降降血脂药的副作用zetia副作用
点击联系发帖人
时间：2016-11-15 21:55
君，已阅读到文档的结尾了呢~~
扫扫二维码，随身浏览文档
手机或平板扫扫即可继续访问
降血脂综述
举报该文档为侵权文档。
举报该文档含有违规或不良信息。
反馈该文档无法正常浏览。
举报该文档为重复文档。
推荐理由：
将文档分享至：
分享完整地址
文档地址：
粘贴到BBS或博客
flash地址：
支持嵌入FLASH地址的网站使用
html代码：
&embed src='/DocinViewer-4.swf' width='100%' height='600' type=application/x-shockwave-flash ALLOWFULLSCREEN='true' ALLOWSCRIPTACCESS='always'&&/embed&
450px*300px480px*400px650px*490px
支持嵌入HTML代码的网站使用
您的内容已经提交成功
您所提交的内容需要审核后才能发布，请您等待！
3秒自动关闭窗口新功能、新界面、新体验，扫描即可下载生物谷APP!
>> 新年伊始，当头一棒！默沙东降脂药Zetia和Vytorin扩大适应症申请遭FDA否决
新年伊始，当头一棒！默沙东降脂药Zetia和Vytorin扩大适应症申请遭FDA否决
来源：生物谷
日 讯 /生物谷BIOON/ --美国制药巨头默沙东（Merck & Co）最近悲剧了，降脂药Zetia（ezetimibe，依折麦布）和Vytorin（Zetia和辛伐他汀的复方药）减少冠心病患者心血管事件风险的扩大适应症申请，继去年底被FDA顾问小组以10:5的投票否决之后，近日也被FDA正式拒绝。
目前，Zetia和Vytorin已在美国上市销售，其适应症为结合健康饮食降低高血脂患者升高的低密度脂蛋白胆固醇（LDL-C）水平。而默沙东所提交的申请，寻求批准扩大这2种药物的治疗范畴，纳入降低冠心病患者发生心血管疾病的风险，具体包括心脏病发作、中风、心血管死亡、不稳定性心绞痛住院、血管重建等。
该申请是依据2015年初发布的IMPROVE-IT临床研究的结果，该研究规模非常庞大，涉及1.8万例患者，前后历时七年，耗资巨大。研究结果显示，将Zetia添加至他汀类疗法，使心血管并发症风险实现统计学意义的显著降低。具体为，使用Vytorin（Zetia+辛伐他汀的复方药）7年比单独使用辛伐他汀降低2个百分点的心肌梗塞和中风事件（32.7%对34.7%），即7年心血管事件相对风险降低6.4%，达到复合终点。
但是FDA顾问小组认为，Vytorin减少心血管事件风险6.4%，尽管这个数据在统计学上具有显著差异性，但疗效实际较小，而且还只是针对特定类型的患者，如老年人和糖尿病患者。换算过来，也就是50个病人使用7年（按现在Vytorin的价格就要花88万美元）才能避免一例心肌梗塞或中风事件。并且Vytorin并没有降低死亡率，只是减少了心肌梗塞或中风事件。
之前，FDA顾问小组成员之一贝勒大学医学中心博士Milton Packer表示，对于Vytorin和Zetia而言，这些疗效太小，不够显著，不足以改变其药物标签。而且这点疗效，甚至小到你一眨眼就错过了，小到你自己都质疑是否需要在乎这点疗效。
不过也有一些小组成员不赞同Milton Packer的观点。至少一个成员表示，FDA的任务是确定临床结果是否有统计学上的显著意义，至于这些数据是否能达到临床实际效果的意义，则应该由其他人来决定，包括患者和纳税人。
很显然，FDA的正式拒绝对默沙东而言无疑是当头一棒。针对这一情况，默沙东表示，正在仔细审查FDA的意见，以便下一步的行动。
另外，业界预测这一状况也将对降脂领域的新一代降脂药PCSK9抑制剂的商业前景带来短期影响。之前曾有分析师预计，安进的降脂药Repatha和赛诺菲/再生元的降脂药Praluent将受益于默沙东IMPROVE-IT研究的结果，即一种附加的非他汀类药物通过更大幅度降低低密度脂蛋白胆固醇（LDL-C）水平，可能降低心血管风险。这2个药物各自的早期临床数据预计在今年晚些时候能够获得。（生物谷）
原始出处：
本文系生物谷原创编译整理，欢迎转载！点击
。更多资讯请下载。
温馨提示：87%用户都在上阅读，扫描立刻下载! 天天精彩！
...（全文约2240字）
旗下网站： |
Copyright&2001- 版权所有 不得转载.关注今日：13 | 主题：410843
微信扫一扫
扫一扫，下载丁香园 App
即送15丁当
【科普】可以替代他汀类药物的降脂药
页码直达：
丁香园准中级站友
这个帖子发布于6年零118天前，其中的信息可能已发生改变或有所发展。
Ask the doctor: What are the alternatives to a statin for lowering cholesterol?Q. I have tried all of the statin drugs to lower my cholesterol, but each one has caused severe muscle pain. Are there any non-statin medications I could try using to lower my cholesterol?A. Have you tried niacin yet? It is an excellent drug for reducing cardiac risk in almost every way — it lowers harmful LDL cholesterol, raises beneficial HDL, and reduces cardiac complications. One reason it plays second fiddle to statins is that it causes side effects like itching and flushing in many people. These side effects can often be minimized or even eliminated by taking an aspirin before niacin, by gradually building up the dose, or by taking the intermediate-release type called Niaspan, which is available by prescription only.Two other drugs that may be used in place of a statin are ezetimibe (Zetia) and colesevelam (Welchol). Both of these medications work in the intestines, rather than the bloodstream, and so are less likely than statins to cause side effects. Ezetimibe blocks cholesterol in food from crossing the intestinal wall and getting into the bloodstream. Colesevelam grabs cholesterol-rich bile acids in the intestine and locks them into a watery goo that is excreted in the stool.Ezetimibe has been controversial since trials showed it adds little to cardiac protection. Colesevelam might be a good choice if you have diabetes because it lowers blood sugar as well as cholesterol.What you eat can help lower cholesterol. Switching from an average American diet to a Mediterranean-type diet can lower cholesterol and blood pressure. Researchers at the University of Toronto created what they called a &dietary portfolio of cholesterol-lowering foods& that included margarine enriche oats, barley, psyllium, okra, and eggplant, all r and whole almonds. A diet emphasizing these foods substantially lowered LDL, triglycerides, and blood pressure, and did not harm HDL. Eating nuts can modestly lower cholesterol.Fish oil and garlic have long been touted as cholesterol reducers, but meta-analyses of clinical trials show they have little effect on cholesterol. Substances that do lower cholesterol are plant sterols and stanols. They have been added to margarine (Benecol, Promise, others), orange juice, granola bars, chocolate, and other foods. They are also available as plain, no-calorie pills.— Thomas Lee, M.D.Editor in chief, Harvard Heart Letter
不知道邀请谁？试试他们
微信扫一扫
广告宣传推广
政治敏感、违法虚假信息
恶意灌水、重复发帖
违规侵权、站友争执
附件异常、链接失效
qiuyuming edited on
丁香园准中级站友
认领此文，48小时内上交。
微信扫一扫
广告宣传推广
政治敏感、违法虚假信息
恶意灌水、重复发帖
违规侵权、站友争执
附件异常、链接失效
丁香园准中级站友
降脂药，他汀类药物的选择Ask the doctor: What are the alternatives to a statin for lowering cholesterol?Q. I have tried all of the statin drugs to lower my cholesterol, but each one has caused severe muscle pain. Are there any non-statin medications I could try using to lower my cholesterol?问：为了降低血胆固醇，我尝试了各种他汀类药物，但每一种他汀药物服用后均引起剧烈的肌肉疼痛。我想知道，临床上有没有其他的药物用于降低胆固醇？A. Have you tried niacin yet? It is an excellent drug for reducing cardiac risk in almost every way — it lowers harmful LDL cholesterol, raises beneficial HDL, and reduces cardiac complications. One reason it plays second fiddle to statins is that it causes side effects like itching and flushing in many people. These side effects can often be minimized or even eliminated by taking an aspirin before niacin, by gradually building up the dose, or by taking the intermediate-release type called Niaspan, which is available by prescription only.答：不知道你有没有服用过烟酸这种药？烟酸可以通过各种机制来降低心血管疾病的风险，比如，它能降低对人体有害的低密度脂蛋白胆固醇，升高对人体有益的高密度脂蛋白胆固醇，并可以减少心血管并发症。临床应用中，烟酸与他汀类相比，烟酸一般不作为首选，这是由于烟酸能引起部分人皮肤发痒和面部潮红，临床上一般采用如下方法来减少或消除这些副作用，比如在服用烟酸前先口服一片阿司匹林，或者使用逐渐增加烟酸剂量的办法，或者服用一种叫Niaspan的中间释放剂型（Niaspan是处方药）。Two other drugs that may be used in place of a statin are ezetimibe (Zetia) and colesevelam (Welchol). Both of these medications work in the intestines, rather than the bloodstream, and so are less likely than statins to cause side effects. Ezetimibe blocks cholesterol in food from crossing the intestinal wall and getting into the bloodstream. Colesevelam grabs cholesterol-rich bile acids in the intestine and locks them into a watery goo that is excreted in the stool.另外还有两种可以替代他汀类药的是Ezetimibe和Colesevelam。这两种药物都是在肠道内而非血液内发挥作用，所以较少引起象他汀类药物那样的副作用。Ezetimibe通过阻止食物中的胆固醇经肠道吸收进入血液，而Colesevelam的作用机理是在肠道内竞争结合胆汁酸中的胆固醇，然后随粪便一道排出。Ezetimibe has been controversial since trials showed it adds little to cardiac protection. 自从有试验表明Ezetimibe不具有心血管保护作用，对其是否应该使用长期以来一直争议不断。Colesevelam might be a good choice if you have diabetes because it lowers blood sugar as well as cholesterol.如果高胆固醇血症的患者同时还伴有糠尿病，那么使用Colesevelam将是一个较好的选择，因为其不仅能降低胆固醇，还能降低血糠。What you eat can help lower cholesterol. Switching from an average American diet to a Mediterranean-type diet can lower cholesterol and blood pressure. Researchers at the University of Toronto created what they called a &dietary portfolio of cholesterol-lowering foods& that included margarine enriche oats, barley, psyllium, okra, and eggplant, all r and whole almonds. A diet emphasizing these foods substantially lowered LDL, triglycerides, and blood pressure, and did not harm HDL. Eating nuts can modestly lower cholesterol.日常的饮食习惯对血液中的胆固醇影响较大。如果美洲居民采用了地中海地区居民的饮食习惯，将有助于降低其较高的胆固醇和血压。多伦多大学的研究人员发明一种新的饮食搭配，将其命名为“低胆固醇饮食组合”，其组成包括：富含植物固醇的人造黄油；富含可溶性纤维的燕麦片、大麦、车前子、黄秋葵、茄子；大豆蛋白；杏仁等。这个饮食搭配能有力地降低低密度脂蛋白胆固醇、甘油三酯和血压，对高密度脂蛋白胆固醇却没有影响。坚果类食物也能轻度降低胆固醇。Fish oil and garlic have long been touted as cholesterol reducers, but meta-analyses of clinical trials show they have little effect on cholesterol. Substances that do lower cholesterol are plant sterols and stanols. They have been added to margarine (Benecol, Promise, others), orange juice, granola bars, chocolate, and other foods. They are also available as plain, no-calorie pills.— Thomas Lee, M.D.Editor in chief, Harvard Heart Letter 长期以来，人们一直信奉鱼油和大蒜能强力降低胆固醇，但是，临床试验的meta分析显示，这两食物对降低胆固醇基本没有作用。食物中确定具有降低胆固醇作用的是植物固醇。目前，人们已经在人造黄油、桔汁、燕麦条、巧克力及其它一些食物中添加了植物固醇。植物固醇也被制成了不含添加剂的无热量糖丸。编译
（大约857字）降脂药，他汀类药物的选择问：为了降低血胆固醇，我尝试了各种他汀类药物，但每一种他汀药物服用后均引起剧烈的肌肉疼痛。我想知道，临床上有没有其他的药物用于降低胆固醇？答：不知道你有没有服用过烟酸这种药？烟酸可以通过各种机制来降低心血管疾病的风险，比如，它能降低对人体有害的低密度脂蛋白胆固醇，升高对人体有益的高密度脂蛋白胆固醇，并可以减少心血管并发症。临床应用中，烟酸与他汀类相比，烟酸一般不作为首选，这是由于烟酸能引起部分人皮肤发痒和面部潮红，临床上一般采用如下方法来减少或消除这些副作用，比如在服用烟酸前先口服一片阿司匹林，或者使用逐渐增加烟酸剂量的办法，或者服用一种叫Niaspan的中间释放剂型（Niaspan是处方药）。另外还有两种可以替代他汀类药的是Ezetimibe和Colesevelam。这两种药物都是在肠道内而非血液内发挥作用，所以较少引起象他汀类药物那样的副作用。Ezetimibe通过阻止食物中的胆固醇经肠道吸收进入血液，而Colesevelam的作用机理是在肠道内竞争结合胆汁酸中的胆固醇，然后随粪便一道排出。自从有试验表明Ezetimibe不具有心血管保护作用，对其是否应该使用长期以来一直争议不断。如果高胆固醇血症的患者同时还伴有糠尿病，那么使用Colesevelam将是一个较好的选择，因为其不仅能降低胆固醇，还能降低血糠。日常的饮食习惯对血液中的胆固醇影响较大。如果美洲居民采用了地中海地区居民的饮食习惯，将有助于降低其较高的胆固醇和血压。多伦多大学的研究人员发明一种新的饮食搭配，将其命名为“低胆固醇饮食组合”，其组成包括：富含植物固醇的人造黄油；富含可溶性纤维的燕麦片、大麦、车前子、黄秋葵、茄子；大豆蛋白；杏仁等。这个饮食搭配能有力地降低低密度脂蛋白胆固醇、甘油三酯和血压，对高密度脂蛋白胆固醇却没有影响。坚果类食物也能轻度降低胆固醇。长期以来，人们一直信奉鱼油和大蒜能强力降低胆固醇，但是，临床试验的meta分析显示，这两食物对降低胆固醇基本没有作用。食物中确定具有降低胆固醇作用的是植物固醇。目前，人们已经在人造黄油、桔汁、燕麦条、巧克力及其它一些食物中添加了植物固醇。植物固醇也被制成了不含添加剂的无热量糖丸。丁香
微信扫一扫
广告宣传推广
政治敏感、违法虚假信息
恶意灌水、重复发帖
违规侵权、站友争执
附件异常、链接失效
关于丁香园& Ezetimibe, SCH-58235, Ezetrol, Zetia,-1, -
Ezetimibe, SCH-58235, Ezetrol, Zetia,-1, -
摘 要：Ezetimibe, SCH-58235, Ezetrol, Zetia,-1, -3 ([3R-[3alpha(R*),4beta]]-isomer),C24-H21-F2-N-O3,1-(4-Fluorophenyl)-3(R)-[3(S)-(4-fluorophenyl)-3-hydroxypropyl]-4(S)-(4-hydroxyphenyl)azetidin-2-one
【药物名称】Ezetimibe, SCH-58235, Ezetrol, Zetia
【化学名】1-(4-Fluorophenyl)-3(R)-[3(S)-(4-fluorophenyl)-3-hydroxypropyl]-4(S)-(4-hydroxyphenyl)azetidin-2-one
【CAS登记号】-1, -3 ([3R-[3alpha(R*),4beta]]-isomer)
【结构式】
【分子式】C24-H21-F2-N-O3
【分子量】409.437
【原研厂家】Essex (Originator), Schering-Plough (Originator), Merck & Co. (Licensee)
【作用类别】ENDOCRINE DRUGS, Lipoprotein Disorders, Treatment of , METABOLIC DRUGS, Therapy of Inborn Errors of Metabolism, Treatment of Diabetic Complications, Cholesterol Absorption Inhibitors
【研发状态】Launched-2002
【合成情况】
〖来源〗J Med Chem
〖合成路线〗
〖标题〗Discovery of 1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]-(4S)-(4-hydroxyphenyl)-2-azetidinone (SCH 58235): A designed, potent, orally active inhibitor of cholesterol absorption
〖合成方法〗Treatment of acid chloride (I) with tributylamine generated the corresponding ketene, which was cyclocondensed to imine (II) to produce the racemic trans b-lactam (III). Resolution of (III) into enantiomers was then achieved by preparative HPLC on a Chiralcel OD column. Subsequent saponification of the desired enantiomer with methanolic LiOH afforded acid (IV), which was converted to acid chloride (V) upon treatment with oxalyl chloride. Further Pd-mediated coupling of (V) with the arylzinc reagent (VI) provided ketone (VII). Then, carbonyl reduction with BH3-Me2S, followed by chromatographic separation of the isomers furnished alcohol (VIII), which was finally deprotected by hydrogenolysis over Pd/C to afford the target phenol.
〖作者〗Afonso, A.; Davis, H.R. Jr.; Huynh, T.; Yumibe, N.; Clader, J.W.; Burnett, D.A.; Rosenblum, S.B.
〖参考〗Afonso, A.; Davis, H.R. Jr.; Huynh, T.; Yumibe, N.; Clader, J.W.; Burnett, D.A.; Rosenblum, S.B.; Discovery of 1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]-(4S)-(4-hydroxyphenyl)-2-azetidinone (SCH 58235): A designed, potent, orally act (free base)/li>
li>??p耀?ul class="old_db">li>span>
〖出处〗J Med Chem):973
〖备注〗Treatment of acid chloride (I) with tributylamine generated the corresponding ketene, which was cyclocondensed to imine (II) to produce the racemic trans b-lactam (III). Resolution of (III) into enantiomers was then achieved by preparative HPLC on a Chiralcel OD column. Subsequent saponification of the desired enantiomer with methanolic LiOH afforded acid (IV), that was converted to acid chloride (V) upon treatment with oxalyl chloride. Further Pd-mediated coupling of (V) with the arylzinc reagent (VI) provided ketone (VII). Then, carbonyl reduction with BH3Me2S, followed by chromatographic separation of the isomers furnished alcohol (VIII), which was finally deprotected by hydrogenolysis over Pd/C to afford the target phenol.
〖来源〗Drugs Fut
〖合成路线〗
〖标题〗Ezetimibe
〖合成方法〗1) The cyclization of 4(S)-hydroxytetrahydrofuran-2-one (I) with the benzylideneimine derivative (II) by means of LDA gives the trans-azetidinone (III), which is separated from its cis-isomer by crystallization. The oxidation of (III) with NaIO4 in acetonitrile yields the carbaldehyde (IV), which is condensed with the silylated enol ether (V), prepared from 4'-fluoroacetophenone (VI), Li and TMSCl, to afford compound (VII). The dehydration of (VII) by means of TsOH gives the enone (VIII), which is hydrogenated and debenzylated with H2 over Pd/C in ethanol, providing the saturated ketone (IX). Finally, this compound is enantioselectively reduced with borane and the chiral catalyst (R)-1-methyl-3,3-diphenylperhydropyrrolo[1,2-c][1,3,2]oxaazaborole (CBS).
2) Alternatively, the reduction of enone (VIII) with H2 over RhCl(PPh3)3 in dichloromethane gives the benzylated saturated ketone (X), which is enantioselectively reduced with borane and CBS, yielding the benzylated alcohol (XI). Finally, this compound is debenzylated with H2 over Pd/C in ethanol.
〖作者〗Castaer, R.M.; Sorbera, L.A.; Castaer, J.
〖参考〗Castaer, R.M.; Sorbera, L.A.; Castaer, J.; Ezetimibe. Drugs Fut , 679
〖出处〗Drugs Fut):679
〖备注〗Synthesis of Ezetimibe (EN:224366):
Ezetimibe can be obtained by several different ways:
1) The cyclization of 4(S)-hydroxytetrahydrofuran-2-one (I) with the benzylideneimine derivative (II) by means of LDA gives the trans-azetidinone (III) which is separated from its cis-isomer by crystallization. The oxidation of (III) with NaIO4 in acetonitrile yields the carbaldehyde (IV), which is condensed with the silylated enol ether (V), prepared from 4'-fluoroacetophenone (VI), Li and TMSCl, to afford compound (VII). The dehydration of (VII) by means of TsOH gives the enone (VIII), which is hydrogenated and debenzylated with H2 over Pd/C in ethanol, providing the saturated ketone (IX). Finally, this compound is enantioselectively reduced with borane and the chiral catalyst (R)-1-methyl-3,3-diphenylperhydropyrrolo[1,2-c][1,3,2]oxaazaborole (CBS) (1-3) (Scheme a).
2) Alternatively, the reduction of enone (VIII) with H2 over RhCl(PPh3)3 in dichloromethane gives the benzylated saturated ketone (X), which is enantioselectively reduced with borane and CBS, yielding the benzylated alcohol (XI). Finally, this compound is debenzylated with H2 over Pd/C in ethanol (1-3) (Scheme a).
3) The reaction of 4-hydroxybenzaldehyde (XII) with benzyl bromide and K2CO3 in acetone gives 4-(benzyloxy)benzaldehyde (XIII), which is condensed with 4-fluoroaniline (XIV) in isopropanol, yielding the imine (II). Cyclization of (II) with methyl 4-(chloroformyl)butyrate (XV) by means of tributylamine in toluene affords the trans-azetidinone (XVI), which is hydrolyzed with LiOH in THF/water to provide the propionic acid derivative (XVII). The reaction of (XVII) with oxalyl chloride in dichloromethane gives the corresponding acyl chloride (XVIII), which is condensed with 4-fluorophenylmagnesium bromide (XIX) by means of ZnCl2 and Pd(PPh3)4 in THF to yield a racemic mixture of saturated trans-azetidinones that was resolved by chiral HPLC to the trans-(3R,4S)-enantiomer (XX). The enantioselective reduction of (XX) with BH3 and the chiral oxaborole catalyst CBS gives the benzylated alcohol (XI) which is finally debenzylated as before with H2 over Pd/C in ethanol (4) (Scheme b).
4) The reaction of methyl 4-(chloroformyl)butyrate (XV) with the chiral oxazolidinone (XXI) by means of DMAP and TEA in dichloromethane gives the acylated oxazolidinone (XXII), which is cyclized with the benzylideneimine (II) by means of TiCl4, titanium isopropoxide and TBAF in dichloromethane, yielding trans-(3R,4S)-azetidinone (XXIII). This chiral compound (XXIII) is worked up to give ezetimibe by the same reaction sequence used for its racemic analog (XVI) but without optical resolution (5) (Scheme c).
5) Racemic trans-azetidinone (XVI) can be submitted to chiral chromatography (Chiracel OD column) (6), microbial or enzymatic subtractive resolution to provide the trans-(3R,4S)-azetidinone (XXIII) (7) or direct microbial or enzymatic hydrolytic resolution to directly provide the trans-(3R,4S)-azetidinone-propionic acid (XXIV) (7), the compound also obtained by hydrolysis of (XXIII) with LiOH (6,7). This (3R,4S)-free acid (XXIV) is treated with oxalyl chloride giving the (3R,4S)-acyl chloride (XXV) which by condensation with 4-fluorophenylmagnesium bromide (XIX) yields the (3R,4S)-azetidinone (XX). Reduction of (XX) with borane-dimethylsulfide complex in THF affords an equal mixture of diasteromeric alcohols that was submitted to chiral chromatography on a Chiracel OD column providing the benzylated (3'S)-alcohol (XI) (6) (Scheme c).
6) The reaction of 5-(4-fluorophenyl)-4-pentenoic acid (XXVI) with oxalyl chloride gives the acyl chloride (XXVII), which is condensed with the chiral oxazolidinone (XXI) by means of DMAP and DIEA in dichloromethane, yielding the acyloxazolidinone (XXVIII). Condensation of (XXVIII) with the benzylideneimine (II) by means of TiCl4 affords adduct (XXIX), which is cyclized to the chiral azetidinone (XXX). The oxidation of the double bond of (XXX) with benzoquinone and HClO4 catalyzed by Pd(OAc)2 in acetonitrile/water provides the already reported trans-(3R,4S)-azetidinone (XX), which is worked up to give azetimibe as described before (8) (Scheme d).
Manufacturer
Schering-Plough Corporation (US).
References
1. Wu, G.Z, Wong, Y.S, Chen, X., Ding, Z.; A novel one-step diastereo- and enantioselective formation of trans-azetidinones and its application to the total synthesis of cholesterol a J Org Chem 14-8.
2. Wu, G.-Z., Chen, X., Wong, Y.-S., Schumacher, D.P., Steinman, M. (Schering Corp.); 3-Hydroxy gamma-lactone based enantioselective synth WO 9745406.
3. Wu, G.-Z., Chen, X., Wong, Y.-S., Schumacher, D.P., Steinman, M. (Schering Corp.); 3-Hydroxy gamma-lactone based enantioselective synth US 5886171.
4. Vaccaro, W.D., Sher, R., Davis, H.R. Jr.; 2-Azetidinone cholesterol absorption inhibitors: Increased potency by substitution of the C-4 Bioorg Med Chem 29-37.
5. Rosenblum, S.B., Dugar, S., Burnett, D.A., Clader, J.W., McKittrick, B.A. (Schering Corp.); Hydroxy-substd. azetidinone cpds. useful as hypoch EP 0720599, JP , US 5631365, US 5767115, WO 9508532.
6. Rosenblum, S.B., Huynh, T., Afonso, A., Davis, H.R. Jr., Yumibe, N., Clader, J.W., Burnett, D.A.; Discovery of 1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]-(4S)-(4-hydroxyphenyl)-2-azetidinone (SCH 58235): A designed, potent, orally active inhibitor of ch J Med Chem 3-980.
7. Homann, M.J., Morgan, W.B. (Schering Corp.); Resolution of trans-2-(alkoxycarbonylethyl)-lactams useful in the synthesis of 1-(4-fluoro-phenyl)-3(R)-[(S)-hydroxy-3-(4-fluorophenyl)-propyl]-4(S)-(4-hydroxyphenyl)-2- US 5919672.
8. Shankar, B.B. (Schering Corp.); Process for preparing 1-(4-fluorophenyl)-3(R)-(3(S)-hydroxy-3-([phenyl or 4-fluorophenyl])-propyl)-4(S)-(4-hydroxyphenyl)-2- US 5856473, WO 9716424.
〖来源〗J Org Chem
〖合成路线〗
〖标题〗A novel one-step diastereo- and enantioselective formation of trans-azetidinones and its application to the total synthesis of cholesterol absorption inhibitors
〖合成方法〗1) The cyclization of 4(S)-hydroxytetrahydrofuran-2-one (I) with the benzylideneimine derivative (II) by means of LDA gives the trans-azetidinone (III), which is separated from its cis-isomer by crystallization. The oxidation of (III) with NaIO4 in acetonitrile yields the carbaldehyde (IV), which is condensed with the silylated enol ether (V), prepared from 4'-fluoroacetophenone (VI), Li and TMSCl, to afford compound (VII). The dehydration of (VII) by means of TsOH gives the enone (VIII), which is hydrogenated and debenzylated with H2 over Pd/C in ethanol, providing the saturated ketone (IX). Finally, this compound is enantioselectively reduced with borane and the chiral catalyst (R)-1-methyl-3,3-diphenylperhydropyrrolo[1,2-c][1,3,2]oxaazaborole (CBS).
2) Alternatively, the reduction of enone (VIII) with H2 over RhCl(PPh3)3 in dichloromethane gives the benzylated saturated ketone (X), which is enantioselectively reduced with borane and CBS, yielding the benzylated alcohol (XI). Finally, this compound is debenzylated with H2 over Pd/C in ethanol.
〖作者〗Wu, G.Z.; Chen, X.; Ding, Z.; Wong, Y.S.
〖参考〗Wu, G.Z.; Chen, X.; Ding, Z.; Wong, Y.S.; A novel one-step diastereo- and enantioselective formation of trans-azetidinones and its application to the total synthesis of cholesterol absorption inhibitors. J Org Chem , 3714
〖出处〗J Org Chem):3714
〖来源〗Bioorg Med Chem
〖合成路线〗
〖标题〗2-Azetidinone cholesterol absorption inhibitors: Increased potency by substitution of the C-4 phenyl ring
〖合成方法〗3) The reaction of 4-hydroxybenzaldehyde (XII) with benzyl bromide and K2CO3 in acetone gives 4-(benzyloxy)benzaldehyde (XIII), which is condensed with 4-fluoroaniline (XIV) in isopropanol, yielding the imine (II). Cyclization of (II) with methyl 4-(chloroformyl)butyrate (XV) by means of tributylamine in toluene affords the trans-azetidinone (XVI), which is hydrolyzed with LiOH in THF/water to provide the propionic acid derivative (XVII). The reaction of (XVII) with oxalyl chloride in dichloromethane gives the corresponding acyl chloride (XVIII), which is condensed with 4-fluorophenylmagnesium bromide (XIX) by means of ZnCl2 and Pd(PPh3)4 in THF to yield a racemic mixture of saturated trans-azetidinones that was resolved by chiral HPLC to the trans-(3R,4S)-enantiomer (XX). The enantioselective reduction of (XX) with BH3 and the chiral oxaborole catalyst CBS gives the benzylated alcohol (XI), which is finally debenzylated as before with H2 over Pd/C in ethanol.
〖作者〗Vaccaro, W.D.; Sher, R.; Davis, H.R. Jr.
〖参考〗Vaccaro, W.D.; Sher, R.; Davis, H.R. Jr.; 2-Azetidinone cholesterol absorption inhibitors: Increased potency by substitution of the C-4 phenyl ring. Bioorg Med Chem , 1429
〖出处〗Bioorg Med Chem):1429
〖来源〗Drugs Fut
〖合成路线〗
〖标题〗Ezetimibe
〖合成方法〗3) The reaction of 4-hydroxybenzaldehyde (XII) with benzyl bromide and K2CO3 in acetone gives 4-(benzyloxy)benzaldehyde (XIII), which is condensed with 4-fluoroaniline (XIV) in isopropanol, yielding the imine (II). Cyclization of (II) with methyl 4-(chloroformyl)butyrate (XV) by means of tributylamine in toluene affords the trans-azetidinone (XVI), which is hydrolyzed with LiOH in THF/water to provide the propionic acid derivative (XVII). The reaction of (XVII) with oxalyl chloride in dichloromethane gives the corresponding acyl chloride (XVIII), which is condensed with 4-fluorophenylmagnesium bromide (XIX) by means of ZnCl2 and Pd(PPh3)4 in THF to yield a racemic mixture of saturated trans-azetidinones that was resolved by chiral HPLC to the trans-(3R,4S)-enantiomer (XX). The enantioselective reduction of (XX) with BH3 and the chiral oxaborole catalyst CBS gives the benzylated alcohol (XI), which is finally debenzylated as before with H2 over Pd/C in ethanol.
〖作者〗Castaer, R.M.; Sorbera, L.A.; Castaer, J.
〖参考〗Castaer, R.M.; Sorbera, L.A.; Castaer, J.; Ezetimibe. Drugs Fut , 679
〖出处〗Drugs Fut):679
〖备注〗Synthesis of Ezetimibe (EN:224366):
Ezetimibe can be obtained by several different ways:
1) The cyclization of 4(S)-hydroxytetrahydrofuran-2-one (I) with the benzylideneimine derivative (II) by means of LDA gives the trans-azetidinone (III) which is separated from its cis-isomer by crystallization. The oxidation of (III) with NaIO4 in acetonitrile yields the carbaldehyde (IV), which is condensed with the silylated enol ether (V), prepared from 4'-fluoroacetophenone (VI), Li and TMSCl, to afford compound (VII). The dehydration of (VII) by means of TsOH gives the enone (VIII), which is hydrogenated and debenzylated with H2 over Pd/C in ethanol, providing the saturated ketone (IX). Finally, this compound is enantioselectively reduced with borane and the chiral catalyst (R)-1-methyl-3,3-diphenylperhydropyrrolo[1,2-c][1,3,2]oxaazaborole (CBS) (1-3) (Scheme a).
2) Alternatively, the reduction of enone (VIII) with H2 over RhCl(PPh3)3 in dichloromethane gives the benzylated saturated ketone (X), which is enantioselectively reduced with borane and CBS, yielding the benzylated alcohol (XI). Finally, this compound is debenzylated with H2 over Pd/C in ethanol (1-3) (Scheme a).
3) The reaction of 4-hydroxybenzaldehyde (XII) with benzyl bromide and K2CO3 in acetone gives 4-(benzyloxy)benzaldehyde (XIII), which is condensed with 4-fluoroaniline (XIV) in isopropanol, yielding the imine (II). Cyclization of (II) with methyl 4-(chloroformyl)butyrate (XV) by means of tributylamine in toluene affords the trans-azetidinone (XVI), which is hydrolyzed with LiOH in THF/water to provide the propionic acid derivative (XVII). The reaction of (XVII) with oxalyl chloride in dichloromethane gives the corresponding acyl chloride (XVIII), which is condensed with 4-fluorophenylmagnesium bromide (XIX) by means of ZnCl2 and Pd(PPh3)4 in THF to yield a racemic mixture of saturated trans-azetidinones that was resolved by chiral HPLC to the trans-(3R,4S)-enantiomer (XX). The enantioselective reduction of (XX) with BH3 and the chiral oxaborole catalyst CBS gives the benzylated alcohol (XI) which is finally debenzylated as before with H2 over Pd/C in ethanol (4) (Scheme b).
4) The reaction of methyl 4-(chloroformyl)butyrate (XV) with the chiral oxazolidinone (XXI) by means of DMAP and TEA in dichloromethane gives the acylated oxazolidinone (XXII), which is cyclized with the benzylideneimine (II) by means of TiCl4, titanium isopropoxide and TBAF in dichloromethane, yielding trans-(3R,4S)-azetidinone (XXIII). This chiral compound (XXIII) is worked up to give ezetimibe by the same reaction sequence used for its racemic analog (XVI) but without optical resolution (5) (Scheme c).
5) Racemic trans-azetidinone (XVI) can be submitted to chiral chromatography (Chiracel OD column) (6), microbial or enzymatic subtractive resolution to provide the trans-(3R,4S)-azetidinone (XXIII) (7) or direct microbial or enzymatic hydrolytic resolution to directly provide the trans-(3R,4S)-azetidinone-propionic acid (XXIV) (7), the compound also obtained by hydrolysis of (XXIII) with LiOH (6,7). This (3R,4S)-free acid (XXIV) is treated with oxalyl chloride giving the (3R,4S)-acyl chloride (XXV) which by condensation with 4-fluorophenylmagnesium bromide (XIX) yields the (3R,4S)-azetidinone (XX). Reduction of (XX) with borane-dimethylsulfide complex in THF affords an equal mixture of diasteromeric alcohols that was submitted to chiral chromatography on a Chiracel OD column providing the benzylated (3'S)-alcohol (XI) (6) (Scheme c).
6) The reaction of 5-(4-fluorophenyl)-4-pentenoic acid (XXVI) with oxalyl chloride gives the acyl chloride (XXVII), which is condensed with the chiral oxazolidinone (XXI) by means of DMAP and DIEA in dichloromethane, yielding the acyloxazolidinone (XXVIII). Condensation of (XXVIII) with the benzylideneimine (II) by means of TiCl4 affords adduct (XXIX), which is cyclized to the chiral azetidinone (XXX). The oxidation of the double bond of (XXX) with benzoquinone and HClO4 catalyzed by Pd(OAc)2 in acetonitrile/water provides the already reported trans-(3R,4S)-azetidinone (XX), which is worked up to give azetimibe as described before (8) (Scheme d).
Manufacturer
Schering-Plough Corporation (US).
References
1. Wu, G.Z, Wong, Y.S, Chen, X., Ding, Z.; A novel one-step diastereo- and enantioselective formation of trans-azetidinones and its application to the total synthesis of cholesterol a J Org Chem 14-8.
2. Wu, G.-Z., Chen, X., Wong, Y.-S., Schumacher, D.P., Steinman, M. (Schering Corp.); 3-Hydroxy gamma-lactone based enantioselective synth WO 9745406.
3. Wu, G.-Z., Chen, X., Wong, Y.-S., Schumacher, D.P., Steinman, M. (Schering Corp.); 3-Hydroxy gamma-lactone based enantioselective synth US 5886171.
4. Vaccaro, W.D., Sher, R., Davis, H.R. Jr.; 2-Azetidinone cholesterol absorption inhibitors: Increased potency by substitution of the C-4 Bioorg Med Chem 29-37.
5. Rosenblum, S.B., Dugar, S., Burnett, D.A., Clader, J.W., McKittrick, B.A. (Schering Corp.); Hydroxy-substd. azetidinone cpds. useful as hypoch EP 0720599, JP , US 5631365, US 5767115, WO 9508532.
6. Rosenblum, S.B., Huynh, T., Afonso, A., Davis, H.R. Jr., Yumibe, N., Clader, J.W., Burnett, D.A.; Discovery of 1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]-(4S)-(4-hydroxyphenyl)-2-azetidinone (SCH 58235): A designed, potent, orally active inhibitor of ch J Med Chem 3-980.
7. Homann, M.J., Morgan, W.B. (Schering Corp.); Resolution of trans-2-(alkoxycarbonylethyl)-lactams useful in the synthesis of 1-(4-fluoro-phenyl)-3(R)-[(S)-hydroxy-3-(4-fluorophenyl)-propyl]-4(S)-(4-hydroxyphenyl)-2- US 5919672.
8. Shankar, B.B. (Schering Corp.); Process for preparing 1-(4-fluorophenyl)-3(R)-(3(S)-hydroxy-3-([phenyl or 4-fluorophenyl])-propyl)-4(S)-(4-hydroxyphenyl)-2- US 5856473, WO 9716424.
〖来源〗J Med Chem
〖合成路线〗
〖标题〗Discovery of 1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]-(4S)-(4-hydroxyphenyl)-2-azetidinone (SCH 58235): A designed, potent, orally active inhibitor of cholesterol absorption
〖合成方法〗4) The reaction of methyl 4-(chloroformyl)butyrate (XV) with the chiral oxazolidinone (XXI) by means of DMAP and TEA in dichloromethane gives the acylated oxazolidinone (XXII), which is cyclized with the benzylideneimine (II) by means of TiCl4, titanium isopropoxide and TBAF in dichloromethane, yielding trans-(3R,4S)-azetidinone (XXIII). This chiral compound (XXIII) is worked up to give ezetimibe by the same reaction sequence used for its racemic analogue (XVI) but without optical resolution.
5) Racemic trans-azetidinone (XVI) can be submitted to chiral chromatography (Chiracel OD column), microbial or enzymatic subtractive resolution to provide the trans-(3R,4S)-azetidinone (XXIII) or direct microbial or enzymatic hydrolytic resolution to directly provide the trans-(3R,4S)-azetidinone-propionic acid (XXIV), the compound also obtained by hydrolysis of (XXIII) with LiOH. This (3R,4S)-free acid (XXIV) is treated with oxalyl chloride giving the (3R,4S)-acyl chloride (XXV), which by condensation with 4-fluorophenylmagnesium bromide (XIX) yields the (3R,4S)-azetidinone (XX). Reduction of (XX) with borane-dimethylsulfide complex in THF affords an equal mixture of diasteromeric alcohols that was submitted to chiral chromatography on a Chiracel OD column providing the benzylated (3'S)-alcohol (XI).
〖作者〗Afonso, A.; Davis, H.R. Jr.; Huynh, T.; Yumibe, N.; Clader, J.W.; Burnett, D.A.; Rosenblum, S.B.
〖参考〗Afonso, A.; Davis, H.R. Jr.; Huynh, T.; Yumibe, N.; Clader, J.W.; Burnett, D.A.; Rosenblum, S.B.; Discovery of 1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]-(4S)-(4-hydroxyphenyl)-2-azetidinone (SCH 58235): A designed, potent, orally act (free base)/li>
li>??p耀?ul class="old_db">li>span>
〖出处〗J Med Chem):973
〖备注〗Treatment of acid chloride (I) with tributylamine generated the corresponding ketene, which was cyclocondensed to imine (II) to produce the racemic trans b-lactam (III). Resolution of (III) into enantiomers was then achieved by preparative HPLC on a Chiralcel OD column. Subsequent saponification of the desired enantiomer with methanolic LiOH afforded acid (IV), that was converted to acid chloride (V) upon treatment with oxalyl chloride. Further Pd-mediated coupling of (V) with the arylzinc reagent (VI) provided ketone (VII). Then, carbonyl reduction with BH3Me2S, followed by chromatographic separation of the isomers furnished alcohol (VIII), which was finally deprotected by hydrogenolysis over Pd/C to afford the target phenol.
〖来源〗Drugs Fut
〖合成路线〗
〖标题〗Ezetimibe
〖合成方法〗4) The reaction of methyl 4-(chloroformyl)butyrate (XV) with the chiral oxazolidinone (XXI) by means of DMAP and TEA in dichloromethane gives the acylated oxazolidinone (XXII), which is cyclized with the benzylideneimine (II) by means of TiCl4, titanium isopropoxide and TBAF in dichloromethane, yielding trans-(3R,4S)-azetidinone (XXIII). This chiral compound (XXIII) is worked up to give ezetimibe by the same reaction sequence used for its racemic analogue (XVI) but without optical resolution.
5) Racemic trans-azetidinone (XVI) can be submitted to chiral chromatography (Chiracel OD column), microbial or enzymatic subtractive resolution to provide the trans-(3R,4S)-azetidinone (XXIII) or direct microbial or enzymatic hydrolytic resolution to directly provide the trans-(3R,4S)-azetidinone-propionic acid (XXIV), the compound also obtained by hydrolysis of (XXIII) with LiOH. This (3R,4S)-free acid (XXIV) is treated with oxalyl chloride giving the (3R,4S)-acyl chloride (XXV), which by condensation with 4-fluorophenylmagnesium bromide (XIX) yields the (3R,4S)-azetidinone (XX). Reduction of (XX) with borane-dimethylsulfide complex in THF affords an equal mixture of diasteromeric alcohols that was submitted to chiral chromatography on a Chiracel OD column providing the benzylated (3'S)-alcohol (XI).
〖作者〗Castaer, R.M.; Sorbera, L.A.; Castaer, J.
〖参考〗Castaer, R.M.; Sorbera, L.A.; Castaer, J.; Ezetimibe. Drugs Fut , 679
〖出处〗Drugs Fut):679
〖备注〗Synthesis of Ezetimibe (EN:224366):
Ezetimibe can be obtained by several different ways:
1) The cyclization of 4(S)-hydroxytetrahydrofuran-2-one (I) with the benzylideneimine derivative (II) by means of LDA gives the trans-azetidinone (III) which is separated from its cis-isomer by crystallization. The oxidation of (III) with NaIO4 in acetonitrile yields the carbaldehyde (IV), which is condensed with the silylated enol ether (V), prepared from 4'-fluoroacetophenone (VI), Li and TMSCl, to afford compound (VII). The dehydration of (VII) by means of TsOH gives the enone (VIII), which is hydrogenated and debenzylated with H2 over Pd/C in ethanol, providing the saturated ketone (IX). Finally, this compound is enantioselectively reduced with borane and the chiral catalyst (R)-1-methyl-3,3-diphenylperhydropyrrolo[1,2-c][1,3,2]oxaazaborole (CBS) (1-3) (Scheme a).
2) Alternatively, the reduction of enone (VIII) with H2 over RhCl(PPh3)3 in dichloromethane gives the benzylated saturated ketone (X), which is enantioselectively reduced with borane and CBS, yielding the benzylated alcohol (XI). Finally, this compound is debenzylated with H2 over Pd/C in ethanol (1-3) (Scheme a).
3) The reaction of 4-hydroxybenzaldehyde (XII) with benzyl bromide and K2CO3 in acetone gives 4-(benzyloxy)benzaldehyde (XIII), which is condensed with 4-fluoroaniline (XIV) in isopropanol, yielding the imine (II). Cyclization of (II) with methyl 4-(chloroformyl)butyrate (XV) by means of tributylamine in toluene affords the trans-azetidinone (XVI), which is hydrolyzed with LiOH in THF/water to provide the propionic acid derivative (XVII). The reaction of (XVII) with oxalyl chloride in dichloromethane gives the corresponding acyl chloride (XVIII), which is condensed with 4-fluorophenylmagnesium bromide (XIX) by means of ZnCl2 and Pd(PPh3)4 in THF to yield a racemic mixture of saturated trans-azetidinones that was resolved by chiral HPLC to the trans-(3R,4S)-enantiomer (XX). The enantioselective reduction of (XX) with BH3 and the chiral oxaborole catalyst CBS gives the benzylated alcohol (XI) which is finally debenzylated as before with H2 over Pd/C in ethanol (4) (Scheme b).
4) The reaction of methyl 4-(chloroformyl)butyrate (XV) with the chiral oxazolidinone (XXI) by means of DMAP and TEA in dichloromethane gives the acylated oxazolidinone (XXII), which is cyclized with the benzylideneimine (II) by means of TiCl4, titanium isopropoxide and TBAF in dichloromethane, yielding trans-(3R,4S)-azetidinone (XXIII). This chiral compound (XXIII) is worked up to give ezetimibe by the same reaction sequence used for its racemic analog (XVI) but without optical resolution (5) (Scheme c).
5) Racemic trans-azetidinone (XVI) can be submitted to chiral chromatography (Chiracel OD column) (6), microbial or enzymatic subtractive resolution to provide the trans-(3R,4S)-azetidinone (XXIII) (7) or direct microbial or enzymatic hydrolytic resolution to directly provide the trans-(3R,4S)-azetidinone-propionic acid (XXIV) (7), the compound also obtained by hydrolysis of (XXIII) with LiOH (6,7). This (3R,4S)-free acid (XXIV) is treated with oxalyl chloride giving the (3R,4S)-acyl chloride (XXV) which by condensation with 4-fluorophenylmagnesium bromide (XIX) yields the (3R,4S)-azetidinone (XX). Reduction of (XX) with borane-dimethylsulfide complex in THF affords an equal mixture of diasteromeric alcohols that was submitted to chiral chromatography on a Chiracel OD column providing the benzylated (3'S)-alcohol (XI) (6) (Scheme c).
6) The reaction of 5-(4-fluorophenyl)-4-pentenoic acid (XXVI) with oxalyl chloride gives the acyl chloride (XXVII), which is condensed with the chiral oxazolidinone (XXI) by means of DMAP and DIEA in dichloromethane, yielding the acyloxazolidinone (XXVIII). Condensation of (XXVIII) with the benzylideneimine (II) by means of TiCl4 affords adduct (XXIX), which is cyclized to the chiral azetidinone (XXX). The oxidation of the double bond of (XXX) with benzoquinone and HClO4 catalyzed by Pd(OAc)2 in acetonitrile/water provides the already reported trans-(3R,4S)-azetidinone (XX), which is worked up to give azetimibe as described before (8) (Scheme d).
Manufacturer
Schering-Plough Corporation (US).
References
1. Wu, G.Z, Wong, Y.S, Chen, X., Ding, Z.; A novel one-step diastereo- and enantioselective formation of trans-azetidinones and its application to the total synthesis of cholesterol a J Org Chem 14-8.
2. Wu, G.-Z., Chen, X., Wong, Y.-S., Schumacher, D.P., Steinman, M. (Schering Corp.); 3-Hydroxy gamma-lactone based enantioselective synth WO 9745406.
3. Wu, G.-Z., Chen, X., Wong, Y.-S., Schumacher, D.P., Steinman, M. (Schering Corp.); 3-Hydroxy gamma-lactone based enantioselective synth US 5886171.
4. Vaccaro, W.D., Sher, R., Davis, H.R. Jr.; 2-Azetidinone cholesterol absorption inhibitors: Increased potency by substitution of the C-4 Bioorg Med Chem 29-37.
5. Rosenblum, S.B., Dugar, S., Burnett, D.A., Clader, J.W., McKittrick, B.A. (Schering Corp.); Hydroxy-substd. azetidinone cpds. useful as hypoch EP 0720599, JP , US 5631365, US 5767115, WO 9508532.
6. Rosenblum, S.B., Huynh, T., Afonso, A., Davis, H.R. Jr., Yumibe, N., Clader, J.W., Burnett, D.A.; Discovery of 1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]-(4S)-(4-hydroxyphenyl)-2-azetidinone (SCH 58235): A designed, potent, orally active inhibitor of ch J Med Chem 3-980.
7. Homann, M.J., Morgan, W.B. (Schering Corp.); Resolution of trans-2-(alkoxycarbonylethyl)-lactams useful in the synthesis of 1-(4-fluoro-phenyl)-3(R)-[(S)-hydroxy-3-(4-fluorophenyl)-propyl]-4(S)-(4-hydroxyphenyl)-2- US 5919672.
8. Shankar, B.B. (Schering Corp.); Process for preparing 1-(4-fluorophenyl)-3(R)-(3(S)-hydroxy-3-([phenyl or 4-fluorophenyl])-propyl)-4(S)-(4-hydroxyphenyl)-2- US 5856473, WO 9716424.
〖来源〗Drugs Fut
〖合成路线〗
〖标题〗Ezetimibe
〖合成方法〗6) The reaction of 5-(4-fluorophenyl)-4-pentenoic acid (XXVI) with oxalyl chloride gives the acyl chloride (XXVII), which is condensed with the chiral oxazolidinone (XXI) by means of DMAP and DIEA in dichloromethane, yielding the acyloxazolidinone (XXVIII). Condensation of (XXVIII) with the benzylideneimine (II) by means of TiCl4 affords adduct (XXIX), which is cyclized to the chiral azetidinone (XXX). The oxidation of the double bond of (XXX) with benzoquinone and HClO4 catalyzed by Pd(OAc)2 in acetonitrile/water provides the previously reported trans-(3R,4S)-azetidinone (XX), which is worked up to give azetimibe as described before.
〖作者〗Castaer, R.M.; Sorbera, L.A.; Castaer, J.
〖参考〗Castaer, R.M.; Sorbera, L.A.; Castaer, J.; Ezetimibe. Drugs Fut , 679
〖出处〗Drugs Fut):679
〖备注〗Synthesis of Ezetimibe (EN:224366):
Ezetimibe can be obtained by several different ways:
1) The cyclization of 4(S)-hydroxytetrahydrofuran-2-one (I) with the benzylideneimine derivative (II) by means of LDA gives the trans-azetidinone (III) which is separated from its cis-isomer by crystallization. The oxidation of (III) with NaIO4 in acetonitrile yields the carbaldehyde (IV), which is condensed with the silylated enol ether (V), prepared from 4'-fluoroacetophenone (VI), Li and TMSCl, to afford compound (VII). The dehydration of (VII) by means of TsOH gives the enone (VIII), which is hydrogenated and debenzylated with H2 over Pd/C in ethanol, providing the saturated ketone (IX). Finally, this compound is enantioselectively reduced with borane and the chiral catalyst (R)-1-methyl-3,3-diphenylperhydropyrrolo[1,2-c][1,3,2]oxaazaborole (CBS) (1-3) (Scheme a).
2) Alternatively, the reduction of enone (VIII) with H2 over RhCl(PPh3)3 in dichloromethane gives the benzylated saturated ketone (X), which is enantioselectively reduced with borane and CBS, yielding the benzylated alcohol (XI). Finally, this compound is debenzylated with H2 over Pd/C in ethanol (1-3) (Scheme a).
3) The reaction of 4-hydroxybenzaldehyde (XII) with benzyl bromide and K2CO3 in acetone gives 4-(benzyloxy)benzaldehyde (XIII), which is condensed with 4-fluoroaniline (XIV) in isopropanol, yielding the imine (II). Cyclization of (II) with methyl 4-(chloroformyl)butyrate (XV) by means of tributylamine in toluene affords the trans-azetidinone (XVI), which is hydrolyzed with LiOH in THF/water to provide the propionic acid derivative (XVII). The reaction of (XVII) with oxalyl chloride in dichloromethane gives the corresponding acyl chloride (XVIII), which is condensed with 4-fluorophenylmagnesium bromide (XIX) by means of ZnCl2 and Pd(PPh3)4 in THF to yield a racemic mixture of saturated trans-azetidinones that was resolved by chiral HPLC to the trans-(3R,4S)-enantiomer (XX). The enantioselective reduction of (XX) with BH3 and the chiral oxaborole catalyst CBS gives the benzylated alcohol (XI) which is finally debenzylated as before with H2 over Pd/C in ethanol (4) (Scheme b).
4) The reaction of methyl 4-(chloroformyl)butyrate (XV) with the chiral oxazolidinone (XXI) by means of DMAP and TEA in dichloromethane gives the acylated oxazolidinone (XXII), which is cyclized with the benzylideneimine (II) by means of TiCl4, titanium isopropoxide and TBAF in dichloromethane, yielding trans-(3R,4S)-azetidinone (XXIII). This chiral compound (XXIII) is worked up to give ezetimibe by the same reaction sequence used for its racemic analog (XVI) but without optical resolution (5) (Scheme c).
5) Racemic trans-azetidinone (XVI) can be submitted to chiral chromatography (Chiracel OD column) (6), microbial or enzymatic subtractive resolution to provide the trans-(3R,4S)-azetidinone (XXIII) (7) or direct microbial or enzymatic hydrolytic resolution to directly provide the trans-(3R,4S)-azetidinone-propionic acid (XXIV) (7), the compound also obtained by hydrolysis of (XXIII) with LiOH (6,7). This (3R,4S)-free acid (XXIV) is treated with oxalyl chloride giving the (3R,4S)-acyl chloride (XXV) which by condensation with 4-fluorophenylmagnesium bromide (XIX) yields the (3R,4S)-azetidinone (XX). Reduction of (XX) with borane-dimethylsulfide complex in THF affords an equal mixture of diasteromeric alcohols that was submitted to chiral chromatography on a Chiracel OD column providing the benzylated (3'S)-alcohol (XI) (6) (Scheme c).
6) The reaction of 5-(4-fluorophenyl)-4-pentenoic acid (XXVI) with oxalyl chloride gives the acyl chloride (XXVII), which is condensed with the chiral oxazolidinone (XXI) by means of DMAP and DIEA in dichloromethane, yielding the acyloxazolidinone (XXVIII). Condensation of (XXVIII) with the benzylideneimine (II) by means of TiCl4 affords adduct (XXIX), which is cyclized to the chiral azetidinone (XXX). The oxidation of the double bond of (XXX) with benzoquinone and HClO4 catalyzed by Pd(OAc)2 in acetonitrile/water provides the already reported trans-(3R,4S)-azetidinone (XX), which is worked up to give azetimibe as described before (8) (Scheme d).
Manufacturer
Schering-Plough Corporation (US).
References
1. Wu, G.Z, Wong, Y.S, Chen, X., Ding, Z.; A novel one-step diastereo- and enantioselective formation of trans-azetidinones and its application to the total synthesis of cholesterol a J Org Chem 14-8.
2. Wu, G.-Z., Chen, X., Wong, Y.-S., Schumacher, D.P., Steinman, M. (Schering Corp.); 3-Hydroxy gamma-lactone based enantioselective synth WO 9745406.
3. Wu, G.-Z., Chen, X., Wong, Y.-S., Schumacher, D.P., Steinman, M. (Schering Corp.); 3-Hydroxy gamma-lactone based enantioselective synth US 5886171.
4. Vaccaro, W.D., Sher, R., Davis, H.R. Jr.; 2-Azetidinone cholesterol absorption inhibitors: Increased potency by substitution of the C-4 Bioorg Med Chem 29-37.
5. Rosenblum, S.B., Dugar, S., Burnett, D.A., Clader, J.W., McKittrick, B.A. (Schering Corp.); Hydroxy-substd. azetidinone cpds. useful as hypoch EP 0720599, JP , US 5631365, US 5767115, WO 9508532.
6. Rosenblum, S.B., Huynh, T., Afonso, A., Davis, H.R. Jr., Yumibe, N., Clader, J.W., Burnett, D.A.; Discovery of 1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]-(4S)-(4-hydroxyphenyl)-2-azetidinone (SCH 58235): A designed, potent, orally active inhibitor of ch J Med Chem 3-980.
7. Homann, M.J., Morgan, W.B. (Schering Corp.); Resolution of trans-2-(alkoxycarbonylethyl)-lactams useful in the synthesis of 1-(4-fluoro-phenyl)-3(R)-[(S)-hydroxy-3-(4-fluorophenyl)-propyl]-4(S)-(4-hydroxyphenyl)-2- US 5919672.
8. Shankar, B.B. (Schering Corp.); Process for preparing 1-(4-fluorophenyl)-3(R)-(3(S)-hydroxy-3-([phenyl or 4-fluorophenyl])-propyl)-4(S)-(4-hydroxyphenyl)-2- US 5856473, WO 9716424.
〖来源〗J Label Compd Radiopharm
〖合成路线〗
〖标题〗Synthesis of 3H, 14C and 13C6 labelled Sch 58235
〖合成方法〗The 3H-labeling of SCH-58235 has been performed by hydrogen/tritium exchange catalyzed by Crabtree's catalyst [Ir(COD)(Cy3P)PyF6] in dichloromethane.
〖作者〗Hesk, D.; et al.
〖参考〗Hesk, D.; et al.; Synthesis of 3H, 14C and 13C6 labelled Sch 58235. J Label Compd Radiopharm , 145
〖出处〗J Label Compd Radiopharm):145
〖来源〗J Label Compd Radiopharm
〖合成路线〗
〖标题〗Synthesis of 3H, 14C and 13C6 labelled Sch 58235
〖合成方法〗The enantioselective reduction of the oxazolidinone (I) with BH3/SMe2 and a chiral borinated catalyst gives the (S)-alcohol (II), which is condensed with the labeled imine (III) (prepared by reaction of 4-fluoroaniline (IV) and 13C-labeled 4-hydroxybenzaldehyde (V)) by means of TiCl4 in dichloromethane to yield the silylated adduct (VI) (previously the reactants are silylated with Tms-Cl and DIEA). Finally, adduct (VI) is resilylated with bis(trimethylsilyl)acetamide and cyclized and desilylated by treatment with TBAF in dichloromethane to afford the target 13C-labeled SCH-58235.
〖作者〗Hesk, D.; et al.
〖参考〗Hesk, D.; et al.; Synthesis of 3H, 14C and 13C6 labelled Sch 58235. J Label Compd Radiopharm , 145
〖出处〗J Label Compd Radiopharm):145
〖来源〗J Label Compd Radiopharm
〖合成路线〗
〖标题〗Synthesis of 3H, 14C and 13C6 labelled Sch 58235
〖合成方法〗The enantioselective reduction of the oxazolidinone (I) with BH3/SMe2 and a chiral borinated catalyst gives the (S)-alcohol (II), which is condensed with the labeled imine (III) (prepared by reaction of 4-fluoroaniline (IV) and 14C-labeled 4-hydroxybenzaldehyde (V)) by means of TiCl4 in dichloromethane to yield the silylated adduct (VI) (previously the reactants are silylated with Tms-Cl and DIEA). Finally, adduct (VI) is resilylated with bis(trimethylsilyl)acetamide and cyclized and desilylated by treatment with TBAF in dichloromethane to afford the target 14C-labeled SCH-58235.
〖作者〗Hesk, D.; et al.
〖参考〗Hesk, D.; et al.; Synthesis of 3H, 14C and 13C6 labelled Sch 58235. J Label Compd Radiopharm , 145
〖出处〗J Label Compd Radiopharm):145
〖来源〗Tetrahedron Lett
〖合成路线〗
〖标题〗Process for preparing ezetimibe intermediate by an acid enhanced chemo- and enantioselective CBS catalyzed ketone reduction
〖合成方法〗The activation of 5-(4-fluorophenyl)-5-oxopentanoic acid (I) with pivaloyl chloride (II) gives the mixed anhydride (III), which is condensed with the chiral oxazolidinone (IV) by means of DMAP to yield the acylated oxazolidine (V) (1). The asymmetric reduction of (V) by means of BH3/Me2S catalyzed by the chiral boron catalyst (VI) affords the chiral alcohol (VII) (1-3), which is condensed with the imine (VIII) by means of Tms-Cl, DIEA and TiCl4 to provide the adduct (IX). The cyclization of (IX) by means of bis(trimethylsilyl)acetamide and TBAF gives the protected azetidinone (X), which is finally desilylated by means of sulfuric acid in isopropanol
〖作者〗Fu, X.Y.; et al.
〖参考〗Fu, X.Y.; et al.; Process for preparing ezetimibe intermediate by an acid enhanced chemo- and enantioselective CBS catalyzed ketone reduction. Tetrahedron Lett , 801
〖出处〗Tetrahedron Lett):801
〖来源〗WO 9745406
〖合成路线〗
〖标题〗3-Hydroxy gamma-lactone based enantioselective synthesis of azetidinones
〖合成方法〗1) The cyclization of 4(S)-hydroxytetrahydrofuran-2-one (I) with the benzylideneimine derivative (II) by means of LDA gives the trans-azetidinone (III), which is separated from its cis-isomer by crystallization. The oxidation of (III) with NaIO4 in acetonitrile yields the carbaldehyde (IV), which is condensed with the silylated enol ether (V), prepared from 4'-fluoroacetophenone (VI), Li and TMSCl, to afford compound (VII). The dehydration of (VII) by means of TsOH gives the enone (VIII), which is hydrogenated and debenzylated with H2 over Pd/C in ethanol, providing the saturated ketone (IX). Finally, this compound is enantioselectively reduced with borane and the chiral catalyst (R)-1-methyl-3,3-diphenylperhydropyrrolo[1,2-c][1,3,2]oxaazaborole (CBS).
2) Alternatively, the reduction of enone (VIII) with H2 over RhCl(PPh3)3 in dichloromethane gives the benzylated saturated ketone (X), which is enantioselectively reduced with borane and CBS, yielding the benzylated alcohol (XI). Finally, this compound is debenzylated with H2 over Pd/C in ethanol.
〖作者〗Steinman, M.; Schumacher, D.P.; Chen, X.; Wu, G.-Z.; Wong, Y.-S. (Schering Corp.)
〖参考〗Steinman, M.; Schumacher, D.P.; Chen, X.; Wu, G.-Z.; Wong, Y.-S. (Schering Corp.); 3-Hydroxy gamma-lactone based enantioselective synthesis of azetidinones. WO 9745406
〖出处〗WO 9745406,,():
〖来源〗US 5886171
〖合成路线〗
〖标题〗3-Hydroxy gamma-lactone based enantioselective synthesis of azetidinones
〖合成方法〗1) The cyclization of 4(S)-hydroxytetrahydrofuran-2-one (I) with the benzylideneimine derivative (II) by means of LDA gives the trans-azetidinone (III), which is separated from its cis-isomer by crystallization. The oxidation of (III) with NaIO4 in acetonitrile yields the carbaldehyde (IV), which is condensed with the silylated enol ether (V), prepared from 4'-fluoroacetophenone (VI), Li and TMSCl, to afford compound (VII). The dehydration of (VII) by means of TsOH gives the enone (VIII), which is hydrogenated and debenzylated with H2 over Pd/C in ethanol, providing the saturated ketone (IX). Finally, this compound is enantioselectively reduced with borane and the chiral catalyst (R)-1-methyl-3,3-diphenylperhydropyrrolo[1,2-c][1,3,2]oxaazaborole (CBS).
2) Alternatively, the reduction of enone (VIII) with H2 over RhCl(PPh3)3 in dichloromethane gives the benzylated saturated ketone (X), which is enantioselectively reduced with borane and CBS, yielding the benzylated alcohol (XI). Finally, this compound is debenzylated with H2 over Pd/C in ethanol.
〖作者〗Wu, G.-Z.; Chen, X.; Wong, Y.-S.; Schumacher, D.P.; Steinman, M.
〖参考〗Wu, G.-Z.; Chen, X.; Wong, Y.-S.; Schumacher, D.P.; Steinman, M.; 3-Hydroxy gamma-lactone based enantioselective synthesis of azetidinones. US 5886171
〖出处〗US 5886171,,():
〖来源〗EP 0720599; JP ; US 5631365; WO 9508532
〖合成路线〗
〖标题〗Hydroxy-substd. azetidinone cpds. useful as hypocholesterolemic agents
〖合成方法〗3) The reaction of 4-hydroxybenzaldehyde (XII) with benzyl bromide and K2CO3 in acetone gives 4-(benzyloxy)benzaldehyde (XIII), which is condensed with 4-fluoroaniline (XIV) in isopropanol, yielding the imine (II). Cyclization of (II) with methyl 4-(chloroformyl)butyrate (XV) by means of tributylamine in toluene affords the trans-azetidinone (XVI), which is hydrolyzed with LiOH in THF/water to provide the propionic acid derivative (XVII). The reaction of (XVII) with oxalyl chloride in dichloromethane gives the corresponding acyl chloride (XVIII), which is condensed with 4-fluorophenylmagnesium bromide (XIX) by means of ZnCl2 and Pd(PPh3)4 in THF to yield a racemic mixture of saturated trans-azetidinones that was resolved by chiral HPLC to the trans-(3R,4S)-enantiomer (XX). The enantioselective reduction of (XX) with BH3 and the chiral oxaborole catalyst CBS gives the benzylated alcohol (XI), which is finally debenzylated as before with H2 over Pd/C in ethanol.
〖作者〗Rosenblum, S.B.; Dugar, S.; Burnett, D.A.; Clader, J.W.; McKittrick, B.A. (Schering Corp.)
〖参考〗Rosenblum, S.B.; Dugar, S.; Burnett, D.A.; Clader, J.W.; McKittrick, B.A. (Schering Corp.); Hydroxy-substd. azetidinone cpds. useful as hypocholesterolemic agents. EP 0720599; JP ; US 5631365; WO 9508532
〖出处〗EP 0720599; JP ; US 5631365; WO 9508532,,():
〖来源〗US 5919672
〖合成路线〗
〖标题〗Resolution of trans-2-(alkoxycarbonylethyl)-lactams useful in the synthesis of 1-(4-fluoro-phenyl)-3(R)-[(S)-hydroxy-3-(4-fluorophenyl)-propyl]-4(S)-(4-hydroxyphenyl)-2-azetidinone
〖合成方法〗4) The reaction of methyl 4-(chloroformyl)butyrate (XV) with the chiral oxazolidinone (XXI) by means of DMAP and TEA in dichloromethane gives the acylated oxazolidinone (XXII), which is cyclized with the benzylideneimine (II) by means of TiCl4, titanium isopropoxide and TBAF in dichloromethane, yielding trans-(3R,4S)-azetidinone (XXIII). This chiral compound (XXIII) is worked up to give ezetimibe by the same reaction sequence used for its racemic analogue (XVI) but without optical resolution.
5) Racemic trans-azetidinone (XVI) can be submitted to chiral chromatography (Chiracel OD column), microbial or enzymatic subtractive resolution to provide the trans-(3R,4S)-azetidinone (XXIII) or direct microbial or enzymatic hydrolytic resolution to directly provide the trans-(3R,4S)-azetidinone-propionic acid (XXIV), the compound also obtained by hydrolysis of (XXIII) with LiOH. This (3R,4S)-free acid (XXIV) is treated with oxalyl chloride giving the (3R,4S)-acyl chloride (XXV), which by condensation with 4-fluorophenylmagnesium bromide (XIX) yields the (3R,4S)-azetidinone (XX). Reduction of (XX) with borane-dimethylsulfide complex in THF affords an equal mixture of diasteromeric alcohols that was submitted to chiral chromatography on a Chiracel OD column providing the benzylated (3'S)-alcohol (XI).
〖作者〗Homann, M.J.; Morgan, W.B. (Schering Corp.)
〖参考〗Homann, M.J.; Morgan, W.B. (Schering Corp.); Resolution of trans-2-(alkoxycarbonylethyl)-lactams useful in the synthesis of 1-(4-fluoro-phenyl)-3(R)-[(S)-hydroxy-3-(4-fluorophenyl)-propyl]-4(S)-(4-hydroxyphenyl)-2-azetidinone. US 5919672
〖出处〗US 5919672,,():
〖来源〗US 5856473; WO 9716424
〖合成路线〗
〖标题〗Process for preparing 1-(4-fluorophenyl)-3(R)-(3(S)-hydroxy-3-([phenyl or 4-fluorophenyl])-propyl)-4(S)-(4-hydroxyphenyl)-2-azetidinone
〖合成方法〗6) The reaction of 5-(4-fluorophenyl)-4-pentenoic acid (XXVI) with oxalyl chloride gives the acyl chloride (XXVII), which is condensed with the chiral oxazolidinone (XXI) by means of DMAP and DIEA in dichloromethane, yielding the acyloxazolidinone (XXVIII). Condensation of (XXVIII) with the benzylideneimine (II) by means of TiCl4 affords adduct (XXIX), which is cyclized to the chiral azetidinone (XXX). The oxidation of the double bond of (XXX) with benzoquinone and HClO4 catalyzed by Pd(OAc)2 in acetonitrile/water provides the previously reported trans-(3R,4S)-azetidinone (XX), which is worked up to give azetimibe as described before.
〖作者〗Shankar, B.B. (Schering Corp.)
〖参考〗Shankar, B.B. (Schering Corp.); Process for preparing 1-(4-fluorophenyl)-3(R)-(3(S)-hydroxy-3-([phenyl or 4-fluorophenyl])-propyl)-4(S)-(4-hydroxyphenyl)-2-azetidinone. US 5856473; WO 9716424
〖出处〗US 5856473; WO 9716424,,():
〖来源〗US ; WO 0279174
〖合成路线〗
〖标题〗Enantioselective synthesis of azetidinone intermediate cpds.
〖合成方法〗The activation of 5-(4-fluorophenyl)-5-oxopentanoic acid (I) with pivaloyl chloride (II) gives the mixed anhydride (III), which is condensed with the chiral oxazolidinone (IV) by means of DMAP to yield the acylated oxazolidine (V) (1). The asymmetric reduction of (V) by means of BH3/Me2S catalyzed by the chiral boron catalyst (VI) affords the chiral alcohol (VII) (1-3), which is condensed with the imine (VIII) by means of Tms-Cl, DIEA and TiCl4 to provide the adduct (IX). The cyclization of (IX) by means of bis(trimethylsilyl)acetamide and TBAF gives the protected azetidinone (X), which is finally desilylated by means of sulfuric acid in isopropanol
〖作者〗Thiruvengadam, T.K.; Tann, C.-H.; Fu, X.; McAllister, T.L. (Schering Corp.)
〖参考〗Thiruvengadam, T.K.; Tann, C.-H.; Fu, X.; McAllister, T.L. (Schering Corp.); Enantioselective synthesis of azetidinone intermediate cpds.. US ; WO 0279174
〖出处〗US ; WO 0279174,,():
本文导航：
Ezetimibe, SCH-58235, Ezetrol, Zetia,-1, -
上一篇：暂无}
扫扫二维码，随身浏览文档
手机或平板扫扫即可继续访问
降血脂综述
举报该文档为侵权文档。
举报该文档含有违规或不良信息。
反馈该文档无法正常浏览。
举报该文档为重复文档。
推荐理由：
将文档分享至：
分享完整地址
文档地址：
粘贴到BBS或博客
flash地址：
支持嵌入FLASH地址的网站使用
html代码：
&embed src='/DocinViewer-4.swf' width='100%' height='600' type=application/x-shockwave-flash ALLOWFULLSCREEN='true' ALLOWSCRIPTACCESS='always'&&/embed&
450px*300px480px*400px650px*490px
支持嵌入HTML代码的网站使用
您的内容已经提交成功
您所提交的内容需要审核后才能发布，请您等待！
3秒自动关闭窗口新功能、新界面、新体验，扫描即可下载生物谷APP!
>> 新年伊始，当头一棒！默沙东降脂药Zetia和Vytorin扩大适应症申请遭FDA否决
新年伊始，当头一棒！默沙东降脂药Zetia和Vytorin扩大适应症申请遭FDA否决
来源：生物谷
日 讯 /生物谷BIOON/ --美国制药巨头默沙东（Merck & Co）最近悲剧了，降脂药Zetia（ezetimibe，依折麦布）和Vytorin（Zetia和辛伐他汀的复方药）减少冠心病患者心血管事件风险的扩大适应症申请，继去年底被FDA顾问小组以10:5的投票否决之后，近日也被FDA正式拒绝。
目前，Zetia和Vytorin已在美国上市销售，其适应症为结合健康饮食降低高血脂患者升高的低密度脂蛋白胆固醇（LDL-C）水平。而默沙东所提交的申请，寻求批准扩大这2种药物的治疗范畴，纳入降低冠心病患者发生心血管疾病的风险，具体包括心脏病发作、中风、心血管死亡、不稳定性心绞痛住院、血管重建等。
该申请是依据2015年初发布的IMPROVE-IT临床研究的结果，该研究规模非常庞大，涉及1.8万例患者，前后历时七年，耗资巨大。研究结果显示，将Zetia添加至他汀类疗法，使心血管并发症风险实现统计学意义的显著降低。具体为，使用Vytorin（Zetia+辛伐他汀的复方药）7年比单独使用辛伐他汀降低2个百分点的心肌梗塞和中风事件（32.7%对34.7%），即7年心血管事件相对风险降低6.4%，达到复合终点。
但是FDA顾问小组认为，Vytorin减少心血管事件风险6.4%，尽管这个数据在统计学上具有显著差异性，但疗效实际较小，而且还只是针对特定类型的患者，如老年人和糖尿病患者。换算过来，也就是50个病人使用7年（按现在Vytorin的价格就要花88万美元）才能避免一例心肌梗塞或中风事件。并且Vytorin并没有降低死亡率，只是减少了心肌梗塞或中风事件。
之前，FDA顾问小组成员之一贝勒大学医学中心博士Milton Packer表示，对于Vytorin和Zetia而言，这些疗效太小，不够显著，不足以改变其药物标签。而且这点疗效，甚至小到你一眨眼就错过了，小到你自己都质疑是否需要在乎这点疗效。
不过也有一些小组成员不赞同Milton Packer的观点。至少一个成员表示，FDA的任务是确定临床结果是否有统计学上的显著意义，至于这些数据是否能达到临床实际效果的意义，则应该由其他人来决定，包括患者和纳税人。
很显然，FDA的正式拒绝对默沙东而言无疑是当头一棒。针对这一情况，默沙东表示，正在仔细审查FDA的意见，以便下一步的行动。
另外，业界预测这一状况也将对降脂领域的新一代降脂药PCSK9抑制剂的商业前景带来短期影响。之前曾有分析师预计，安进的降脂药Repatha和赛诺菲/再生元的降脂药Praluent将受益于默沙东IMPROVE-IT研究的结果，即一种附加的非他汀类药物通过更大幅度降低低密度脂蛋白胆固醇（LDL-C）水平，可能降低心血管风险。这2个药物各自的早期临床数据预计在今年晚些时候能够获得。（生物谷）
原始出处：
本文系生物谷原创编译整理，欢迎转载！点击
。更多资讯请下载。
温馨提示：87%用户都在上阅读，扫描立刻下载! 天天精彩！
...（全文约2240字）
旗下网站： |
Copyright&2001- 版权所有 不得转载.关注今日：13 | 主题：410843
微信扫一扫
扫一扫，下载丁香园 App
即送15丁当
【科普】可以替代他汀类药物的降脂药
页码直达：
丁香园准中级站友
这个帖子发布于6年零118天前，其中的信息可能已发生改变或有所发展。
Ask the doctor: What are the alternatives to a statin for lowering cholesterol?Q. I have tried all of the statin drugs to lower my cholesterol, but each one has caused severe muscle pain. Are there any non-statin medications I could try using to lower my cholesterol?A. Have you tried niacin yet? It is an excellent drug for reducing cardiac risk in almost every way — it lowers harmful LDL cholesterol, raises beneficial HDL, and reduces cardiac complications. One reason it plays second fiddle to statins is that it causes side effects like itching and flushing in many people. These side effects can often be minimized or even eliminated by taking an aspirin before niacin, by gradually building up the dose, or by taking the intermediate-release type called Niaspan, which is available by prescription only.Two other drugs that may be used in place of a statin are ezetimibe (Zetia) and colesevelam (Welchol). Both of these medications work in the intestines, rather than the bloodstream, and so are less likely than statins to cause side effects. Ezetimibe blocks cholesterol in food from crossing the intestinal wall and getting into the bloodstream. Colesevelam grabs cholesterol-rich bile acids in the intestine and locks them into a watery goo that is excreted in the stool.Ezetimibe has been controversial since trials showed it adds little to cardiac protection. Colesevelam might be a good choice if you have diabetes because it lowers blood sugar as well as cholesterol.What you eat can help lower cholesterol. Switching from an average American diet to a Mediterranean-type diet can lower cholesterol and blood pressure. Researchers at the University of Toronto created what they called a &dietary portfolio of cholesterol-lowering foods& that included margarine enriche oats, barley, psyllium, okra, and eggplant, all r and whole almonds. A diet emphasizing these foods substantially lowered LDL, triglycerides, and blood pressure, and did not harm HDL. Eating nuts can modestly lower cholesterol.Fish oil and garlic have long been touted as cholesterol reducers, but meta-analyses of clinical trials show they have little effect on cholesterol. Substances that do lower cholesterol are plant sterols and stanols. They have been added to margarine (Benecol, Promise, others), orange juice, granola bars, chocolate, and other foods. They are also available as plain, no-calorie pills.— Thomas Lee, M.D.Editor in chief, Harvard Heart Letter
不知道邀请谁？试试他们
微信扫一扫
广告宣传推广
政治敏感、违法虚假信息
恶意灌水、重复发帖
违规侵权、站友争执
附件异常、链接失效
qiuyuming edited on
丁香园准中级站友
认领此文，48小时内上交。
微信扫一扫
广告宣传推广
政治敏感、违法虚假信息
恶意灌水、重复发帖
违规侵权、站友争执
附件异常、链接失效
丁香园准中级站友
降脂药，他汀类药物的选择Ask the doctor: What are the alternatives to a statin for lowering cholesterol?Q. I have tried all of the statin drugs to lower my cholesterol, but each one has caused severe muscle pain. Are there any non-statin medications I could try using to lower my cholesterol?问：为了降低血胆固醇，我尝试了各种他汀类药物，但每一种他汀药物服用后均引起剧烈的肌肉疼痛。我想知道，临床上有没有其他的药物用于降低胆固醇？A. Have you tried niacin yet? It is an excellent drug for reducing cardiac risk in almost every way — it lowers harmful LDL cholesterol, raises beneficial HDL, and reduces cardiac complications. One reason it plays second fiddle to statins is that it causes side effects like itching and flushing in many people. These side effects can often be minimized or even eliminated by taking an aspirin before niacin, by gradually building up the dose, or by taking the intermediate-release type called Niaspan, which is available by prescription only.答：不知道你有没有服用过烟酸这种药？烟酸可以通过各种机制来降低心血管疾病的风险，比如，它能降低对人体有害的低密度脂蛋白胆固醇，升高对人体有益的高密度脂蛋白胆固醇，并可以减少心血管并发症。临床应用中，烟酸与他汀类相比，烟酸一般不作为首选，这是由于烟酸能引起部分人皮肤发痒和面部潮红，临床上一般采用如下方法来减少或消除这些副作用，比如在服用烟酸前先口服一片阿司匹林，或者使用逐渐增加烟酸剂量的办法，或者服用一种叫Niaspan的中间释放剂型（Niaspan是处方药）。Two other drugs that may be used in place of a statin are ezetimibe (Zetia) and colesevelam (Welchol). Both of these medications work in the intestines, rather than the bloodstream, and so are less likely than statins to cause side effects. Ezetimibe blocks cholesterol in food from crossing the intestinal wall and getting into the bloodstream. Colesevelam grabs cholesterol-rich bile acids in the intestine and locks them into a watery goo that is excreted in the stool.另外还有两种可以替代他汀类药的是Ezetimibe和Colesevelam。这两种药物都是在肠道内而非血液内发挥作用，所以较少引起象他汀类药物那样的副作用。Ezetimibe通过阻止食物中的胆固醇经肠道吸收进入血液，而Colesevelam的作用机理是在肠道内竞争结合胆汁酸中的胆固醇，然后随粪便一道排出。Ezetimibe has been controversial since trials showed it adds little to cardiac protection. 自从有试验表明Ezetimibe不具有心血管保护作用，对其是否应该使用长期以来一直争议不断。Colesevelam might be a good choice if you have diabetes because it lowers blood sugar as well as cholesterol.如果高胆固醇血症的患者同时还伴有糠尿病，那么使用Colesevelam将是一个较好的选择，因为其不仅能降低胆固醇，还能降低血糠。What you eat can help lower cholesterol. Switching from an average American diet to a Mediterranean-type diet can lower cholesterol and blood pressure. Researchers at the University of Toronto created what they called a &dietary portfolio of cholesterol-lowering foods& that included margarine enriche oats, barley, psyllium, okra, and eggplant, all r and whole almonds. A diet emphasizing these foods substantially lowered LDL, triglycerides, and blood pressure, and did not harm HDL. Eating nuts can modestly lower cholesterol.日常的饮食习惯对血液中的胆固醇影响较大。如果美洲居民采用了地中海地区居民的饮食习惯，将有助于降低其较高的胆固醇和血压。多伦多大学的研究人员发明一种新的饮食搭配，将其命名为“低胆固醇饮食组合”，其组成包括：富含植物固醇的人造黄油；富含可溶性纤维的燕麦片、大麦、车前子、黄秋葵、茄子；大豆蛋白；杏仁等。这个饮食搭配能有力地降低低密度脂蛋白胆固醇、甘油三酯和血压，对高密度脂蛋白胆固醇却没有影响。坚果类食物也能轻度降低胆固醇。Fish oil and garlic have long been touted as cholesterol reducers, but meta-analyses of clinical trials show they have little effect on cholesterol. Substances that do lower cholesterol are plant sterols and stanols. They have been added to margarine (Benecol, Promise, others), orange juice, granola bars, chocolate, and other foods. They are also available as plain, no-calorie pills.— Thomas Lee, M.D.Editor in chief, Harvard Heart Letter 长期以来，人们一直信奉鱼油和大蒜能强力降低胆固醇，但是，临床试验的meta分析显示，这两食物对降低胆固醇基本没有作用。食物中确定具有降低胆固醇作用的是植物固醇。目前，人们已经在人造黄油、桔汁、燕麦条、巧克力及其它一些食物中添加了植物固醇。植物固醇也被制成了不含添加剂的无热量糖丸。编译
（大约857字）降脂药，他汀类药物的选择问：为了降低血胆固醇，我尝试了各种他汀类药物，但每一种他汀药物服用后均引起剧烈的肌肉疼痛。我想知道，临床上有没有其他的药物用于降低胆固醇？答：不知道你有没有服用过烟酸这种药？烟酸可以通过各种机制来降低心血管疾病的风险，比如，它能降低对人体有害的低密度脂蛋白胆固醇，升高对人体有益的高密度脂蛋白胆固醇，并可以减少心血管并发症。临床应用中，烟酸与他汀类相比，烟酸一般不作为首选，这是由于烟酸能引起部分人皮肤发痒和面部潮红，临床上一般采用如下方法来减少或消除这些副作用，比如在服用烟酸前先口服一片阿司匹林，或者使用逐渐增加烟酸剂量的办法，或者服用一种叫Niaspan的中间释放剂型（Niaspan是处方药）。另外还有两种可以替代他汀类药的是Ezetimibe和Colesevelam。这两种药物都是在肠道内而非血液内发挥作用，所以较少引起象他汀类药物那样的副作用。Ezetimibe通过阻止食物中的胆固醇经肠道吸收进入血液，而Colesevelam的作用机理是在肠道内竞争结合胆汁酸中的胆固醇，然后随粪便一道排出。自从有试验表明Ezetimibe不具有心血管保护作用，对其是否应该使用长期以来一直争议不断。如果高胆固醇血症的患者同时还伴有糠尿病，那么使用Colesevelam将是一个较好的选择，因为其不仅能降低胆固醇，还能降低血糠。日常的饮食习惯对血液中的胆固醇影响较大。如果美洲居民采用了地中海地区居民的饮食习惯，将有助于降低其较高的胆固醇和血压。多伦多大学的研究人员发明一种新的饮食搭配，将其命名为“低胆固醇饮食组合”，其组成包括：富含植物固醇的人造黄油；富含可溶性纤维的燕麦片、大麦、车前子、黄秋葵、茄子；大豆蛋白；杏仁等。这个饮食搭配能有力地降低低密度脂蛋白胆固醇、甘油三酯和血压，对高密度脂蛋白胆固醇却没有影响。坚果类食物也能轻度降低胆固醇。长期以来，人们一直信奉鱼油和大蒜能强力降低胆固醇，但是，临床试验的meta分析显示，这两食物对降低胆固醇基本没有作用。食物中确定具有降低胆固醇作用的是植物固醇。目前，人们已经在人造黄油、桔汁、燕麦条、巧克力及其它一些食物中添加了植物固醇。植物固醇也被制成了不含添加剂的无热量糖丸。丁香
微信扫一扫
广告宣传推广
政治敏感、违法虚假信息
恶意灌水、重复发帖
违规侵权、站友争执
附件异常、链接失效
关于丁香园& Ezetimibe, SCH-58235, Ezetrol, Zetia,-1, -
Ezetimibe, SCH-58235, Ezetrol, Zetia,-1, -
摘 要：Ezetimibe, SCH-58235, Ezetrol, Zetia,-1, -3 ([3R-[3alpha(R*),4beta]]-isomer),C24-H21-F2-N-O3,1-(4-Fluorophenyl)-3(R)-[3(S)-(4-fluorophenyl)-3-hydroxypropyl]-4(S)-(4-hydroxyphenyl)azetidin-2-one
【药物名称】Ezetimibe, SCH-58235, Ezetrol, Zetia
【化学名】1-(4-Fluorophenyl)-3(R)-[3(S)-(4-fluorophenyl)-3-hydroxypropyl]-4(S)-(4-hydroxyphenyl)azetidin-2-one
【CAS登记号】-1, -3 ([3R-[3alpha(R*),4beta]]-isomer)
【结构式】
【分子式】C24-H21-F2-N-O3
【分子量】409.437
【原研厂家】Essex (Originator), Schering-Plough (Originator), Merck & Co. (Licensee)
【作用类别】ENDOCRINE DRUGS, Lipoprotein Disorders, Treatment of , METABOLIC DRUGS, Therapy of Inborn Errors of Metabolism, Treatment of Diabetic Complications, Cholesterol Absorption Inhibitors
【研发状态】Launched-2002
【合成情况】
〖来源〗J Med Chem
〖合成路线〗
〖标题〗Discovery of 1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]-(4S)-(4-hydroxyphenyl)-2-azetidinone (SCH 58235): A designed, potent, orally active inhibitor of cholesterol absorption
〖合成方法〗Treatment of acid chloride (I) with tributylamine generated the corresponding ketene, which was cyclocondensed to imine (II) to produce the racemic trans b-lactam (III). Resolution of (III) into enantiomers was then achieved by preparative HPLC on a Chiralcel OD column. Subsequent saponification of the desired enantiomer with methanolic LiOH afforded acid (IV), which was converted to acid chloride (V) upon treatment with oxalyl chloride. Further Pd-mediated coupling of (V) with the arylzinc reagent (VI) provided ketone (VII). Then, carbonyl reduction with BH3-Me2S, followed by chromatographic separation of the isomers furnished alcohol (VIII), which was finally deprotected by hydrogenolysis over Pd/C to afford the target phenol.
〖作者〗Afonso, A.; Davis, H.R. Jr.; Huynh, T.; Yumibe, N.; Clader, J.W.; Burnett, D.A.; Rosenblum, S.B.
〖参考〗Afonso, A.; Davis, H.R. Jr.; Huynh, T.; Yumibe, N.; Clader, J.W.; Burnett, D.A.; Rosenblum, S.B.; Discovery of 1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]-(4S)-(4-hydroxyphenyl)-2-azetidinone (SCH 58235): A designed, potent, orally act (free base)/li>
li>??p耀?ul class="old_db">li>span>
〖出处〗J Med Chem):973
〖备注〗Treatment of acid chloride (I) with tributylamine generated the corresponding ketene, which was cyclocondensed to imine (II) to produce the racemic trans b-lactam (III). Resolution of (III) into enantiomers was then achieved by preparative HPLC on a Chiralcel OD column. Subsequent saponification of the desired enantiomer with methanolic LiOH afforded acid (IV), that was converted to acid chloride (V) upon treatment with oxalyl chloride. Further Pd-mediated coupling of (V) with the arylzinc reagent (VI) provided ketone (VII). Then, carbonyl reduction with BH3Me2S, followed by chromatographic separation of the isomers furnished alcohol (VIII), which was finally deprotected by hydrogenolysis over Pd/C to afford the target phenol.
〖来源〗Drugs Fut
〖合成路线〗
〖标题〗Ezetimibe
〖合成方法〗1) The cyclization of 4(S)-hydroxytetrahydrofuran-2-one (I) with the benzylideneimine derivative (II) by means of LDA gives the trans-azetidinone (III), which is separated from its cis-isomer by crystallization. The oxidation of (III) with NaIO4 in acetonitrile yields the carbaldehyde (IV), which is condensed with the silylated enol ether (V), prepared from 4'-fluoroacetophenone (VI), Li and TMSCl, to afford compound (VII). The dehydration of (VII) by means of TsOH gives the enone (VIII), which is hydrogenated and debenzylated with H2 over Pd/C in ethanol, providing the saturated ketone (IX). Finally, this compound is enantioselectively reduced with borane and the chiral catalyst (R)-1-methyl-3,3-diphenylperhydropyrrolo[1,2-c][1,3,2]oxaazaborole (CBS).
2) Alternatively, the reduction of enone (VIII) with H2 over RhCl(PPh3)3 in dichloromethane gives the benzylated saturated ketone (X), which is enantioselectively reduced with borane and CBS, yielding the benzylated alcohol (XI). Finally, this compound is debenzylated with H2 over Pd/C in ethanol.
〖作者〗Castaer, R.M.; Sorbera, L.A.; Castaer, J.
〖参考〗Castaer, R.M.; Sorbera, L.A.; Castaer, J.; Ezetimibe. Drugs Fut , 679
〖出处〗Drugs Fut):679
〖备注〗Synthesis of Ezetimibe (EN:224366):
Ezetimibe can be obtained by several different ways:
1) The cyclization of 4(S)-hydroxytetrahydrofuran-2-one (I) with the benzylideneimine derivative (II) by means of LDA gives the trans-azetidinone (III) which is separated from its cis-isomer by crystallization. The oxidation of (III) with NaIO4 in acetonitrile yields the carbaldehyde (IV), which is condensed with the silylated enol ether (V), prepared from 4'-fluoroacetophenone (VI), Li and TMSCl, to afford compound (VII). The dehydration of (VII) by means of TsOH gives the enone (VIII), which is hydrogenated and debenzylated with H2 over Pd/C in ethanol, providing the saturated ketone (IX). Finally, this compound is enantioselectively reduced with borane and the chiral catalyst (R)-1-methyl-3,3-diphenylperhydropyrrolo[1,2-c][1,3,2]oxaazaborole (CBS) (1-3) (Scheme a).
2) Alternatively, the reduction of enone (VIII) with H2 over RhCl(PPh3)3 in dichloromethane gives the benzylated saturated ketone (X), which is enantioselectively reduced with borane and CBS, yielding the benzylated alcohol (XI). Finally, this compound is debenzylated with H2 over Pd/C in ethanol (1-3) (Scheme a).
3) The reaction of 4-hydroxybenzaldehyde (XII) with benzyl bromide and K2CO3 in acetone gives 4-(benzyloxy)benzaldehyde (XIII), which is condensed with 4-fluoroaniline (XIV) in isopropanol, yielding the imine (II). Cyclization of (II) with methyl 4-(chloroformyl)butyrate (XV) by means of tributylamine in toluene affords the trans-azetidinone (XVI), which is hydrolyzed with LiOH in THF/water to provide the propionic acid derivative (XVII). The reaction of (XVII) with oxalyl chloride in dichloromethane gives the corresponding acyl chloride (XVIII), which is condensed with 4-fluorophenylmagnesium bromide (XIX) by means of ZnCl2 and Pd(PPh3)4 in THF to yield a racemic mixture of saturated trans-azetidinones that was resolved by chiral HPLC to the trans-(3R,4S)-enantiomer (XX). The enantioselective reduction of (XX) with BH3 and the chiral oxaborole catalyst CBS gives the benzylated alcohol (XI) which is finally debenzylated as before with H2 over Pd/C in ethanol (4) (Scheme b).
4) The reaction of methyl 4-(chloroformyl)butyrate (XV) with the chiral oxazolidinone (XXI) by means of DMAP and TEA in dichloromethane gives the acylated oxazolidinone (XXII), which is cyclized with the benzylideneimine (II) by means of TiCl4, titanium isopropoxide and TBAF in dichloromethane, yielding trans-(3R,4S)-azetidinone (XXIII). This chiral compound (XXIII) is worked up to give ezetimibe by the same reaction sequence used for its racemic analog (XVI) but without optical resolution (5) (Scheme c).
5) Racemic trans-azetidinone (XVI) can be submitted to chiral chromatography (Chiracel OD column) (6), microbial or enzymatic subtractive resolution to provide the trans-(3R,4S)-azetidinone (XXIII) (7) or direct microbial or enzymatic hydrolytic resolution to directly provide the trans-(3R,4S)-azetidinone-propionic acid (XXIV) (7), the compound also obtained by hydrolysis of (XXIII) with LiOH (6,7). This (3R,4S)-free acid (XXIV) is treated with oxalyl chloride giving the (3R,4S)-acyl chloride (XXV) which by condensation with 4-fluorophenylmagnesium bromide (XIX) yields the (3R,4S)-azetidinone (XX). Reduction of (XX) with borane-dimethylsulfide complex in THF affords an equal mixture of diasteromeric alcohols that was submitted to chiral chromatography on a Chiracel OD column providing the benzylated (3'S)-alcohol (XI) (6) (Scheme c).
6) The reaction of 5-(4-fluorophenyl)-4-pentenoic acid (XXVI) with oxalyl chloride gives the acyl chloride (XXVII), which is condensed with the chiral oxazolidinone (XXI) by means of DMAP and DIEA in dichloromethane, yielding the acyloxazolidinone (XXVIII). Condensation of (XXVIII) with the benzylideneimine (II) by means of TiCl4 affords adduct (XXIX), which is cyclized to the chiral azetidinone (XXX). The oxidation of the double bond of (XXX) with benzoquinone and HClO4 catalyzed by Pd(OAc)2 in acetonitrile/water provides the already reported trans-(3R,4S)-azetidinone (XX), which is worked up to give azetimibe as described before (8) (Scheme d).
Manufacturer
Schering-Plough Corporation (US).
References
1. Wu, G.Z, Wong, Y.S, Chen, X., Ding, Z.; A novel one-step diastereo- and enantioselective formation of trans-azetidinones and its application to the total synthesis of cholesterol a J Org Chem 14-8.
2. Wu, G.-Z., Chen, X., Wong, Y.-S., Schumacher, D.P., Steinman, M. (Schering Corp.); 3-Hydroxy gamma-lactone based enantioselective synth WO 9745406.
3. Wu, G.-Z., Chen, X., Wong, Y.-S., Schumacher, D.P., Steinman, M. (Schering Corp.); 3-Hydroxy gamma-lactone based enantioselective synth US 5886171.
4. Vaccaro, W.D., Sher, R., Davis, H.R. Jr.; 2-Azetidinone cholesterol absorption inhibitors: Increased potency by substitution of the C-4 Bioorg Med Chem 29-37.
5. Rosenblum, S.B., Dugar, S., Burnett, D.A., Clader, J.W., McKittrick, B.A. (Schering Corp.); Hydroxy-substd. azetidinone cpds. useful as hypoch EP 0720599, JP , US 5631365, US 5767115, WO 9508532.
6. Rosenblum, S.B., Huynh, T., Afonso, A., Davis, H.R. Jr., Yumibe, N., Clader, J.W., Burnett, D.A.; Discovery of 1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]-(4S)-(4-hydroxyphenyl)-2-azetidinone (SCH 58235): A designed, potent, orally active inhibitor of ch J Med Chem 3-980.
7. Homann, M.J., Morgan, W.B. (Schering Corp.); Resolution of trans-2-(alkoxycarbonylethyl)-lactams useful in the synthesis of 1-(4-fluoro-phenyl)-3(R)-[(S)-hydroxy-3-(4-fluorophenyl)-propyl]-4(S)-(4-hydroxyphenyl)-2- US 5919672.
8. Shankar, B.B. (Schering Corp.); Process for preparing 1-(4-fluorophenyl)-3(R)-(3(S)-hydroxy-3-([phenyl or 4-fluorophenyl])-propyl)-4(S)-(4-hydroxyphenyl)-2- US 5856473, WO 9716424.
〖来源〗J Org Chem
〖合成路线〗
〖标题〗A novel one-step diastereo- and enantioselective formation of trans-azetidinones and its application to the total synthesis of cholesterol absorption inhibitors
〖合成方法〗1) The cyclization of 4(S)-hydroxytetrahydrofuran-2-one (I) with the benzylideneimine derivative (II) by means of LDA gives the trans-azetidinone (III), which is separated from its cis-isomer by crystallization. The oxidation of (III) with NaIO4 in acetonitrile yields the carbaldehyde (IV), which is condensed with the silylated enol ether (V), prepared from 4'-fluoroacetophenone (VI), Li and TMSCl, to afford compound (VII). The dehydration of (VII) by means of TsOH gives the enone (VIII), which is hydrogenated and debenzylated with H2 over Pd/C in ethanol, providing the saturated ketone (IX). Finally, this compound is enantioselectively reduced with borane and the chiral catalyst (R)-1-methyl-3,3-diphenylperhydropyrrolo[1,2-c][1,3,2]oxaazaborole (CBS).
2) Alternatively, the reduction of enone (VIII) with H2 over RhCl(PPh3)3 in dichloromethane gives the benzylated saturated ketone (X), which is enantioselectively reduced with borane and CBS, yielding the benzylated alcohol (XI). Finally, this compound is debenzylated with H2 over Pd/C in ethanol.
〖作者〗Wu, G.Z.; Chen, X.; Ding, Z.; Wong, Y.S.
〖参考〗Wu, G.Z.; Chen, X.; Ding, Z.; Wong, Y.S.; A novel one-step diastereo- and enantioselective formation of trans-azetidinones and its application to the total synthesis of cholesterol absorption inhibitors. J Org Chem , 3714
〖出处〗J Org Chem):3714
〖来源〗Bioorg Med Chem
〖合成路线〗
〖标题〗2-Azetidinone cholesterol absorption inhibitors: Increased potency by substitution of the C-4 phenyl ring
〖合成方法〗3) The reaction of 4-hydroxybenzaldehyde (XII) with benzyl bromide and K2CO3 in acetone gives 4-(benzyloxy)benzaldehyde (XIII), which is condensed with 4-fluoroaniline (XIV) in isopropanol, yielding the imine (II). Cyclization of (II) with methyl 4-(chloroformyl)butyrate (XV) by means of tributylamine in toluene affords the trans-azetidinone (XVI), which is hydrolyzed with LiOH in THF/water to provide the propionic acid derivative (XVII). The reaction of (XVII) with oxalyl chloride in dichloromethane gives the corresponding acyl chloride (XVIII), which is condensed with 4-fluorophenylmagnesium bromide (XIX) by means of ZnCl2 and Pd(PPh3)4 in THF to yield a racemic mixture of saturated trans-azetidinones that was resolved by chiral HPLC to the trans-(3R,4S)-enantiomer (XX). The enantioselective reduction of (XX) with BH3 and the chiral oxaborole catalyst CBS gives the benzylated alcohol (XI), which is finally debenzylated as before with H2 over Pd/C in ethanol.
〖作者〗Vaccaro, W.D.; Sher, R.; Davis, H.R. Jr.
〖参考〗Vaccaro, W.D.; Sher, R.; Davis, H.R. Jr.; 2-Azetidinone cholesterol absorption inhibitors: Increased potency by substitution of the C-4 phenyl ring. Bioorg Med Chem , 1429
〖出处〗Bioorg Med Chem):1429
〖来源〗Drugs Fut
〖合成路线〗
〖标题〗Ezetimibe
〖合成方法〗3) The reaction of 4-hydroxybenzaldehyde (XII) with benzyl bromide and K2CO3 in acetone gives 4-(benzyloxy)benzaldehyde (XIII), which is condensed with 4-fluoroaniline (XIV) in isopropanol, yielding the imine (II). Cyclization of (II) with methyl 4-(chloroformyl)butyrate (XV) by means of tributylamine in toluene affords the trans-azetidinone (XVI), which is hydrolyzed with LiOH in THF/water to provide the propionic acid derivative (XVII). The reaction of (XVII) with oxalyl chloride in dichloromethane gives the corresponding acyl chloride (XVIII), which is condensed with 4-fluorophenylmagnesium bromide (XIX) by means of ZnCl2 and Pd(PPh3)4 in THF to yield a racemic mixture of saturated trans-azetidinones that was resolved by chiral HPLC to the trans-(3R,4S)-enantiomer (XX). The enantioselective reduction of (XX) with BH3 and the chiral oxaborole catalyst CBS gives the benzylated alcohol (XI), which is finally debenzylated as before with H2 over Pd/C in ethanol.
〖作者〗Castaer, R.M.; Sorbera, L.A.; Castaer, J.
〖参考〗Castaer, R.M.; Sorbera, L.A.; Castaer, J.; Ezetimibe. Drugs Fut , 679
〖出处〗Drugs Fut):679
〖备注〗Synthesis of Ezetimibe (EN:224366):
Ezetimibe can be obtained by several different ways:
1) The cyclization of 4(S)-hydroxytetrahydrofuran-2-one (I) with the benzylideneimine derivative (II) by means of LDA gives the trans-azetidinone (III) which is separated from its cis-isomer by crystallization. The oxidation of (III) with NaIO4 in acetonitrile yields the carbaldehyde (IV), which is condensed with the silylated enol ether (V), prepared from 4'-fluoroacetophenone (VI), Li and TMSCl, to afford compound (VII). The dehydration of (VII) by means of TsOH gives the enone (VIII), which is hydrogenated and debenzylated with H2 over Pd/C in ethanol, providing the saturated ketone (IX). Finally, this compound is enantioselectively reduced with borane and the chiral catalyst (R)-1-methyl-3,3-diphenylperhydropyrrolo[1,2-c][1,3,2]oxaazaborole (CBS) (1-3) (Scheme a).
2) Alternatively, the reduction of enone (VIII) with H2 over RhCl(PPh3)3 in dichloromethane gives the benzylated saturated ketone (X), which is enantioselectively reduced with borane and CBS, yielding the benzylated alcohol (XI). Finally, this compound is debenzylated with H2 over Pd/C in ethanol (1-3) (Scheme a).
3) The reaction of 4-hydroxybenzaldehyde (XII) with benzyl bromide and K2CO3 in acetone gives 4-(benzyloxy)benzaldehyde (XIII), which is condensed with 4-fluoroaniline (XIV) in isopropanol, yielding the imine (II). Cyclization of (II) with methyl 4-(chloroformyl)butyrate (XV) by means of tributylamine in toluene affords the trans-azetidinone (XVI), which is hydrolyzed with LiOH in THF/water to provide the propionic acid derivative (XVII). The reaction of (XVII) with oxalyl chloride in dichloromethane gives the corresponding acyl chloride (XVIII), which is condensed with 4-fluorophenylmagnesium bromide (XIX) by means of ZnCl2 and Pd(PPh3)4 in THF to yield a racemic mixture of saturated trans-azetidinones that was resolved by chiral HPLC to the trans-(3R,4S)-enantiomer (XX). The enantioselective reduction of (XX) with BH3 and the chiral oxaborole catalyst CBS gives the benzylated alcohol (XI) which is finally debenzylated as before with H2 over Pd/C in ethanol (4) (Scheme b).
4) The reaction of methyl 4-(chloroformyl)butyrate (XV) with the chiral oxazolidinone (XXI) by means of DMAP and TEA in dichloromethane gives the acylated oxazolidinone (XXII), which is cyclized with the benzylideneimine (II) by means of TiCl4, titanium isopropoxide and TBAF in dichloromethane, yielding trans-(3R,4S)-azetidinone (XXIII). This chiral compound (XXIII) is worked up to give ezetimibe by the same reaction sequence used for its racemic analog (XVI) but without optical resolution (5) (Scheme c).
5) Racemic trans-azetidinone (XVI) can be submitted to chiral chromatography (Chiracel OD column) (6), microbial or enzymatic subtractive resolution to provide the trans-(3R,4S)-azetidinone (XXIII) (7) or direct microbial or enzymatic hydrolytic resolution to directly provide the trans-(3R,4S)-azetidinone-propionic acid (XXIV) (7), the compound also obtained by hydrolysis of (XXIII) with LiOH (6,7). This (3R,4S)-free acid (XXIV) is treated with oxalyl chloride giving the (3R,4S)-acyl chloride (XXV) which by condensation with 4-fluorophenylmagnesium bromide (XIX) yields the (3R,4S)-azetidinone (XX). Reduction of (XX) with borane-dimethylsulfide complex in THF affords an equal mixture of diasteromeric alcohols that was submitted to chiral chromatography on a Chiracel OD column providing the benzylated (3'S)-alcohol (XI) (6) (Scheme c).
6) The reaction of 5-(4-fluorophenyl)-4-pentenoic acid (XXVI) with oxalyl chloride gives the acyl chloride (XXVII), which is condensed with the chiral oxazolidinone (XXI) by means of DMAP and DIEA in dichloromethane, yielding the acyloxazolidinone (XXVIII). Condensation of (XXVIII) with the benzylideneimine (II) by means of TiCl4 affords adduct (XXIX), which is cyclized to the chiral azetidinone (XXX). The oxidation of the double bond of (XXX) with benzoquinone and HClO4 catalyzed by Pd(OAc)2 in acetonitrile/water provides the already reported trans-(3R,4S)-azetidinone (XX), which is worked up to give azetimibe as described before (8) (Scheme d).
Manufacturer
Schering-Plough Corporation (US).
References
1. Wu, G.Z, Wong, Y.S, Chen, X., Ding, Z.; A novel one-step diastereo- and enantioselective formation of trans-azetidinones and its application to the total synthesis of cholesterol a J Org Chem 14-8.
2. Wu, G.-Z., Chen, X., Wong, Y.-S., Schumacher, D.P., Steinman, M. (Schering Corp.); 3-Hydroxy gamma-lactone based enantioselective synth WO 9745406.
3. Wu, G.-Z., Chen, X., Wong, Y.-S., Schumacher, D.P., Steinman, M. (Schering Corp.); 3-Hydroxy gamma-lactone based enantioselective synth US 5886171.
4. Vaccaro, W.D., Sher, R., Davis, H.R. Jr.; 2-Azetidinone cholesterol absorption inhibitors: Increased potency by substitution of the C-4 Bioorg Med Chem 29-37.
5. Rosenblum, S.B., Dugar, S., Burnett, D.A., Clader, J.W., McKittrick, B.A. (Schering Corp.); Hydroxy-substd. azetidinone cpds. useful as hypoch EP 0720599, JP , US 5631365, US 5767115, WO 9508532.
6. Rosenblum, S.B., Huynh, T., Afonso, A., Davis, H.R. Jr., Yumibe, N., Clader, J.W., Burnett, D.A.; Discovery of 1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]-(4S)-(4-hydroxyphenyl)-2-azetidinone (SCH 58235): A designed, potent, orally active inhibitor of ch J Med Chem 3-980.
7. Homann, M.J., Morgan, W.B. (Schering Corp.); Resolution of trans-2-(alkoxycarbonylethyl)-lactams useful in the synthesis of 1-(4-fluoro-phenyl)-3(R)-[(S)-hydroxy-3-(4-fluorophenyl)-propyl]-4(S)-(4-hydroxyphenyl)-2- US 5919672.
8. Shankar, B.B. (Schering Corp.); Process for preparing 1-(4-fluorophenyl)-3(R)-(3(S)-hydroxy-3-([phenyl or 4-fluorophenyl])-propyl)-4(S)-(4-hydroxyphenyl)-2- US 5856473, WO 9716424.
〖来源〗J Med Chem
〖合成路线〗
〖标题〗Discovery of 1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]-(4S)-(4-hydroxyphenyl)-2-azetidinone (SCH 58235): A designed, potent, orally active inhibitor of cholesterol absorption
〖合成方法〗4) The reaction of methyl 4-(chloroformyl)butyrate (XV) with the chiral oxazolidinone (XXI) by means of DMAP and TEA in dichloromethane gives the acylated oxazolidinone (XXII), which is cyclized with the benzylideneimine (II) by means of TiCl4, titanium isopropoxide and TBAF in dichloromethane, yielding trans-(3R,4S)-azetidinone (XXIII). This chiral compound (XXIII) is worked up to give ezetimibe by the same reaction sequence used for its racemic analogue (XVI) but without optical resolution.
5) Racemic trans-azetidinone (XVI) can be submitted to chiral chromatography (Chiracel OD column), microbial or enzymatic subtractive resolution to provide the trans-(3R,4S)-azetidinone (XXIII) or direct microbial or enzymatic hydrolytic resolution to directly provide the trans-(3R,4S)-azetidinone-propionic acid (XXIV), the compound also obtained by hydrolysis of (XXIII) with LiOH. This (3R,4S)-free acid (XXIV) is treated with oxalyl chloride giving the (3R,4S)-acyl chloride (XXV), which by condensation with 4-fluorophenylmagnesium bromide (XIX) yields the (3R,4S)-azetidinone (XX). Reduction of (XX) with borane-dimethylsulfide complex in THF affords an equal mixture of diasteromeric alcohols that was submitted to chiral chromatography on a Chiracel OD column providing the benzylated (3'S)-alcohol (XI).
〖作者〗Afonso, A.; Davis, H.R. Jr.; Huynh, T.; Yumibe, N.; Clader, J.W.; Burnett, D.A.; Rosenblum, S.B.
〖参考〗Afonso, A.; Davis, H.R. Jr.; Huynh, T.; Yumibe, N.; Clader, J.W.; Burnett, D.A.; Rosenblum, S.B.; Discovery of 1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]-(4S)-(4-hydroxyphenyl)-2-azetidinone (SCH 58235): A designed, potent, orally act (free base)/li>
li>??p耀?ul class="old_db">li>span>
〖出处〗J Med Chem):973
〖备注〗Treatment of acid chloride (I) with tributylamine generated the corresponding ketene, which was cyclocondensed to imine (II) to produce the racemic trans b-lactam (III). Resolution of (III) into enantiomers was then achieved by preparative HPLC on a Chiralcel OD column. Subsequent saponification of the desired enantiomer with methanolic LiOH afforded acid (IV), that was converted to acid chloride (V) upon treatment with oxalyl chloride. Further Pd-mediated coupling of (V) with the arylzinc reagent (VI) provided ketone (VII). Then, carbonyl reduction with BH3Me2S, followed by chromatographic separation of the isomers furnished alcohol (VIII), which was finally deprotected by hydrogenolysis over Pd/C to afford the target phenol.
〖来源〗Drugs Fut
〖合成路线〗
〖标题〗Ezetimibe
〖合成方法〗4) The reaction of methyl 4-(chloroformyl)butyrate (XV) with the chiral oxazolidinone (XXI) by means of DMAP and TEA in dichloromethane gives the acylated oxazolidinone (XXII), which is cyclized with the benzylideneimine (II) by means of TiCl4, titanium isopropoxide and TBAF in dichloromethane, yielding trans-(3R,4S)-azetidinone (XXIII). This chiral compound (XXIII) is worked up to give ezetimibe by the same reaction sequence used for its racemic analogue (XVI) but without optical resolution.
5) Racemic trans-azetidinone (XVI) can be submitted to chiral chromatography (Chiracel OD column), microbial or enzymatic subtractive resolution to provide the trans-(3R,4S)-azetidinone (XXIII) or direct microbial or enzymatic hydrolytic resolution to directly provide the trans-(3R,4S)-azetidinone-propionic acid (XXIV), the compound also obtained by hydrolysis of (XXIII) with LiOH. This (3R,4S)-free acid (XXIV) is treated with oxalyl chloride giving the (3R,4S)-acyl chloride (XXV), which by condensation with 4-fluorophenylmagnesium bromide (XIX) yields the (3R,4S)-azetidinone (XX). Reduction of (XX) with borane-dimethylsulfide complex in THF affords an equal mixture of diasteromeric alcohols that was submitted to chiral chromatography on a Chiracel OD column providing the benzylated (3'S)-alcohol (XI).
〖作者〗Castaer, R.M.; Sorbera, L.A.; Castaer, J.
〖参考〗Castaer, R.M.; Sorbera, L.A.; Castaer, J.; Ezetimibe. Drugs Fut , 679
〖出处〗Drugs Fut):679
〖备注〗Synthesis of Ezetimibe (EN:224366):
Ezetimibe can be obtained by several different ways:
1) The cyclization of 4(S)-hydroxytetrahydrofuran-2-one (I) with the benzylideneimine derivative (II) by means of LDA gives the trans-azetidinone (III) which is separated from its cis-isomer by crystallization. The oxidation of (III) with NaIO4 in acetonitrile yields the carbaldehyde (IV), which is condensed with the silylated enol ether (V), prepared from 4'-fluoroacetophenone (VI), Li and TMSCl, to afford compound (VII). The dehydration of (VII) by means of TsOH gives the enone (VIII), which is hydrogenated and debenzylated with H2 over Pd/C in ethanol, providing the saturated ketone (IX). Finally, this compound is enantioselectively reduced with borane and the chiral catalyst (R)-1-methyl-3,3-diphenylperhydropyrrolo[1,2-c][1,3,2]oxaazaborole (CBS) (1-3) (Scheme a).
2) Alternatively, the reduction of enone (VIII) with H2 over RhCl(PPh3)3 in dichloromethane gives the benzylated saturated ketone (X), which is enantioselectively reduced with borane and CBS, yielding the benzylated alcohol (XI). Finally, this compound is debenzylated with H2 over Pd/C in ethanol (1-3) (Scheme a).
3) The reaction of 4-hydroxybenzaldehyde (XII) with benzyl bromide and K2CO3 in acetone gives 4-(benzyloxy)benzaldehyde (XIII), which is condensed with 4-fluoroaniline (XIV) in isopropanol, yielding the imine (II). Cyclization of (II) with methyl 4-(chloroformyl)butyrate (XV) by means of tributylamine in toluene affords the trans-azetidinone (XVI), which is hydrolyzed with LiOH in THF/water to provide the propionic acid derivative (XVII). The reaction of (XVII) with oxalyl chloride in dichloromethane gives the corresponding acyl chloride (XVIII), which is condensed with 4-fluorophenylmagnesium bromide (XIX) by means of ZnCl2 and Pd(PPh3)4 in THF to yield a racemic mixture of saturated trans-azetidinones that was resolved by chiral HPLC to the trans-(3R,4S)-enantiomer (XX). The enantioselective reduction of (XX) with BH3 and the chiral oxaborole catalyst CBS gives the benzylated alcohol (XI) which is finally debenzylated as before with H2 over Pd/C in ethanol (4) (Scheme b).
4) The reaction of methyl 4-(chloroformyl)butyrate (XV) with the chiral oxazolidinone (XXI) by means of DMAP and TEA in dichloromethane gives the acylated oxazolidinone (XXII), which is cyclized with the benzylideneimine (II) by means of TiCl4, titanium isopropoxide and TBAF in dichloromethane, yielding trans-(3R,4S)-azetidinone (XXIII). This chiral compound (XXIII) is worked up to give ezetimibe by the same reaction sequence used for its racemic analog (XVI) but without optical resolution (5) (Scheme c).
5) Racemic trans-azetidinone (XVI) can be submitted to chiral chromatography (Chiracel OD column) (6), microbial or enzymatic subtractive resolution to provide the trans-(3R,4S)-azetidinone (XXIII) (7) or direct microbial or enzymatic hydrolytic resolution to directly provide the trans-(3R,4S)-azetidinone-propionic acid (XXIV) (7), the compound also obtained by hydrolysis of (XXIII) with LiOH (6,7). This (3R,4S)-free acid (XXIV) is treated with oxalyl chloride giving the (3R,4S)-acyl chloride (XXV) which by condensation with 4-fluorophenylmagnesium bromide (XIX) yields the (3R,4S)-azetidinone (XX). Reduction of (XX) with borane-dimethylsulfide complex in THF affords an equal mixture of diasteromeric alcohols that was submitted to chiral chromatography on a Chiracel OD column providing the benzylated (3'S)-alcohol (XI) (6) (Scheme c).
6) The reaction of 5-(4-fluorophenyl)-4-pentenoic acid (XXVI) with oxalyl chloride gives the acyl chloride (XXVII), which is condensed with the chiral oxazolidinone (XXI) by means of DMAP and DIEA in dichloromethane, yielding the acyloxazolidinone (XXVIII). Condensation of (XXVIII) with the benzylideneimine (II) by means of TiCl4 affords adduct (XXIX), which is cyclized to the chiral azetidinone (XXX). The oxidation of the double bond of (XXX) with benzoquinone and HClO4 catalyzed by Pd(OAc)2 in acetonitrile/water provides the already reported trans-(3R,4S)-azetidinone (XX), which is worked up to give azetimibe as described before (8) (Scheme d).
Manufacturer
Schering-Plough Corporation (US).
References
1. Wu, G.Z, Wong, Y.S, Chen, X., Ding, Z.; A novel one-step diastereo- and enantioselective formation of trans-azetidinones and its application to the total synthesis of cholesterol a J Org Chem 14-8.
2. Wu, G.-Z., Chen, X., Wong, Y.-S., Schumacher, D.P., Steinman, M. (Schering Corp.); 3-Hydroxy gamma-lactone based enantioselective synth WO 9745406.
3. Wu, G.-Z., Chen, X., Wong, Y.-S., Schumacher, D.P., Steinman, M. (Schering Corp.); 3-Hydroxy gamma-lactone based enantioselective synth US 5886171.
4. Vaccaro, W.D., Sher, R., Davis, H.R. Jr.; 2-Azetidinone cholesterol absorption inhibitors: Increased potency by substitution of the C-4 Bioorg Med Chem 29-37.
5. Rosenblum, S.B., Dugar, S., Burnett, D.A., Clader, J.W., McKittrick, B.A. (Schering Corp.); Hydroxy-substd. azetidinone cpds. useful as hypoch EP 0720599, JP , US 5631365, US 5767115, WO 9508532.
6. Rosenblum, S.B., Huynh, T., Afonso, A., Davis, H.R. Jr., Yumibe, N., Clader, J.W., Burnett, D.A.; Discovery of 1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]-(4S)-(4-hydroxyphenyl)-2-azetidinone (SCH 58235): A designed, potent, orally active inhibitor of ch J Med Chem 3-980.
7. Homann, M.J., Morgan, W.B. (Schering Corp.); Resolution of trans-2-(alkoxycarbonylethyl)-lactams useful in the synthesis of 1-(4-fluoro-phenyl)-3(R)-[(S)-hydroxy-3-(4-fluorophenyl)-propyl]-4(S)-(4-hydroxyphenyl)-2- US 5919672.
8. Shankar, B.B. (Schering Corp.); Process for preparing 1-(4-fluorophenyl)-3(R)-(3(S)-hydroxy-3-([phenyl or 4-fluorophenyl])-propyl)-4(S)-(4-hydroxyphenyl)-2- US 5856473, WO 9716424.
〖来源〗Drugs Fut
〖合成路线〗
〖标题〗Ezetimibe
〖合成方法〗6) The reaction of 5-(4-fluorophenyl)-4-pentenoic acid (XXVI) with oxalyl chloride gives the acyl chloride (XXVII), which is condensed with the chiral oxazolidinone (XXI) by means of DMAP and DIEA in dichloromethane, yielding the acyloxazolidinone (XXVIII). Condensation of (XXVIII) with the benzylideneimine (II) by means of TiCl4 affords adduct (XXIX), which is cyclized to the chiral azetidinone (XXX). The oxidation of the double bond of (XXX) with benzoquinone and HClO4 catalyzed by Pd(OAc)2 in acetonitrile/water provides the previously reported trans-(3R,4S)-azetidinone (XX), which is worked up to give azetimibe as described before.
〖作者〗Castaer, R.M.; Sorbera, L.A.; Castaer, J.
〖参考〗Castaer, R.M.; Sorbera, L.A.; Castaer, J.; Ezetimibe. Drugs Fut , 679
〖出处〗Drugs Fut):679
〖备注〗Synthesis of Ezetimibe (EN:224366):
Ezetimibe can be obtained by several different ways:
1) The cyclization of 4(S)-hydroxytetrahydrofuran-2-one (I) with the benzylideneimine derivative (II) by means of LDA gives the trans-azetidinone (III) which is separated from its cis-isomer by crystallization. The oxidation of (III) with NaIO4 in acetonitrile yields the carbaldehyde (IV), which is condensed with the silylated enol ether (V), prepared from 4'-fluoroacetophenone (VI), Li and TMSCl, to afford compound (VII). The dehydration of (VII) by means of TsOH gives the enone (VIII), which is hydrogenated and debenzylated with H2 over Pd/C in ethanol, providing the saturated ketone (IX). Finally, this compound is enantioselectively reduced with borane and the chiral catalyst (R)-1-methyl-3,3-diphenylperhydropyrrolo[1,2-c][1,3,2]oxaazaborole (CBS) (1-3) (Scheme a).
2) Alternatively, the reduction of enone (VIII) with H2 over RhCl(PPh3)3 in dichloromethane gives the benzylated saturated ketone (X), which is enantioselectively reduced with borane and CBS, yielding the benzylated alcohol (XI). Finally, this compound is debenzylated with H2 over Pd/C in ethanol (1-3) (Scheme a).
3) The reaction of 4-hydroxybenzaldehyde (XII) with benzyl bromide and K2CO3 in acetone gives 4-(benzyloxy)benzaldehyde (XIII), which is condensed with 4-fluoroaniline (XIV) in isopropanol, yielding the imine (II). Cyclization of (II) with methyl 4-(chloroformyl)butyrate (XV) by means of tributylamine in toluene affords the trans-azetidinone (XVI), which is hydrolyzed with LiOH in THF/water to provide the propionic acid derivative (XVII). The reaction of (XVII) with oxalyl chloride in dichloromethane gives the corresponding acyl chloride (XVIII), which is condensed with 4-fluorophenylmagnesium bromide (XIX) by means of ZnCl2 and Pd(PPh3)4 in THF to yield a racemic mixture of saturated trans-azetidinones that was resolved by chiral HPLC to the trans-(3R,4S)-enantiomer (XX). The enantioselective reduction of (XX) with BH3 and the chiral oxaborole catalyst CBS gives the benzylated alcohol (XI) which is finally debenzylated as before with H2 over Pd/C in ethanol (4) (Scheme b).
4) The reaction of methyl 4-(chloroformyl)butyrate (XV) with the chiral oxazolidinone (XXI) by means of DMAP and TEA in dichloromethane gives the acylated oxazolidinone (XXII), which is cyclized with the benzylideneimine (II) by means of TiCl4, titanium isopropoxide and TBAF in dichloromethane, yielding trans-(3R,4S)-azetidinone (XXIII). This chiral compound (XXIII) is worked up to give ezetimibe by the same reaction sequence used for its racemic analog (XVI) but without optical resolution (5) (Scheme c).
5) Racemic trans-azetidinone (XVI) can be submitted to chiral chromatography (Chiracel OD column) (6), microbial or enzymatic subtractive resolution to provide the trans-(3R,4S)-azetidinone (XXIII) (7) or direct microbial or enzymatic hydrolytic resolution to directly provide the trans-(3R,4S)-azetidinone-propionic acid (XXIV) (7), the compound also obtained by hydrolysis of (XXIII) with LiOH (6,7). This (3R,4S)-free acid (XXIV) is treated with oxalyl chloride giving the (3R,4S)-acyl chloride (XXV) which by condensation with 4-fluorophenylmagnesium bromide (XIX) yields the (3R,4S)-azetidinone (XX). Reduction of (XX) with borane-dimethylsulfide complex in THF affords an equal mixture of diasteromeric alcohols that was submitted to chiral chromatography on a Chiracel OD column providing the benzylated (3'S)-alcohol (XI) (6) (Scheme c).
6) The reaction of 5-(4-fluorophenyl)-4-pentenoic acid (XXVI) with oxalyl chloride gives the acyl chloride (XXVII), which is condensed with the chiral oxazolidinone (XXI) by means of DMAP and DIEA in dichloromethane, yielding the acyloxazolidinone (XXVIII). Condensation of (XXVIII) with the benzylideneimine (II) by means of TiCl4 affords adduct (XXIX), which is cyclized to the chiral azetidinone (XXX). The oxidation of the double bond of (XXX) with benzoquinone and HClO4 catalyzed by Pd(OAc)2 in acetonitrile/water provides the already reported trans-(3R,4S)-azetidinone (XX), which is worked up to give azetimibe as described before (8) (Scheme d).
Manufacturer
Schering-Plough Corporation (US).
References
1. Wu, G.Z, Wong, Y.S, Chen, X., Ding, Z.; A novel one-step diastereo- and enantioselective formation of trans-azetidinones and its application to the total synthesis of cholesterol a J Org Chem 14-8.
2. Wu, G.-Z., Chen, X., Wong, Y.-S., Schumacher, D.P., Steinman, M. (Schering Corp.); 3-Hydroxy gamma-lactone based enantioselective synth WO 9745406.
3. Wu, G.-Z., Chen, X., Wong, Y.-S., Schumacher, D.P., Steinman, M. (Schering Corp.); 3-Hydroxy gamma-lactone based enantioselective synth US 5886171.
4. Vaccaro, W.D., Sher, R., Davis, H.R. Jr.; 2-Azetidinone cholesterol absorption inhibitors: Increased potency by substitution of the C-4 Bioorg Med Chem 29-37.
5. Rosenblum, S.B., Dugar, S., Burnett, D.A., Clader, J.W., McKittrick, B.A. (Schering Corp.); Hydroxy-substd. azetidinone cpds. useful as hypoch EP 0720599, JP , US 5631365, US 5767115, WO 9508532.
6. Rosenblum, S.B., Huynh, T., Afonso, A., Davis, H.R. Jr., Yumibe, N., Clader, J.W., Burnett, D.A.; Discovery of 1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]-(4S)-(4-hydroxyphenyl)-2-azetidinone (SCH 58235): A designed, potent, orally active inhibitor of ch J Med Chem 3-980.
7. Homann, M.J., Morgan, W.B. (Schering Corp.); Resolution of trans-2-(alkoxycarbonylethyl)-lactams useful in the synthesis of 1-(4-fluoro-phenyl)-3(R)-[(S)-hydroxy-3-(4-fluorophenyl)-propyl]-4(S)-(4-hydroxyphenyl)-2- US 5919672.
8. Shankar, B.B. (Schering Corp.); Process for preparing 1-(4-fluorophenyl)-3(R)-(3(S)-hydroxy-3-([phenyl or 4-fluorophenyl])-propyl)-4(S)-(4-hydroxyphenyl)-2- US 5856473, WO 9716424.
〖来源〗J Label Compd Radiopharm
〖合成路线〗
〖标题〗Synthesis of 3H, 14C and 13C6 labelled Sch 58235
〖合成方法〗The 3H-labeling of SCH-58235 has been performed by hydrogen/tritium exchange catalyzed by Crabtree's catalyst [Ir(COD)(Cy3P)PyF6] in dichloromethane.
〖作者〗Hesk, D.; et al.
〖参考〗Hesk, D.; et al.; Synthesis of 3H, 14C and 13C6 labelled Sch 58235. J Label Compd Radiopharm , 145
〖出处〗J Label Compd Radiopharm):145
〖来源〗J Label Compd Radiopharm
〖合成路线〗
〖标题〗Synthesis of 3H, 14C and 13C6 labelled Sch 58235
〖合成方法〗The enantioselective reduction of the oxazolidinone (I) with BH3/SMe2 and a chiral borinated catalyst gives the (S)-alcohol (II), which is condensed with the labeled imine (III) (prepared by reaction of 4-fluoroaniline (IV) and 13C-labeled 4-hydroxybenzaldehyde (V)) by means of TiCl4 in dichloromethane to yield the silylated adduct (VI) (previously the reactants are silylated with Tms-Cl and DIEA). Finally, adduct (VI) is resilylated with bis(trimethylsilyl)acetamide and cyclized and desilylated by treatment with TBAF in dichloromethane to afford the target 13C-labeled SCH-58235.
〖作者〗Hesk, D.; et al.
〖参考〗Hesk, D.; et al.; Synthesis of 3H, 14C and 13C6 labelled Sch 58235. J Label Compd Radiopharm , 145
〖出处〗J Label Compd Radiopharm):145
〖来源〗J Label Compd Radiopharm
〖合成路线〗
〖标题〗Synthesis of 3H, 14C and 13C6 labelled Sch 58235
〖合成方法〗The enantioselective reduction of the oxazolidinone (I) with BH3/SMe2 and a chiral borinated catalyst gives the (S)-alcohol (II), which is condensed with the labeled imine (III) (prepared by reaction of 4-fluoroaniline (IV) and 14C-labeled 4-hydroxybenzaldehyde (V)) by means of TiCl4 in dichloromethane to yield the silylated adduct (VI) (previously the reactants are silylated with Tms-Cl and DIEA). Finally, adduct (VI) is resilylated with bis(trimethylsilyl)acetamide and cyclized and desilylated by treatment with TBAF in dichloromethane to afford the target 14C-labeled SCH-58235.
〖作者〗Hesk, D.; et al.
〖参考〗Hesk, D.; et al.; Synthesis of 3H, 14C and 13C6 labelled Sch 58235. J Label Compd Radiopharm , 145
〖出处〗J Label Compd Radiopharm):145
〖来源〗Tetrahedron Lett
〖合成路线〗
〖标题〗Process for preparing ezetimibe intermediate by an acid enhanced chemo- and enantioselective CBS catalyzed ketone reduction
〖合成方法〗The activation of 5-(4-fluorophenyl)-5-oxopentanoic acid (I) with pivaloyl chloride (II) gives the mixed anhydride (III), which is condensed with the chiral oxazolidinone (IV) by means of DMAP to yield the acylated oxazolidine (V) (1). The asymmetric reduction of (V) by means of BH3/Me2S catalyzed by the chiral boron catalyst (VI) affords the chiral alcohol (VII) (1-3), which is condensed with the imine (VIII) by means of Tms-Cl, DIEA and TiCl4 to provide the adduct (IX). The cyclization of (IX) by means of bis(trimethylsilyl)acetamide and TBAF gives the protected azetidinone (X), which is finally desilylated by means of sulfuric acid in isopropanol
〖作者〗Fu, X.Y.; et al.
〖参考〗Fu, X.Y.; et al.; Process for preparing ezetimibe intermediate by an acid enhanced chemo- and enantioselective CBS catalyzed ketone reduction. Tetrahedron Lett , 801
〖出处〗Tetrahedron Lett):801
〖来源〗WO 9745406
〖合成路线〗
〖标题〗3-Hydroxy gamma-lactone based enantioselective synthesis of azetidinones
〖合成方法〗1) The cyclization of 4(S)-hydroxytetrahydrofuran-2-one (I) with the benzylideneimine derivative (II) by means of LDA gives the trans-azetidinone (III), which is separated from its cis-isomer by crystallization. The oxidation of (III) with NaIO4 in acetonitrile yields the carbaldehyde (IV), which is condensed with the silylated enol ether (V), prepared from 4'-fluoroacetophenone (VI), Li and TMSCl, to afford compound (VII). The dehydration of (VII) by means of TsOH gives the enone (VIII), which is hydrogenated and debenzylated with H2 over Pd/C in ethanol, providing the saturated ketone (IX). Finally, this compound is enantioselectively reduced with borane and the chiral catalyst (R)-1-methyl-3,3-diphenylperhydropyrrolo[1,2-c][1,3,2]oxaazaborole (CBS).
2) Alternatively, the reduction of enone (VIII) with H2 over RhCl(PPh3)3 in dichloromethane gives the benzylated saturated ketone (X), which is enantioselectively reduced with borane and CBS, yielding the benzylated alcohol (XI). Finally, this compound is debenzylated with H2 over Pd/C in ethanol.
〖作者〗Steinman, M.; Schumacher, D.P.; Chen, X.; Wu, G.-Z.; Wong, Y.-S. (Schering Corp.)
〖参考〗Steinman, M.; Schumacher, D.P.; Chen, X.; Wu, G.-Z.; Wong, Y.-S. (Schering Corp.); 3-Hydroxy gamma-lactone based enantioselective synthesis of azetidinones. WO 9745406
〖出处〗WO 9745406,,():
〖来源〗US 5886171
〖合成路线〗
〖标题〗3-Hydroxy gamma-lactone based enantioselective synthesis of azetidinones
〖合成方法〗1) The cyclization of 4(S)-hydroxytetrahydrofuran-2-one (I) with the benzylideneimine derivative (II) by means of LDA gives the trans-azetidinone (III), which is separated from its cis-isomer by crystallization. The oxidation of (III) with NaIO4 in acetonitrile yields the carbaldehyde (IV), which is condensed with the silylated enol ether (V), prepared from 4'-fluoroacetophenone (VI), Li and TMSCl, to afford compound (VII). The dehydration of (VII) by means of TsOH gives the enone (VIII), which is hydrogenated and debenzylated with H2 over Pd/C in ethanol, providing the saturated ketone (IX). Finally, this compound is enantioselectively reduced with borane and the chiral catalyst (R)-1-methyl-3,3-diphenylperhydropyrrolo[1,2-c][1,3,2]oxaazaborole (CBS).
2) Alternatively, the reduction of enone (VIII) with H2 over RhCl(PPh3)3 in dichloromethane gives the benzylated saturated ketone (X), which is enantioselectively reduced with borane and CBS, yielding the benzylated alcohol (XI). Finally, this compound is debenzylated with H2 over Pd/C in ethanol.
〖作者〗Wu, G.-Z.; Chen, X.; Wong, Y.-S.; Schumacher, D.P.; Steinman, M.
〖参考〗Wu, G.-Z.; Chen, X.; Wong, Y.-S.; Schumacher, D.P.; Steinman, M.; 3-Hydroxy gamma-lactone based enantioselective synthesis of azetidinones. US 5886171
〖出处〗US 5886171,,():
〖来源〗EP 0720599; JP ; US 5631365; WO 9508532
〖合成路线〗
〖标题〗Hydroxy-substd. azetidinone cpds. useful as hypocholesterolemic agents
〖合成方法〗3) The reaction of 4-hydroxybenzaldehyde (XII) with benzyl bromide and K2CO3 in acetone gives 4-(benzyloxy)benzaldehyde (XIII), which is condensed with 4-fluoroaniline (XIV) in isopropanol, yielding the imine (II). Cyclization of (II) with methyl 4-(chloroformyl)butyrate (XV) by means of tributylamine in toluene affords the trans-azetidinone (XVI), which is hydrolyzed with LiOH in THF/water to provide the propionic acid derivative (XVII). The reaction of (XVII) with oxalyl chloride in dichloromethane gives the corresponding acyl chloride (XVIII), which is condensed with 4-fluorophenylmagnesium bromide (XIX) by means of ZnCl2 and Pd(PPh3)4 in THF to yield a racemic mixture of saturated trans-azetidinones that was resolved by chiral HPLC to the trans-(3R,4S)-enantiomer (XX). The enantioselective reduction of (XX) with BH3 and the chiral oxaborole catalyst CBS gives the benzylated alcohol (XI), which is finally debenzylated as before with H2 over Pd/C in ethanol.
〖作者〗Rosenblum, S.B.; Dugar, S.; Burnett, D.A.; Clader, J.W.; McKittrick, B.A. (Schering Corp.)
〖参考〗Rosenblum, S.B.; Dugar, S.; Burnett, D.A.; Clader, J.W.; McKittrick, B.A. (Schering Corp.); Hydroxy-substd. azetidinone cpds. useful as hypocholesterolemic agents. EP 0720599; JP ; US 5631365; WO 9508532
〖出处〗EP 0720599; JP ; US 5631365; WO 9508532,,():
〖来源〗US 5919672
〖合成路线〗
〖标题〗Resolution of trans-2-(alkoxycarbonylethyl)-lactams useful in the synthesis of 1-(4-fluoro-phenyl)-3(R)-[(S)-hydroxy-3-(4-fluorophenyl)-propyl]-4(S)-(4-hydroxyphenyl)-2-azetidinone
〖合成方法〗4) The reaction of methyl 4-(chloroformyl)butyrate (XV) with the chiral oxazolidinone (XXI) by means of DMAP and TEA in dichloromethane gives the acylated oxazolidinone (XXII), which is cyclized with the benzylideneimine (II) by means of TiCl4, titanium isopropoxide and TBAF in dichloromethane, yielding trans-(3R,4S)-azetidinone (XXIII). This chiral compound (XXIII) is worked up to give ezetimibe by the same reaction sequence used for its racemic analogue (XVI) but without optical resolution.
5) Racemic trans-azetidinone (XVI) can be submitted to chiral chromatography (Chiracel OD column), microbial or enzymatic subtractive resolution to provide the trans-(3R,4S)-azetidinone (XXIII) or direct microbial or enzymatic hydrolytic resolution to directly provide the trans-(3R,4S)-azetidinone-propionic acid (XXIV), the compound also obtained by hydrolysis of (XXIII) with LiOH. This (3R,4S)-free acid (XXIV) is treated with oxalyl chloride giving the (3R,4S)-acyl chloride (XXV), which by condensation with 4-fluorophenylmagnesium bromide (XIX) yields the (3R,4S)-azetidinone (XX). Reduction of (XX) with borane-dimethylsulfide complex in THF affords an equal mixture of diasteromeric alcohols that was submitted to chiral chromatography on a Chiracel OD column providing the benzylated (3'S)-alcohol (XI).
〖作者〗Homann, M.J.; Morgan, W.B. (Schering Corp.)
〖参考〗Homann, M.J.; Morgan, W.B. (Schering Corp.); Resolution of trans-2-(alkoxycarbonylethyl)-lactams useful in the synthesis of 1-(4-fluoro-phenyl)-3(R)-[(S)-hydroxy-3-(4-fluorophenyl)-propyl]-4(S)-(4-hydroxyphenyl)-2-azetidinone. US 5919672
〖出处〗US 5919672,,():
〖来源〗US 5856473; WO 9716424
〖合成路线〗
〖标题〗Process for preparing 1-(4-fluorophenyl)-3(R)-(3(S)-hydroxy-3-([phenyl or 4-fluorophenyl])-propyl)-4(S)-(4-hydroxyphenyl)-2-azetidinone
〖合成方法〗6) The reaction of 5-(4-fluorophenyl)-4-pentenoic acid (XXVI) with oxalyl chloride gives the acyl chloride (XXVII), which is condensed with the chiral oxazolidinone (XXI) by means of DMAP and DIEA in dichloromethane, yielding the acyloxazolidinone (XXVIII). Condensation of (XXVIII) with the benzylideneimine (II) by means of TiCl4 affords adduct (XXIX), which is cyclized to the chiral azetidinone (XXX). The oxidation of the double bond of (XXX) with benzoquinone and HClO4 catalyzed by Pd(OAc)2 in acetonitrile/water provides the previously reported trans-(3R,4S)-azetidinone (XX), which is worked up to give azetimibe as described before.
〖作者〗Shankar, B.B. (Schering Corp.)
〖参考〗Shankar, B.B. (Schering Corp.); Process for preparing 1-(4-fluorophenyl)-3(R)-(3(S)-hydroxy-3-([phenyl or 4-fluorophenyl])-propyl)-4(S)-(4-hydroxyphenyl)-2-azetidinone. US 5856473; WO 9716424
〖出处〗US 5856473; WO 9716424,,():
〖来源〗US ; WO 0279174
〖合成路线〗
〖标题〗Enantioselective synthesis of azetidinone intermediate cpds.
〖合成方法〗The activation of 5-(4-fluorophenyl)-5-oxopentanoic acid (I) with pivaloyl chloride (II) gives the mixed anhydride (III), which is condensed with the chiral oxazolidinone (IV) by means of DMAP to yield the acylated oxazolidine (V) (1). The asymmetric reduction of (V) by means of BH3/Me2S catalyzed by the chiral boron catalyst (VI) affords the chiral alcohol (VII) (1-3), which is condensed with the imine (VIII) by means of Tms-Cl, DIEA and TiCl4 to provide the adduct (IX). The cyclization of (IX) by means of bis(trimethylsilyl)acetamide and TBAF gives the protected azetidinone (X), which is finally desilylated by means of sulfuric acid in isopropanol
〖作者〗Thiruvengadam, T.K.; Tann, C.-H.; Fu, X.; McAllister, T.L. (Schering Corp.)
〖参考〗Thiruvengadam, T.K.; Tann, C.-H.; Fu, X.; McAllister, T.L. (Schering Corp.); Enantioselective synthesis of azetidinone intermediate cpds.. US ; WO 0279174
〖出处〗US ; WO 0279174,,():
本文导航：
Ezetimibe, SCH-58235, Ezetrol, Zetia,-1, -
上一篇：暂无}
我要回帖
更多关于 降血脂药有什么副作用 的文章
更多推荐
- ·05345051095属于0534开头的是什么电话号码？
- ·缅甸语翻译成中文软件翻译傣文？
- ·幼儿园小朋友喜欢吃的食物的小朋友吃什么蛋糕？
- ·六岁6岁多小女孩胸有点鼓起怎么办部有一边有点大是怎么回事？
- ·重庆一外初中部师资力量外国语学校有几个校区
- ·这些小商小贩问题给毛派分子打报告你玛莎毕
- ·我到底应不应该出国留学去日本留学
- ·什么金属保温装饰一体板并且抗氧化
- ·90振动锤铝芯线需用多少平方电线
- ·dn250闸阀尺寸250铸铁尺寸370
- ·一畦一块菜地的总面积是多大，例如:一般面积？
- ·什么大地表示看的词语有什
- ·人如果青云志为什么没有鬼厉奖厉和批评会怎么样
- ·我们可以你睡着以后猫看着你对方睡 法语
- ·去日本读本科如果放弃英语 留考大概可以报什么学校 先不要轻易放弃管留考多少分
- ·哮喘喷雾剂副作用反复咳嗽长期用激素药副作用大吗
- ·指定过敏原怎么检测过敏原
- ·小孩白蛋白偏高,烧不退,医院开了更昔洛韦,喜炎平小孩能用吗,这药效果好不好？
- ·降降血脂药的副作用zetia副作用
- ·9岁孩子两个门牙摔断了怎么办办
- ·16年11月男11个月宝宝16斤叫李焱好吗
- ·冬天皮肤过敏后干燥起皱干燥还不断过敏怎么办
- ·牛黄消炎片,琥乙红霉素干混悬剂片和维生素e, c能一起喝吗
- ·世东我的世界鸡骨头mod头
- ·儿童医院哪家好镇江哪家宠物医院好
- ·怎掉看肺部ct片子怎么看t
- ·肝癌最多能活多久晚期腹胀怎么办
- ·和老公同房后出血之前隔三差五的和我同房,现在十多天没和我同房了这代表什么
- ·余庆县人民医院最好男科医院
- ·孕妇应该多孕妇吃什么食物好最好
- ·有过肝损伤，吃甲巯咪唑肝功能升高正常了，能吃雷贝拉唑吗
- ·乳腺癌。外上象限浸润性导管癌死亡率2级。请帮我解答一下参数的含义。需要化疗bu
- ·湘乡华西妇女儿童医院院的情况
