降压药物厄贝沙坦的合成新法
|
摘要
高血压是世界各国最常见的心血管疾病,目前全世界约有十亿人患有高血压病,我国是世界上高血压患者最多的国家。高血压病不仅是一个独立的疾病,同时可导致心、脑、肾、血管、眼底的结构和功能发生改变和损害,引起相关的疾病。高血压引起的并发症具有高度的致死率和致残率,给患者及其家人带来沉重的精神负担和经济负担。目前高血压病的治疗以药物治疗为主要手段,治疗高血压的药物分为六大类,其特点各异。其中,血管紧张素Ⅱ受体拮抗剂以其降压作用确切,不良反应轻微,具有广阔的应用前景。而血管紧张素Ⅱ受体拮抗剂中的厄贝沙坦其生物利用度最高,血浆半衰期长,是可以实现1日1次的长效抗高血压药物,而且没有活性代谢物,并能有效预防和逆转高血压所致的左心室肥厚,具有较大的研究意义。
传统的合成厄贝沙坦的方法需使用有剧毒的氰化物,危害环境,不易大规模生产。而且在合成中间体2-丁基-1,3-二氮杂螺[4,4]壬-1-烯-4-酮时会产生其异构体2-丁基-1,3-二氮杂螺[4,4]壬-1-烯-8-酮,该物质参与下一步反应,形成杂质不易去除,影响产物纯度。本文提出了新的合成方法合成厄贝沙坦,本文提出的合成路线分两个阶段,第一阶段以甘氨酸为起始原料,经酯化、酰胺化、脱水、闭环,水解制得环亮氨酸盐酸盐。第二阶段以环亮氨酸盐酸盐为起始原料,经酰胺化、脱水缩合、偶联、与叠氮化钠反应制得厄贝沙坦。本文的合成方法避免了使用氰化物,且原料易得,单步反应收率高,产物易纯化。此外,在制备中间体2-丁基-1,3-二氮杂螺[4,4]壬-1-烯-4-酮时采用间接闭环,避免了异构体产生,反应条件温和,极大的缩短了闭环反应的时间。本文路线的总收率为17.22%,第一阶段制备环亮氨酸盐酸盐总收率为54.16%,若环亮氨酸盐酸盐能工业化生产,那么以环亮氨酸盐酸盐为起始原料制备厄贝沙坦总收率可达31.81%。
Hypertension is a commonly and frequently encountered disease that severely endangered human health nowadays.There are about one billion people of the whole world suffering from this kind of disease and the number is increasing year by year. There are the most patients in our country.Hypertension is not only an independent disease,but also it can lead to the changes of structure and function in heart,brain, kidney,blood vessels,which could cause some related diseases.High rates of death and disability caused by complications of hypertension,which made patients and their families a heavy burden of spirit and financial.At present,the drug therapy is a primary means in the treatment of hypertension,which include six different kinds of drug categories.Because of its role in the exact step-down,minor adverse reactions, angiotensinⅡreceptor antagonist have broad application prospects.Irbesartan is the one of angiotensinⅡreceptor antagonist.It owns highest bioavailability,long plasma half-life,which can realize one time a day.There is no active metabolite and to be effective in preventing and reversal of hypertension-induced left ventricular hypertrophy,which has important practical significance.
In the traditional method,it required the use of cyanide in the synthesis of Irbesartan.Cyanide is highly toxic,hazardous to the environment and not mass production.In the mean time,2-(n-Butyl) -1,3-diazaspiro[4,4]ono-1-ene-8-one would be produced,which is the isomer of 2-(n-Butyl) -1,3- diazaspiro[4,4]ono -1-ene-4-one.This by-product involved in the next step,which was difficult to be removed.This paper puts forward a new method of synthesis of irbesartan.The process includes two stages:first,glycine as the starting material,cycloleucine hydrochlorate was obtained by esterification,amidation,dehydration,a closed-loop and hydrolysis.And then,cycloleucine hydrochlorate as the starting material,the irbesartan was obtained by amidation,dehydration condensation,and coupled with the sodium azide.In this paper,the new synthesis method,it can not only avoid the use of cyanide,easy to get raw materials,high-yield of single-step reaction and easily purified,but also avoid the production of isomer,the mild rection conditions which can greatly shorten the time the cyclization reaction.In this paper,the total yield is 17.22%.The yield of first stage is 54.16%.If cycloleucine hydrochlorate could realize industrial production,the yield of Irbesartan will up to 31.81%.
传统的合成厄贝沙坦的方法需使用有剧毒的氰化物,危害环境,不易大规模生产。而且在合成中间体2-丁基-1,3-二氮杂螺[4,4]壬-1-烯-4-酮时会产生其异构体2-丁基-1,3-二氮杂螺[4,4]壬-1-烯-8-酮,该物质参与下一步反应,形成杂质不易去除,影响产物纯度。本文提出了新的合成方法合成厄贝沙坦,本文提出的合成路线分两个阶段,第一阶段以甘氨酸为起始原料,经酯化、酰胺化、脱水、闭环,水解制得环亮氨酸盐酸盐。第二阶段以环亮氨酸盐酸盐为起始原料,经酰胺化、脱水缩合、偶联、与叠氮化钠反应制得厄贝沙坦。本文的合成方法避免了使用氰化物,且原料易得,单步反应收率高,产物易纯化。此外,在制备中间体2-丁基-1,3-二氮杂螺[4,4]壬-1-烯-4-酮时采用间接闭环,避免了异构体产生,反应条件温和,极大的缩短了闭环反应的时间。本文路线的总收率为17.22%,第一阶段制备环亮氨酸盐酸盐总收率为54.16%,若环亮氨酸盐酸盐能工业化生产,那么以环亮氨酸盐酸盐为起始原料制备厄贝沙坦总收率可达31.81%。
Hypertension is a commonly and frequently encountered disease that severely endangered human health nowadays.There are about one billion people of the whole world suffering from this kind of disease and the number is increasing year by year. There are the most patients in our country.Hypertension is not only an independent disease,but also it can lead to the changes of structure and function in heart,brain, kidney,blood vessels,which could cause some related diseases.High rates of death and disability caused by complications of hypertension,which made patients and their families a heavy burden of spirit and financial.At present,the drug therapy is a primary means in the treatment of hypertension,which include six different kinds of drug categories.Because of its role in the exact step-down,minor adverse reactions, angiotensinⅡreceptor antagonist have broad application prospects.Irbesartan is the one of angiotensinⅡreceptor antagonist.It owns highest bioavailability,long plasma half-life,which can realize one time a day.There is no active metabolite and to be effective in preventing and reversal of hypertension-induced left ventricular hypertrophy,which has important practical significance.
In the traditional method,it required the use of cyanide in the synthesis of Irbesartan.Cyanide is highly toxic,hazardous to the environment and not mass production.In the mean time,2-(n-Butyl) -1,3-diazaspiro[4,4]ono-1-ene-8-one would be produced,which is the isomer of 2-(n-Butyl) -1,3- diazaspiro[4,4]ono -1-ene-4-one.This by-product involved in the next step,which was difficult to be removed.This paper puts forward a new method of synthesis of irbesartan.The process includes two stages:first,glycine as the starting material,cycloleucine hydrochlorate was obtained by esterification,amidation,dehydration,a closed-loop and hydrolysis.And then,cycloleucine hydrochlorate as the starting material,the irbesartan was obtained by amidation,dehydration condensation,and coupled with the sodium azide.In this paper,the new synthesis method,it can not only avoid the use of cyanide,easy to get raw materials,high-yield of single-step reaction and easily purified,but also avoid the production of isomer,the mild rection conditions which can greatly shorten the time the cyclization reaction.In this paper,the total yield is 17.22%.The yield of first stage is 54.16%.If cycloleucine hydrochlorate could realize industrial production,the yield of Irbesartan will up to 31.81%.
引文
[1]肖洲,刘伟,肖萍.抗高血压药物使用调查分析[J].新疆医学,2007,37:165-169.
[2]林静,梁坤.抗高血压药物概述[J].实用心脑肺血管病杂志,2007,15(4):320-324.
[3]黄体钢.利尿药在抗高血压治疗中的应用及其限度[J].中国现代神经疾病志,2006,6(4):299-303.
[4]殷鸿,王兴东,尹海宁.一线抗高血压药的评价及展望[J].伤残医学杂志,2001,9(4):62-64.
[5]陈健.抗高血压药物研究进展[J],天津医科大学学报.2004,10:186-189.
[6]刘元华,洪明星,刘明雪,等.传统手法治疗高血压的探讨[J].中医外治杂志,2005,14(2):32-33.
[7]孙海燕.肾素-血管紧张素系统在高血压发病机制及药物治疗中的作用[J].深圳职业技术学院学报,2005,(2):43-46.
[8]邢玥.抗高血压药物概述[J].中国社区医师,2003,23:22-25.
[9]钱之玉.抗高血压药物的评价与研究进展[J].药学进展,2004,28(4):145-148.
[10]王维刚.AT1受体及其拮抗剂的研究进展与临床应用[J].卫生职业教育,2006,24(16):130-131.
[11]李正化.药物化学[M].北京:人民卫生出版社.1994.
[12]王维刚.AT1受体及其拮抗剂的研究进展与临床应用[J].卫生职业教育,2006,24(16):130-131.
[13]Gillis JC,Markham A.Irbesartan:a review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in the management of hypertension[J].Drugs,1997,54(6):885-902.
[14]唐树德,戚文航.血管紧张素Ⅱ受体拮抗剂-伊贝沙坦[J].上海医药,1999,20(7):32-33.
[15]孟德泉.血管紧张素Ⅱ受体抑制剂对逆转高血压左心室肥厚及舒张功能的疗效观察[J].华北煤炭医学院学报,2006,8(1):63-64.
[16]岑均达,马霞.厄贝沙坦的合成[J].中国医药工业杂志2007,38(3):230-240.
[17]Bernhart C,Breliere JC.N-Substituted heterocyclic derivatives,their preparation and the pharmaceutical compositions in which they are present [P].US,5270317.1993-12-14.
[18]李能刚,王超志,刘炳朋等.2-正丁基-1,3-二氮杂螺[4,4]壬-1-烯-4-酮的合成[J].中国新药杂志,2002,11(6):479-480.
[19]沈敬山,李剑峰,毛睿等.2-正丁基-1,3-二氮杂螺[4,4]壬烷-1-烯-4-酮的改进的生产工艺[P].CN,1194971C,2005-03-30.
[20]Francis G.Spinale,Charleston,S.C.Method of treating or preventing cardiac arrhythmia employing an N-substituted heterocyclic derivative[P].US,5541209.1996-07-30.
[21]Claude Bernhart,Jean-Claude Breliere,Jacques Clement,et al.Method for N-substituted heterocyclic derivatives[P].US,5559233.1996-09-24.
[22]Antoine Caron,Dominique Chantreux,et al.Process for the preparation of a tetrazole derivative in two crystalline forms and novel the crystalline forms thereof[P].US,5629311.1997-05-13.
[23]Ben-Zion Dolitzky,Julia Kaftanov,Boris Pertsikov,et al.Novel synthesis of 2-butyl-3-(2' -(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl)-1,3-diazaspiro[4,4]-non-ene-4-one[P].US,20040242894.2004-12-02.
[24]Satyanarayana B.;Sumalatha Y.;Venkatraman S.et al.Improved synthesis of irbesartan[J].Synth.Commun.2005,35(14):1979-1982.
[25]Kumar Yatendra,Prasad Mohan,et al.Processes for the preparation of highly pure irbesartan[P].WO,2005051943,2005-09-06.
[26]B.Satyanarayana,Y.Sumalatha,C.Sridhar,et al.New synthesis of analogues of the antihyptensive active pharmaceutical ingredient irbesartan[J].Synth.Commun.2006,36(15):2079-2086.
[27]Pandurang Balant Deshpande,Parven Kumar Luthra,et al.Process for preparation of Irbesartan[P].US,20070099973A1.2007-05-03.
[28]Ben-Zion Dolitzky,Julia Kaftanov,et al.Novel synthesis of 2-butyl-3-(2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl)-1,3 -diazaspiro[4,4]-non-ene-4-one[P].US,20060128967A1.2006-06-15.
[29]沈敬山,严铁马,李卉君等.伊贝沙坦的合成工艺改进[J].中国药物化学杂志,2001,11(1):104-106.
[30]Lin Shi-lin,Liu Jing-yuan,Wang Jian-mei.The synthesis of cyclic amino acids[J].Chinese Chemical Letters,2003,14(9):883-884.
[31]Douglas K,Kondareddiar R,Ronald W.A facile procedure for the preparation of alicyclic a-amino acids[J].Synth.Comm,1985,15:267-272.
[32]Sambasivarao Kotha,Atsuo Kuki.A simple method for the synthesis of cyclic a-amino acids[J].Tetrahedron letters,33(12):1565-1568.
[33]Connors T.A.;Ross W.C.T.Some derivatives of 1-aminocyclopentane carboxylic acid and related compounds[J].J.Chem.Soc.1960,2119-2132.
[34]Gaudette Roger R,Stallman John B,et al.Preparation of a-amino carboxylic acid amides.WO,9831657.1998-07-23.
[35]庄俊钰,王三永,李春荣等.三元环氨基酸的合成工艺改进[J].合成化学,2007,15(1):120-122.
[36]张本田,赵传江.甘氨酸乙酯盐酸盐的生产方法.CN,1733705A,2006-02-15.
[2]林静,梁坤.抗高血压药物概述[J].实用心脑肺血管病杂志,2007,15(4):320-324.
[3]黄体钢.利尿药在抗高血压治疗中的应用及其限度[J].中国现代神经疾病志,2006,6(4):299-303.
[4]殷鸿,王兴东,尹海宁.一线抗高血压药的评价及展望[J].伤残医学杂志,2001,9(4):62-64.
[5]陈健.抗高血压药物研究进展[J],天津医科大学学报.2004,10:186-189.
[6]刘元华,洪明星,刘明雪,等.传统手法治疗高血压的探讨[J].中医外治杂志,2005,14(2):32-33.
[7]孙海燕.肾素-血管紧张素系统在高血压发病机制及药物治疗中的作用[J].深圳职业技术学院学报,2005,(2):43-46.
[8]邢玥.抗高血压药物概述[J].中国社区医师,2003,23:22-25.
[9]钱之玉.抗高血压药物的评价与研究进展[J].药学进展,2004,28(4):145-148.
[10]王维刚.AT1受体及其拮抗剂的研究进展与临床应用[J].卫生职业教育,2006,24(16):130-131.
[11]李正化.药物化学[M].北京:人民卫生出版社.1994.
[12]王维刚.AT1受体及其拮抗剂的研究进展与临床应用[J].卫生职业教育,2006,24(16):130-131.
[13]Gillis JC,Markham A.Irbesartan:a review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in the management of hypertension[J].Drugs,1997,54(6):885-902.
[14]唐树德,戚文航.血管紧张素Ⅱ受体拮抗剂-伊贝沙坦[J].上海医药,1999,20(7):32-33.
[15]孟德泉.血管紧张素Ⅱ受体抑制剂对逆转高血压左心室肥厚及舒张功能的疗效观察[J].华北煤炭医学院学报,2006,8(1):63-64.
[16]岑均达,马霞.厄贝沙坦的合成[J].中国医药工业杂志2007,38(3):230-240.
[17]Bernhart C,Breliere JC.N-Substituted heterocyclic derivatives,their preparation and the pharmaceutical compositions in which they are present [P].US,5270317.1993-12-14.
[18]李能刚,王超志,刘炳朋等.2-正丁基-1,3-二氮杂螺[4,4]壬-1-烯-4-酮的合成[J].中国新药杂志,2002,11(6):479-480.
[19]沈敬山,李剑峰,毛睿等.2-正丁基-1,3-二氮杂螺[4,4]壬烷-1-烯-4-酮的改进的生产工艺[P].CN,1194971C,2005-03-30.
[20]Francis G.Spinale,Charleston,S.C.Method of treating or preventing cardiac arrhythmia employing an N-substituted heterocyclic derivative[P].US,5541209.1996-07-30.
[21]Claude Bernhart,Jean-Claude Breliere,Jacques Clement,et al.Method for N-substituted heterocyclic derivatives[P].US,5559233.1996-09-24.
[22]Antoine Caron,Dominique Chantreux,et al.Process for the preparation of a tetrazole derivative in two crystalline forms and novel the crystalline forms thereof[P].US,5629311.1997-05-13.
[23]Ben-Zion Dolitzky,Julia Kaftanov,Boris Pertsikov,et al.Novel synthesis of 2-butyl-3-(2' -(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl)-1,3-diazaspiro[4,4]-non-ene-4-one[P].US,20040242894.2004-12-02.
[24]Satyanarayana B.;Sumalatha Y.;Venkatraman S.et al.Improved synthesis of irbesartan[J].Synth.Commun.2005,35(14):1979-1982.
[25]Kumar Yatendra,Prasad Mohan,et al.Processes for the preparation of highly pure irbesartan[P].WO,2005051943,2005-09-06.
[26]B.Satyanarayana,Y.Sumalatha,C.Sridhar,et al.New synthesis of analogues of the antihyptensive active pharmaceutical ingredient irbesartan[J].Synth.Commun.2006,36(15):2079-2086.
[27]Pandurang Balant Deshpande,Parven Kumar Luthra,et al.Process for preparation of Irbesartan[P].US,20070099973A1.2007-05-03.
[28]Ben-Zion Dolitzky,Julia Kaftanov,et al.Novel synthesis of 2-butyl-3-(2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl)-1,3 -diazaspiro[4,4]-non-ene-4-one[P].US,20060128967A1.2006-06-15.
[29]沈敬山,严铁马,李卉君等.伊贝沙坦的合成工艺改进[J].中国药物化学杂志,2001,11(1):104-106.
[30]Lin Shi-lin,Liu Jing-yuan,Wang Jian-mei.The synthesis of cyclic amino acids[J].Chinese Chemical Letters,2003,14(9):883-884.
[31]Douglas K,Kondareddiar R,Ronald W.A facile procedure for the preparation of alicyclic a-amino acids[J].Synth.Comm,1985,15:267-272.
[32]Sambasivarao Kotha,Atsuo Kuki.A simple method for the synthesis of cyclic a-amino acids[J].Tetrahedron letters,33(12):1565-1568.
[33]Connors T.A.;Ross W.C.T.Some derivatives of 1-aminocyclopentane carboxylic acid and related compounds[J].J.Chem.Soc.1960,2119-2132.
[34]Gaudette Roger R,Stallman John B,et al.Preparation of a-amino carboxylic acid amides.WO,9831657.1998-07-23.
[35]庄俊钰,王三永,李春荣等.三元环氨基酸的合成工艺改进[J].合成化学,2007,15(1):120-122.
[36]张本田,赵传江.甘氨酸乙酯盐酸盐的生产方法.CN,1733705A,2006-02-15.