成的盐、与酸性或碱性氨基酸成的盐等。
作为无机酸盐的优选例,例如可以举出与盐酸、氢溴酸、硫酸、硝酸、磷酸等成的盐;作为有机酸盐的优选例,例如可以举出与醋酸、琥珀酸、富马酸、马来酸、酒石酸、柠檬酸、乳酸、硬脂酸、安息香酸、甲磺酸、乙磺酸、对甲苯磺酸等成的盐。
作为与无机碱成盐的优选例,例如可以举出钠盐、钾盐等碱金属盐、钙盐、镁盐等碱土金属盐、铝盐、铵盐等。作为与有机碱成盐的优选例,例如可以举出与二乙基胺、二乙醇胺、甲葡胺(meglumine)、N,N-二苄基乙二胺等成的盐。
作为与酸性氨基酸成盐的优选例,例如可以举出与天冬氨酸、谷氨酸等成的盐,作为与碱性氨基酸成盐的优选例,例如可以举出与精氨酸、赖氨酸、鸟氨酸等成的盐。
本发明中使用的“离去基团”只要是在有机合成时通常作为离去基团的基团,可以是任意基团,没有特别限定,具体可以举出例如,氯原子、溴原子、碘原子等卤原子;例如,甲磺酰氧基、三氟甲磺酰氧基、乙磺酰氧基等烷基磺酰氧基;例如,苯磺酰氧基、对甲苯磺酰氧基等芳基磺酰氧基;例如,甲氧基、乙氧基等烷氧基;例如,甲硫基、乙硫基等烷硫基等。作为该“离去基团”,优选氯原子、溴原子、碘原子等卤原子,较优选氯原子。
下面详细说明本发明的制备方法。
制备方法1脲(A-1)的制备方法
[式中,各符号表示与上述相同的含义。]
[步骤1-1]
该步骤是使氯甲酸苯酯等氨基甲酸酯化试剂(A-3)与化合物(A-4)反应得到化合物(A-2)的步骤。作为反应溶剂,可以使用二甲基亚砜、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、四氢呋喃、乙酸乙酯等。反应中还可以使用吡啶等碱。相对化合物(A-4)可以使用1当量~2当量氨基甲酸酯试剂(A-3)。相对化合物(A-4)可以使用1当量~5当量碱。反应时间为10分钟~30小时。反应温度为0℃~加热回流温度,优选O℃~室温。
[步骤1-2]
该步骤是使胺衍生物R1-NH2与化合物(A-2)反应得到化合物(A-1)的步骤。作为反应溶剂,可以使用二甲基亚砜、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、四氢呋喃、乙酸乙酯、乙腈、甲苯、氯仿等。反应中还可以使用有机碱(例如,吡啶、三乙胺、二异丙基乙基胺等)或无机碱(碱金属的碳酸盐(例如,碳酸铯、碳酸钾、碳酸钠等)、碱金属的氢化物(例如,氢化钾、氢化钠等))。相对化合物(A-2)可以使用1当量~3当量胺衍生物。相对化合物(A-2)可以使用1当量~3当量碱。反应时间为10分钟~30小时。反应温度为0℃~加热回流温度,优选0℃~室温。
制备方法2化合物(C)的制备方法
[式中,各符号表示与上述相同的含义。]
[步骤2]
该步骤是使化合物(A-1)与化合物(B)反应得到化合物(C)的步骤。作为反应溶剂,可以使用1-甲基吡咯烷酮、二甲基亚砜、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、1,3-二甲基-2-咪唑啉酮、甲苯、氯苯等。作为适当的碱,可以添加有机碱(例如,吡啶、2,6-二甲基吡啶、三甲基吡啶、三乙胺、二异丙基乙基胺、二氮杂双环[5.4.0]十一碳-7-烯等)或无机碱(碱金属的碳酸盐(例如,碳酸铯、碳酸钾、碳酸钠等)、碱金属的醇盐(例如,叔丁醇钾、乙醇钠等)、碱金属的氢化物(例如,氢化钾、氢化钠等)、碱金属的氢氧化物(例如,氢氧化钾、氢氧化钠等))。作为该碱,优选碱金属的碳酸盐或碱金属的醇盐,较优选碳酸铯、碳酸钾或叔丁醇钾。相对化合物(B)使用1当量~2当量化合物(A-1)。相对化合物(B)使用1当量~2当量碱。反应时间为10分钟~48小时。反应温度为室温~加热回流温度,优选40℃~80℃。
上述反应结束后,根据要求,利用常规的处理方法进行精制,例如,可以利用使用硅胶或吸附树脂等的柱色谱或利用适当的溶剂重结晶。
实施例
为了更容易地理解本发明,列举以下实施例,但本发明并不限定于此。
(实施例1)N-(2-氯-4-羟基苯基)氨基甲酸苯酯
将4-氨基-3-氯苯酚(23.7g)悬浊在N,N-二甲基甲酰胺(100mL)中,在冰冷却下加入吡啶(23.4mL)后,于20℃或20℃以下滴入氯甲酸苯酯(23.2mL)。在室温下搅拌30分钟后,加入水(400mL)、乙酸乙酯(300mL)、6N-HCl(48mL),搅拌后分离有机层。用10%食盐水(200mL)洗涤2次有机层,然后用硫酸镁干燥。蒸馏除去溶剂,得到46g固体状标题化合物。
1H-NMR(CDCl3):5.12(1h,br s),6.75(1H,dd,J=9.2,2.8Hz),6.92(1H,d,J=2.8Hz),7.18-7.28(4H,m),7.37-7.43(2H,m),7.94(1H,br s)
(实施例2)1-(2-氯-4羟基苯基)-3-环丙基脲
将N-(2-氯-4-羟基苯基)氨基甲酸苯酯溶解于N,N-二甲基甲酰胺(100mL),在冰冷却下加入环丙基胺(22.7mL),于室温下搅拌过夜。加入水(400mL)、乙酸乙酯(300mL)、6N-HCl(55mL),搅拌后分离有机层。用10%食盐水(200mL)洗涤2次有机层,然后用硫酸镁干燥。用庚烷洗涤,过滤浓缩溶剂得到的棱晶,得到22.8g标题化合物。(从4-氨基-3-氯苯酚开始计算,收率为77%)
1H-NMR(CDCl3):0.72-0.77(2H,m),0.87-0.95(2H,m),2.60-2.65(1H,m),4.89(1H,br s),5.60(1H,br s),6.71(1H,dd,J=8.8,2.8Hz),6.88(1H,d,J=2.8Hz),7.24-7.30(1H,br s),7.90(1H,d,J=8.8H)
(实施例3)4-(3-氯-4-(环丙基氨基羰基)氨基苯氧基)-7-甲氧基-6-喹啉甲酰胺
在二甲基亚砜(20mL)中添加7-甲氧基-4-氯-喹啉-6-甲酰胺(0.983g)、1-(2-氯-4-羟基苯基)-3-环丙基脲(1.13g)以及碳酸铯(2.71g),于70℃下加热搅拌23小时。将反应液恢复至室温后,加入水(50mL),过滤生成的结晶,得到1.56g标题化合物。(收率88%)
1H-NMR(d6-DMSO):0.41(2H,m),0.66(2H,m),2.56(1H,m),4.01(3H,s),6.51(1H,d,J=5.6Hz),7.18(1H,d,J=2.8Hz),7.23(1H,dd,J=2.8,8.8Hz),7.48(1H,d,J=2.8Hz),7.50(1H,s),7.72(1H,s),7.84(1H,s),7.97(1H,s),8.25(1H,d,J=8.8Hz),8.64(1H,s),8.65(1H,d,J=5.6Hz)
(实施例4)4-(3-氯-4-(环丙基氨基羰基)氨基苯氧基)-7-甲氧基-6-喹啉甲酰胺
在氮气氛围中,向反应容器中依次加入7-甲氧基-4-氯-喹啉-6-甲酰胺(5.00kg、21.13mol)、二甲基亚砜(55.05kg)、1-(2-氯-4-羟基苯基)-3-环丙基脲(5.75kg、25.35mol)以及叔丁醇钾(2.85kg、25.35mol)。然后在20℃下搅拌30分钟,接下来,经2.5小时将温度升至65℃。在同温度下搅拌19小时后,经3.5小时滴入33%(v/v)丙酮水溶液(5.0L)以及水(10.0L)。滴完后,在60℃下搅拌2小时,然后在55℃或55℃以上经1小时滴入33%(v/v)丙酮水溶液(20.0L)以及水(40.0L)。在40℃下搅拌16小时后,利用氮气压式过滤器过滤析出的结晶,依次用33%(v/v)丙酮水溶液(33.3L)、水(66.7L)以及丙酮(50.0L)洗涤结晶。利用圆锥式减压干燥机,在60℃下将得到的结晶干燥22小时,得到7.78kg标题化合物。(收率96.3%)
利用本发明的脲衍生物的制备方法,能制备有效预防或治疗伴随血管新生异常增殖的各种疾病的脲衍生物,且该制备方法效率高、可工业化。另外,本发明的脲衍生物的中间体作为用于高效制备上述脲衍生物的中间体是有用的。
产业上的可利用性
利用本发明的脲衍生物的制备方法,能制备有效预防或治疗伴随血管新生异常增殖的各种疾病的脲衍生物,且该制备方法效率高、可工业化。另外,本发明的脲衍生物的中间体作为用于高效制备上述脲衍生物的中间体是有用的。
Claims (5)
2.如权利要求1所述的制备方法,其中,R1为氢原子、甲基、乙基、正丙基或环丙基。
3.如权利要求1所述的制备方法,其中,R1为环丙基。
4.如权利要求1~3任一项所述的制备方法,其中,R2为氢原子。
5.如权利要求1~3任一项所述的制备方法,其中,L是氯原子。
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EP1683785A4 (en) | 2007-08-29 |
IL175363A (en) | 2013-10-31 |
JP4303726B2 (ja) | 2009-07-29 |
US7683172B2 (en) | 2010-03-23 |
US8058474B2 (en) | 2011-11-15 |
CN101337930A (zh) | 2009-01-07 |
US20090171112A1 (en) | 2009-07-02 |
CN100450998C (zh) | 2009-01-14 |
CN1878751A (zh) | 2006-12-13 |
EP1683785A1 (en) | 2006-07-26 |
WO2005044788A1 (ja) | 2005-05-19 |
JPWO2005044788A1 (ja) | 2007-11-29 |
US20070037849A1 (en) | 2007-02-15 |
IL175363A0 (en) | 2006-09-05 |
EP1683785B1 (en) | 2013-10-16 |
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