CN1222513A - 甲酰咪唑的制备方法 - Google Patents

甲酰咪唑的制备方法 Download PDF

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CN1222513A
CN1222513A CN98124192A CN98124192A CN1222513A CN 1222513 A CN1222513 A CN 1222513A CN 98124192 A CN98124192 A CN 98124192A CN 98124192 A CN98124192 A CN 98124192A CN 1222513 A CN1222513 A CN 1222513A
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J·海维林
A·韦林
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Abstract

本发明描述了一种催化转化羟甲基咪唑为甲酰咪唑的新颖方法。催化反应在过氧化物的存在下进行。甲酰咪唑是药物活性成分的重要中间体。

Description

甲酰咪唑的制备方法
本发明涉及如下通式所示甲酰咪唑的新颖制备方法或
Figure A9812419200042
其中R1为氢原子或可被任意取代的烷基，R2为氢原子或可被任意取代的烷基，芳基或芳烷基，R3为氢原子或可被任意取代的烷基，所述方法系将如下通式所示的羟甲基咪唑催化氧化或
Figure A9812419200044
其中R1、R2、R3定义如上。
甲酰咪唑是重要的中间体，例如制备药物活性成分，如利尿剂或抗高血压药(WO-A 92/0651)。迄今已知一些甲酰咪唑制备方法。CH-A 685496描述了一种方法，其中羟甲基咪唑催化氧化生成甲酰咪唑是在贵金属催化剂如铂-铋、铂黑、活性炭披铂或钯的存在下通入氧气而进行的。
该方法的缺点是反应时间长达数小时，且形成副产物。
因此，本发明的目的是提供没有上述缺点的经济的甲酰咪唑制备方法。
按照本发明，本目的用权利要求1的方法达到。将如下通式的羟甲基咪唑
Figure A9812419200051
或其中R1、R2和R3定义如上，在贵金属催化剂和过氧化物的存在下，进行催化氧化，生成如下通式的甲酰咪唑
Figure A9812419200053
或
Figure A9812419200054
其中R1、R2和R3定义如上。
R1和R2互相独立地为氢原子或可被任意取代的烷基，特别是直链或支链C1-6烷基。可被提名的基团是甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、戊基及其异构体和己基及其异构体。R2还可是任选地被取代的芳基或芳基烷基，特别是苯基或苯基烷基，在这种情况下，苯基烷基被认为以苯基C1-6烷基为佳，特别好的是苄基。烷基或芳基官能团的芳环***的便利的取代基为例如卤素、氨基、烷氨基、二烷基氨基、烷氧基或羟基，烷基较佳的为如上所述的C1-6烷基，较佳的烷氧基为C1-6烷氧基，例如甲氧基或乙氧基。此处和下文中所用的卤素是指氟、氯、溴或碘。特别好的意义中，R1为丁基，R2为氢原子。
R3为氢原子或可被任意取代的烷基，特别是直链或支链C1-6烷基。可被提名的有甲基、乙基、丙基、异丙基、异丁基、丁基、叔丁基、戊基及其异构体及已基及其异构体。取代基可以是上面给出的那些。R3特别优选的是氢原子。
起始化合物羟甲基咪唑可按简单的方式加以制备，例如，WO-A 92/20651的方法或E.F.Godefroi et al.,Trav.Chim.Receuil Pays-Bas,91,1383(1972)。
贵金属催化剂可以是铂、钯、铑或金。贵金属可与其它作为第二成分的金属如铋、铅、铈或铟便利地合用。优选使用铂/铋或铂/铅。
贵金属催化剂可直接使用或固定在支承物(如活性炭、二氧化硅、氧化铝、氧化硅铝、氧化锆或氧化钛)上加以使用。较佳的为结合在活性炭上。
结合在活性炭上的贵金属催化剂有市售，例如可购自Degussa。
结合在支承物上的贵金属的量在0.1-15重量％之间，较佳为0.5-7％之间(以支承物的重量计)。
贵金属催化剂的用量以相对于羟甲基咪唑的贵金属量计，以0.05-1.0摩尔％为佳，以0.1-0.4摩尔％为特佳。
所用的过氧化物为有机或无机过氧化物。合适的过氧化物的例子为过氧化氢、过硼酸盐、过羧酸、叔丁基化过氧氢、氢过氧化枯烯、过苯甲酸、间氯过苯甲酸、单过氧邻苯二甲酸或过乙酸。特别合适的过氧化物为过氧化氢，它以10-30％浓度的水溶液使用。
催化氧化在水、与水互溶的溶剂、与水不互溶的有机溶剂或其混合物的存在下，在碱性介质中便利地进行。
与水互溶的合适溶剂的例子为醇类或具有1-6个碳原子的羧酸，或酮类，例如丙酮或甲基乙基酮。合适的与水不互溶的有机溶剂的例子为异丁基甲基酮或乙酸乙酯。
较好的为水。
将碱金属氢氧化物、碱金属碳酸盐或碱金属乙酸盐加到反应混合物中被发现有益于产生碱性介质。按通式Ⅲ或Ⅳ所示羟甲基咪唑的用量计，碱金属氢氧化物以1∶0.05-1.2的比例为佳，最好是1∶0.1-1。
催化氧化在20-120℃温度进行为宜，在50-80℃更好。
在约1小时的常规过氧化物计量时间后，在足够的后反应时间后可以本领域技术人员惯用的方法分离通式Ⅰ或Ⅰ所示化合物。
根据溶剂***，可通过结晶过滤或用合适的溶剂萃取来分离产物。
所用的催化剂可重复使用而不失去活性。
实施例：
实施例1
2-正丁基-5-甲酰咪唑的制备
将1.5g 2-正丁基-5-羟甲基咪唑、1.5g十二烷(GC内标)、0.3g活性炭披5％铂和5％铋(含61.3％水)、20g异丁基甲基酮和2.4g浓度为1.6％的NaOH溶液搅拌加热至约58℃。于58-64℃，经45分钟滴加浓度为15.7％的H2O2水溶液。然后使反应混合物反应15分钟并过滤。将滤液转入分液漏斗，分去H2O相，有机相浓缩并冷却，产物结晶析出并过滤。用GC(内标)测定产率。反应得率为88.2％(起始物质6.75％)。
实施例2
2-正丁基-5-甲酰咪唑的制备
将2g 2-正丁基-5-羟甲基咪唑、0.3g活性炭披5％铂和5％铋(含61.3％水)、13ml IN NaOH溶液和7g水搅拌加热至约60℃。于60-64℃，经45分钟滴加浓度为15％的H2O2水溶液。然后使反应混合物反应15分钟并过滤。用20％硫酸将滤液的pH从13.4调节至9.0，结果形成淡黄色悬浮液。将其冷却，滤取粗产物和/或用二氯甲烷萃取。
用GC分析监测反应情况。
反应得率为100％(起始物质0％)。
实施例3
2-正丁基-5-甲酰咪唑的制备
重复实施例2中描述的方法，但用0.3g活性炭披5％铂和5％铅(含55.7％水)代替0.3g活性炭披5％铂和5％铋。
反应得率：99.5％(0.5％起始物质)。
实施例4
2-正丁基-5-甲酰咪唑的制备
将4.0g 2-正丁基-5-羟甲基咪唑、0.6g活性炭披5％铂和5％铋(含61.3％水)和25.6ml 1N NaOH溶液搅拌加热至约60℃。于60-64℃，经45分钟滴加6.8克浓度为15％的H2O2水溶液。然后使反应混合物反应15分钟并过滤。用20％硫酸将滤液的pH从13.2调节至9.0，结果形成黄色悬浮液。将其冷却，滤取粗产物和/或用二氯甲烷萃取。
用GC分析监测反应情况。
反应得率为98.2％(起始物质1.8％)。
实施例5
2-正丁基-5-甲酰咪唑的制备
重复实施例4中描述的方法，但在50-54℃而不是60-64℃滴加浓度为15％的H2O2溶液。
反应得率：97.6％(起始物质2.4％)。
实施例6
2-正丁基-5-甲酰咪唑的制备
重复实施例4中描述的方法，但在70-74℃而不是60-64℃滴加浓度为15％的H2O2溶液。
反应得率：97.7％(起始物质2.1％)。
实施例7
从粗起始物质制备2-正丁基-5-甲酰咪唑
将4.4g 2-正丁基-5-羟甲基咪唑(粗起始物质90.4％)、0.6g活性炭披5％铂和5％铋(含61.3％水)、25.6ml 1N NaOH溶液和5ml甲醇搅拌加热至约60℃。于60-64℃，经45分钟滴加6.8克浓度为15％的H2O2水溶液。然后使反应混合物反应15分钟并过滤。用20％硫酸将滤液的pH从13.0调节至9.0，结果形成黄色悬浮液。将其冷却，滤取粗产物和/或用二氯甲烷萃取。
用GC分析监测反应情况。
反应得率为94.5％(起始物质3.5％)。
实施例8(按CH-A 685 496用空气作氧化剂的比较实验)
2-正丁基-5-甲酰咪唑的制备
将4.6g 2-正丁基-5-羟甲基咪唑、4.6g十二烷(作为内标)、0.6g活性炭披5％铂和5％铋(含61.3％水)、42g异丁基甲基酮和7.5g浓度为1.6％的NaOH溶液搅拌加热至约80℃。于80℃，在溶液中通入每小时3.6升空气(STP)直至氧气完全吸收(350分钟！)。将反应混合物过滤。将滤液转入分液漏斗。分离掉水相，将有机溶剂相浓缩并冷却，产物结晶析出并过滤。
用GC分析(内标)监测反应情况。
反应得率为90.0％(起始物质0.3％)。
实施例9(催化剂再循环)
将20.9g 2-正丁基-5-羟甲基咪唑(粗起始物质95.3％)、3.2g活性炭披5％铂和5％铅(含55.7％水)、130ml 1N NaOH溶液和22ml甲醇搅拌加热至约60℃。于60℃，经60分钟滴加22.5克浓度为20％的H2O2水溶液。然后使反应混合物反应10分钟并过滤。用20％硫酸将滤液的pH从12.8调节至7.5，结果形成黄色悬浮液。蒸去甲醇和一些水，将悬浮液冷却至2℃，滤出产物。在60℃和30mbar下将产物于燥。催化剂第一次使用后，分离得18g淡黄色物质(含量：98.5％，HPLC，重量％)。分离产率为90％。
用GC(内标)分析检测催化剂再使用的能力(标准％)。催化剂共使用8次。催化剂丢失量不作补充。
催化剂使用     2-正丁基-5-甲酰咪唑〔GC标准％ 〕 未反应的2-正丁基-5-羟甲基咪唑〔GC标准％〕
    1     97.9     1
    2     97.5     1.3
    3     97.0     1.9
    4     97.5     1.7
    5     98.0     0
    6     97.2     1.7
    7     95.9     2.9
    8     96.6     1.9

Claims (8)

1．如下通式所示的甲酰咪唑的制备方法
Figure A9812419200021
或
Figure A9812419200022
其中R1为氢原子或可被任意取代的烷基，R2为氢原子或可被任意取代的烷基、芳基或芳烷基，R3为氢原子或可被任意取代的烷基，所述方法系在贵金属催化剂的存在下将如下通式所示的羟甲基咪唑催化氧化
Figure A9812419200023
或
Figure A9812419200024
其中R1、R2、R3定义如上，该方法的特征在于：催化氧化在过氧化物的存在下进行。
2．如权利要求1所述的方法，其特征在于：R1为丁基。
3．如权利要求1或2所述的方法，其特征在于：R2和R3为氢原子。
4．如权利要求1-3之一所述的方法，其特征在于：该贵金属催化剂为铂/铋催化剂或铂/铅催化剂。
5．如权利要求1-4之一所述的方法，其特征在于：该过氧化物为过氧化氢。
6．如权利要求1-5之一所述的方法，其特征在于：催化氧化在水、与水互溶的溶剂、与水不互溶的有机溶剂或其混合物的存在下，在碱性介质中进行。
7．如权利要求6所述的方法，其特征在于：将碱金属氢氧化物、碱金属碳酸盐或碱金属乙酸盐加到反应混合物中得到碱性介质。
8．如权利要求1-7之一所述的方法，其特征在于：反应在20-120℃温度下进行。
CN98124192A 1997-11-14 1998-11-13 甲酰咪唑的制备方法 Expired - Fee Related CN1115335C (zh)

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EP0965590A1 (de) * 1998-06-18 1999-12-22 Lonza A.G. Verfahren zur Herstellung von Formylimidazolen
EP1871745B1 (en) 2005-04-15 2010-10-20 Dishman Pharmaceuticals and Chemicals Ltd. Preparation of 2-substituted 4-chloro-5-formylimidazoles by vilsmeier reaction of the condensation product of glycine and an imido ester with a formamide in the presence of a triflate (trifluormethanesulphonate) catalyst

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JP3391837B2 (ja) * 1993-02-16 2003-03-31 日本合成化学工業株式会社 ５−ホルミルイミダゾール類の製造方法
JP3400039B2 (ja) * 1993-09-28 2003-04-28 株式会社クラレ クロマン化合物の製造方法
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NO309979B1 (no) 2001-04-30
IL127024A0 (en) 1999-09-22
KR19990045006A (ko) 1999-06-25
DK0916659T3 (da) 2002-09-09
CZ291601B6 (cs) 2003-04-16
ATE218128T1 (de) 2002-06-15
JP4423685B2 (ja) 2010-03-03
HU228231B1 (en) 2013-02-28
CA2253901A1 (en) 1999-05-14
PT916659E (pt) 2002-10-31
JPH11228544A (ja) 1999-08-24
SK282701B6 (sk) 2002-11-06
EP0916659A1 (de) 1999-05-19
HUP9802646A2 (hu) 1999-06-28
CA2253901C (en) 2009-01-20
IL127024A (en) 2004-06-20
CN1115335C (zh) 2003-07-23
NO985296D0 (no) 1998-11-13
HU9802646D0 (en) 1999-01-28
NO985296L (no) 1999-05-18
EP0916659B1 (de) 2002-05-29
CZ366598A3 (cs) 1999-06-16
PL329669A1 (en) 1999-05-24
SK153898A3 (en) 1999-06-11
PL197850B1 (pl) 2008-05-30
DE59804233D1 (de) 2002-07-04
KR100567183B1 (ko) 2006-06-13
US6040457A (en) 2000-03-21
HUP9802646A3 (en) 2001-11-28
ES2174376T3 (es) 2002-11-01

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