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Preparation method for Ezetimibe

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CN102993077A
CN102993077A CN 201210549943 CN201210549943A CN102993077A CN 102993077 A CN102993077 A CN 102993077A CN 201210549943 CN201210549943 CN 201210549943 CN 201210549943 A CN201210549943 A CN 201210549943A CN 102993077 A CN102993077 A CN 102993077A
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preparation
method
ezetimibe
compound
invention
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CN 201210549943
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CN102993077B (en )
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于振鹏
王国平
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上海现代制药股份有限公司
上海现代制药海门有限公司
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Abstract

The invention relates to the technical field of preparation methods for Ezetimibe. The preparation method for Ezetimibe disclosed by the invention comprises the following steps of: preparing via SHI oxidation reaction on the basis of an olefin compound to obtain a new intermediate, namely, an epoxy compound 1, and performing loop opening and hydrogenation on the compound 1 to prepare a high-chiral-selectivity Ezetimibe product. Via the preparation method, an expensive and unstable chiral catalyst is avoided, and replaced by a cheap and easily-gotten fructose derivative, so that the preparation method is economic, efficient, cost-saving, simple and practical in aftertreatment, and suitable for industrialized production.

Description

一种依折麦布的制备方法技术领域[0001] 本发明涉及依折麦布制备方法技术领域。 One kind of ezetimibe TECHNICAL FIELD ezetimibe preparation involves BACKGROUND [0001] present invention. 背景技术[0002] 心脑血管疾病是当前危害人类生命和健康最严重的病症,是中老年人的常见病和多发病。 [0002] Cardiovascular disease is the most serious condition endanger human life and health, is a common disease in the elderly. 在许多国家是发病率和死亡率的首位。 In many countries, it is the first morbidity and mortality. 动脉粥样硬化是许多心脑血管疾病的基础, 大量的实验和临床资料证明动脉粥样硬化和血脂代谢的异常密切相关。 Atherosclerosis is the basis of many cardiovascular and cerebrovascular diseases, a large number of experimental and clinical data to prove atherosclerosis and lipid metabolism disorder is associated. 因此,调血脂药物成为当前新药研究的重要领域。 Therefore, lipid regulating drugs has become an important area of ​​current drug research. [0003] 通过前瞻性、随即和对照的临床研究,已经证明一些他汀类药物可以减少动脉粥样硬化和冠心病的发生,降低了冠心病所致的死亡率,降低了心肌梗死的发生率,而且进一步证明降至药物的治疗可以减少粥样硬化斑块内脂质的含量。 [0003] prospective, controlled clinical study, and then have to prove some of statins may reduce the incidence of atherosclerosis and coronary heart disease, coronary heart disease due to reduced mortality, reduced the incidence of myocardial infarction, and further evidence of drug therapy can be reduced to reduce the content of atherosclerotic plaque lipids. 加固纤维脂而稳定斑块,减少斑块破裂而引发的心肌梗死和脑梗死等等严重事件。 Fat and fiber reinforced plaque stabilization, reduction of myocardial infarction and cerebral infarction and so on serious incidents caused by plaque rupture. 此外,调血脂药还可恢复受损血管内皮细胞的功能,加强纤溶性和防止血栓形成,并且延缓人的动脉粥样硬化的进展和消退已形成的斑块。 In addition, lipid regulators may restore damaged vascular endothelial cell function, and to strengthen the fibrinolytic prevent thrombosis, plaque and delaying people's progression of atherosclerosis and regression of already formed. 因此,积极使用调血脂药物治疗是减轻动脉粥样硬化和减少冠心病的发生的重要措施。 Therefore, the active use of lipid regulating drugs is to reduce atherosclerosis and an important measure to reduce the occurrence of coronary heart disease. [0004]目前临床和常用的调节血脂的药物品种较多,例如HMG-CoA还原酶抑制剂类,苯氧芳酸类,离子交换树脂或胆酸螯合剂,烟酸类以及其他调血脂类药物。 [0004] commonly used in clinical and lipid regulating drugs more varieties, such as HMG-CoA reductase inhibitors, phenoxy aromatic acids, ion exchange resins, or bile acid sequestrants, nicotinic acid and other lipid regulating drugs . 其中依折麦布(结构式如下)作为选择性抑制胆固醇吸收的新型调节血脂药物,表现出良好的效果。 Wherein ezetimibe (structural formula shown below) as a novel lipid regulating drugs that selectively inhibit cholesterol absorption, showing good results. [0005] [0005]

Figure CN102993077AD00051

[0006] 合成依折麦布的方法有很多,但是难点在于分子中手性S-羟基的构建。 [0006] There are many synthesis of ezetimibe according to the method, but the difficulty is to construct the molecule chiral S- hydroxy group. 目前使用最广泛的方法就是先构建潜手性中间体芳酮(参考专利文献:CN1131416,W02006137080, W02007119106,W02007120824,W02009067960 等)或芳酮衍生物(参考专利文献:W00034240, W02005049592, W0200506120等),通过不对称氢化还原构建s_羟基。 The most widely used method is to construct intermediate prochiral aromatic ketones (refer to Patent Document: CN1131416, W02006137080, W02007119106, W02007120824, W02009067960 and the like), or an aryl ketone derivative (refer to Patent Literature: W00034240, W02005049592, W0200506120, etc.), s_ constructed by asymmetric reduction hydroxyhydrocinnamate. [0007] [0007]

Figure CN102993077AD00052

[0008] 现存不对称氢化的方法及不足:1.用含有过渡金属Ru等的均相催化齐U,回收困难,造成成本增加,并且会导致重金属污染(如专利文献EP1953140,W02007144780, W02007/120824等公开的方法);2.用(_)_ 二异松菔基氯硼烷(专利文献W02005049592和W02005066120公开的方法)或R-2-甲基-CBS-恶唑硼烷(专利文献W02008/032338, W02009067960等公开的方法)为手性催化剂,虽然还原的de值非常理想,但是存在着催化剂不稳定,价格昂贵,反应条件苛刻,反应操作繁琐等不足。 [0008] The existing method for the asymmetric hydrogenation and disadvantages: 1 with a homogeneous transition metal catalyst comprising Ru, Qi U, recycling is difficult, resulting in an increase in cost, and will lead to heavy metal contamination (e.g. Patent Document EP1953140, W02007144780, W02007 / 120824 and other methods disclosed); 2. with (_) _ diisopropyl loose turnip borane chloride (Patent documents W02005049592 and W02005066120 methods disclosed) or R-2- methyl -CBS- oxazaborolidine (Patent Document W02008 / 032338, W02009067960 and other methods disclosed herein) of a chiral catalyst, although reduced de ideal value, but there is a catalyst unstable, expensive, harsh reaction conditions, such as lack of cumbersome reaction operations.

[0009] SHI氧化是近年来不对称环氧化领域出现的新技术,以果糖衍生物为手性催化剂,经济高效将烯烃化合物氧化成高手性选择性的环氧化物。 [0009] SHI is the oxidation of asymmetric epoxidation of new technologies in the field appear to fructose derivative is chiral catalysts, cost-effective oxidation of the olefin compound master epoxide selectivity. 另外,果糖来源广泛,价格便宜,催化剂合成便捷,从而引起越来越多人们的关注。 In addition, a wide range of sources of fructose, cheap, convenient synthesis catalyst, causing more and more people's attention.

发明内容 SUMMARY

[0010] 本发明的目的就是解决现有技术的上述问题,提供一种新的依折麦布制备方法,跟现有技术相比,本发明方法简单方便,选择性高,毒性低,适于工业化生产。 [0010] The object of the present invention is to solve the aforementioned problems of the prior art, to provide a new method for preparing ezetimibe, compared with the prior art, the method of the present invention is simple and convenient, high selectivity, low toxicity, suitable for Industrial production.

·[0011] 为达上述目的,本发明采取的技术方案如下: * [0011] To achieve the above object, the present invention takes the following technical solutions:

[0012] 依折麦布的制备方法,包括如下步骤: [0012] By preparing ezetimibe comprising the steps of:

[0013] I)溶剂中,将化合物I加入硼氢化碱金属盐和二苯联硒反应体系,再加入碱和氧化剂反应即可得目标产物化合物4 : [0013] I) a solvent, the compound I and the alkali metal borohydride is added diphenyl diselenide reaction system, adding a base and an oxidizing agent to obtain the target product Compound 4:

[0014] [0014]

Figure CN102993077AD00061

[0015] R1为氢原子、芳基甲基、单取代或多取代的芳基甲基、取代的硅烷基或四氢-2Η-吡喃基,优选苄基。 [0015] R1 is a hydrogen atom, an aryl group, a substituted or mono-substituted aryl group, a substituted silyl or tetrahydropyran -2Η- pyranyl, preferably benzyl. 其中,芳基甲基优选苄基或三苯甲基;单取代或多取代的芳基甲基中所述的取代基为卤素、硝基、含C1-C6的烷基取代基、含C1-C6的烷氧基取代基或含C6-C10的芳基取代基,优选氯原子、氟原子、硝基、甲氧基或苯基;取代的硅烷基中所述的取代基为含C1-C6的烷基取代基、含c6-cl0的芳基取代基。 Wherein the arylmethyl group is preferably a benzyl or trityl group; a substituted or mono-substituted aryl-methyl group in the substituent is halo, nitro, C1-C6 alkyl group having a substituent containing C1- substituted C6 alkoxy group or C6-C10 aryl-containing substituent, preferably a chlorine atom, a fluorine atom, a nitro group, a methoxy group or a phenyl group; a substituted silyl group in the substituent group containing a C1-C6 substituted alkyl group, an aryl group having a substituent group c6-cl0.

[0016] 2 )将化合物4氢化还原得依折麦布: [0016] 2) Compound 4 may, in accordance hydrogenation ezetimibe:

[0017] [0017]

Figure CN102993077AD00071

[0018] 上述依折麦布的制备方法,步骤I)中化合物4的制备方法,优选的技术方案是,原料化合物I加入后24小时内再加入碱和氧化剂,反应完全。 [0018] The method for preparing ezetimibe ezetimibe, preparation 4) in step I compounds, preferred technical solution, the starting compound I is added a base and an oxidizing agent was added within 24 hours, the reaction was complete.

[0019] 上述依折麦布的制备方法,步骤I)中化合物4的制备方法,所述的溶剂优选C1-C4的醇类溶剂。 [0019] The method for preparing ezetimibe ezetimibe, preparation 4) in the compound of step I, the solvent is preferably a C1-C4 alcoholic solvent.

[0020] 上述依折麦布的制备方法,步骤I)中化合物4的制备方法,硼氢化碱金属盐优选硼氢化钠,且硼氢化钠与二苯联硒的摩尔比为O. 5-1 :1,优选O. 55 :1。 [0020] The ezetimibe preparation of ezetimibe, the preparation method 4, an alkali metal borohydride, preferably sodium borohydride) in the compound of step I, and the molar ratio of sodium borohydride to diphenyl diselenide is O. 5-1 : 1, preferably O. 55: 1.

[0021] 上述依折麦布的制备方法,步骤I)中化合物4的制备方法,反应所用的碱为碳酸氢钠、碳酸氢钾、碳酸钠、碳酸钾、氢氧化钠、氢氧化钾等碱金属盐或含有Cl-Cio的有机含氮碱,如吡啶、吡咯、三乙胺、二乙胺、二丙胺或二异丙基乙胺等;优选为碳酸氢钠或吡啶。 [0021] The production method of ezetimibe ezetimibe, prepared in step 4 I) compound, used in the reaction base is sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, alkali or a metal salt containing Cl-Cio organic nitrogen bases such as pyridine, pyrrole, triethylamine, diethylamine, dipropylamine, or diisopropylethylamine and the like; preferably sodium bicarbonate or pyridine.

[0022] 上述依折麦布的制备方法,步骤I)中化合物4的制备方法,氧化剂优选为高碘酸钠或双氧水。 [0022] The method for preparing ezetimibe ezetimibe, preparation 4) in the compound of step I, the oxidizing agent is preferably hydrogen peroxide or sodium periodate.

[0023] 上述依折麦布的制备方法,步骤I)中化合物4的制备方法,加入碱和氧化剂以后反应温度优选为0°c -780C,更优选在20-60°C。 [0023] The method for preparing ezetimibe ezetimibe, preparation 4) in the compound of step I, after addition of a base and an oxidizing agent The reaction temperature is preferably 0 ° c -780C, more preferably at 20-60 ° C.

[0024] 上述依折麦布的制备方法,步骤2)的氢化还原用现有的各种成熟技术方法均可。 [0024] The ezetimibe preparation of ezetimibe, step 2) using conventional hydride reduction may be various methods mature technology.

[0025] 进一步的,上述依折麦布的制备方法,化合物I的制备选用如下的方法: [0025] Further, the above-described method for preparing ezetimibe ezetimibe prepared following the method of selection of compounds I:

[0026] 式I化合物的制备方法,该方法是:在溶剂中,化合物2在氧化剂的作用下反应生成目标化合物1: [0026] The method of preparing the compounds of formula I, which is: in a solvent, compound 2 generates target compound under the action of an oxidizing agent in the reaction:

[0027] [0027]

Figure CN102993077AD00072

[0028] 上述式I化合物的制备方法,所述氧化剂可选用间氯过氧苯甲酸、过氧乙酸、过氧化叔丁醇、双氧水、过硫酸氢钾复合盐(商品名0Χ0ΝΕ)等过氧化物,优选间氯过氧苯甲酸。 [0028] The method of preparing the compounds of formula I, the oxidant can be selected inter-chloroperbenzoic acid, peracetic acid, tert-butyl alcohol, hydrogen peroxide, potassium persulfate salt compound (trade name 0Χ0ΝΕ) peroxide and the like , preferably m-chloroperbenzoic acid. 氧化剂选用过硫酸氢钾复合盐(商品名0Χ0ΝΕ)时,摩尔比OXONE :化合物2=1-5 :1优选2倍摩尔量。 Oxidant selected composite salt Oxone (trade name 0Χ0ΝΕ), the molar ratio of OXONE: 2 = compound 1-5: 1 preferably 2-fold molar amount. 氧化剂选用间氯过氧苯甲酸、过氧乙酸、过氧化叔丁醇或双氧水时,用量为化合物2的1-3倍摩尔量,优选1. 3倍摩尔量。 Selection between the oxidizing agent m-chloroperbenzoic acid, peracetic acid, when the hydrogen peroxide or peroxide, t-butanol, in an amount of 1-3 times the molar amount of the compound 2, preferably 1.3-fold molar amount.

[0029] 式I化合物的制备方法,溶剂为能促进反应进行的合适溶剂即可,如Cl-ClO的卤代烃、脂肪烃,Cl-ClO的腈基取代的烃类、醚类、水、水的缓冲溶液或任意的混合溶剂等。 [0029] The method of preparing the compounds of Formula I, suitable solvents to facilitate the reaction could be solvents, such as Cl-ClO halogenated hydrocarbons, aliphatic hydrocarbons, Cl-ClO nitrile-substituted hydrocarbons, ethers, water, any buffer, or a mixed solvent of water and the like. excellent

选二氯甲烷、水的缓冲溶液、乙腈、二丙二醇二甲醚、二丙二醇二甲醚与乙腈的混合溶剂。 Is selected from methylene chloride, water, a buffer solution, acetonitrile, dipropylene glycol dimethyl ether, dipropylene glycol dimethyl ether mixed solvent and acetonitrile. 当选用二丙二醇二甲醚与乙腈的混合溶剂时,二丙二醇二甲醚与乙腈的摩尔比为0.01-10 :1,优选1:2。 When a mixed solvent of dipropylene glycol dimethyl ether and acetonitrile elected by the molar ratio of dipropylene glycol dimethyl ether and acetonitrile from 0.01 to 10: 1, preferably 1: 2.

[0030] 上述式I化合物的制备方法,另一方法是:采用SHI氧化技术氧化式2化合物得到目标化合物I。 [0030] The method of preparing the compounds of formula I, another method is: The compound of formula 2 SHI oxide oxidation to give target compound I. 其具体步骤包括:将式I化合物溶解于溶剂中,加入相转移催化剂和手性催化剂,同时加入氧化剂和碱,反应完全即可。 Specific steps include: a compound of Formula I is dissolved in a solvent, adding a phase transfer catalyst and a chiral catalyst while adding an oxidizing agent and a base, to complete the reaction.

[0031] 采用SHI氧化技术制备式I化合物的方法时,所使用的手性催化剂为下述的通式7、8、9所示,用量为式I化合物O. 1-2倍的摩尔量,优选O. 3倍的摩尔量: [0031] When using a compound of formula I the SHI oxidation, chiral catalyst used is shown by the following formula 7,8,9, an amount of a compound of formula I O. 1-2 fold molar amount, preferably O. 3-fold molar amount of:

[0032] [0032]

Figure CN102993077AD00081

[0033] R2,R3,R4,R5SC1-C6的烷基,优选甲基;R6为含有Cl-ClO的烷基或被取代的烷基、 [0033] R2, R3, R4, R5SC1-C6 alkyl group, preferably methyl; R6 is a Cl-ClO alkyl group containing or substituted alkyl,

酰基或被取代的酰基、烷氧基或被取代的烷氧基,优选叔丁氧羰基;R7、R8为C1-C6的酰基或被取代的酰基,优选乙酰基。 Acyl or substituted acyl, alkoxy or substituted alkoxy group, preferably t-butoxycarbonyl; R7, R8 is C1-C6 acyl or substituted acyl group, preferably acetyl.

[0034] 采用SHI氧化技术制备式I化合物的方法时,氧化剂优选使用过硫酸氢钾复合盐(商品名OXONE), OXONE 可配成O. 05-0. 4g/ml 的KT4M Na2 (EDTA)水溶液,优选O. 15g/ml。 [0034] When using a compound of formula I SHI oxidation, the oxidizing agent used is preferably potassium hydrogen sulfate salt compound (trade name OXONE), OXONE may be formulated KT4M Na2 O. 05-0. 4g / ml of (EDTA) aqueous solution , preferably O. 15g / ml.

[0035] 采用SHI氧化技术制备式I化合物的方法时,溶剂选自水或水的缓冲溶液、Cl-ClO腈基取代的烃类、醚类或混合溶剂,优选(O. 05M硼酸钠溶解于10_4M Na2 (EDTA)水溶液)硼酸钠缓冲溶液和乙腈-二丙二醇二甲醚(1:2)的混合溶液。 [0035] When using a compound of formula I SHI oxidation, the solvent is selected from water, a buffer solution or water, Cl-ClO nitrile-substituted hydrocarbons, ethers or a mixed solvent, preferably sodium (O. 05M acid were dissolved in 10_4M Na2 (EDTA) aqueous solution) of sodium borate buffer solution and acetonitrile - dipropylene glycol dimethyl ether (1: 2) mixed solution.

[0036] 采用SHI氧化技术制备式I化合物的方法时,溶剂中要加入碱溶液和缓冲溶液维持反应体系pH=7-14,更优选pH=10-12。 [0036] When using a compound of formula I SHI oxidation technique, a solvent and an alkali solution was added to maintain the reaction system, a buffer solution pH = 7-14, more preferably pH = 10-12. 碱选自碳酸根、碳酸氢根等碱金属盐,优选碳酸钾。 Base is selected from carbonate, bicarbonate, alkali metal, preferably potassium carbonate. 配成O. 04-04g/ml的水溶液使用,优选O. 14g/ml。 Aqueous dubbed O. 04-04g / ml is used, preferably O. 14g / ml.

[0037] 采用SHI氧化技术制备式I化合物的方法时,相转移催化剂为冠醚或四烷基取代的季铵盐类,优选四丁基硫酸氢铵。 [0037] When using a compound of formula I SHI oxidation, phase transfer catalyst is a crown ether or tetraalkyl-substituted quaternary ammonium salts, preferably tetrabutylammonium hydrogen sulfate. 四丁基硫酸氢铵优选为O. 04-2倍的摩尔量,最优选O. 4倍的摩尔量。 Tetrabutylammonium hydrogen sulfate is preferably O. 04-2 times the molar amount, and most preferably 4 times the molar amount O..

[0038] 采用SHI氧化技术制备式I化合物的方法时,反应温度在-30-50 °C,优选-20-20°C,最优选(TC。 When [0038] The process for preparing compounds of formula I SHI oxidation, the reaction temperature is -30-50 ° C, preferably -20-20 ° C, most preferably (TC.

[0039] 在不违背本领域常识的基础上,上述各优选条件,可任意组合,即得本发明各较佳实例。 [0039] On the basis of general knowledge in the art without departing from the present on each of the preferred conditions, it can be any combination, i.e., to obtain various preferred examples of the present invention.

[0040] 本发明所用试剂和原料如没有特别说明,均市售可得。 [0040] The present invention is used as the reagents and materials is not particularly described, are commercially available.

[0041 ] 本发明的有益效果: [0041] Advantageous effects of the invention:

[0042] 本发明以烯烃化合物为基础,通过SHI氧化反应制备得到新的中间体环氧化合物1,化合物I通过开环,氢化制备出高手性选择的依折麦布产品。 [0042] In the present invention, an olefin-based compound, a compound I, prepared by hydrogenation of ring-opening the master selection ezetimibe products are new intermediate epoxy compounds prepared SHI oxidation reaction. SHI氧化是近年来不对称环氧化领域出现的新技术,以果糖衍生物(例如本发明中公开的化合物7,8,9)为手性催化齐IJ,经济高效将烯烃化合物氧化成高手性选择性的环氧化物;同时,果糖来源广泛,价格便宜,催化剂合成便捷,避免了使用昂贵且不稳定的手性催化剂,用廉价易得的果糖衍生物替代,经济高效,节约成本,且后处理简便易行,适用于工业化生产。 SHI is the oxidation of asymmetric epoxidation of new technology field appears to (a compound of the present invention are disclosed in, for example, 7,8,9) fructose derivative is a chiral catalyst together IJ, cost effective olefin oxidation of a compound of the master selective epoxide; meanwhile, widely sources of fructose, cheap, convenient catalyst synthesis, avoiding the use of expensive and unstable chiral catalysts, with inexpensive, readily available fructose derivatives alternative, cost-effective, cost, and the rear process is simple, suitable for industrial production.

[0043] 本发明提供了一种与现有技术完全不同的制备依折麦布方法,选择性高,利用环氧化合物I作为中间体制得化合物4后,在后续制备依折麦布时,同样反应路线短,操作方法简单,消耗少,节约成本,可以制备出高de值产品,适用于工业化生产。 [0043] The present invention provides a completely different from the prior art preparation method of ezetimibe, high selectivity, an epoxy compound Compound I as an intermediate system 4, in the subsequent preparation of ezetimibe, the same Scheme short, simple operation, less consumption, cost savings, can be prepared de higher value products, suitable for industrial production.

具体实施方式 detailed description

[0044] 下面通过实施例的方式进一步说明本发明,但并不因此将本发明限制在所述的实施例范围之中。 [0044] The present invention is further described below by way of example, but not to limit the invention thus described embodiments within the scope of embodiments. 下列实施例中未注明具体条件的实验方法,按照常规方法和条件,或按照商品说明书选择。 Experimental methods without specific conditions in the examples below, in accordance with conventional methods and conditions, according to the product specification or selection.

[0045] 使用仪器:Varian Inova型核磁共振仪(内标TMS,溶剂⑶Cl3) ;Finn ignMAT212型质谱仪。 [0045] Instrumentation: Varian Inova NMR spectrometer type (internal standard TMS, solvent ⑶Cl3); Finn ignMAT212 mass spectrometer.

[0046] 实施例1:化合物I的制备(R1为四氢-2H-吡喃基) [0046] Example 1: Preparation of Compound I (R1 is tetrahydro -2H- pyran-yl)

[0047] IOOmL三颈瓶中加入5g化合物2,二氯甲烷50mL,磁力搅拌冰水浴下加入间氯过氧苯甲酸2. 74g,TLC判断反应结束,加入lmol/L碳酸钾水溶液洗两次,干燥,过滤,蒸干,乙醇重结晶,得到化合物cl. 41g,收率27. 3%,de值95%。 [0047] IOOmL three-necked flask was added 5g of Compound 2, methylene chloride 50mL, under magnetic stirring between ice-water bath was added m-chloroperbenzoic acid 2. 74g, TLC determined the end of the reaction, lmol / L potassium carbonate aqueous solution was washed twice, dried, filtered, evaporated to dryness, and recrystallized from ethanol to give compound cl. 41g, yield 27. 3%, de 95% value.

[0048] 实施例2 :化合物I的制备(R1为二甲基叔丁基硅烷基) [0048] Example 2: Preparation of Compound I (R1 is t-butyl dimethyl silyl)

[0049] IOOmL三颈瓶中加入5g (10. 4mmol)化合物2,二氯甲烷50mL,磁力搅拌冰水浴下加入间氯过氧苯甲酸2. 74g,TLC判断反应结束,加入lmol/L碳酸钾水溶液洗两次,干燥,过滤,蒸干,乙醇重结晶,得到化合物cl. 55g,收率30%,de值95. 5%。 [0049] IOOmL three-necked flask was added 5g (10. 4mmol) of Compound 2, methylene chloride 50mL, under magnetic stirring ice water bath-chloroperbenzoic acid 2. 74g, TLC determined the end of the reaction, lmol / L potassium carbonate aqueous solution was washed twice, dried, filtered, evaporated to dryness, and recrystallized from ethanol to give compound cl. 55g, yield 30%, de 95.5% value.

[0050] 实施例3-9中取代基R1均采用苄基。 [0050] Example 3-9 substituents R1 are benzyl employed.

[0051] 实施例3 :化合物I的制备 Compound I: Example 3 [0051] Embodiment

[0052] IOOmL三颈瓶中加入5g (10. 4mmol)化合物2, 二氯甲烧50mL,磁力搅拌冰水浴下加入间氯过氧苯甲酸2. 74g,TLC判断反应结束,加入lmol/L碳酸钾水溶液洗两次,干燥,过滤,蒸干,乙醇重结晶,得到化合物cl. 45g,收率28%,de值95. 3%。 [0052] IOOmL three-necked flask was added 5g (10. 4mmol) of Compound 2, methylene burning 50mL, magnetic-chloroperbenzoic acid under ice-cooling with stirring 2. 74g, TLC determined the end of the reaction, lmol / L carbonate aqueous potassium washed twice, dried, filtered, evaporated to dryness, and recrystallized from ethanol to give compound cl. 45g, yield 28%, de 95.3% value.

[0053] MS (ESI) :500 (M+H+) [0053] MS (ESI): 500 (M + H +)

[0054] 1H NMR(400MHz, DMS0) δ (ppm) :1. 645-1. 799 (m,2H);3. 126-3. 157 (m, 1H) ; 3. 366-3. 407 (m, 1H) ; 4. 170-4. 180 (d, 1H) ; 4. 804-4. 809 (d, 1H), 5. 061 (s, 2H) ; 6. 993-7. 424 (m, I7H)。 [0054] 1H NMR (400MHz, DMS0) δ (ppm):..... 1 645-1 799 (m, 2H); 3 126-3 157 (m, 1H); 3. 366-3 407 (m , 1H);. 4. 170-4 180 (d, 1H);. 4. 804-4 809 (d, 1H), 5. 061 (s, 2H);. 6. 993-7 424 (m, I7H ).

[0055] 实施例4 :化合物I的制备 Compound I: Example 4 [0055] Embodiment

[0056] IOOmL 三颈瓶中加入1. 5g (10. 4mmol)化合物2,乙腈-DMM (l:2)50mL, (O. 05M 硼酸钠溶解于IO-4M Na2 (EDTA)水溶液)硼酸钠缓冲溶液31ml,四丁基硫酸氢铵427mg,配体7 (R2, R3, R4, R5为甲基)225mg,磁力搅拌20°C下,1. 5小时内同时同速滴入OXONE及碳酸钾相应浓度溶液各19ml,滴加完毕,TLC判断反应结束,乙酸乙酯提取,无水硫酸钠干燥,乙醇重结晶,得到化合物829mg,收率55. 3%,de值96. 7%。 [0056] IOOmL three-necked flask was added 1. 5g (10. 4mmol) of compound 2, acetonitrile -DMM (l: 2) 50mL, (O. 05M sodium borate was dissolved in IO-4M Na2 (EDTA) aqueous solution) of sodium borate buffer, solution 31ml, tetrabutylammonium hydrogen sulfate 427mg, ligand 7 (R2, R3, R4, R5 is methyl) 225mg, magnetic stirring at 20 ° C, within 1.5 hours at the same speed while potassium carbonate was added dropwise and the corresponding OXONE 19ml of each solution concentration, the addition was complete, as judged by TLC the reaction ended, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and recrystallized from ethanol to give compound 829 mg, yield 55. 3%, de 96.7% value.

[0057] MS (ESI) :500 (M+H+) [0057] MS (ESI): 500 (M + H +)

[0058] 1H NMR(400MHz, DMS0) δ (ppm) :1. 662-1. 842 (m,2H);3. 165-3. 199 (m, 1H) ; 3. 403-3. 445 (m, 1H) ; 4. 192-4. 203 (d, 1H) ; 4. 832-4. 838 (d, 1H),5. 087 (s, 2H) ; 7. 012-7. 446 (m, I7H)。 [0058] 1H NMR (400MHz, DMS0) δ (ppm):..... 1 662-1 842 (m, 2H); 3 165-3 199 (m, 1H); 3. 403-3 445 (m , 1H); 4. 192-4 203 (d, 1H);... 4. 832-4 838 (d, 1H), 5 087 (s, 2H);. 7. 012-7 446 (m, I7H ).

[0059] 实施例5 :化合物I的制备[0060] IOOmL 三颈瓶中加入1. 5g (10. 4mmol)化合物2,乙腈DMM (1:2) 50mL,(O. 05M 硼酸钠溶解于IO-4M Na2 (EDTA)水溶液)硼酸钠缓冲溶液31ml,四丁基硫酸氢铵427mg,配体8 (R2,R3为甲基,R6为叔丁氧羰基)225mg,磁力搅拌(TC下,1. 5小时内同时同速滴入OXONE及碳酸钾相应浓度溶液各19ml,滴加完毕,TLC判断反应结束,乙酸乙酯提取,无水硫酸钠干燥,乙醇重结晶,得到化合物836mg,收率55. 8%,de值95. 3%。 [0059] Example 5: Preparation of Compound I [0060] IOOmL three-necked flask was added 1. 5g (10. 4mmol) of compound 2, acetonitrile DMM. (1: 2) 50mL, (O 05M sodium borate was dissolved in IO- 4M Na2 (EDTA) aqueous solution) of sodium borate buffer solution 31ml, tetrabutylammonium hydrogen sulfate 427mg, ligand 8 (R2, R3 is methyl, R6 is tert-butoxycarbonyl) 225mg, magnetic stirring (at TC, 1. 5 within hours with the same speed and the appropriate concentration of the OXONE solution is added dropwise potassium 19ml each, addition was complete, TLC determined the reaction was completed, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and recrystallized from ethanol to give compound 836 mg, yield 55.8 %, de value of 95.3%.

[0061] 实施例6 :化合物I的制备 Compound I: Example 6 [0061] Embodiment

[0062] IOOmL 三颈瓶中加入1. 5g (10. 4mmol)化合物2,乙腈-DMM (l:2)50mL, (O. 05M 硼酸钠溶解于IO-4M Na2 (EDTA)水溶液)硼酸钠缓冲溶液31ml,四丁基硫酸氢铵427mg,配体9(R4, R5为甲基,R7, &为乙酰基)225mg,磁力搅拌-20°C下,1. 5小时内同时同速滴入OXONE及碳酸钾相应浓度溶液各19ml,滴加完毕,TLC判断反应结束,乙酸乙酯提取,无水硫酸钠干燥,乙醇重结晶,得到化合物812mg,收率54. 2%,de值96. 5%。 [0062] IOOmL three-necked flask was added 1. 5g (10. 4mmol) of compound 2, acetonitrile -DMM (l: 2) 50mL, (O. 05M sodium borate was dissolved in IO-4M Na2 (EDTA) aqueous solution) of sodium borate buffer, solution 31ml, tetrabutylammonium hydrogen sulfate 427mg, ligand 9 (R4, R5 is methyl, R7, & acetyl) 225mg, magnetic stirring -20 ° C, within 1.5 hours at the same speed simultaneously added dropwise OXONE solution of potassium carbonate and 19ml respective concentrations, the addition was complete, TLC determined the reaction was completed, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and recrystallized from ethanol to give the compound 812mg, 54. 2% yield, 96.5% de value .

[0063] 实施例7 :化合物4的制备 7 [0063] Example: Preparation of Compound 4

[0064] IOOml三颈瓶中,加入乙醇30ml, 二苯联硒194mg,加入硼氢化钠51mg, 15分钟后,加入化合物1400mg,4小时后,加入水5ml,降温至(TC,加入碳酸氢钠438mg,高碘酸钠964mg,升至20°C,搅拌过夜,乙酸乙酯:石油醚=1:3柱层析,得到化合物al52mg,收率38%。 [0064] IOOml three-necked flask, ethanol 30ml, 194 mg of diphenyl diselenide, was added sodium borohydride 51mg, 15 minutes, 1400 mg of compound is added, after 4 hours, water was added 5ml, cooled to (the TC, sodium bicarbonate 438 mg, 964 mg sodium periodate, was raised to 20 ° C, stirred overnight, ethyl acetate: petroleum ether = 1: 3 column chromatography to give compound al52mg, yield 38%.

[0065] 实施例8 :化合物4的制备 Preparation of Compound 4: Example 8 [0065] Embodiment

[0066] IOOml三颈瓶中,加入乙醇30ml, 二苯联硒194mg,加入硼氢化钠51mg, 15分钟后,加入化合物1400mg,4小时后,加入吡啶200mg,30%双氧水600mg,升温至60°C,搅拌4小时,乙酸乙酯:石油醚=1:3柱层析,得到化合物al43mg,收率35. 8%。 [0066] IOOml three-necked flask, ethanol 30ml, 194 mg of diphenyl diselenide, was added sodium borohydride 51mg, 15 minutes, 1400 mg of compound is added, after 4 hours, pyridine was added 200mg, 30% hydrogen peroxide 600mg, warmed to 60 ° C, stirred for 4 hours, ethyl acetate: petroleum ether = 1: 3 column chromatography to give compound al43mg, 35. 8% yield.

[0067] 实施例9 :依折麦布的制备 [0067] Example 9: Preparation of ezetimibe ezetimibe

[0068] 250ml氢化爸中,乙醇15ml,化合物4150mg,(含水68. 3%) 10%湿IE碳60mg,氢压7atm,反应4小时,过滤,蒸干,异丙醇-水体系析晶,得到依折麦布109mg,收率89%, de值99. 1%。 [0068] 250ml Dad hydrogenation in ethanol 15ml, compound 4150mg, (water content 68.3%) IE carbon 10% wet 60mg, 7 atm of hydrogen pressure, for 4 hours, filtered, evaporated to dryness, isopropanol - water system crystallization, ezetimibe obtained 109mg, yield 89%, de 99.1% value.

[0069] MS (ESI) :410 (M+H+) [0069] MS (ESI): 410 (M + H +)

[0070] 1H NMR (500MHz, DMS0) δ (ppm) :1. 683-1. 774 (m, 2H) ;1. 796-1. 854 (m, 2H) ; 3. 059-3. 082 (m, 1H); [0070] 1H NMR (500MHz, DMS0) δ (ppm):..... 1 683-1 774 (m, 2H); 1 796-1 854 (m, 2H); 3. 059-3 082 (m , 1H);

[0071] 4. 486-4. 495 (d, 1H) ; 4. 795-4. 800 (d, 1H) ; 5. 235-5. 262 (d, 1H) ;6. 744-6. 761 (d, 2H) ; 7. 092-7. 140 (m, 4H) ; 7. 200-7. 224 (m, 4H) ; 7. 285-7. 314 (m, 2H) ; 9. 499 (s, 1H)。 . [0071] 4. 486-4 495 (d, 1H);. 4. 795-4 800 (d, 1H);. 5. 235-5 262 (d, 1H);.. 6 744-6 761 ( d, 2H);. 7. 092-7 140 (m, 4H);. 7. 200-7 224 (m, 4H);. 7. 285-7 314 (m, 2H); 9. 499 (s, 1H).

Claims (28)

1.依折麦布的制备方法,包括如下步骤: 1)溶剂中,将化合物I加入硼氢化碱金属盐和二苯联硒反应体系,再加入碱和氧化剂反应即可得目标产物化合物4 : 1. ezetimibe preparing ezetimibe comprising the steps of: 1) a solvent, the compound I and the alkali metal borohydride is added diphenyl diselenide reaction system, adding a base and an oxidizing agent to obtain the target product Compound 4:
Figure CN102993077AC00021
R1为氢原子、芳基甲基、单取代或多取代的芳基甲基、取代的硅烷基或四氢-2H-吡喃基; 2)将化合物4氢化还原得依折麦布: R1 is a hydrogen atom, an aryl group, a substituted or mono-substituted aryl group, a substituted silyl group or tetrahydro -2H- pyran; 2) Compound 4 may, in accordance hydrogenation ezetimibe:
Figure CN102993077AC00022
2.如权利要求1所述的依折麦布的制备方法,其特征在于:所说的芳基甲基为苄基或三苯甲基。 A method as claimed in claim 2. The preparation of ezetimibe of the Mab 1, wherein: said arylmethyl group is benzyl or trityl.
3.如权利要求1或2所述的依折麦布的制备方法,其特征在于=R1为芳环上被卤素、硝基、含C1-C6的烷基或含C1-C6烷氧基取代的芳基甲基。 A method as claimed in claim preparing ezetimibe or ezetimibe claim 1 or 2, wherein = R1 is on the aromatic ring by halogen, nitro, C1-C6 alkyl group-containing or an unsubstituted C1-C6 alkoxy aryl group.
4.如权利要求1所述的依折麦布的制备方法,其特征在于=R1为C1-C6的烷基或C6-C10的芳基取代的硅烷基。 A method as claimed in claim preparing ezetimibe according to the Mab 1, wherein = R1 is a C1-C6 alkyl or C6-C10 aryl-substituted silyl group.
5.如权利要求1所述的依折麦布的制备方法,其特征在于=R1为二甲基叔丁基硅烷基。 A method as claimed in claim 5. The preparation of ezetimibe of the Mab 1, wherein = R1 is a t-butyl dimethyl silyl.
6.如权利要求1所述的依折麦布的制备方法,其特征在于:步骤I)中原料化合物I加入后24小时内再加入碱和氧化剂。 6. A method as claimed in claim preparing ezetimibe according to the Mab 1, characterized in that: a base and an oxidizing agent was added within 24 hours after step I) starting compound I is added.
7.如权利要求1所述的依折麦布的制备方法,其特征在于:步骤I)中硼氢化碱金属盐为硼氢化钠,且硼氢化钠与二苯联硒的摩尔比为O. 5-1 :1。 A method as claimed in claim 7. The preparation of ezetimibe of the Mab 1, wherein: in step I) the alkali metal borohydride is sodium borohydride, and the molar ratio of sodium borohydride to diphenyl diselenide is O. 5-1: 1.
8.如权利要求7所述的依折麦布的制备方法,其特征在于:硼氢化钠与二苯联硒的摩尔比为O. 55 :lo A method as claimed in claim preparation of ezetimibe of the Mab 7, wherein: the molar ratio of sodium borohydride to diphenyl diselenide O. 55: lo
9.如权利要求1所述的依折麦布的制备方法,其特征在于:步骤I)反应所用的碱为碳酸氢钠、碳酸氢钾、碳酸钠、碳酸钾、氢氧化钠、氢氧化钾或含有Cl-Cio的有机含氮碱。 A method as claimed in claim 9. The preparation of ezetimibe of the Mab 1, wherein: step I) used in the reaction base is sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide Cl-Cio containing or nitrogenous organic bases.
10.如权利要求9所述的依折麦布的制备方法,其特征在于:所说的Cl-ClO的有机含氮碱是指吡啶、吡咯、三乙胺、二乙胺、二丙胺或二异丙基乙胺。 A method as claimed in claim 10. The preparation of ezetimibe ezetimibe claim 9, wherein: said Cl-ClO refers to an organic nitrogenous base is pyridine, pyrrole, triethylamine, diethylamine, dipropylamine or di diisopropylethylamine.
11.如权利要求9所述的依折麦布的制备方法,其特征在于:步骤I)反应所用的碱为碳酸氢钠或吡啶。 A method as claimed in claim 11. The preparation of ezetimibe ezetimibe claim 9, wherein: step I) used in the reaction base is sodium bicarbonate or pyridine.
12.如权利要求1所述的依折麦布的制备方法,其特征在于:步骤I)的氧化剂为高碘酸钠或双氧水。 A method as claimed in claim 12. The preparation of ezetimibe of the Mab 1, wherein: step I) the oxidizing agent is hydrogen peroxide or sodium periodate.
13.如权利要求1所述的依折麦布的制备方法,其特征在于:步骤I)加入碱和氧化剂以后反应温度为0°c -78 °C。 A method as claimed in claim 13. The preparation of ezetimibe of the Mab 1, wherein: step I) a base and an oxidizing agent is added after the reaction temperature is 0 ° c -78 ° C.
14.如权利要求13所述的依折麦布的制备方法,其特征在于:步骤I)加入碱和氧化剂以后反应温度为20°C -60°C。 As claimed in claim 13, the method of preparation of ezetimibe ezetimibe, wherein: step I) after addition of a base and an oxidizing agent The reaction temperature is 20 ° C -60 ° C.
15.如权利要求1-14任意所述的依折麦布的制备方法,其特征在于:化合物I采用下述方法制备:在溶剂中,化合物2在氧化剂的作用下反应生成目标化合物I 15. As to any of the claims 1-14 in the preparation of ezetimibe ezetimibe, wherein: Compound I was prepared using the following method: in a solvent, compound 2 under the action of an oxidizing agent in the production reaction of the target compound I
Figure CN102993077AC00031
16.如权利要求15所述的依折麦布的制备方法,其特征在于:氧化剂选自间氯过氧苯甲酸、过氧乙酸、过氧化叔丁醇、双氧水和过硫酸氢钾复合盐。 As claimed in claim 15, the method of preparation of ezetimibe ezetimibe, wherein: the oxidizing agent is selected from among m-chloroperbenzoic acid, peracetic acid, tert-butyl hydroperoxide, hydrogen peroxide and oxone complex salt.
17.如权利要求16所述的依折麦布的制备方法,其特征在于:氧化剂为间氯过氧苯甲酸。 A method as claimed in claim 17. The preparation of ezetimibe of the Mab 16, wherein: the oxidizing agent is m-chloroperbenzoic acid.
18.如权利要求16所述的依折麦布的制备方法,其特征在于:氧化剂选用过硫酸氢钾复合盐时,过硫酸氢钾复合盐:化合物2摩尔比=1-5 :1 ;氧化剂选用间氯过氧苯甲酸、过氧乙酸、过氧化叔丁醇或双氧水时,用量为化合物2的1-3倍摩尔量。 Oxidant selected oxone complex salt, complex salts of potassium persulfate:: preparing ezetimibe according to the ezetimibe as claimed in claim 16, characterized in that the molar ratio of the compound 2 = 1-5: 1; oxidant when the selection of inter-chloroperbenzoic acid, peracetic acid, hydrogen peroxide or peroxide, t-butanol, in an amount of 1-3 times the molar amount of compound 2.
19.如权利要求1-14任意所述的依折麦布的制备方法,其特征在于:化合物I采用SHI氧化技术氧化式2化合物得到。 19. any one of the claims 1 to 14 in the preparation of ezetimibe ezetimibe, wherein: SHI Compound I using the compound of Formula 2 obtained oxide oxidation.
20.如权利要求19所述的依折麦布的制备方法,其特征在于:具体操作步骤是将式I化合物溶解于溶剂中,加入相转移催化剂和手性催化剂,同时加入氧化剂和碱,反应完全。 20. A method as claimed in claim ezetimibe preparation of ezetimibe of claim 19, wherein: the specific steps compound of formula I is dissolved in a solvent, addition of a phase transfer catalyst and a chiral catalyst while adding an oxidizing agent and a base, the reaction complete.
21.如权利要求20所述的依折麦布的制备方法,其特征在于:所使用的手性催化剂为下述的通式7、8或9所示,用量为式I化合物O. 1-2倍的摩尔量 21. A method for preparing ezetimibe of ezetimibe according to claim 20, wherein: the chiral catalyst used for the following general formula 7, 8 or 9, in an amount of a compound of formula I O. 1- 2-fold molar amount
Figure CN102993077AC00032
R2, R3,R4,R5为C1-C6的烷基;R6为含有Cl-ClO的烷基或被取代的烷基、酰基或被取代的酰基、烷氧基或被取代的烷氧基;R7、R8为C1-C6的酰基或被取代的酰基。 R2, R3, R4, R5 is C1-C6 alkyl group; R6 is an alkyl or substituted Cl-ClO alkyl, or substituted acyl or substituted acyl group, an alkoxyalkoxy group; R7 , R8 is C1-C6 acyl or substituted acyl.
22.如权利要求21所述的依折麦布的制备方法,其特征在于:R2、R3、R4、R5为甲基,R6为叔丁氧羰基,R7、R8为乙酰基。 A method as claimed in claim 22. The preparation of ezetimibe of the Mab 21, wherein: R2, R3, R4, R5 is methyl, R6 is tert-butoxycarbonyl, R7, R8 is acetyl group.
23.如权利要求20所述的依折麦布的制备方法,其特征在于:氧化剂为过硫酸氢钾复合盐。 23. A method for preparing ezetimibe of ezetimibe according to claim 20, wherein: the oxidizing agent is oxone complex salt.
24.如权利要求23所述的依折麦布的制备方法,其特征在于:氧化剂为O. 05-0. 4g/ml的10_4MNa2 (EDTA)过硫酸氢钾复合盐水溶液。 A method as claimed in claim 24. The preparation of ezetimibe of the Mab 23, wherein: the oxidizing agent is O. 05-0 4g / ml of 10_4MNa2 (EDTA) complex aqueous solution of potassium hydrogen sulfate salts.
25.如权利要求20所述的依折麦布的制备方法,其特征在于:反应体系pH=7-14。 25. A method of preparing ezetimibe ezetimibe claim 20, wherein: the reaction system pH = 7-14.
26.如权利要求20所述的依折麦布的制备方法,其特征在于:相转移催化剂为冠醚或四烷基取代的季铵盐类。 26. A method for preparing ezetimibe of ezetimibe according to claim 20, wherein: the phase transfer catalyst is a crown ether or tetraalkyl-substituted quaternary ammonium salts.
27.如权利要求26所述的依折麦布的制备方法,其特征在于:相转移催化剂为四丁基硫酸氢铵。 A method as claimed in claim 27. The preparation of ezetimibe of the Mab 26, wherein: the phase transfer catalyst is tetrabutylammonium hydrogen sulfate.
28.如权利要求20所述的依折麦布的制备方法,其特征在于:制备式I化合物的反应温度为_20-20°C。 28. A method for preparing ezetimibe of ezetimibe according to claim 20, wherein: the reaction temperature of the compound of formula I is _20-20 ° C.
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Citations (1)

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Publication number Priority date Publication date Assignee Title
US5886171A (en) * 1996-05-31 1999-03-23 Schering Corporation 3-hydroxy gamma-lactone based enantioselective synthesis of azetidinones

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5886171A (en) * 1996-05-31 1999-03-23 Schering Corporation 3-hydroxy gamma-lactone based enantioselective synthesis of azetidinones
US6096883A (en) * 1996-05-31 2000-08-01 Schering Corporation 3-hydroxy gamma-lactone based enantioselective synthesis of azetidinones

Non-Patent Citations (1)

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Title
GUANGZHONG WU ET AL: "A Novel One-Step Diastereo- and Enantioselective Formation of trans-Azetidinones and Its Application to the Total Synthesis of Cholesterol Absorption Inhibitors", 《JOURNAL OF ORGANIC CHEMISTRY》, vol. 64, no. 10, 21 April 1999 (1999-04-21), pages 3714 - 3718 *

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