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Publication numberCN101768153 B
Publication typeGrant
Application numberCN 200810205014
Publication date7 Dec 2011
Filing date30 Dec 2008
Priority date30 Dec 2008
Also published asCN101768153A
Publication number200810205014.1, CN 101768153 B, CN 101768153B, CN 200810205014, CN-B-101768153, CN101768153 B, CN101768153B, CN200810205014, CN200810205014.1
Inventors徐自奥, 李晓祥, 陈义朗, 韩硕
Applicant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
Export CitationBiBTeX, EndNote, RefMan
External Links: SIPO, Espacenet
制备高血压治疗药物伊拉地平的方法 The method of preparation of the treatment of hypertension drug isradipine translated from Chinese
CN 101768153 B
Abstract  translated from Chinese
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 present invention is a method comprising: (a) 2-Amino-3-methyl-nitrobenzene is oxidized ring closure to form 4-methyl benzofurazan oxide; (b) such that 4-methyl-benzo furazan oxide reduction to form 4-methyl benzofurazan; (c) 4-methyl-benzofurazan substitution bromination, formation of 4-bromomethyl-benzofurazan; (d) of 4- bromomethyl benzofurazan hydrolyzed to form 4-hydroxymethylbenzo furazanyl; (e) of 4- hydroxymethylbenzo furazan oxidized form 4-benzo furazanyl formaldehyde; and (f ) 4 benzene and formaldehyde furazan with isopropyl β- aminocrotonate grease, etc., 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。 High yield method of the invention, easy to operate, can be obtained with high purity isradipine.
Claims(9)  translated from Chinese
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; CLAIMS 1. A method for producing isradipine, characterized by comprising the steps of: (a) in an inert solvent, 2-amino-3-methyl-nitrobenzene is oxidized ring closure to form 4-methyl-benzo furazan oxide, 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 4-methyl benzofurazan oxide reduction to form 4-methyl benzofurazan, i.e. a 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-benzofuran we subjected to hydrolysis, to form 4-hydroxymethylbenzo furazanyl; (e) in an inert solvent, for 4- hydroxymethylbenzo furazan oxidized form 4-benzo furazanyl formaldehyde; and (f) step (fl) or (f2), the formation of isradipine: (Π) in an inert solvent, benzene and formaldehyde 4- furazan, β- aminocrotonate isopropyl resin is reacted with methyl acetoacetate to form Iraq Pull horizon; or (f2) in an inert solvent, benzene and formaldehyde of 4- furazan dehydration condensation, to form a compound of formula 7, and reacted with β- amino crotonic acid isopropyl ester,
Figure CN101768153BC00023
从而形成伊拉地平。 Thus 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, characterized in that said method further comprises the step of: (g) separation and purification step (f) formed isradipine.
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。 3. The method according to claim, characterized in that said isolated and purified using 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 selected 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 of 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。 The method as claimed in one of the preceding claims, 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, characterized in that said method further comprises one or more of the following characteristics: step (b) carried out at a selected hydroxylamine hydrochloride, or Pd / c- spit reduction system; and / or step (d) selected from sulfuric acid, hydrochloric acid, calcium carbonate, potassium carbonate, lithium hydroxide, sodium hydroxide, or potassium hydroxide hydrolysis reagent; and / or OAc Λ O in step (e), the an oxidizing agent 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 of claim 1, wherein step (fl) in an inert solvent is selected from: ethanol, isopropanol, tert-butanol, or combinations thereof; and / or step (Ώ) in an inert solvent is selected from: a combination of ethanol, isopropanol, tert-butanol, or of any two.
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 of claim 1, wherein the step (f2) in the presence of a catalyst, wherein the catalyst is selected from concentrated hydrochloric acid, concentrated sulfuric acid, and acetic anhydride / concentrated sulfuric acid.
Description  translated from Chinese

制备高血压治疗药物伊拉地平的方法 The method of preparation of the treatment of hypertension drug 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 a method for preparing a compound, and more particularly relates to drug isradipine (Isradipine) preparation.

背景技术 BACKGROUND

[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 was 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 dilation of blood vessels, reducing peripheral vascular resistance and increase coronary blood flow, improve myocardial oxygen function and lower blood pressure goal.

[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 has strong vasodilator effect without cardiac inhibition, hardly cause 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-atherosclerotic effect, to maintain or restore blood flow in the left ventricle through the endothelium to prevent ischemic damage, improve angina and congestive heart failure patients exercise, in the treatment of hypertension, has 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, has a diuretic effect, can expand the renal artery output and output arteries, reducing the renal capillary pressure, has a protective effect on the kidney.

[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 Benzofurazan dihydropyridine class of compounds, the synthesis is more complex, especially in the purified material is 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] US Patent US4466972 and PCT application W02005 / 00437 respectively disclose two synthetic isradipine

方法。 Methods. 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 product prepared by conventional methods contain a certain amount of a formula homologues impurity, the impurity is structured as follows:

[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 as 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 homologue of the impurities with isradipine extremely difficult to separate, resulting in ineffective purification 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] In addition, conventional processes for preparing key intermediates involved in 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 method of the key intermediates is still unsatisfactory. 例如,中国专利申请200510125267(公开号CN1847233A)中 For example, the Chinese Patent 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 4-methyl benzofurazan preparation methods, the 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] It is clear that the above method steps long, dangerous operation, poor control, and 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, efficient and simple isradipine important intermediates for preparing 4-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 to operate 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] In the second object of the present invention is to provide a high yield, simple preparation method of drug isradipine intermediates.

[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] Another object of the present invention is to provide a three-yield, high-purity preparation of β - aminocrotonate isopropyl resin 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 process 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 is oxidized ring closure to 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 4-methyl benzofurazan oxide reduction to form 4-methyl benzofurazan, i.e. a 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, to form 4-hydroxymethylbenzo furazanyl;

[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- hydroxymethylbenzo furazan oxidized form 4-benzo furazanyl formaldehyde; 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), the formation of isradipine:

[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- furazan, β- amino crotonic acid 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, and with the β - amino crotonic acid isopropyl ester (Compound 8) Reaction,

[0028] [0028]

Figure CN101768153BD00061

[0029] 从而形成伊拉地平。 [0029] to form 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 steps of:

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

[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 and purified using 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 from ethanol, to thereby 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] In another preferred embodiment, step (a) is carried out in the presence of potassium hydroxide or sodium hydroxide is selected from an inorganic base.

[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 above solvents, more preferably is 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] In another preferred embodiment, step (a) is carried out in the presence of hypochlorite as an oxidizing agent.

[0037] 在另一优选例中,步骤(a)的反应温度为-20-40C。 [0037] In another preferred embodiment, step (a) the reaction temperature is -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 in, or Pd / C-H2 system for reduction; 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) in the selected 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 combinations 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 an inert solvent is a mixed solvent of t-butanol and ethanol, wherein the 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 inert solvents include: a combination of ethanol, isopropanol, tert-butanol, or of any two.

[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 the 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] In another preferred embodiment, step (Ώ) in the presence of a catalyst, said catalyst comprising of 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 comprising the step (h): The isolated isradipine mixed with a pharmaceutically acceptable carrier, thereby preparing a pharmaceutical composition 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 used 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 in-depth and extensive research to improve the preparation of isradipine, especially formaldehyde, benzene and its intermediate 4-preparation process we furosemide, which can efficiently and easily produce high purity Iraq Pull horizon. 在此基础上完成了本发明。 On this basis, 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 of Chinese alias includes isradipine, easy to pull horizon, guided along the veins. 其外文名包括Isradipine, PN-200-110、COMIR、PRESCAL、DYNACIRC, Vascal。 Its English name include 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 the compounds of formula I, the compounds may further comprise a pharmaceutically acceptable salt of formula I.

[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 (e.g. solvent, the amount of the compound used, reaction temperature, 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0C〜 100c,优选0C〜80C )下进行。 [0053] In the process of the present invention, each reaction is generally in an inert solvent, at room temperature to the reflux temperature (e.g. 0 C~ 100 c, preferably 0 C~80 C) carried out. 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 usually from 0.1 hours -60 hours, preferably 0. 5-48 hours.

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

[0055] [0055]

Figure CN101768153BD00081

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

[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 by oxidation and ring closure to form 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] oxidizing agent used is a 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] base is not particularly limited, and potassium hydroxide, inorganic bases such as sodium hydroxide, preferably potassium hydroxide.

[0061] 反应温度没有特别限制,通常为-20-40C,较佳地为10-25C。 [0061] The reaction temperature is not particularly limited and is usually -20-40 C, preferably to 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, 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, the inert solvent may be used (reaction system) include methanol, ethanol, isopropanol, or any combination of a 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] can be used to restore the system hydroxylamine hydrochloride / base, or Pd / C-H2 as the reduction 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, an inert solvent, preferably toluene, and the use of trihydrocarbyl phosphine as a reducing agent, preferably triphenylphosphine.

8[0067] 反应温度没有特别限制,通常为0-100C,较佳地为75_90C。 8 [0067] The reaction temperature is not particularly limited and is usually 0-100 C, preferably for 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). Preparation of compound 6 from compound 3 may be a conventional method, for example, according to the literature Eur. J.Med. Chem (1996) 31, 3-10 embodiment.

[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 substituted bromination reaction, the formation of 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, the inert solvent may be used include chlorobenzene, carbon tetrachloride and other inert solvents.

[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] brominating agent is not particularly limited, and may be conventional in the art of bromine, bromosuccinimide (NBQ and other brominating reagents. A preferred brominating agent is 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] available initiators include (but are not limited to): benzoyl peroxide or azobis butyronitrile, preferably benzoyl peroxide.

[0074] 反应温度没有特别限制,通常为25_100C,较佳地为70-90C。 [0074] The reaction temperature is not particularly limited and is usually 25_100 C, preferably to 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 4-hydroxymethylbenzo 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 above-mentioned 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 hydrolysis reagent 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。 A preferred hydrolysis agent is calcium carbonate.

[0079] 反应温度没有特别限制,通常为50-100C,优选在回流温度下进行。 [0079] The reaction temperature is not particularly limited, 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). 5 by oxidation reaction of the compound, form 4-benzo furazanyl formaldehyde (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, the 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10-100C,较佳地为50-70C。 [0084] The reaction temperature is not particularly limited, is usually 10-100 C, preferably to 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 for 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), the formation of isradipine:

[0087] (f 1)将化合物6经脱水缩合得到化合物7。 [0087] (f 1) Compound 6 obtained by dehydration condensation of compound 7. 该脱水缩合反应宜采用醋酐-硫酸为催化剂。 The dehydration condensation reaction should adopt acetic anhydride - 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, by reacting the 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] Then, the compound 7 with compound 8 obtained by the condensation reaction of compound 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 ethanol, isopropanol, tert-butanol, or of any two. 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 the 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 as nitrogen, argon and other inert gas protection.

[0092] 反应温度没有特别限制,通常为5_70C,较佳地为15_25C。 [0092] The reaction temperature is not particularly limited and is usually 5_70 C, preferably for 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 for a reaction time of 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 8-24 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) and methyl acetoacetate-pot reaction, the formation of isradipine.

[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 ethanol, isopropanol, tert-butanol, or of any two. 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 the 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 as nitrogen, argon and other inert gas protection.

[0097] 反应温度没有特别限制,通常为5_70C,较佳地为15_25C。 [0097] The reaction temperature is not particularly limited and is usually 5_70 C, preferably for 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 for a reaction time of 2-36 hours, more preferably for 8-24 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 process requires the catalytic reaction, the catalyst may be employed are concentrated hydrochloric acid, concentrated sulfuric acid, acetic anhydride / concentrated sulfuric acid, preferably acetic anhydride / concentrated sulfuric acid system.

[0100] 本发明方法的主要优点在于: [0100] The main advantages of the present invention is a method comprising:

[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。 Synthesis of [0101] (a) Compound 2, by oxidation cyclization method, the disadvantage of using azide reaction to abandon the original method.

[0102] (b)化合物6的合成,工艺稳定,产品质量稳定。 [0102] (b) Synthesis of Compound 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) synthesis process using t-butanol / ethanol mixture system as a solvent, effectively out of the final product compound impurities homologues, 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] below 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 merely illustrative of 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 case does not indicate the specific conditions of the following examples, generally in accordance with conventional conditions, or conditions in accordance with the manufacturer's recommendations.

[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, the melting point with MEL-TEMP melting point apparatus, a thermometer and are uncorrected; IH-NMR with a Varian Mercury 400 NMR spectrometer records, chemical shifts δ (ppm) represented; unspecified 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 elemental analyzer type; Mass with AgilentllOO LC-MS mass spectrometry; 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] Under IL three-necked round bottom flask was added compound 1 8g, 0. 15mol), followed by addition of KOH (IOg) in ethanol OOOml), was added dropwise under ice cooling Natno solution (IOOml), to continue the addition was complete the ice-water bath 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, the system was added CH2Cl2 (150ml) was stirred, insolubles were filtered off, the filtrate was separated and the organic phase was dried over anhydrous Na2SO4, and concentrated. 得20.77g粗产物。 The crude product was 20.77g. 加乙酸乙酯重结晶得15. 5g黄色针状晶体,产率68.9%。 Ethyl acetate was added to give 15. 5g recrystallized 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-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) 500mL three-necked round bottom flask was added compound 1 (30. 4g, 0. 2mol), water (80mL) and concentrated hydrochloric acid (45mL), ice-cooled solution of sodium nitrite (14. 5g , 0. 21mol) in water (50mL), After the addition, heat stirred for 1 hour.

[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), addition is complete, heat stirred for 1 hour, filtration, filter cake 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) during the resulting cake was fitted into toluene (60mL) of three round-bottomed flask was slowly warmed to reflux, refluxed for 5 hours, the system was cooled down 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OC,然后边搅拌边加入K0IK23. 4g,417. 9mmol)的水溶液(150ml),加完后,加热回流。 34- methyl-benzo [0112] Example furazan (Compound 3) [0113] Compound 2 (17. 4g, 116. Ommo 1) was dissolved in ethanol QOOml), force Jie into NH2OH HCl (9. 7g , 139. 6mmol) of an aqueous solution, the mixture was cooled to O C, then added with stirring K0IK23. 4g, 417. 9mmol) in water (150ml), addition is complete, heat to reflux. TLC板监测。 TLC plates monitored. 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。 Completion of the reaction, the reaction was cooled to room temperature, and extracted with n-hexane (400ml X 2,200ml X 2), n-hexane phase was washed with water (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] 44- bromomethylbenzo Example furazan (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80-85C反应,反应完毕,体系降至40C, 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) was dissolved in carbon tetrachloride (150ml) then added NBS (23. 5g, 132mmol) and Bz2O2 (0. 29g, 1. 2mmol), the mixture was warmed to 80 -85 C the reaction, the reaction is complete, 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 forming a milky yellow powdery crystals, i.e., 4-bromomethyl-benzofurazan (18.47g). 产率为72%。 The yield was 72%. (HPLC测定,纯度为88% ) (HPLC measured purity of 88%)

[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 54- hydroxymethylbenzo embodiment and furazanyl (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 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, TLC plate reaction was monitored. 反应完毕,过滤, 浓缩。 Completion of the reaction, 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) dissolved with stirring the solution was separated, 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., 4- hydroxymethylbenzo furazan (6. 68g), HPLC assay 98.7% purity, 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] 64- formaldehyde and benzene embodiment furazan (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60C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- formaldehyde benzo furazanyl 6 (5. 9g), a yield of 92.0%.

[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) [0124] Example 7 β - amino crotonic acid isopropyl ester (Compound 8)

[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110-120C 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 remainder is less than 3 Compound 6 When the 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 (55ml), washed with water (45ml X Magic, dried, concentrated, drain pump, to give 6. 7g end yellow foam-like solid. Ethanol QOml) dissolved by heating, stirring crystallization (overnight) to give a pale yellow powder isradipine (4. 3g) (HPLC purity> 99.8%, impurity content homologues thereof are less than 0.1), yield 66.8%.

[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 by the United States Patent US4466972:

[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 (65ml) were mixed and stirred, the liquid phase monitoring, when the compound 6 is less than 3.7% remaining, the reaction is 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 (55ml), washed with water (45ml X Magic, dried, concentrated, drain pump, to give 6. 3g end yellow foam-like solid. Ethanol OOml) was dissolved by heating, stirring crystallization (overnight) to give a pale yellow powder isradipine (4. Ig) (HPLC purity: 99.0%, impurity content was 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%), was the content of impurities isradipine homologs prepared in Example 1-8 is less than 0.1% by the embodiment of the present invention.

[0134] 实施例10伊拉地平 [0134] The 10 cases of 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 t-butanol / ethanol (1: 2,70ml) or t-butanol / ethanol O: 1, 70ml) replaces t-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 isradipine yield of about 62%, the test substance impurity content of less than 0.1% homologous.

[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] All documents are referenced in the present invention is referred to herein as a reference, as if each individual document was cited as a reference that. 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。 It should also be understood that, after reading the above teachings of the present invention, those skilled in the art may make various modifications of the present invention or modifications, and these equivalents fall as defined in the appended claims the scope of claims of the present application.

Patent Citations
Cited PatentFiling datePublication dateApplicantTitle
CN1847233A21 Nov 200518 Oct 2006圣玛精细化工有限责任公司Method for preparing 4-formoxylbenzofuran
US446697219 Mar 198221 Aug 1984Sandoz Ltd.Benzoxadiazoles and benzothiadiazoles, their preparation and pharmaceutical compositions containing them
WO2005005437A115 Jul 200420 Jan 2005Shasun Chemicals And Drugs LimitedAn improved process for the manufacture of isradipine.
Non-Patent Citations
Reference
1Paymaneh Y.F. et al..Inhibition of Nucleoside Transport By New Analogues of Nitrobenzylthioinosine.《Bioorganic&Medicinal Chemistry》.2003,第11卷第899-908.
Referenced by
Citing PatentFiling datePublication dateApplicantTitle
CN103613584B *27 Nov 201327 Apr 2016沈阳药科大学一种伊拉地平合成产物后处理的方法
Classifications
International ClassificationC07D413/04, A61K31/4439, A61P9/12
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7 Dec 2011C14Granted