CN101768153B - The method of preparation of the antihypertensives of isradipine - Google Patents

The method of preparation of the antihypertensives of isradipine Download PDF

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CN101768153B
CN101768153B CN 200810205014 CN200810205014A CN101768153B CN 101768153 B CN101768153 B CN 101768153B CN 200810205014 CN200810205014 CN 200810205014 CN 200810205014 A CN200810205014 A CN 200810205014A CN 101768153 B CN101768153 B CN 101768153B
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isradipine
methyl
inert solvent
benzofurazan
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CN101768153A (en
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徐自奥
李晓祥
陈义朗
韩硕
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上海阳帆医药科技有限公司
安徽省新星药物开发有限责任公司
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Abstract

本发明涉及制备高血压治疗药物伊拉地平的方法。 The present invention relates to a process for the preparation of antihypertensives isradipine. 具体地,本发明方法包括:(a)将2-氨基-3-甲基硝基苯进行氧化关环,形成4-甲基苯并呋咱氧化物;(b)使得4-甲基苯并呋咱氧化物还原,形成4-甲基苯并呋咱;(c)对4-甲基苯并呋咱进行取代溴化,形成4-溴甲基苯并呋咱;(d)对4-溴甲基苯并呋咱进行水解,形成4-羟甲基苯并呋咱;(e)对4-羟甲基苯并呋咱进行氧化,形成4-甲醛基苯并呋咱;和(f)将4-甲醛基苯并呋咱与β-氨基巴豆酸异丙脂等进行反应,形成伊拉地平。 In particular, the method comprises: (a) 2-Amino-3-methyl-nitrobenzene oxidative ring closure, forming 4-methyl benzofurazan oxide; (b) such that 4-methyl-benzo furazan oxide reduction to form 4-methyl benzofurazan; (c) 4-methyl benzofurazan of substitution bromination, formation of 4-bromomethyl-benzofurazan; (d) of 4- bromomethyl benzofurazan hydrolysis, and the formation of 4-hydroxymethyl benzene furazan; (e) for 4-hydroxymethyl benzene and furazan oxidized form 4 furazan formaldehyde and benzene; and (f ) 4-carbaldehyde and benzene with β- furazane isopropyl aminocrotonate like aliphatic react to form isradipine. 本发明方法的收率高,操作简便,可制得高纯度的伊拉地平。 The method of the present invention, high yield, simple operation, can be obtained high purity isradipine.

Description

制备高血压治疗药物伊拉地平的方法 The method of preparation of the antihypertensives of isradipine

技术领域 FIELD

[0001] 本发明涉及化合物的制备方法,更具体地涉及药物伊拉地平(Isradipine)的制备方法。 [0001] The present invention relates to the preparation of compounds, and more particularly relates to a pharmaceutical isradipine (Isradipine) preparation.

背景技术 Background technique

[0002] 伊拉地平(Isradipine)是一种新型的二氢吡啶类钙通道阻滞剂。 [0002] isradipine (Isradipine) is a new dihydropyridine calcium channel blockers. 伊拉地平由瑞士山道士(Sandoz)公司开发,1989年2月由英国汽巴-嘉基(Ciki-Geigy)公司首次推上市场。 Isradipine developed by the Swiss Sandoz (Sandoz) company, in February 1989 by the British Ciba - Geigy (Ciki-Geigy) company for the first time onto the market.

[0003] 伊拉地平通过扩张血管,减少周围血管阻力,增加冠脉血流量,改善心肌供氧功能而达到降低血压的目的。 [0003] isradipine by expansion of blood vessels, reduce peripheral vascular resistance and increase coronary blood flow, improving myocardial oxygen function to achieve the purpose of lowering blood pressure.

[0004] 伊拉地平具有较强的血管扩张作用,而无心脏抑制作用,几乎不引起反射性心动过速。 [0004] isradipine have strong vasodilator action, inhibition of the heart without hardly causing reflex tachycardia. 临床和动物实验证明,该药具有明显的降压作用和抗动脉粥样硬化作用,通过维持或恢复左心室内皮下的血流,防止局部缺血性损害,改善心绞痛及充血性心力衰竭病人的运动量,在治疗高血压的同时,对心脏有保护作用。 Clinical and animal experiments show that the drug has significant antihypertensive effect and anti-atherosclerosis action artery, by maintaining or restoring blood flow in the left ventricular endothelium, prevent ischemic damage, and improved angina congestive heart failure patients physical activity, in the treatment of high blood pressure, have a protective effect on the heart. 伊拉地平能增加钠离子和水的排泄,有利尿作用,能扩张肾输出动脉和输出动脉,减少肾毛细血管压,对肾有保护作用。 Isradipine can increase sodium and water excretion, a diuretic effect, expansion of renal artery and outputs output arterial, capillary pressure reducing kidney, renal protective effect.

[0005] 据报导,研究人员发现治疗高血压药伊拉地平还可以延缓、甚至中止巴金森氏症病情。 [0005] According to reports, the researchers found that the treatment of hypertension drug isradipine also postpone or even suspend Parkinson's disease condition.

[0006] 伊拉地平是一类苯并呋咱二氢吡啶类化合物,其合成比较复杂,特别是原料的纯化尤为困难。 [0006] isradipine is a class of benzofurazan-dihydropyridine compounds, their synthesis is more complex, especially purified material particularly difficult.

[0007] 美国专利US4466972和PCT申请W02005/00437分别公开了两种伊拉地平的合成 [0007] U.S. Patent No. US4466972 and PCT Application W02005 / 00437 discloses the synthesis of each of the two kinds of isradipine

方法。 method. 然而,现有方法制备的产物都含有一定量的下式同系物杂质,杂质结构如下: However, the conventional method of preparation of the product contains a certain amount of the impurity of formula homologs, impurity following structure:

[0008] [0008]

Figure CN101768153BD00041

[0009] 式中,R1, R2同时或分别为甲基、乙基及异丙基。 [0009] wherein, R1, R2 simultaneously or separately methyl, ethyl and isopropyl. 将所述的同系物杂质与伊拉地平分开极为困难,导致无法有效纯化伊拉地平。 The homologs isradipine impurity is extremely difficult to separate, resulting in efficient purification not isradipine.

[0010] 此外,现有制备工艺中涉及关键的中间体4-甲基苯并呋咱。 [0010] Further, the conventional manufacturing process involves the key intermediate 4-methyl benzofurazan. 然而,该关键中间体的制备方法尚难以令人满意。 However, the preparation of the key intermediates is still unsatisfactory. 例如,中国专利申请200510125267(公开号CN1847233A)中 For example, Chinese Patent Application No. 200 510 125 267 (Publication No. CN1847233A) in

公开了一种中间体4-甲基苯并呋咱的制备方法,其制备流程如下: Discloses an intermediate preparation of 4-methyl benzofurazan we, their preparation process is as follows:

[0011] [0011]

Figure CN101768153BD00051

[0012] 很显然,以上方法步骤长、操作危险、可控性差,而且造成大量的污染。 [0012] Obviously, the above method steps long, dangerous operation, poor controllability, but also cause a lot of pollution.

[0013] 因此,本领域迫切需要开发新的、高效简便的制备伊拉地平及其重要中间体4-甲基苯并呋咱的方法。 [0013] Accordingly, there is an urgent need to develop new, simple and efficient preparation of important intermediates and isradipine methyl benzofurazan method.

发明内容 SUMMARY

[0014] 本发明的目的之一在于提供一种收率高,纯度高且操作简便的制备药物伊拉地平的方法。 [0014] One object of the present invention is to provide a high yield, high purity and easy operation method of preparing a pharmaceutical isradipine.

[0015] 在本发明的目的之二在于提供一种收率高,操作简便的制备药物伊拉地平中间体的方法。 [0015] provided that in the second object of the present invention provide a high yield, simple manufacture of pharmaceutical intermediates isradipine method.

[0016] 本发明的目的之三在于提供一种收率高,纯度高的制备β -氨基巴豆酸异丙脂的方法。 [0016] A further object of the present invention provides a high yield and high purity preparation of β - amino crotonic acid isopropyl fat method.

[0017] 在本发明的第一方面,提供了一种伊拉地平的制备方法,包括步骤: [0017] In a first aspect of the present invention, there is provided a method for preparing isradipine, comprising the steps of:

[0018] (a)在惰性溶剂中,将2-氨基-3-甲基硝基苯进行氧化关环,形成4_甲基苯并呋咱氧化物,即式2化合物; [0018] (a) in an inert solvent, 2-amino-3-methyl-nitrobenzene oxidation cyclized form 4_ methyl benzofurazan oxide, i.e. a compound of Formula 2;

[0019] [0019]

Figure CN101768153BD00052

[0020] (b)在惰性溶剂中,使得4-甲基苯并呋咱氧化物还原,形成4-甲基苯并呋咱,即式3化合物; [0020] (b) in an inert solvent, such that the 4-methyl benzofurazan oxide reduction to form 4-methyl benzofurazan, i.e. the compound of formula 3;

[0021] [0021]

Figure CN101768153BD00053

[0022] (c)在惰性溶剂中,对4-甲基苯并呋咱进行取代溴化,形成4-溴甲基苯并呋咱; [0022] (c) in an inert solvent, for 4-methyl benzofurazan substitution bromination, formation of 4-bromomethyl-benzofurazan;

[0023] (d)在惰性溶剂中,对4-溴甲基苯并呋咱进行水解,形成4-羟甲基苯并呋咱; [0023] (d) in an inert solvent, for 4-bromomethyl-benzofurazan by hydrolysis, and the formation of 4-hydroxymethyl benzene furazane;

[0024] (e)在惰性溶剂中,对4-羟甲基苯并呋咱进行氧化,形成4-甲醛基苯并呋咱;和 [0024] (e) in an inert solvent, for 4-hydroxymethyl benzene and oxidized furazan, benzene and formaldehyde to form 4 furazan; and

[0025] (f)通过步骤(f 1)或(f2),形成伊拉地平: [0025] (f) by step (f 1) or (f2), isradipine form:

[0026] (fl)在惰性溶剂中,将4-甲醛基苯并呋咱、β-氨基巴豆酸异丙脂(化合物8)与乙酰乙酸甲酯反应,形成伊拉地平;或者 [0026] (fl) in an inert solvent, benzene and formaldehyde 4- furazane, [beta] aminocrotonate isopropyl ester (Compound 8) is reacted with methyl acetoacetate to form isradipine; or

[0027] (f2)在惰性溶剂中,对4-甲醛基苯并呋咱进行脱水缩合,形成式7化合物,并与β -氨基巴豆酸异丙脂(化合物8)反应, [0027] (f2) in an inert solvent, benzene and formaldehyde of 4- furazan dehydration condensation to form a compound of Formula 7, with β - aminocrotonate reaction isopropyl ester (Compound 8),

[0028] [0028]

Figure CN101768153BD00061

[0029] 从而形成伊拉地平。 [0029] thereby forming isradipine.

[0030] 在另一优选例中,所述方法还包括步骤: [0030] In another preferred embodiment, the method further comprising the step of:

[0031] (g)分离纯化步骤(f)中形成的伊拉地平。 [0031] isradipine (g) separation and purification step (f) is formed.

[0032] 在另一优选例中,所述分离纯化采用结晶法。 [0032] In another preferred embodiment, the isolated purified by crystallization.

[0033] 在另一优选例中,将步骤(f)中形成的伊拉地平在乙醇中进行结晶,从而制得纯度> 99% (更佳地> 99. 5% )的伊拉地平。 [0033] In another preferred embodiment, the step (f) formed isradipine crystallized in ethanol to obtain a purity of> 99% (more preferably> 99.5%) of isradipine.

[0034] 在另一优选例中,步骤(a)中在选自氢氧化钾或氢氧化钠的无机碱存在下进行。 [0034] Step (a) is carried out in the presence of potassium hydroxide or sodium hydroxide is selected from inorganic bases In a further preferred embodiment.

[0035] 在另一优选例中,步骤(a)中惰性溶剂包括甲醇、乙醇、异丙醇、水或上述溶剂的任意组合,更佳地为乙醇。 [0035] In another preferred embodiment, step (a) in an inert solvent include methanol, ethanol, isopropanol, water or any combination of the foregoing solvents, more preferably ethanol.

[0036] 在另一优选例中,步骤(a)中在作为氧化剂的次氯酸盐存在下进行。 [0036] Step (a) is carried out in the presence of hypochlorite as an oxidant In a further preferred embodiment.

[0037] 在另一优选例中,步骤(a)的反应温度为-20-40°C。 [0037] In another preferred embodiment, the reaction temperature in step (a) of -20-40 ° C.

[0038] 在另一优选例中,所述方法还包括以下一个或多个特征: [0038] In another preferred embodiment, the method further comprises one or more of the following features:

[0039] 步骤(b)在选自盐酸羟胺、或Pd/C-H2的还原体系下进行;和/或 [0039] Step (b) is selected from hydroxylamine hydrochloride is carried out at, or Pd / C-H2 reduction systems of; and / or

[0040] 步骤(d)在选自硫酸、盐酸、碳酸钙、碳酸钾、氢氧化锂、氢氧化钠、或氢氧化钾的水解试剂下进行;和/或 [0040] step (d) is carried out at selected from sulfuric acid, hydrochloric acid, calcium carbonate, potassium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, or hydrolysis reagent; and / or

[0042] 在另一优选例中,步骤(fl)中的惰性溶剂包括:乙醇、异丙醇、叔丁醇或其组合。 [0042] In another preferred embodiment, step (fl) in inert solvents include: ethanol, isopropanol, tert-butanol, or a combination thereof.

[0043] 在另一优选例中,步骤(fl)中的惰性溶剂为叔丁醇与乙醇的混合溶剂,其中叔丁醇/乙醇的混合比例为5 : 1-1 : 5。 [0043] In another preferred embodiment, step (fl) in the inert solvent is a mixed solvent of tert-butanol and ethanol, wherein tert-butanol / ethanol mixing ratio of 5: 1 to 1: 5.

[0044] 在另一优选例中,该骤(fl2)中的惰性溶剂包括:乙醇、异丙醇、叔丁醇或其任意两者的组合。 [0044] In another preferred embodiment, the step (FL2) in the inert solvent include: a combination of isopropanol, any two ethanol, tert-butanol or the.

[0045] 在另一优选例中,所述的惰性溶剂是叔丁醇与乙醇的混合溶剂,其中叔丁醇/乙醇的混合比例为5 : 1-1 : 5。 [0045] In another preferred embodiment, the inert solvent is a mixed solvent of t-butanol and ethanol, wherein tert-butanol / ethanol mixing ratio of 5: 1 to 1: 5.

[0046] 在另一优选例中,步骤(Ώ)在催化剂存在下进行,所述的催化剂包括浓盐酸、浓硫酸、和醋酐/浓硫酸。 [0046] step (Ώ) carried out in the presence of a catalyst In another preferred embodiment, the catalyst comprises a concentrated hydrochloric acid, concentrated sulfuric acid and acetic anhydride / concentrated sulfuric acid.

[0047] 在另一优选例中,所述方法还包括步骤(h):将分离的伊拉地平与药学上可接受的载体混合,从而制得含伊拉地平的药物组合物。 [0047] In another preferred embodiment, the method further comprises the step of (h): The isolated isradipine mixed with a pharmaceutically acceptable carrier to prepare pharmaceutical compositions containing isradipine thereof.

[0041 ] 在步骤(e)中,使用的氧化剂包括:DMP具体实施方式 [0041] In step (e), the oxidizing agent include: DMP DETAILED DESCRIPTION

[0048] 本发明人经过深入而广泛的研究,改进了伊拉地平的制备工艺,尤其是其中间体4-甲醛基苯并呋咱的制备工艺,从而可高效、简便地制备高纯度的伊拉地平。 [0048] The present inventors have conducted intensive and extensive studies to improve the preparation process of isradipine, particularly its intermediate 4-carbaldehyde and benzene we preparation of furosemide, which can efficiently and easily producing high purity Iraq isradipine. 在此基础上完成了本发明。 Based on this completed the present invention.

[0049] 如本文所用,术语“伊拉地平”指结构如下式I表示的化合物: [0049] As used herein, the term "isradipine" refers to a compound represented by structural formula I:

[0050] [0050]

Figure CN101768153BD00071

[0051] 伊拉地平的中文别名包括依拉地平、易拉地平、导脉顺。 [0051] isradipine in Chinese names include isradipine, isradipine easy to guide along veins. 其外文名包括Isradipine, PN-200-110、COMIR、PRESCAL、DYNACIRC, Vascal。 Its English name, including Isradipine, PN-200-110, COMIR, PRESCAL, DYNACIRC, Vascal. 应理解,所述术语不仅包括式I化合物,还可包括式I化合物的药学上可接受的盐。 It should be understood, the term includes not only compounds of Formula I, further comprising a pharmaceutically acceptable compound of formula I the salt.

[0052] 下面更具体地描述本发明的制备方法。 [0052] Next, production method of the present invention is more specifically described. 然而,应理解,本发明并不局限于以下所给出的具体反应条件(如溶剂、所用化合物的量、反应温度、反应所需时间等)。 However, it should be understood that the present invention is not limited to the specific reaction conditions given below (such as a solvent, the amount of compound used, reaction temperature, desired reaction time, etc.).

[0053] 在本发明的流程中,各反应通常在惰性溶剂中,在室温至回流温度(如0°C〜 100°c,优选0°C〜80°C )下进行。 [0053] Each reaction is usually carried out at room temperature to reflux temperature (e.g., 0 ° C~ 100 ° c, preferably 0 ° C~80 ° C) in the process under the present invention in an inert solvent. 反应时间通常为0. 1小时-60小时,较佳地为0. 5-48小时。 The reaction time is generally 0.1 hours -60 hours, preferably for 0. 5-48 hours.

[0054] 本发明的制备方法可用以下流程表示: [0054] The production method of the present invention can be represented by the following scheme:

[0055] [0055]

Figure CN101768153BD00081

[0056] 下面更具体的描述流程1 : [0056] the following more particular description of a process:

[0057] (a). 2-氨基-3-甲基硝基苯经氧化关环,形成4_甲基苯并呋咱氧化物(化合物2) [0057] (a). 2- amino-3-methyl-nitrobenzene was oxidized ring closure forming 4_ methyl benzofurazan oxide (Compound 2)

[0058] 在该步骤中,可使用的惰性溶剂包括甲醇、乙醇、异丙醇、水或上述溶剂的任意组合。 [0058] In this step, the inert solvent may be used include methanol, ethanol, isopropanol, water or any combination of the above solvents. 一种优选的溶剂是乙醇。 A preferred solvent is ethanol.

[0059] 所使用的氧化剂为次氯酸盐。 [0059] The oxidizing agent used is hypochlorite.

[0060] 碱没有特别限制,可以采用氢氧化钾、氢氧化钠等无机碱,优选氢氧化钾。 [0060] The base is not particularly limited, and potassium hydroxide, an inorganic base such as sodium hydroxide, preferably potassium hydroxide.

[0061] 反应温度没有特别限制,通常为-20-40°C,较佳地为10-25°C。 [0061] The reaction temperature is not particularly limited and is usually -20-40 ° C, preferably of 10-25 ° C.

[0062] 反应时间没有特别限制,通常为3-20小时,较佳地为5-10小时。 [0062] The reaction time is not particularly limited and is usually 3-20 hours, preferably 5-10 hours.

[0063] (b).化合物2经还原反应,形成4-甲基苯并呋咱(化合物3) [0063] (b). Compound 2 by reduction reaction to form 4-methyl benzofurazan (Compound 3)

[0064] 在该步骤中,可使用的惰性溶剂(反应体系)包括甲醇、乙醇、异丙醇或其任意组合的质子型溶剂。 [0064] In this step, an inert solvent (reaction system) can be used includes methanol, ethanol, isopropanol, or any combination of the protic solvent. 一种特别优选的溶剂是乙醇。 A particularly preferred solvent is ethanol.

[0065] 还原体系可使用盐酸羟胺/碱、或Pd/C-H2作为还原体系,优选盐酸羟胺/碱体系。 [0065] The reduction system may be used hydroxylamine hydrochloride / base, or Pd / C-H2 as reducing system, preferably hydroxylamine hydrochloride / base system.

[0066] 此外,该步骤还可采用惰性溶剂作反应溶剂,优选甲苯,并采用三烃基膦作为还原试剂,优选三苯基膦。 [0066] In addition, this step can also be used as a reaction solvent is an inert solvent, preferably toluene, and using as a reducing agent, preferably a trihydrocarbyl phosphine is triphenylphosphine.

8[0067] 反应温度没有特别限制,通常为0-100°C,较佳地为75_90°C。 8 [0067] The reaction temperature is not particularly limited and is usually 0-100 ° C, preferably of 75_90 ° C.

[0068] 反应时间没有特别限制,通常为1-12小时,较佳地为3-8小时。 [0068] The reaction time is not particularly limited and is usually 1 to 12 hours, preferably for 3-8 hours.

[0069] (c).由化合物3制备化合物6可常规方法,例如按文献Eur. J.Med. Chem (1996) 31, 3-10实施。 [0069] (c)., According to the literature, for example, Eur. J.Med. Chem (1996) 31, 3-10 embodiment Preparation of Compound 6 from Compound 3 may be a conventional method.

[0070] 化合物3经取代溴化反应,形成4-溴甲基苯并呋咱(化合物4)。 [0070] Compound 3 was substituted bromination reaction to form 4-bromomethyl-benzofurazan (Compound 4).

[0071] 在该步骤中,可使用的惰性溶剂包括氯苯、四氯化碳等惰性溶剂。 [0071] In this step, inert solvents may be used include an inert solvent, chlorobenzene, carbon tetrachloride and the like.

[0072] 溴化试剂没有特别限制,可采用本领域常规的溴素、溴代琥珀酰亚胺(NBQ及其他溴化试剂。一种优选的溴化试剂是NBS。 [0072] The brominating agent is not particularly limited, and conventional in the art bromine, bromosuccinimide (NBQs and other brominating reagents. A preferred bromination agent is of NBS.

[0073] 可用的引发剂包括(但并不限于):过氧苯甲酰、或偶氮二丁腈,优选过氧苯甲酰。 [0073] Useful initiators include (but are not limited to): benzoyl peroxide or azobis butyronitrile, benzoyl peroxide is preferred.

[0074] 反应温度没有特别限制,通常为25_100°C,较佳地为70-90°C。 [0074] The reaction temperature is not particularly limited and is usually 25_100 ° C, preferably of 70-90 ° C.

[0075] 反应时间没有特别限制,通常为IM小时,较佳地为2-5小时。 [0075] The reaction time is not particularly limited and is usually IM hours, preferably for 2-5 hours.

[0076] (d).化合物4经水解反应,形成4-羟甲基苯并呋咱(化合物5)。 [0076] (d). Compound 4 by hydrolysis, to form benzene and 4-hydroxymethyl furazan (Compound 5).

[0077] 在该步骤中,可使用的惰性溶剂包括(但并不限于):1,4_ 二氧六环、四氢呋喃、 乙醇、甲醇、异丙醇、水或上述溶剂的任意组合。 [0077] In this step, the inert solvent may be used include (but are not limited to): 1,4_ dioxane, any combination of tetrahydrofuran, ethanol, methanol, isopropanol, water or the aforementioned solvents. 一种优选的溶剂是四氢呋喃和水的混合物(两者的混合比例为1 : 1至5 : 1)。 A preferred solvent is a mixture of tetrahydrofuran and water (mixing ratio between them is 1: 1 to 5: 1).

[0078] 可使用的水解试剂包括(但并不限于):无机酸(如硫酸、盐酸等),或者无机碱(如碳酸钙、碳酸钾、氢氧化锂、氢氧化钠、氢氧化钾等)。 [0078] The hydrolytic agent may be used include (but are not limited to): an inorganic acid (such as sulfuric acid, hydrochloric acid, etc.) or an inorganic base (such as calcium carbonate, potassium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, etc.) . 一种优选的水解试剂是碳酸钙。 One preferred hydrolyzing agent is calcium carbonate.

[0079] 反应温度没有特别限制,通常为50-100°C,优选在回流温度下进行。 [0079] The reaction temperature is not particularly limited and is usually 50-100 ° C, preferably at reflux temperature.

[0080] 反应时间没有特别限制,通常为1-48小时,较佳地为3-M小时。 [0080] The reaction time is not particularly limited and is usually 1 to 48 hours, preferably for 3-M h.

[0081] (e).化合物5经氧化反应,形成4-甲醛基苯并呋咱(化合物6) [0081] (e). Compound 5 by an oxidation reaction, benzene and formaldehyde to form 4-furazan (Compound 6)

[0082] 在该步骤中,可采用的惰性溶剂包括(但并不限于):二氯甲烷、氯苯、四氯化碳、 氯仿或其组合。 [0082] In this step, an inert solvent may be employed include (but are not limited to): dichloromethane, chlorobenzene, carbon tetrachloride, chloroform, or combinations thereof. 一种优选的惰性溶剂是氯苯。 A preferred inert solvent is chlorobenzene.

氧化锰。 Manganese oxide. 优选的氧化剂是二氧化锰。 The preferred oxidizing agent is manganese dioxide.

Figure CN101768153BD00091

[0084] 反应温度没有特别限制,通常为10-100°C,较佳地为50-70°C。 [0084] The reaction temperature is not particularly limited and is usually 10-100 ° C, preferably of 50-70 ° C.

[0085] 反应时间没有特别限制,通常为IM小时,较佳地为3-10小时。 [0085] The reaction time is not particularly limited and is usually IM hours, preferably 3-10 hours.

[0086] (f) ·通过步骤(f 1)或(f2),形成伊拉地平: [0086] (f) · in step (f 1) or (f2), isradipine form:

[0087] (f 1)将化合物6经脱水缩合得到化合物7。 [0087] (f 1) Compound 6 Compound 7 obtained by dehydration condensation. 该脱水缩合反应宜采用醋酐-硫酸为催化剂。 The dehydration condensation reaction using acetic anhydride should - sulfuric acid as a catalyst.

[0088] 乙酰乙酸异丙酯和甲酸铵在溶剂中反应制备化合物8。 [0088] isopropyl acetoacetate and ammonium formate in a solvent prepared by reacting Compound 8.

[0089] 然后,将化合物7与化合物8经缩合反应得到化合物伊拉地平。 [0089] Thereafter, the condensation reaction of compound 7 compound 8 compound was isradipine.

[0090] 在该步骤中,可使用的惰性溶剂包括(但并不限于):乙醇、异丙醇、叔丁醇或其任意两者的组合。 [0090] In this step, the inert solvent may be used include (but are not limited to): a combination of isopropanol, any two ethanol, tert-butanol or the. 一种优选的惰性溶剂是叔丁醇与乙醇的混合溶剂,其中叔丁醇/乙醇的混合比例为5 : 1-1 : 5,较佳地为2 : 1-1 : 2(如1 : 1)。 A preferred inert solvent is a mixed solvent of t-butanol and ethanol, wherein tert-butanol / ethanol mixing ratio of 5: 1 to 1: 5, preferably 2: 1-1: 2 (e.g., 1: 1 ).

[0091] 在该步骤中,反应体系宜采用氮气、氩气等惰性气体保护。 [0091] In this step, the reaction system should be used inert gas as nitrogen, argon and the like.

[0092] 反应温度没有特别限制,通常为5_70°C,较佳地为15_25°C。 [0092] The reaction temperature is not particularly limited and is usually 5_70 ° C, preferably of 15_25 ° C.

[0093] 反应时间没有特别限制,通常为1-72小时,较佳地为反应时间为2-36小时,更佳 [0093] The reaction time is not particularly limited and is usually 1 to 72 hours, preferably the reaction time is 2-36 hours, more preferably

[0083] 可使用的氧化剂包括(但并不限于):DMP地为8-24小时。 [0083] The oxidizing agent may be used include (but are not limited to): DMP for 8 to 24 hours.

[0094] (f2)化合物6、β-氨基巴豆酸异丙脂(化合物8)与乙酰乙酸甲酯一锅反应,形成伊拉地平。 [0094] (f2) Compound 6, β- amino crotonic acid isopropyl ester (Compound 8) is reacted with methyl acetoacetate pot, isradipine formed.

[0095] 在该步骤中,可使用的惰性溶剂包括(但并不限于):乙醇、异丙醇、叔丁醇或其任意两者的组合。 [0095] In this step, the inert solvent may be used include (but are not limited to): a combination of isopropanol, any two ethanol, tert-butanol or the. 一种优选的惰性溶剂是叔丁醇与乙醇的混合溶剂,其中叔丁醇/乙醇的混合比例为5 : 1-1 : 5,较佳地为2 : 1-1 : 2(如1 : 1)。 A preferred inert solvent is a mixed solvent of t-butanol and ethanol, wherein tert-butanol / ethanol mixing ratio of 5: 1 to 1: 5, preferably 2: 1-1: 2 (e.g., 1: 1 ).

[0096] 在该步骤中,反应体系宜采用氮气、氩气等惰性气体保护。 [0096] In this step, the reaction system should be used inert gas as nitrogen, argon and the like.

[0097] 反应温度没有特别限制,通常为5_70°C,较佳地为15_25°C。 [0097] The reaction temperature is not particularly limited and is usually 5_70 ° C, preferably of 15_25 ° C.

[0098] 反应时间没有特别限制,通常为1-72小时,较佳地为反应时间为2-36小时,更佳地为8-24小时。 [0098] The reaction time is not particularly limited and is usually 1 to 72 hours, preferably the reaction time is 2-36 hours, more preferably for 8 to 24 hours.

[0099] 反应过程需要催化剂催化反应,可采用的催化剂有浓盐酸、浓硫酸、醋酐/浓硫酸,优选为醋酐/浓硫酸体系。 [0099] The reaction requires a catalyst during the catalytic reaction, the catalyst can be employed with a concentrated hydrochloric acid, sulfuric acid, acetic anhydride / concentrated sulfuric acid, preferably acetic anhydride / sulfuric acid system.

[0100] 本发明方法的主要优点在于: [0100] The main advantage of the method of the present invention wherein:

[0101] (a)化合物2的合成,采用氧化关环方法,摒弃原方法的采用叠氮反应的缺点。 [0101] (a) Synthesis of compound 2, by oxidation cyclization method using the reaction of an azide disadvantage abandon the original method.

[0102] (b)化合物6的合成,工艺稳定,产品质量稳定。 [0102] Synthesis of compound (b) 6, process stability, product quality and stability.

[0103] (c)化合物8以及伊拉地平(Isradipine)的合成过程中采用叔丁醇/乙醇混合体系作为溶剂,有效地出去了终产物中的同系化合物杂质,能够很方便地得到合格的产品。 [0103] (c) Compound 8 and isradipine (Isradipine) employed during the synthesis of tert-butanol / ethanol mixture as the solvent system, homologues out effectively impurities in the final product compound can be easily obtained qualified products .

[0104] 下面结合具体实施例,进一步阐述本发明。 [0104] The following embodiments with reference to specific embodiments, further illustrate the present invention. 应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。 It should be understood that these embodiments are illustrative only and the present invention is not intended to limit the scope of the invention. 下列实施例中未注明具体条件的实验方法,通常按照常规条件,或按照制造厂商所建议的条件。 Experimental methods without specific conditions in the examples below, are performed under routine conditions, or in accordance with the conditions recommended by the manufacturer.

[0105] 所有实施例中,熔点用MEL-TEMP熔点仪测定,温度计未校正;IH-NMR用Varian Mercury 400核磁共振仪记录,化学位移以δ (ppm)表示;分离用硅胶未说明的均为200-300目。 [0105] In all embodiments, m.p. MEL-TEMP melting point apparatus with a thermometer uncorrected; IH-NMR Varian Mercury 400 NMR spectrometer with recorded Chemical shifts are expressed in δ (ppm); not illustrated are separated by silica gel 200-300 mesh. 元素分析用Elementa Vario EL III型元素分析仪测定;质谱用AgilentllOO LC-MS质谱仪测定;HPLC为岛津系统。 Elemental Analysis Elementa Vario EL III element type Analyzer; mass spectrometer measurement AgilentllOO LC-MS; HPLC Shimadzu system.

[0106] 实施例14-甲基苯并呋咱氧化物(化合物2) [0106] Example 14 methyl benzofurazan oxide (Compound 2)

[0107] IL三口圆底烧瓶中加入化合物1 8g,0. 15mol),然后加入KOH(IOg)的乙醇溶液OOOml),冰浴冷却下滴加Natno溶液(IOOml),滴加完毕继续冰水浴下反应。 [0107] in the presence of IL-neck round bottom flask was added compound 1 8g, 0. 15mol), followed by addition of ethanol solution OOOml KOH (IOg)), the solution was added dropwise under ice-cooling Natno (IOOml), an ice-water bath to continue complete addition reaction. 反应完毕, 体系中加入CH2Cl2(150ml)搅拌,滤去不溶物,滤液分出有机相,无水Na2SO4干燥,浓缩。 Completion of the reaction system was added CH2Cl2 (150ml) was stirred, insolubles were filtered off, and the filtrate the organic phase was separated, dried over anhydrous Na2SO4, and concentrated. 得20.77g粗产物。 To give 20.77g of crude product. 加乙酸乙酯重结晶得15. 5g黄色针状晶体,产率68.9%。 Recrystallized from ethyl acetate was added 15. 5g of yellow needle crystals, yield 68.9%.

[0108] 实施例甲基苯并呋咱氧化物(化合物2) [0108] Example embodiments we methyl benzofurazan oxide (Compound 2)

[0109] (a)500mL三口圆底烧瓶中加入化合物1(30. 4g,0. 2mol),水(80mL)和浓盐酸(45mL),冰浴冷却后,滴加亚硝酸钠(14. 5g,0. 21mol)的水溶液(50mL),滴加结束后,保温搅拌1小时。 After [0109] (a) was added 1 (30. 4g, 0. 2mol), water (80 mL) and concentrated hydrochloric acid (45mL), ice-cooled compound 500mL three neck round bottom flask, the solution of sodium nitrite (14. 5g , an aqueous solution of 0. 21mol) in (50 mL), after the addition, stirred for 1 hour incubation.

[0110] (b)抽滤,滤液倒入IL烧杯中,冰浴条件下分批加叠氮钠(13g,0.2mol),加完后, 保温搅拌1小时,抽滤,滤饼水洗(lOOmL,2次)。 [0110] (b) filtration, the filtrate was poured into a IL beaker was added portionwise under ice-cooling, sodium azide (13g, 0.2mol), after addition, heat stirred for 1 hour, filtered off with suction, the filter cake was washed with water (lOOmL ,2 times).

[0111] (c)将(b)过程中所得滤饼投入装有甲苯(60mL)的三口圆底烧瓶中,缓慢升温至回流,回流反应5小时,体系降温至室温,抽滤出去不溶物,滤液浓缩,残留物冷却析晶,抽滤干燥得化合物粗品(15g),乙酸乙酯重结晶得11. 5g黄色针状晶体,产率38. 3%。 [0111] (c) to (b) the resultant cake was put in during three round bottom flask equipped toluene (60 mL) is slowly warmed to reflux, refluxed for 5 hours, cooling the system to room temperature, insoluble matter was suction filtered out, The filtrate was concentrated and the residue was cooled crystallization, filtration and dried to give crude compound (15g), recrystallized from ethyl acetate to give 11. 5g of yellow needle crystals, yield 38.3%.

[0112] 实施例3 4-甲基苯并呋咱(化合物3)[0113]将化合物 2(17. 4g, 116. Ommo 1)溶于乙醇QOOml),力卩入NH2OH · HCl (9. 7g, 139. 6mmol)的水溶液,混合物冷至O°C,然后边搅拌边加入K0IK23. 4g,417. 9mmol)的水溶液(150ml),加完后,加热回流。 [0112] Example 3 4-Methyl-benzofurazan was dissolved in ethanol QOOml (Compound 3) [0113] Compound 2 (17. 4g, 116. Ommo 1)), the force Jie NH2OH · HCl (9. 7g , 139. 6mmol) in an aqueous solution, the mixture was cooled to O ° C, then added with stirring K0IK23. 4g, 417. 9mmol) in water (150ml), after addition, it was heated to reflux. TLC板监测。 TLC monitoring board. 反应完毕,将反应物冷至室温,正己烷萃取(400ml X 2,200ml X 2),正己烷相水洗(500ml),无水Na2SO4干燥,浓缩。 After the reaction, the reaction was cooled to room temperature, and extracted with n-hexane (400ml X 2,200ml X 2), washed with hexane (500ml), dried over anhydrous Na2SO4, and concentrated. 得4-甲基苯并呋咱,为橙色粉末(11. 55g),产率为74. 3%。 Give 4-methyl benzofurazan as an orange powder (11. 55g), in a yield of 74.3%.

[0114] 1H-NMR(CDCl3) :7. 64-7. 61 (1H, d),7. 32-7. 27 (lH,m),7. 11-7. 09 (1H, d),2. 65 (3H, [0114] 1H-NMR (CDCl3):...... 7 64-7 61 (1H, d), 7 32-7 27 (lH, m), 7 11-7 09 (1H, d), 2 . 65 (3H,

S) S)

[0115] 实施例4 4-溴甲基苯并呋咱(化合物4) [0115] 4-Bromo-4-methyl-benzo furazanyl Example (Compound 4)

[0116] 将化合物3(16. lg,120mmol)溶于四氯化碳(150ml)中,然后加入NBS (23. 5g, 132mmol)和Bz2O2 (0. 29g, 1. 2mmol),混合物升温至80-85°C反应,反应完毕,体系降至40°C, 过滤,滤液水洗OOOml X 2),有机相无水Na2SO4干燥,减压浓缩,得粗产物6g),石油醚(80ml)重结晶,形成乳黄色粉末状晶体,即4-溴甲基苯并呋咱(18.47g)。 [0116] Compound 3 (16. Lg, 120mmol) dissolved in carbon tetrachloride (150ml), followed by addition of NBS (23. 5g, 132mmol) and Bz2O2 (0. 29g, 1. 2mmol), the mixture was warmed to 80 -85 ° C, the reaction is completed, the system down to 40 ° C, filtered and the filtrate washed with water OOOml X 2), the organic phase was dried over anhydrous Na2SO4, concentrated under reduced pressure to give the crude product 6g), petroleum ether (80ml) was recrystallized milk powder crystals, i.e., 4-bromomethyl benzofurazan (18.47g). 产率为72%。 The yield was 72%. (HPLC测定,纯度为88% ) (HPLC assay 88% purity)

[0117] 1H-WR (CDCl3) -J. 83-7. 80 (1H, m),7. 47-7. 39 (2H, m),4. 83 (2H, s) [0117] 1H-WR (CDCl3) -J. 83-7. 80 (1H, m), 7. 47-7. 39 (2H, m), 4. 83 (2H, s)

[0118] 实施例5 4-羟甲基苯并呋咱(化合物5) [0118] Example 5 and 4-hydroxymethyl benzene furazan embodiment (Compound 5)

[0119] 三口瓶中,化合物4(18. 0g,84.5mmol)溶于四氢呋喃QOOml),然后加入CaCO3 (42. lg,421mmol)和水QOOml),混合物加热回流,TLC板监测反应。 [0119] three-neck flask, compound 4 (18. 0g, 84.5mmol) was dissolved in tetrahydrofuran QOOml), followed by addition of CaCO3 (42. lg, 421mmol) and water QOOml), the mixture was heated to reflux, the reaction was monitored TLC plate. 反应完毕,过滤, 浓缩。 The mixture was then filtered and concentrated. 残留物加CH2Cl2 (90ml)和H2O(IOOml)搅拌溶解,分液,水相CH2Cl2 (50ml X 2)萃取, 干燥,浓缩得12. 37g粗产物,乙酸乙酯重结晶得黄色针状晶体,即4-羟甲基苯并呋咱(6. 68g),HPLC测定的纯度为98. 7%,产率为52. 7%0 The residue was added CH2Cl2 (90ml) and H2O (IOOml) was dissolved with stirring, liquid separation, the aqueous phase CH2Cl2 (50ml X 2), dried, and concentrated to give 12. 37g of crude product was recrystallized from ethyl acetate to give yellow needles, i.e., and 4-hydroxymethyl benzene furazan (6. 68g), purity measured by HPLC was 98.7%, yield 52.7% 0

[0120] 1H-WR (CDCl3) :7. 76-7. 73 (1H, m),7. 43-7. 39 (2H, m),5. 11-5. 09 (2H, d) [0120] 1H-WR (CDCl3):...... 7 76-7 73 (1H, m), 7 43-7 39 (2H, m), 5 11-5 09 (2H, d)

[0121] 实施例6 4-甲醛基苯并呋咱(化合物6) [0121] Example 64- carbaldehyde and furazan benzene (Compound 6)

[0122]将化合物 5(6. 5g,43. 3mmol)溶于氯苯Q70ml)中,加入MnO2 (34. 7g,398. 9mmol), 混合物60°C搅拌,反应完毕,过滤,滤饼氯苯(60ml)洗涤。 [0122] Compound 5 (6. 5g, 43. 3mmol) was dissolved in chlorobenzene Q70ml) was added MnO2 (34. 7g, 398. 9mmol), the mixture was stirred for 60 ° C, the reaction is completed, the filter cake was chlorobenzene (60ml) and washed. 滤液浓缩,得浅黄色固体状的4-甲醛基苯并呋咱6 (5. 9g),产率92.0%。 The filtrate was concentrated to give a pale yellow solid 4-carbaldehyde and benzene furazan 6 (5. 9g), 92.0% yield.

[0123] 1H-NMR(CDCl3) :10. 40 (1H, s) , 8. 19-8. 17 (1H, m) , 8. 09-8. 07 (1H, m), 7. 68-7. 65 (1H, m) [0123] 1H-NMR (CDCl3):... 10 40 (1H, s), 8. 19-8 17 (1H, m), 8. 09-8 07 (1H, m), 7. 68-7 . 65 (1H, m)

[0124] 实施例7 β -氨基巴豆酸异丙脂(化合物8) Amino crotonic acid isopropyl ester (Compound 8) - [0124] Example 7 β embodiment

[0125] 将乙酰乙酸异丙酯(72.0g,0. 5mol)、醋酸铵(57. 8g,0. 75mol)和叔丁醇/乙醇(1 : 1,600ml)混合于IOOOml烧瓶中,加入300目分子筛(50g),加热回流,TLC板监测。 [0125] The isopropyl acetoacetate (72.0g, 0 5mol.), Ammonium acetate (57. 8g, 0 75mol.) And tert-butanol / ethanol (1: 1,600ml) were mixed in IOOOml flask, 300 mesh sieve (50g), heated to reflux, TLC plate monitor. 反应基本结束后,降至室温,过滤,滤液浓缩至无液体蒸出,残留液体减压蒸馏,收集110-120°C 馏分(真空度0. IMPa)得化合物8 (66. Og)。 After the reaction is substantially completed, cooled to room temperature, filtered and the filtrate was concentrated until no liquid was distilled off, the residual liquid was distilled under reduced pressure to collect 110-120 ° C fraction (degree of vacuum of 0. IMPa) to give compound 8 (66. Og). Y = 92. 4%。 Y = 92. 4%.

[0126] 1H-WR(CDCl3) :5. 02-4. 95 (1H, m) ,4. 48 (1H, s),1. 88 (3H, d),1. 23-1. 21 (6H, d) [0126] 1H-WR (CDCl3):...... 5 02-4 95 (1H, m), 4 48 (1H, s), 1 88 (3H, d), 1 23-1 21 (6H , d)

[0127] 实施例8伊拉地平(Isradipine) [0127] Example 8 isradipine (Isradipine)

[0128] 在队保护下,三口瓶中将化合物6(3.0g,20mmol)、i3-氨基巴豆酸异丙脂(化合物8) (2. 7g, 16. 6mmol)、乙酰乙酸甲酯(3. 50g, 30mol)、Ac2O (2. 05g, 20mmol)、浓H2SO4 (0. 4g, 4mmol)和叔丁醇/乙醇(1 : 1,65ml)混合搅拌,液相监测,当化合物6剩余少于3. 7%时, 中止反应。 [0128] In the protection teams, three-necked flask Compound 6 (3.0g, 20mmol), i3- amino crotonic acid isopropyl ester (Compound 8) (2. 7g, 16. 6mmol), methyl acetoacetate (3. 50g, 30mol), Ac2O (2. 05g, 20mmol), conc. H2SO4 (0. 4g, 4mmol) and tert-butanol / ethanol (1: 1,65ml) mixing the liquid phase monitoring, when the remaining less than 3 compound 6 when 7% to terminate the reaction. 将反应物浓缩,残留物CH2Cl2溶解(55ml),水洗(45ml X幻,干燥,浓缩,油泵抽干,得6. 7g黄色泡末状固体。加乙醇QOml)加热溶解,搅拌析晶(过夜),得淡黄色粉末伊拉地平(4. 3g) (HPLC纯度> 99.8%,同系物杂质含量都小于0. ),产率66.8%。 The reaction was concentrated, the residue was dissolved CH2Cl2 (55 ml of), washed with water (45ml X phantom, dried, and concentrated to an oil pump drained to give a yellow foam end 6. 7g solid. Ethanol QOml) dissolved by heating with stirring crystallization (overnight) to give a pale yellow powder isradipine (4. 3g) (HPLC purity> 99.8%, impurity content of less than 0.1 are homologs), 66.8% yield.

[0129] 1H-WR(CDCl3) :7. 62-7. 60(lH,m),7. 31-7. 26(2H,m) ,5. 46(lH,s),4. 92-4. 86 (1H, m),3. 57 (3H, s),2. 32-2. 30 (6H, m),1. 21-1. 19 (3H, d),0. 95-0. 94 (3H, d) [0129] 1H-WR (CDCl3):...... 7 62-7 60 (lH, m), 7 31-7 26 (2H, m), 5 46 (lH, s), 4 92-4 . 86 (1H, m), 3. 57 (3H, s), 2. 32-2. 30 (6H, m), 1. 21-1. 19 (3H, d), 0. 95-0. 94 (3H, d)

[0130] 对比实施例1 [0130] Comparative Example 1

[0131] 伊拉地平(Isradipine)按美国专利US4466972方法制备: [0131] isradipine (Isradipine) prepared according to U.S. Patent US4466972 Method:

[0132] 在队保护下,三口瓶中将化合物6(3.0g,20mmol)、i3-氨基巴豆酸异丙脂(化合物8) (2. 7g, 16. 6mmol)、乙酰乙酸甲酯(3. 50g, 30mol)、Ac2O (2. 05g, 20mmol)、浓H2SO4 (0. 4g, 4mmol)和乙醇(65ml)混合搅拌,液相监测,当化合物6剩余少于3. 7%时,中止反应。 [0132] In the protection teams, three-necked flask Compound 6 (3.0g, 20mmol), i3- amino crotonic acid isopropyl ester (Compound 8) (2. 7g, 16. 6mmol), methyl acetoacetate (3. 50g, 30mol), Ac2O (2. 05g, 20mmol), conc. H2SO4 (0. 4g, 4mmol) and ethanol (65 ml of) were mixed and stirred, the liquid phase monitoring, when the compound is less than 3.7% residual 6, reaction was stopped. 将反应物浓缩,残留物CH2Cl2溶解(55ml),水洗(45ml X幻,干燥,浓缩,油泵抽干,得6. 3g黄色泡末状固体。加乙醇OOml)加热溶解,搅拌析晶(过夜),得淡黄色粉末伊拉地平(4. Ig) (HPLC纯度:99. 0%,同系物杂质含量都大于0.3% ),产率63. 7%。 The reaction was concentrated, the residue was dissolved CH2Cl2 (55 ml of), washed with water (45ml X phantom, dried, and concentrated to an oil pump drained to give a yellow foam end 6. 3g solid. Ethanol OOml) dissolved by heating with stirring crystallization (overnight) to give a pale yellow powder isradipine (4. Ig) (HPLC purity: 990% free of contaminants homologues greater than 0.3%), a yield of 63.7%.

[0133] 与对比实施例1相比(同系物杂质含量都大于0. 3% ),通过本发明实施例1-8所制备的伊拉地平中同系物杂质含量小于0. 1%。 [0133] Compared with Comparative Example 1 (homolog impurity content was greater than 0.3%), impurity content was isradipine homologues prepared in Examples 1-8 is less than 0.1% by the embodiment of the present invention.

[0134] 实施例10伊拉地平 [0134] Example 10 isradipine

[0135] 重复实施例8,不同点在于,用叔丁醇/乙醇(1 : 2,70ml)或叔丁醇/乙醇O : 1, 70ml)替换叔丁醇/乙醇(1 : 1,65ml) 0 [0135] Example 8 was repeated, except that, with tert-butanol / ethanol (1: 2,70ml) or tert-butanol / ethanol O: 1, 70ml) replacing tert-butanol / ethanol (1: 1,65ml) 0

[0136] 结果表明,伊拉地平的产率约62%,经测定同系物杂质含量小于0. 1%。 [0136] The results showed that the yield of about 62% isradipine, impurity content was determined homologues thereof is less than 0.1%.

[0137] 在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。 [0137] The present application are incorporated in all documents mentioned herein incorporated by reference, as if each reference were individually incorporated by reference above. 此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。 Furthermore, it should be understood that, after reading the above teachings of the present invention, those skilled in the art that various changes or modifications may be made to the present invention, and these equivalents also fall within the present application as defined in the appended claims scope.

Claims (9)

1. 一种伊拉地平的制备方法,其特征在于,包括步骤:(a)在惰性溶剂中,将2-氨基-3-甲基硝基苯进行氧化关环,形成4-甲基苯并呋咱氧化物,即式2化合物; 1. A method for preparation of isradipine, characterized by comprising the steps of: (a) in an inert solvent, 2-amino-3-methyl-nitrobenzene oxidation cyclized to form 4-methyl-benzo furazan oxide, i.e. a compound of formula 2;
Figure CN101768153BC00021
(b)在惰性溶剂中,使得4-甲基苯并呋咱氧化物还原,形成4-甲基苯并呋咱,即式3化合物; (B) in an inert solvent, such that the 4-methyl benzofurazan oxide reduction to form 4-methyl benzofurazan, i.e. the compound of formula 3;
Figure CN101768153BC00022
(c)在惰性溶剂中,对4-甲基苯并呋咱进行取代溴化,形成4-溴甲基苯并呋咱;(d)在惰性溶剂中,对4-溴甲基苯并呋咱进行水解,形成4-羟甲基苯并呋咱;(e)在惰性溶剂中,对4-羟甲基苯并呋咱进行氧化,形成4-甲醛基苯并呋咱;和(f)通过步骤(fl)或(f2),形成伊拉地平:(Π)在惰性溶剂中,将4-甲醛基苯并呋咱、β-氨基巴豆酸异丙脂与乙酰乙酸甲酯反应,形成伊拉地平;或者(f2)在惰性溶剂中,对4-甲醛基苯并呋咱进行脱水缩合,形成式7化合物,并与β-氨基巴豆酸异丙脂反应, (C) in an inert solvent, for 4-methyl benzofurazan substitution bromination, formation of 4-bromomethyl-benzofurazan; (d) in an inert solvent, for 4-bromomethyl benzofurazan we hydrolysis, and the formation of 4-hydroxymethyl benzene furazan; (e) in an inert solvent, for 4-hydroxymethyl benzene and furazan oxidized form 4 furazan formaldehyde and benzene; and (f) step (fl) or (F2), formed isradipine: (Π) in an inert solvent, benzene and formaldehyde 4- furazane, crotonic acid isopropyl [beta] aliphatic amino reacted with methyl acetoacetate to form Iraq isradipine; or (f2) in an inert solvent, benzene and formaldehyde of 4- furazan dehydration condensation to form a compound of formula 7, and reacted with an amino crotonic acid isopropyl β- fat,
Figure CN101768153BC00023
从而形成伊拉地平。 Thereby forming isradipine.
2.如权利要求1所述的方法,其特征在于,所述方法还包括步骤: (g)分离纯化步骤(f)中形成的伊拉地平。 2. The method according to claim 1, wherein said method further comprises the step of: isradipine (g) separation and purification step (f) is formed.
3.如权利要求2所述的方法,其特征在于,所述分离纯化采用结晶法。 The method according to claim 2, wherein said isolated purified by crystallization.
4.如权利要求1所述的方法,其特征在于,步骤(a)中在选自氢氧化钾或氢氧化钠的无机碱存在下进行。 4. The method according to claim 1, wherein step (a) is carried out in the presence of an inorganic base chosen from potassium hydroxide or sodium hydroxide.
5.如权利要求1所述的方法,其特征在于,步骤(a)中惰性溶剂选自甲醇、乙醇、异丙醇、水或上述溶剂的任意组合。 5. The method according to claim 1, wherein step (a) in an inert solvent selected from methanol, ethanol, isopropanol, water or any combination of the above solvents.
6.如权利要求1所述的方法,其特征在于,步骤(a)中在作为氧化剂的次氯酸盐存在下进行。 6. The method according to claim 1, wherein step (a) is carried out in the presence of hypochlorite as an oxidizing agent.
7.如权利要求1所述的方法,其特征在于,所述方法还包括以下一个或多个特征: 步骤(b)在选自盐酸羟胺、或Pd/c-吐的还原体系下进行;和/或步骤(d)在选自硫酸、盐酸、碳酸钙、碳酸钾、氢氧化锂、氢氧化钠、或氢氧化钾的水解试剂下进行;和/或OAc Λ O在步骤(e)中,使用的氧化剂选自: 7. The method according to claim 1, wherein said method further comprises one or more of the following features: the step (b) under reducing system is selected from hydroxylamine hydrochloride, or Pd / c- spit; and / or step (d) selected from sulfuric acid, hydrochloric acid, calcium carbonate, potassium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide or the hydrolytic agent is; and / or OAc Λ O in step (e), the the oxidizing agent used is selected from:
Figure CN101768153BC00031
或二氧化锰。 Or manganese dioxide.
8.如权利要求1所述的方法,其特征在于,步骤(fl)中的惰性溶剂选自:乙醇、异丙醇、叔丁醇或其组合;和/或步骤(Ώ)中的惰性溶剂选自:乙醇、异丙醇、叔丁醇或其任意两者的组合。 8. The method according to claim 1, wherein the step of (fl) in an inert solvent is selected from: ethanol, isopropanol, tert-butanol or combinations thereof; inert solvent and / or step (Ώ) of selected: a combination of isopropanol, any two ethanol, tert-butanol or the.
9.如权利要求1所述的方法,其特征在于,步骤(f2)在催化剂存在下进行,所述的催化剂选自浓盐酸、浓硫酸、和醋酐/浓硫酸。 9. The method according to claim 1, wherein the step (f2) in the presence of a catalyst, said catalyst is selected from concentrated hydrochloric acid, concentrated sulfuric acid and acetic anhydride / concentrated sulfuric acid.
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