CN1120158C - 甲酰基咪唑的制备方法 - Google Patents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members 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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- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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Abstract
本发明涉及新的将卤代羟甲基咪唑催化转化成卤代甲酰基咪唑的方法,所述的催化反应是在过氧化物存在下进行的。卤代甲酰基咪唑是制备药物活性成分的重要中间体。
Description
甲酰基咪唑是重要的中间体,用于制备例如利尿剂或抗高血压药之类的药物活性成分(WO-A92/20651)。目前已经知道几种制备甲酰基咪唑的方法。CH-A685496说明了一种方法,即在例如铂-铋、铂黑、活性炭上的铂或钯之类的贵金属催化剂存在下,在通氧条件下将羟甲基咪唑催化氧化成甲酰基咪唑。
该方法的缺点在于反应时间长达数小时,而且有副产物形成。
所以,本发明的目的是提供一种克服上述缺点,经济的制备甲酰基咪唑的方法。
根据本发明,上述目的是通过以下技术方案实现的。
在贵金属催化剂和某种过氧化物存在下将通式如下的羟甲基咪唑(其中的R1、R2和R3如前文所述):或
R1和R2各自为氢或烷基,尤其是具有1至6个碳原子、取代或非取代的直链或支链烷基。它们可以是甲基、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还可以是芳基或芳基烷基,尤其是取代或非取代的苯基或苯基烷基。苯基烷基以苯基C1-6烷基为佳,苄基更好。烷基或芳基官能团的芳性体系上的常规取代基有例如卤素、氨基、烷基氨基、二烷基氨基、烷氧基或羟基。此处及后文所述的卤素是指氟、氯、溴或碘。尤其好的是,R1是丁基,R2是氢。
R3是卤素,以氯为佳。
起始化合物羟甲基咪唑的制备很简便,例如根据WO-A92/20651或根据E.F.Godefrol等在Trav.Chim.Receuil Pays-Bas 91,1383(1972)所述的方法来制备。
贵金属催化剂可以是铂、钯、铑或金。按常规,贵金属一般与以下作为第二成份的金属合用,例如铋、铅、铈或铟。优选的是铂/铋或铂/铅催化剂。
贵金属催化剂可以就这样使用,也可以与某种支持材料结合后使用,所述的支持材料例如活性炭、二氧化硅、氧化铝、氧化硅铝、氧化锆或氧化钛。优选的是与活性炭结合。
与活性炭结合的贵金属催化剂是可以购得的,例如向Degussa购买。
与支持材料结合的贵金属的量按支持材料的重量计一般在0.1重量%至15重量%之间,以0.5重量%至7重量%为佳。
较好的是,贵金属催化剂的用量为贵金属相对于通式III或IV的羟甲基咪唑为介于0.05至1.0摩尔%之间,尤其好的是贵金属相对于通式III或IV的羟甲基咪唑为介于0.1至0.4摩尔%之间。
所用的过氧化物是有机或无机过氧化物。合适的过氧化物为例如过氧化氢、过硼酸、过氧羧酸、叔丁基氢过氧化物、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。特别适合的过氧化物是过氧化氢,最好使用其浓度为10至30%的水溶液。
催化氧化反应一般在碱性介质中,在水、水互溶性极性溶剂、非水互溶性非极性溶剂或它们的混合物的存在下进行。
合适的水互溶性极性溶剂为例如具有1至6个碳原子的醇或羧酸,或者丙酮或丁酮之类的酮。
合适的非水互溶性非极性溶剂为例如异丁基·甲基酮或乙酸乙酯。
优选的是使用水与水互溶性极性溶剂(最好是醇,特别好是甲醇)形成的混合物。使用水与非水互溶性非极性溶剂(最好是异丁基·甲基酮)也是较好的。已经发现,通过在反应混合物中添加碱金属氢氧化物、碱金属碳酸盐或碱金属乙酸盐形成碱性介质十分有利。碱金属氢氧化物的用量最好是通式III或IV羟甲基咪唑摩尔用量的1∶0.05至1.2,1∶0.1至1更好。
催化氧化反应一般在20至120℃进行,50至80℃更好。
在约1小时的常规过氧化物计量时间之后,在经过足够长的反应后时间,利用本领域熟知的技术可以分离出通式I或II化合物。
根据所用的溶剂系统,产物通常通过结晶和过滤,或者通过用合适溶剂萃取来分离。所用的催化剂可以重复利用,而其活性没有损失。
实施例:
实施例1
2-正丁基-4-氯-5-甲酰基咪唑的制备方法
将4.0克2-正丁基-4-氯-5-羟甲基咪唑,21.5毫升1N的NaOH和13.6毫升甲醇加热至60℃形成溶液。加入0.6克5%Pt-5%Bi/C(Degussa,含60%H2O)。在60至62℃,用60分钟滴加20%浓度的H2O2水溶液。混合物然后再反应15分钟;然后过滤,接着用5毫升甲醇洗涤催化剂。用32%浓度的盐酸将滤液从pH12.4调节至pH7.5。加入15毫升水,然后在旋转蒸发器上部分蒸发混合物(去除甲醇)。然后在充分搅拌的同时让混合物冷却,并在20℃过滤生成的白色悬浮液。然后用5毫升H2O洗涤滤饼,干燥后得3.4克白色至浅黄色物质。根据1H-NMR,其中含32.6摩尔%2-正丁基-4-氯-5-羟甲基咪唑和67.3摩尔%2-正丁基-4-氯-5-甲酰基咪唑。
2-正丁基-4-氯-5-甲酰基咪唑的1H-NMR数据:
(DMSO-d16,400MHz)δ:13.3(1H,bs);9.6(1H,s);2.64(2H,t);1.63(2H,m);1.27(2H,m);0.88(3H,t)。
实施例2
2-正丁基-4-氯-5-甲酰基咪唑的制备方法
将4.0克2-正丁基-4-氯-5-羟甲基咪唑,4毫升1N的NaOH,6毫升H2O和12.6毫升甲醇加热至60℃形成溶液。加入0.6克5%Pt-5%Bi/C(Degussa,含60%H2O)。
在60至62℃,用60分钟滴加4.2克20%浓度的H2O2水溶液。混合物然后再反应15分钟;然后过滤,接着用5毫升甲醇洗涤催化剂。用32%浓度的盐酸将滤液从pH8.4调节至pH7.5。加入15毫升水,然后在旋转蒸发器上部分蒸发混合物(去除甲醇)。然后在充分搅拌的同时让混合物冷却,并在20℃过滤生成的白色悬浮液。然后用5毫升H2O洗涤滤饼,干燥后得3.7克白色物质。根据1H-NMR,其中含36.9摩尔%2-正丁基-4-氯-5-羟甲基咪唑和63.1摩尔%2-正丁基-4-氯-5-甲酰基咪唑。
实施例3
2-正丁基-4-氯-5-甲酰基咪唑的制备方法
将3.0克2-正丁基-4-氯-5-羟甲基咪唑,1.2克5%Pt-5%Bi/C(Degussa,含60%H2O),44克甲基·异丁基酮,1.3毫升1N的NaOH,6.8克水搅拌加热至59℃。在60至62℃,用75分钟滴加4.0克20%浓度的H2O2水溶液。混合物然后再反应15分钟;然后过滤。用10%浓度的盐酸将滤液从pH10.4调节至pH7.0。将混合物加入分液漏斗,分离出水相并用10毫升甲基·异丁基酮萃取。将两份有机相合并后在旋转蒸发器上蒸发。蒸发后的残留物为3.1克白色结晶。根据1H-NMR,其中含93.5摩尔%2-正丁基-4-氯-5-甲酰基咪唑和6.5摩尔%2-正丁基-4-氯-5-羟甲基咪唑。
Claims (8)
2.根据权利要求1所述的方法,其特征在于,其中的R1是丁基。
3.根据权利要求1或2所述的方法,其特征在于,其中的R2是氢。
4.根据权利要求1所述的方法,其特征在于,其中的贵金属催化剂是铂/铋催化剂或铂/铅催化剂。
5.根据权利要求1所述的方法,其特征在于,其中的过氧化物是过氧化氢。
6.根据权利要求1所述的方法,其特征在于,其中的催化氧化反应是在碱性介质中,在水、水互溶性极性溶剂、非水互溶性非极性溶剂或它们的混合物存在下进行的。
7.根据权利要求6所述的方法,其特征在于,所述的碱性介质是通过在反应混合物中添加碱金属氢氧化物、碱金属碳酸盐或碱金属乙酸盐获得的。
8.根据权利要求1所述的方法,其特征在于,其中的反应是在20至120℃进行的。
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CH2504/1997 | 1997-10-29 | ||
CH2504/97 | 1997-10-29 | ||
CH250497 | 1997-10-29 |
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CN1220990A CN1220990A (zh) | 1999-06-30 |
CN1120158C true CN1120158C (zh) | 2003-09-03 |
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US (1) | US5917051A (zh) |
EP (1) | EP0913394B1 (zh) |
JP (1) | JP4423684B2 (zh) |
KR (1) | KR100587187B1 (zh) |
CN (1) | CN1120158C (zh) |
AT (1) | ATE313533T1 (zh) |
CA (1) | CA2251401C (zh) |
CZ (1) | CZ291600B6 (zh) |
DE (1) | DE59813294D1 (zh) |
DK (1) | DK0913394T3 (zh) |
ES (1) | ES2255726T3 (zh) |
HU (1) | HU221057B1 (zh) |
NO (1) | NO309980B1 (zh) |
PL (1) | PL197849B1 (zh) |
PT (1) | PT913394E (zh) |
SK (1) | SK282651B6 (zh) |
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US20010014743A1 (en) | 1997-11-14 | 2001-08-16 | Lonza Ag | Procedure for producing formylimidazoles |
CN1285824A (zh) * | 1997-11-14 | 2001-02-28 | 隆扎股份公司 | 制备甲酰咪唑的方法 |
IL140170A0 (en) * | 1998-06-15 | 2002-02-10 | Lonza Ag | Procedure for producing formyl imidazoles |
EP0965590A1 (de) * | 1998-06-18 | 1999-12-22 | Lonza A.G. | Verfahren zur Herstellung von Formylimidazolen |
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- 1998-10-21 SK SK1457-98A patent/SK282651B6/sk not_active IP Right Cessation
- 1998-10-22 DK DK98120019T patent/DK0913394T3/da active
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- 1998-10-22 DE DE59813294T patent/DE59813294D1/de not_active Expired - Lifetime
- 1998-10-23 JP JP30257098A patent/JP4423684B2/ja not_active Expired - Fee Related
- 1998-10-23 CA CA002251401A patent/CA2251401C/en not_active Expired - Fee Related
- 1998-10-23 US US09/176,935 patent/US5917051A/en not_active Expired - Lifetime
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Publication number | Publication date |
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HUP9802495A2 (hu) | 1999-07-28 |
EP0913394B1 (de) | 2005-12-21 |
CN1220990A (zh) | 1999-06-30 |
HU9802495D0 (en) | 1999-01-28 |
HU221057B1 (hu) | 2002-07-29 |
US5917051A (en) | 1999-06-29 |
JPH11209348A (ja) | 1999-08-03 |
DK0913394T3 (da) | 2006-05-08 |
CA2251401A1 (en) | 1999-04-29 |
ES2255726T3 (es) | 2006-07-01 |
CA2251401C (en) | 2007-09-25 |
NO985013D0 (no) | 1998-10-28 |
CZ291600B6 (cs) | 2003-04-16 |
EP0913394A1 (de) | 1999-05-06 |
NO309980B1 (no) | 2001-04-30 |
HUP9802495A3 (en) | 2000-04-28 |
NO985013L (no) | 1999-04-30 |
PL329422A1 (en) | 1999-05-10 |
JP4423684B2 (ja) | 2010-03-03 |
DE59813294D1 (de) | 2006-01-26 |
PT913394E (pt) | 2006-05-31 |
CZ339598A3 (cs) | 1999-05-12 |
SK145798A3 (en) | 1999-05-07 |
KR19990037077A (ko) | 1999-05-25 |
SK282651B6 (sk) | 2002-11-06 |
TW466235B (en) | 2001-12-01 |
KR100587187B1 (ko) | 2006-10-24 |
ATE313533T1 (de) | 2006-01-15 |
PL197849B1 (pl) | 2008-05-30 |
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