CN1199947C - 吡啶衍生物的制备方法 - Google Patents
吡啶衍生物的制备方法 Download PDFInfo
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Abstract
本发明提供一种高收率、低成本且不会产生公害问题地制备高纯度吡啶衍生物的方法。一种吡啶衍生物的制备方法,其特征在于,使1,2,4-三嗪化合物与乙烯酯化合物反应。
Description
技术领域
本发明涉及一种吡啶衍生物的制备方法,能够低成本、高收率且高纯度地得到在药品、农药、催化剂配体、卤化银感光材料、液晶、电子照相和有机电致发光元件等领域中使用的有机感光体或染料等的制造中作为重要中间体的吡啶衍生物。
背景技术
取代吡啶类的制备方法已有种种报道。例如报道了在添加有铂的Pd-C存在下使吡啶化合物和吡啶化合物的N-氧化物加热缩合的方法(药学杂志(Yakugaku Zasshi),99(12),pp.1176、1181(1979)),但是收率低。另外,还报道了利用格利雅(Grignard)反应的交联偶合反应(特开昭64-003169号),但是存在下述问题,即为得到吡啶类的格利雅试剂所必须的碘化吡啶化合物的获得和合成很困难,必须有特殊的设备等。
进而,提出了卤化吡啶化合物之间的乌尔曼缩合反应(Khim.Geol.Nauk.,pp.114(1970)),以及在Pd催化剂存在下使卤化吡啶化合物与各种金属衍生物交联偶合的方法。例如已经报道了使之与硼烷衍生物交联偶合的方法(Chem.Pharm.Bull.,33(11),pp.4755(1985);Heterocycles,23(9),pp.2375(1985))、使之与烷基锡衍生物交联偶合的方法(TetrahedronLett.,33,pp.2199(1992))、在Ni催化剂存在下使卤化吡啶化合物交联偶合的方法(WO9852922号)等。
但是,这些方法在大量生产方面均存在较多的问题,或是使用的催化剂和试剂昂贵,或是产生的金属废液必须进行特殊处理。另外,这些反应的副反应产物多,分离非常困难,不能得到可作为药品或电子材料等的中间体耐用的高纯度物质。
另一方面,自古以来已知使用2,5-降冰片二烯由1,2,4-三嗪化合物合成吡啶衍生物的方法(例如Tetrahedron Lett.,39,pp.8817、8821、8825(1998))。
但是,在大量生产的场合存在较多的问题,即2,5-降冰片二烯相对于底物必须为10当量以上的大量过剩量;反应时间长;价格昂贵;有毒,即使吸入微量即会引起头痛;以及工业规模的稳定供给性方面存在问题。
另外,已报道了通过1,2,4-三嗪和醋酸乙烯酯得到吡啶化合物的方法(Tetrahedron Lett.,59,pp.5171(1969)),但是收率低,另外仅限适用于在1,2,4-三嗪的3,5,6位具有烷氧基羰基的高活性底物。
发明内容
本发明的目的在于提供一种能够高纯度、高收率、低成本地获得作为药品、农药、液晶等的中间体有用的吡啶衍生物,而且不产生公害问题,并能够工业规模实施的吡啶衍生物的制备方法。
按照本发明,提供下述吡啶衍生物的制备方法,从而实现本发明的上述目的。
(1)一种吡啶衍生物的制备方法,其特征在于,使1,2,4-三嗪化合物与下述通式(I)表示的羧酸乙烯酯类反应。
式中,R表示碳原子数3以上的烷基、取代或未取代的芳基、或者取代或未取代的杂环残基。
(2)如上述(1)所述的吡啶衍生物的制备方法,通式(I)中,R为碳原子数7~17的烷基。
(3)如上述(1)所述的吡啶衍生物的制备方法,通式(I)中,R为取代或未取代的苯基、或者取代或未取代的含氮杂环残基。
(4)如上述(1)所述的吡啶衍生物的制备方法,使下述通式(III)表示的1,2,4-三嗪化合物与上述通式(I)表示的羧酸乙烯酯类反应。
式中,R1、R2和R3可以相同或不同,表示氢原子、烷基、芳基、杂环残基、烷硫基、烷基亚硫酰基、烷基磺酰基、芳基亚硫酰基、芳基磺酰基、烷氧基、苯氧基、烷氧基羰基或苯氧基羰基。另外,R2和R3也可以互相结合形成环。
(5)如上述(4)所述的吡啶衍生物的制备方法,通式(III)中,R1为苯基或含氮杂环残基。
(6)如上述(1)所述的吡啶衍生物的制备方法,相对于1,2,4-三嗪化合物1mol,使用羧酸乙烯酯类1.01~20mol。
(7)如上述(1)所述的吡啶衍生物的制备方法,相对于1,2,4-三嗪化合物1mol,使用羧酸乙烯酯类1.5~5mol。
(8)如上述(1)所述的吡啶衍生物的制备方法,使用沸点为100℃以上的反应溶剂。
(9)如上述(1)所述的吡啶衍生物的制备方法,使用沸点为180~250℃的反应溶剂。
(10)一种吡啶衍生物的制备方法,其特征在于,使1,2,4-三嗪化合物与下述通式(II)表示的羧酸乙烯酯类反应。
式中,n表示0~18的整数。
(11)如上述(10)所述的吡啶衍生物的制备方法,通式(II)中,n为3~12的整数。
(12)如上述(10)所述的吡啶衍生物的制备方法,使下述通式(III)表示的1,2,4-三嗪化合物与上述通式(II)表示的羧酸乙烯酯类反应。
式中,R1、R2和R3可以相同或不同,表示氢原子、烷基、芳基、杂环残基、烷硫基、烷基亚硫酰基、烷基磺酰基、芳基亚硫酰基、芳基磺酰基、烷氧基、苯氧基、烷氧基羰基或苯氧基羰基。另外,R2和R3也可以互相结合形成环。
(13)如上述(12)所述的吡啶衍生物的制备方法,通式(III)中,R1为苯基或含氮杂环残基。
(14)如上述(10)所述的吡啶衍生物的制备方法,相对于1,2,4-三嗪化合物1mol,使用羧酸乙烯酯类0.505~10mol。
(15)如上述(10)所述的吡啶衍生物的制备方法,相对于1,2,4-三嗪化合物1mol,使用羧酸乙烯酯类0.75~2.5mol。
(16)如上述(10)所述的吡啶衍生物的制备方法,使用沸点为100℃以上的反应溶剂。
(17)如上述(10)所述的吡啶衍生物的制备方法,使用沸点为180~250℃的反应溶剂。
具体实施方式
以下更详细地说明本发明。
上述通式(I)或(II)表示的羧酸乙烯酯类中的R表示直链状、支链状或环状的碳原子数3以上的烷基、取代或未取代的芳基、或者取代或未取代的杂环残基。作为芳基、杂环残基上取代的基团,可以例举哈米特(Hammett)的取代基常数σm为-0.21~0.39范围内的取代基,可以是单取代或多取代,多取代的场合,各取代基可以相同,也可以不同。其中,作为哈米特的σm值为-0.21~0.39范围内的取代基,具体例如甲基、叔丁基等烷基,环戊基、环己基等环烷基,苯基、萘基等芳基,甲氧基、乙氧基等烷氧基,氨基、二甲氨基等氨基,硝基,氯原子、溴原子等卤素原子等。
作为R中的直链状、支链状或环状的碳原子数3以上,优选碳原子数5以上,更优选碳原子数7~17的烷基,例如丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、环戊基、异戊基、新戊基、叔戊基、1-甲基丁基、2-甲基丁基、1-乙基丙基、1,2-二甲基丙基、2,2-二甲基丙基、己基、环己基、1-甲基戊基、2-甲基戊基、3-甲基戊基、4-甲基戊基、1-乙基丁基、2-乙基丁基、1,2-二甲基丁基、1,3-二甲基丁基、2,3-二甲基丁基、1,1-二甲基丁基、2,2-二甲基丁基、3,3-二甲基丁基、1-乙基-2-甲基-丙基、庚基、1-甲基己基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、1-乙基戊基、2-乙基戊基、3-乙基戊基、1,2-二甲基戊基、1,3-二甲基戊基、1,4-二甲基戊基、2,3-二甲基戊基、2,4-二甲基戊基、3,4-二甲基戊基、1,1-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、4,4-二甲基戊基、2-乙基-1-甲基-丁基、1-乙基-2-甲基-丁基、1-乙基-3-甲基丁基、1-乙基-3-甲基丁基、2-乙基-3-甲基丁基、1-乙基-1-甲基丁基、2-乙基-2-甲基丁基、1,2,3-三甲基丁基、1,1,2-三甲基丁基、1,2,2-三甲基丁基、1,1,3-三甲基丁基、1,3,3-三甲基丁基、2,2,3-三甲基丁基、2,3,3-三甲基丁基、1-异丙基-2-甲基丙基、辛基、1-甲基庚基、2-甲基庚基、3-甲基庚基、4-甲基庚基、5-甲基庚基、6-甲基庚基、1-乙基己基、2-乙基己基、3-乙基己基、4-乙基己基、1-丙基戊基、2-丙基戊基、1-丁基丁基、1,2-二甲基己基、1,3-二甲基己基、1,4-二甲基己基、1,5-二甲基己基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、3,4-二甲基己基、3,5-二甲基己基、4,5-二甲基己基、1,1-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、5,5-二甲基己基、1,2,3-三甲基戊基、1,2,4-三甲基戊基、2,3,4-三甲基戊基、2-乙基-1-甲基戊基、3-乙基-1-甲基戊基、1-乙基-2-甲基戊基、3-乙基-2-甲基戊基、1-乙基-3-甲基戊基、2-乙基-3-甲基戊基、1-乙基-4-甲基戊基、2-乙基-1-甲基戊基、1-乙基-1-甲基戊基、2-乙基-2-甲基戊基、3-乙基-3-甲基戊基、1,2-二乙基丁基、1,1-二乙基丁基、2,2-二乙基丁基、壬基、异壬基、仲壬基、叔壬基、新壬基、癸基、异癸基、仲癸基、叔癸基、新癸基、十一烷基、异十一烷基、仲十一烷基、叔十一烷基、新十一烷基、十二烷基、异十二烷基、仲十二烷基、叔十二烷基、新十二烷基、十三烷基、异十三烷基、仲十三烷基、叔十三烷基、新十三烷基、十四烷基、异十四烷基、仲十四烷基、叔十四烷基、新十四烷基、十五烷基、异十五烷基、仲十五烷基、叔十五烷基、新十五烷基、十六烷基、异十六烷基、仲十六烷基、叔十六烷基、新十六烷基、十七烷基、异十七烷基、仲十七烷基、叔十七烷基、新十七烷基、十八烷基、异十八烷基、仲十八烷基、叔十八烷基、新十八烷基、十九烷基、异十九烷基、仲十九烷基、叔十九烷基、新十九烷基等。
作为R中的芳基,例如苯基、萘基、甲苯基、二甲苯基、异丙苯基、三甲苯基、二甲氨基苯基、二苯基氨基苯基、甲氧基苯基、苯氧基苯基、环己基苯基、硝基苯基、氯苯基、溴苯基、氟苯基、碘苯基、三氟苯基、羟基苯基、羧基苯基、甲氧基羰基苯基、氰基苯基等。
作为R中的杂环残基,例如吡啶基、吡嗪基、嘧啶基、喹啉基、异喹啉基、吡咯基、吡唑基、咪唑基、噻吩基、呋喃基、噻唑基、异噻唑基、恶唑基、异恶唑基、甲基吡啶基、苯基吡啶基、硝基吡啶基、氯吡啶基、溴吡啶基、甲氧基吡啶基、二苯基氨基吡啶基、甲基吡嗪基、苯基吡嗪基、硝基吡嗪基、氯吡嗪基、溴吡嗪基、甲氧基吡嗪基、二苯基氨基吡嗪基等。
通式(II)的n为0~18的整数,优选3~12的整数。
另外,在上述通式(I)中,如果R为碳原子数1或2的烷基,则1,2,4-三嗪化合物与羧酸乙烯酯类的反应进行显著迟缓,不适于工业生产吡啶衍生物。
通式(I)中,优选R为碳原子数7~17的烷基。另外,还优选R为取代或未取代的苯基、或者取代或未取代的含氮杂环残基。
作为R的优选具体实例,例如丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、环戊基、异戊基、新戊基、叔戊基、1-甲基丁基、2-甲基丁基、1-乙基丙基、1,2-二甲基丙基、2,2-二甲基丙基、己基、环己基、1-甲基戊基、2-甲基戊基、3-甲基戊基、4-甲基戊基、1-乙基丁基、2-乙基丁基、1,2-二甲基丁基、1,3-二甲基丁基、2,3-二甲基丁基、1,1-二甲基丁基、2,2-二甲基丁基、3,3-二甲基丁基、庚基、1-甲基己基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、1-乙基戊基、2-乙基戊基、3-乙基戊基、1,2-二甲基戊基、1,3-二甲基戊基、1,4-二甲基戊基、2,3-二甲基戊基、2,4-二甲基戊基、3,4-二甲基戊基、1,1-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、4,4-二甲基戊基、辛基、1-甲基庚基、2-甲基庚基、3-甲基庚基、4-甲基庚基、5-甲基庚基、6-甲基庚基、1-乙基己基、2-乙基己基、3-乙基己基、4-乙基己基、1-丙基戊基、2-丙基戊基、1-丁基丁基、1,2-二甲基己基、1,3-二甲基己基、1,4-二甲基己基、1,5-二甲基己基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、3,4-二甲基己基、3,5-二甲基己基、4,5-二甲基己基、1,1-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、5,5-二甲基己基、1,2-二乙基丁基、1,1-二乙基丁基、2,2-二乙基丁基、壬基、异壬基、仲壬基、叔壬基、新壬基、癸基、异癸基、仲癸基、叔癸基、新癸基、苯基、萘基、甲苯基、二甲苯基、异丙苯基、三甲苯基、硝基苯基、氯苯基、溴苯基、氟苯基、碘苯基、三氟苯基、氰基苯基、吡啶基、吡嗪基、嘧啶基、喹啉基、异喹啉基、吡咯基、吡唑基、咪唑基、噻吩基、呋喃基等。
作为1,2,4-三嗪化合物,优选下述通式(III)表示的1,2,4-三嗪化合物。
式中,R1、R2和R3可以相同或不同,表示氢原子、烷基、芳基、杂环残基、烷硫基、烷基亚硫酰基、烷基磺酰基、芳基亚硫酰基、芳基磺酰基、烷氧基、苯氧基、烷氧基羰基或苯氧基羰基。另外,R2和R3也可以互相结合形成环。
首先,为了更详细地说明本发明的方法,详细叙述使1,2,4-三嗪化合物和羧酸乙烯酯类反应的一种方式,但是本发明的范围决不限定于此。
1,2,4-三嗪化合物(III)与羧酸乙烯酯类的反应按照下式进行,生成吡啶衍生物(a)。
式中,R与上述定义相同。n为0~18的整数,优选3~12的整数。另外,R1、R2和R3与上述定义相同。
以下,详细叙述上述通式(a)和通式(III)中的R1、R2、R3。
作为烷基,可以例举碳原子数1~18的直链状或支链状的烷基。优选甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基等碳原子数1~4个的烷基,更优选能够衍生为羧酸或醛的甲基。
作为芳基,具体例如取代或未取代的苯基、萘基、蒽基、菲基等。优选取代或未取代的苯基、萘基,更优选取代或未取代的苯基。
作为具有取代基的芳基的该取代基,可以例举哈米特的取代基常数σm为-0.21~0.39范围内的取代基,可以是单取代或多取代,多取代的场合,各取代基可以相同,也可以不同。其中,作为哈米特的σm值为-0.21~0.39范围内的取代基,具体例如甲基、叔丁基等烷基,环戊基、环己基等环烷基,苯基、萘基等芳基,甲氧基、乙氧基等烷氧基,氨基、二甲氨基等氨基,硝基,氯原子、溴原子等卤素原子等。
作为杂环残基,具体例如取代或未取代的吡啶基、吡嗪基、嘧啶基、喹啉基、异喹啉基、吡咯基、吡唑基、咪唑基、噻吩基、呋喃基、噻唑基、异噻唑基、恶唑基、异恶唑基。优选取代或未取代的吡啶基、吡嗪基、嘧啶基、喹啉基、异喹啉基、吡咯基、吡唑基,更优选取代或未取代的吡啶基、吡嗪基、嘧啶基、喹啉基、异喹啉基。
作为具有取代基的杂环残基的该取代基,可以例举哈米特的取代基常数σm为-0.21~0.39范围内的取代基,可以是单取代或多取代,多取代的场合,各取代基可以相同,也可以不同。其中,作为哈米特的σm值为-0.21~0.39范围内的取代基,具体例如甲基、叔丁基等烷基,环戊基、环己基等环烷基,苯基、萘基等芳基,甲氧基、乙氧基等烷氧基,氨基、二甲氨基等氨基,硝基,氯原子、溴原子等卤素原子等。
作为烷硫基,具体例如碳原子数1~18的直链状或支链状的烷硫基,优选甲硫基、乙硫基、丙硫基、异丙硫基、丁硫基、仲丁硫基、叔丁硫基等碳原子数1~4个的烷硫基,更优选甲硫基、乙硫基。
作为烷基亚硫酰基(-SOR)和烷基磺酰基(-SO2R),可以例举具有与烷硫基相同的烷基的烷基亚硫酰基或烷基磺酰基。优选甲基亚硫酰基、乙基亚硫酰基、甲基磺酰基、乙基磺酰基。
作为芳基亚硫酰基(-SOAr),可以例举具有取代或未取代的芳基的基团,优选苯亚硫酰基、甲苯亚硫酰基。
作为具有取代基的芳基亚硫酰基的该取代基,可以例举哈米特的取代基常数σm为-0.21~0.39范围内的取代基,可以是单取代或多取代,多取代的场合,各取代基可以相同,也可以不同。其中,作为哈米特的σm值为-0.21~0.39范围内的取代基,具体例如甲基、叔丁基等烷基,环戊基、环己基等环烷基,苯基、萘基等芳基,甲氧基、乙氧基等烷氧基,氨基、二甲氨基等氨基,硝基,氯原子、溴原子等卤素原子等。
作为芳基磺酰基(-SO2Ar),可以例举具有取代或未取代的芳基的基团,优选苯磺酰基、甲苯磺酰基。
作为具有取代基的芳基磺酰基的该取代基,可以例举哈米特的取代基常数σm为-0.21~0.39范围内的取代基,可以是单取代或多取代,多取代的场合,各取代基可以相同,也可以不同。其中,作为哈米特的σm值为-0.21~0.39范围内的取代基,具体例如甲基、叔丁基等烷基,环戊基、环己基等环烷基,苯基、萘基等芳基,甲氧基、乙氧基等烷氧基,氨基、二甲氨基等氨基,硝基,氯原子、溴原子等卤素原子等。
作为烷氧基,具体例如碳原子数1~18的直链状或支链状的烷氧基。优选甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、仲丁氧基、叔丁氧基等碳原子数1~4的烷氧基,更优选甲氧基、乙氧基、丙氧基、丁氧基等直链状的碳原子数1~4的烷氧基。
作为烷氧基羰基(-COOR),可以例举具有上述烷氧基的烷氧基羰基。优选甲氧基羰基、乙氧基羰基。
在通式(III)中,作为R1、R2、R3的优选实例,可以相同或不同,例如氢原子、烷基、芳基、杂环残基。进而,R1更优选的实例可以例举烷基、芳基、杂环残基,特别优选的实例为苯基或含氮杂环残基。
另外,R2和R3优选为同-基团。
本发明的原料1,2,4-三嗪化合物可以采用下述(1)~(4)的方法制备。
(1)使氰基杂环化合物和肼反应,衍生得到氨基腙,再使二酮类反应,得到1,2,4-三嗪化合物的方法(Tetrahedron Lett.,39,pp.8817、8821、8825(1998))。另外,也发现了向该反应系中添加水制备1,2,4-三嗪化合物的方法(特愿平11-167308号)。其一种方式如下所示。
(2)由氰基杂环化合物经由氨基甲酸酯和氨基腙,得到1,2,4-三嗪化合物的方法(J.Korean.Chem.Soc.,39(9),pp.755(1995))。其一种方式如下所示。
(3)在醋酸溶剂中,使酰肼和二酮与醋酸铵反应,得到1,2,4-三嗪化合物的方法(Tetrahedron,1,pp.103(1957))。其一种方式如下所示。
(4)使α-卤代酮和酰肼反应,得到1,2,4-三嗪化合物的方法(Tetrahedron,33,pp.1043(1977))。其一种方式如下所示。
本发明中使用的通式(I)或(II)表示的羧酸乙烯酯类可以由含有碳原子数3以上的烷基、取代或未取代的芳基、取代或未取代的杂环残基的羧酸,按照以下记载的方法容易地制备,但是并不限于这些方法。另外,这些羧酸乙烯酯已有多种在市售,能够容易地获得,可以直接使用。
作为上述羧酸乙烯酯类的制备方法,可以例举直接乙烯化法(J.Am.Chem.Soc.,69,pp.2439(1947);J.Polymer.Sci.,1,pp.207(1951);Trans.Faraday Soc.,49,pp.1108(1953);USPat.2,992,246号(1961);European Polymer J.,4,pp.373(1968))、乙烯基交换法(J.Org.Chem.,25,pp.623(1960);Makromol.Chem.,73,pp.173(1964);Makromol.Chem.,29,pp.119(1959);J.Polymer Sci.,27,pp.269(1958);高分子化学,17,pp.227(1960);J.Sci.Eng.Res.Indian Inst.Technol.Kharagpur,4,pp.265(1960))、哈尔昆(Halcon)法(J.Am.Chem.Soc.,81,pp.2552(1959))等。
羧酸乙烯酯类具体例如丁酸乙烯酯、己酸乙烯酯、辛酸乙烯酯、癸酸乙烯酯、十二烷酸乙烯酯、肉豆蔻酸乙烯酯、棕榈酸乙烯酯、硬脂酸乙烯酯、环己烷甲酸乙烯酯、新戊酸乙烯酯、辛酸乙烯酯、一氯醋酸乙烯酯、己二酸二乙烯酯、甲基丙烯酸乙烯酯、巴豆酸乙烯酯、山梨酸乙烯酯、苯甲酸乙烯酯、肉桂酸乙烯酯、新癸酸乙烯酯、新壬酸乙烯酯、4-叔丁基苯甲酸乙烯酯、三氟醋酸乙烯酯、2-吡啶甲酸乙烯酯、烟酸乙烯酯、异烟酸乙烯酯、2-呋喃甲酸乙烯酯、2-噻吩甲酸乙烯酯、己二酸二乙烯酯。
优选丁酸乙烯酯、己酸乙烯酯、辛酸乙烯酯、癸酸乙烯酯、十二烷酸乙烯酯、肉豆蔻酸乙烯酯、棕榈酸乙烯酯、环己烷甲酸乙烯酯、新戊酸乙烯酯、辛酸乙烯酯、苯甲酸乙烯酯、新癸酸乙烯酯、新壬酸乙烯酯、三氟醋酸乙烯酯、己二酸二乙烯酯,特别优选反应结束后容易分离的碳原子数多的己酸乙烯酯、辛酸乙烯酯、癸酸乙烯酯、十二烷酸乙烯酯、环己烷甲酸乙烯酯、辛酸乙烯酯、苯甲酸乙烯酯、新癸酸乙烯酯、新壬酸乙烯酯、己二酸二乙烯酯。
羧酸乙烯酯类的用量只要相对于1,2,4-三嗪为等mol以上即可,并没有限定,通式(I)的羧酸乙烯酯类的场合,相对于1,2,4-三嗪(1mol),通常在1.01~20mol的范围内使用,优选1.2~10.0mol,更优选1.5~5.0mol。通式(II)的羧酸乙烯酯类的场合,由于分子内存在2个反应部位,因此用(I)的场合的一半量反应即可进行。也就是说,相对于1,2,4-三嗪(1mol),通常在0.505~10mol的范围内使用通式(II)的羧酸乙烯酯类,优选0.6~5.0mol,更优选0.75~2.5mol。
本发明中,可以不使用反应溶剂,也可以使用反应溶剂。优选的反应溶剂是沸点为100℃以上的溶剂,更优选130~300℃的溶剂,进一步优选180~250℃的溶剂。
另外,作为反应溶剂,优选芳香族化合物。
作为可以用作反应溶剂的沸点在100℃以上的芳香族化合物,可以例举以下物质。
(i)芳香族烃化合物
甲苯、二甲苯、二乙基苯、二异丙基苯、乙基苯、丙基苯、丁基苯、1-苯基己烷、氯苯、二氯苯、三氯苯、溴苯、二溴苯、甲氧基苯、甲氧基苯酚、二甲氧基苯、硝基苯、1,4-环己基苯、二苯基甲烷、1,2,3,4-四氢萘等。
(ii)芳香族杂环化合物
2,4-二氯嘧啶、2,3,5-三氯吡啶、喹啉、喹唑啉、1,4-苯并二氧六环等。
(iii)氢化芳香族杂环化合物
1,2,3,4-四氢喹啉、5,6,7,8-四氢喹啉、1,2,3,4-四氢异喹啉、5,6,7,8-四氢异喹啉、1-苯基哌啶、1-苯基哌嗪、二氢吲哚、久洛里定(julolidine)等。
另外,作为可以用作反应溶剂的沸点在100℃以上的脂肪族化合物,可以例举以下物质。
(iv)饱和脂肪族化合物
辛烷、壬烷、癸烷、十一烷、十二烷、十三烷、乙基环己烷、2-甲基十二烷、4-乙基十一烷、十四烷、十五烷、3,3-二甲基十三烷、十六烷、十七烷、2-甲基-4-乙基十四烷等。
(v)饱和环式脂肪族化合物
二环己基、十氢萘、十二氢芴等。
(vi)饱和杂环脂肪族化合物
1,3-二甲基-2-咪唑烷酮(DMI)、1,4,7-三硫杂环壬烷、1,4,7-三硫杂环癸烷、1,4,7,10-四氧杂环十二烷、1,4,7,10,13-五氧杂环十五烷、1,4,7-三氮杂环壬烷、1,4,7,10-四氮杂环十二烷。
这些溶剂可以单独使用1种,也可以2种以上组合作为反应溶剂使用。
上述反应溶剂中,优选二乙基苯、二异丙基苯、喹啉、硝基苯、1,3-二甲基-2-咪唑烷酮(DMI),特别优选二异丙基苯、二乙基苯。通过使用这些溶剂,反应在短时间内结束,能够以高收率得到目的产物。
反应溶剂的用量相对于1,2,4-三嗪0.1mol,通常在1~1000ml的范围内使用,优选5~500ml,更优选10~200ml。
反应温度通常是在80~350℃的范围内进行,优选在120~300℃的范围内进行,更优选在180~250℃的范围内进行。反应时间通常是3~6小时,即可确认1,2,4-三嗪化合物消失。
反应结束后,添加稀盐酸,使目的产物转移至水层,进行分液,再将水层调节至碱性后,用乙酸乙酯或甲苯等溶剂萃取,减压浓缩溶剂,添加醇或己烷等,进行晶析,从而可以得到高纯度的吡啶衍生物。另外,也可以通过蒸馏进行精制。
按照本发明得到的吡啶衍生物的优选具体实例如下述(A-1)~(D-11)所示,但是本发明并不限定于此。
实施例
其次结合实施例更具体地说明本发明,但是本发明并不限定于此。另外,纯度的评价采用高效液相色谱法(以下简记为“HPLC”)。
另外,以下记载有“HPLC分析”的场合,是按照下述条件进行测定的,在改变了条件的场合将详细记载其条件。
(HPLC分析的测定条件)
柱:YMC-A-312
检测UV波长:254nm
洗脱剂:乙腈/水=25/75,作为缓冲液含有醋酸和三乙胺各0.2质量%
洗脱剂流量:1.0ml/min
合成例1(原料3-(4-吡啶基)-1,2,4-三嗪的合成)
在2000ml的四颈烧瓶中装入水200ml、4-氰基吡啶200.0g(1.92mol)、肼一水合物192.0g(3.84mol),搅拌条件、50℃下反应4小时。通过HPLC分析确认原料消失后,添加甲苯400ml,蒸馏除去过剩的肼一水合物,再进行该操作1次。加入水800ml,接着加入40%乙二醛水溶液278.4g(1.92mol),在外部温度100℃的条件下反应2小时。反应结束后,冷却至5℃,得到淡黄色晶体状的目的产物222.4g(收率85.2%)。
实施例1(2,4’-二吡啶基(A-1)的合成)
接着,向500ml的四颈烧瓶中装入二异丙基苯45ml、合成例1中合成的3-(4-吡啶基)-1,2,4-三嗪25.0g(0.158mol)、正癸酸乙烯酯60.1g(0.316mol),搅拌条件、210℃下反应2小时。通过HPLC分析确认原料消失后,用甲苯100ml稀释,用1mol/l盐酸180ml调节至酸性后,分液。用甲苯90ml洗涤得到的水层,该操作再反复进行1次。用9mol/l氢氧化钠水溶液50ml将水层调节至碱性后,用甲苯120ml萃取。减压条件下蒸馏除去溶剂,用己烷进行晶析,得到淡黄色晶体状的目的产物22.4g(收率90.7%)。HPLC分析的结果,纯度为99.3%。熔点60~62℃。
实施例2~7
在实施例1中,除了用下述表1所示的羧酸乙烯酯代替正癸酸乙烯酯以外,与实施例1同样进行操作,合成2,4’-二吡啶基(A-1),评价收率和通过HPLC得到的纯度。
比较例1~2
在实施例1中,除了使用表1记载的物质代替正癸酸乙烯酯以外,与实施例1同样地进行合成。
比较例3
在500ml的四颈烧瓶中装入二甲苯145ml、3-(4-吡啶基)-1,2,4-三嗪25.0g(0.158mol)、2,5-降冰片二烯146g(1.58mol),回流条件下反应4小时。反应结束后,减压条件下蒸馏除去过剩的2,5-降冰片二烯和二甲苯,用己烷进行晶析,得到淡黄色晶体状的目的产物19.8g(收率80.0%)。HPLC分析的结果,纯度为99.2%。
比较例4、5
在高压釜中装入二异丙基苯45ml、3-(4-吡啶基)-1,2,4-三嗪25.0g(0.158mol)、醋酸乙烯酯60.1g(0.316mol),搅拌条件、210℃下分别反应10小时(比较例4)、72小时(比较例5)。这时内压上升至1010kPa。以上的结果如表1所示。
表1
反应试剂 | 反应时间(h) | 收率(%) | 纯度(%) | 备注 | |
实施例1 | 正癸酸乙烯酯 | 2 | 90.7 | 99.3 | |
实施例2 | 正辛酸乙烯酯 | 3 | 90.7 | 99.2 | |
实施例3 | 正己酸乙烯酯 | 16 | 90.4 | 99.2 | |
实施例4 | 苯甲酸乙烯酯 | 6 | 88.9 | 98.9 | |
实施例5 | 新壬酸乙烯酯 | 3 | 91.4 | 99.0 | |
实施例6 | 新戊酸乙烯酯 | 48 | 87.8 | 98.8 | |
实施例7 | 正丁酸乙烯酯 | 42 | 88.6 | 98.5 | |
实施例8 | 2-吡啶甲酸乙烯酯 | 6 | 88.8 | 99.0 | |
实施例9 | 己二酸二乙烯酯 | 2 | 91.5 | 99.0 | |
实施例10 | 棕榈酸乙烯酯 | 2 | 90.1 | 99.1 | |
比较例1 | 醋酸乙烯酯 | 72 | 9.2 | - | 反应不完全 |
比较例2 | 丙酸乙烯酯 | 72 | 15.2 | - | 反应不完全 |
比较例3 | 2,5-降冰片二烯 | 4 | 80.0 | 99.2 | |
比较例4 | 醋酸乙烯酯(使用高压釜) | 10 | 10.0 | - | 反应不完全 |
比较例5 | 醋酸乙烯酯(使用高压釜) | 72 | 10.4 | - | 反应不完全 |
由表1所示的结果可以得知下述内容。
按照本发明的方法(实施例1~10),可以高纯度、高收率地合成2,4’-二吡啶基(A-1)。
比较例1、2是通式(I)所示羧酸乙烯酯的R的碳原子数少至1或2的情况,反应不完全。反应不完全的情况,即使是使用高压釜在加压条件下进行反应的比较例4、5的场合也相同。另外,即使在反应不完全的情况下直接进行后处理,利用酸或碱的分离也很困难,收率和纯度低下。
比较例3是以前所采用的方法,也就是使1,2,4-三嗪化合物与2,5-降冰片二烯反应的方法。这时,2,5-降冰片二烯相对于3-(4-吡啶基)-1,2,4-三嗪必须为10当量以上。而且,2,5-降冰片二烯价格昂贵,因此与本发明的方法相比成本非常高。
实施例11~20
实施例1中,用下述表2、3中记载的三嗪衍生物代替3-(4-吡啶基)-1,2,4-三嗪,通过与实施例1同样的操作合成吡啶衍生物。实施例15、16、19反应3小时,其它反应2小时,分别评价收率和通过HPLC得到的纯度。
表2
三嗪衍生物 吡啶衍生物 收率(%) HPLC含量(%)
实施例12
93.3 99.5
实施例13
88.7 99.0
实施例14
89.4 99.3
实施例15
90.2 99.1
実施例16
90.8 98.9
表3
三嗪衍生物 吡啶衍生物 收率 HPLC含量
(%) (%)
实施例19
85.7 98.8
实施例20
90.0 99.0
观察上述表2、表3可知,采用本发明的方法,可以高纯度、高收率地合成吡啶衍生物。
工业实用性
按照本发明的方法,能够高纯度、高收率、低成本地制备在药品、农药、催化剂配体、卤化银感光材料、液晶、电子照相和有机电致发光元件等领域中的有机感光体或染料等的中间体有用的吡啶衍生物,同时由于不使用有机金属等,因而不产生公害的问题。因此,本发明的吡啶衍生物的制备方法在工业上具有非常高的实用性。
Claims (15)
1、一种吡啶衍生物的制备方法,其特征在于,使通式(III)表示的1,2,4-三嗪化合物
式中,R1、R2和R3可以相同或不同,表示氢原子、具有1-4个碳原子的烷基、苯基、含氮杂环残基、或具有1-4个碳原子的烷氧基羰基,
与下述通式(I)表示的羧酸乙烯酯类反应,
式中,R表示碳原子数3至17的烷基、苯基或吡啶基。
2、如权利要求1所述的吡啶衍生物的制备方法,其特征在于,通式(I)中,R为碳原子数7~17的烷基。
3、如权利要求1所述的吡啶衍生物的制备方法,其特征在于,通式(I)中,R为苯基、或者吡啶基。
4、如权利要求1所述的吡啶衍生物的制备方法,其特征在于,通式(III)中,R1为苯基或含氮杂环残基。
5、如权利要求1所述的吡啶衍生物的制备方法,其特征在于,相对于1,2,4-三嗪化合物1mol,使用羧酸乙烯酯类1.01~20mol。
6、如权利要求1所述的吡啶衍生物的制备方法,其特征在于,相对于1,2,4-三嗪化合物1mol,使用羧酸乙烯酯类1.5~5mol。
7、如权利要求1所述的吡啶衍生物的制备方法,其特征在于,使用沸点为100~250℃的反应溶剂。
8、如权利要求1所述的吡啶衍生物的制备方法,其特征在于,使用沸点为180~250℃的反应溶剂。
9、一种吡啶衍生物的制备方法,其特征在于,使通式(III)表示的1,2,4-三嗪化合物
式中,R1、R2和R3可以相同或不同,表示氢原子、具有1-4个碳原子的烷基、苯基、含氮杂环残基、或具有1-4个碳原子的烷氧基羰基,
与下述通式(II)表示的羧酸乙烯酯类反应,
式中,n表示0~18的整数。
10、如权利要求9所述的吡啶衍生物的制备方法,其特征在于,通式(II)中,n为3~12的整数。
11、如权利要求9所述的吡啶衍生物的制备方法,其特征在于,通式(III)中,R1为苯基或含氮杂环残基。
12、如权利要求9所述的吡啶衍生物的制备方法,其特征在于,相对于1,2,4-三嗪化合物1mol,使用羧酸乙烯酯类0.505~10mol。
13、如权利要求9所述的吡啶衍生物的制备方法,其特征在于,相对于1,2,4-三嗪化合物1mol,使用羧酸乙烯酯类0.75~2.5mol。
14、如权利要求9所述的吡啶衍生物的制备方法,其特征在于,使用沸点为100~250℃的反应溶剂。
15、如权利要求9所述的吡啶衍生物的制备方法,其特征在于,使用沸点为180~250℃的反应溶剂。
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WO2001040186A1 (fr) | 2001-06-07 |
JP4603648B2 (ja) | 2010-12-22 |
CN1402708A (zh) | 2003-03-12 |
EP1243579A4 (en) | 2003-01-29 |
DE60017795T2 (de) | 2005-06-23 |
EP1243579A1 (en) | 2002-09-25 |
DE60017795D1 (de) | 2005-03-03 |
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