药物设计与合成复习-中英对照版课件

1、关于考试的说明考试内容：药物合成部分75分开卷考试，独立完成，严禁互相讨论、抄袭考试时间：2012年11月29日，周四上午8点到11点考题形式：完成反应问答题Advanced Drug Synthesis 张炜程Contents内容Organic Synthesis in Pharmaceutical Industry制药行业中的有机合成Chiral Drugs & Asymmetric Synthesis手性药物&不对称合成An Introduction to Retrosynthetic Analysis逆合成分析简介Alkylation of Enolates烯醇化物的烷基化Reacti

2、on of Carbon Nucleophiles with Carbonyl Derivatives碳亲核试剂与羰基衍生物的反应ContentsOrganometallic Compounds of Mg & Li Mg & Li的有机金属化合物Transition Metals in Drug Synthesis药物合成中的过渡金属Addition Reactions加成反应Substitution Reactions取代反应Reduction还原反应Oxidation氧化反应Protecting Groups保护基团ReferencesStudy Material for this co

3、urseAdvanced organic chemistry, Part B (5th edition, Carey & Sundberg)Merriam-Websters Collegiate Dictionary(online edition: )Outline 概述The pipeline concept of modern drug development现代药物开发的流水线The role of organic synthesis in drug discovery & development有机合成在药物发现与开发中的作用Medicinal synthesis vs. Proces

4、s chemistry药用合成 vs. 过程/工艺化学Case study例子MK-4305CI-1008 (Pregabalin)The Pipeline Concept of Drug Development现代药物开发的流水线Lipinski Rules5 H-bond donors 5个氢键供体10 H-bond acceptors 10个氢键受体MW 500logP 5Poor absorption or permeation are morelikely when以下情况吸收或渗透性差:Preclinical Studies临床前研究Pharmacodynamics (PD) 药效

5、学Pharmacokinetics (PK) 药代动力学absorption, distribution, metabolism, excretion (ADME) 吸收，分布，代谢，排泄Toxicology 毒理学Formulations 剂型Reduce Development Time is the Key to Success“For a drug selling at $400 million annually, a one-day delay in the approval or delivery of the drug substances can cost $1 million

6、!”Medicinal Synthesis药用合成Employ the most expeditious route to prepare the designed compounds for early drug discovery & development在早期药物发现与开发阶段使用最迅捷的路线制备所设计的化合物Practical factors (yield, number of steps, cost, operational simplicity, waste disposal, environmental impact, etc.) are not major concerns实

7、际因素 (产量，反应步数，花费，操作简便性，废物处理，环境影响等）都不是主要考虑的Diversity-oriented synthesis多样性导向合成Process Chemistry过程/工艺化学An efficient route for the large-scale (or commercial) manufacture of the active pharmaceutical ingredient (API)大量（或商业化）制备药物活性成分 (API)的高效路线Progressively optimized with respect to all practical factors

8、有关所有实际因素的逐步优化It may differ significantly from the original medicinal synthesis可能与初始药物合成有显著不同Target-oriented synthesis靶点导向合成Outline 概述Stereochemistry & conformational analysis立体化学 & 构象分析Molecular chirality & chiral drugs手性分子 & 手性药物Asymmetric synthesis不对称合成 Stereochemistry立体化学异构体结构异构体立体异构体顺-反异构体有手性中心的

9、异构体“In the field of observation, chance only favors those minds which have been prepared.”- Louis PasteurJacobus Henricus vant Hoff (1852-1911)1901 Nobel Prize in Chemistryproposed in 1874“An object is chiral if and only if it is not superposable on its mirror image; otherwise it is achiral.”“当且仅当一个

10、物体与其镜像不能重叠时，它具有手性，否则，则为非手性”- K. MislowCahn-Ingold-Prelog (CIP) Priority RulesPriority优先性: 1 2 3 4(based on atomic number根据原子数)clockwise顺时针 Rcounterclockwise逆时针 SSome Chiral MoleculesThe Lock and Key Model锁钥模型Pharmaceutical Significance of Chirality手性在制药中的意义Pharmaceutical Significance of ChiralityPha

11、rmaceutical Significance of Chirality手性在制药中的意义镇静致畸Axial Chirality 轴手性Chiral Environment of Ru(S)-BINAPComplex Ru(S)-BINAP 复合物的手性环境Planar Chirality平面手性JosiPhosEnantiomeric Excess (ee)对映体过量百分数100% ee optically pure (single) enantiomer光学纯 (一种) 对映异构体0% ee racemic mixture (1:1 enantiomers)外消旋混合物 (1:1 对映异

12、构体)Diastereomeric Excess (de)非对映体过量百分数100% de pure (single) diastereomer纯 (一种) 非对映异构体0% de 1:1 diastereomeric mixture1:1 非对映异构体混合物Asymmetric Synthesis不对称合成Resolution拆分Chromatography separation色谱分离Chiral pool synthesis手性池合成Chiral auxiliary based synthesis基于手性辅助基团的合成Asymmetric catalysis不对称催化Classic Re

13、solution 经典拆分Acid (racemic) + Amine (chiral resolving reagent)酸 (外消旋) + 胺 (手性分离试剂)Amine (racemic) + Acid (chiral resolving reagent)胺 (外消旋) + 酸 (手性分离试剂)Kinetic Resolution动力学拆分Maximum yield 50%(like classic resolution)Dynamic Kinetic Resolution动态动力学拆分Maximum yield 100%Chiral Auxiliary手性辅助基团Asymmetric

14、Catalysis不对称催化Lecture 04Alkylation of Enolates烯醇化物的烷基化张炜程2012Asymmetric Alkylation of Enolates烯醇化物的不对称烷基化N-AcyloxazolidinonesDavid A. Evans(Harvard University)Origin of Diastereoselectivity非对映异构选择性的来源Further Transformations进一步转化Pfizers Synthesis of PregabalinLecture 05Reaction of Carbon Nucleophiles

15、 with Carbonyl Derivatives碳亲核试剂与羰基衍生物的反应张炜程2012Mannich ReactionDuloxetineWittig Reaction Nonstabilized YlidesWittig Reaction 不稳定的Ylide试剂Devoid of electron-withdrawing groups at the anionic center在阴离子中心缺乏吸电子基Generated through deprotonation with strong bases通过用强碱脱质子制得Highly reactive & must be handled

16、in inert atmosphere高反应性，必须在惰性气体中操作(Z)-alkenes are preferred product(Z)-烯烃为主要产物Lecture 06Organometallic Compounds of Mg & LiMg & Li的有机金属化合物张炜程2012Retrosynthetic Disconnection using RLi (A) & RMgX (B) Reagents使用RLi (A) & RMgX (B) 试剂逆合成切断CetirizineSteven Weinreb(Penn State University)Weinreb AmideLectu

17、re 07Transition Metals in Drug Synthesis药物合成中的过渡金属张炜程20122010 Nobel Prize in ChemistryEi-ichi NegishiRichard F. HeckAkira Suzukifor palladium-catalyzed cross couplings in organic synthesisHeck ReactionR：烯丙基、烯基、芳基、炔基、苄基R：烷基、烯基、芳基、CO2R、OR碱：Et3N、NaOAc、Na2CO3水溶液Catalytic Cycle 催化循环Suzuki Cross-Coupling铃

18、木交叉偶合反应LosartanLosartan (Cozaar)treatment of hypertensionLecture 08Addition Reactions加成反应张炜程2012Hydroboration-oxidation硼氢化-氧化反应anti Markovnikov addition反马氏加成Hydroboration 硼氢化反应 4-Membered ring transition state四元环过渡态 Regioselectivity: B is added to the less substituted side of a C=C bond 区域选择性: B加在 C

19、=C键取代基少的那一端 Stereoselectivity: B-H cis addition from the less hindered side 立体选择性: B-H与位阻小的一端顺式加成9-BBNCarboxylic Acid Derivatives羧酸衍生物Preparation of Carboxylic Acid Esters羧酸酯的制备 Catalyzed by strong acid (H2SO4, HCl, etc.)强酸催化 (H2SO4, HCl, etc.) Shift the equilibrium to right for better yield 平衡向右端移动

20、产量更高Preparation of Carboxylic Acid Esters羧酸酯的制备高活性中间体Preparation of Carboxylic Acid Esters羧酸酯的制备DMAPPreparation of Carboxylic Acid Esters羧酸酯的制备DCCLecture 10Reduction还原反应张炜程2012Homogeneous Catalytic Hydrogenation syn addition of H2 H2同步加成 cis double bonds are hydrogenated faster than trans double bon

21、ds顺式双键比反式双键氢化速度快 terminal double bonds are hydrogenated faster than internal double bonds末端双键比链内双键氢化速度快 little isomerization of double bonds双键几乎没有异构化 RCN, RNO2, RCl, RCOOH, RCOOR, RC(O)R are not reduced 不被还原LiAlH4 (LAH)NaBH4iBu2AlH (DIBAL-H)BH3THF & BH3SMe2NaBH3CN soluble in H2O, ROH, THF stable at

22、low pH (up to 3) RCONH2, CN, NO2 are not reduced 可溶于H2O, ROH, THF 低pH (最大到3)稳定 RCONH2, CN, NO2 不被还原Reductive Amination还原胺化反应Lecture 12Protecting Groups保护基团张炜程2012Basic Requirements of Protecting Groups保护基团的基本要求Stable to & non-interfering with the projected reactions对主反应稳定，不干扰主反应Easily attached (easy

23、 on)容易连接Easily removed after its task is done (easy off)任务完成后容易去掉Protection of OH with Ethers醚化保护OH Mask the acidic proton of OH掩饰OH的酸性质子Protect OH from being oxidized保护OH不被氧化Stable to basic reaction conditions对碱性条件稳定亲核还原试剂氧化剂甲基醚正丁基醚 Stable under both acidic & basic conditions在酸性和碱性条件下都稳定苄基醚 Also cleaved by (NH4)2Ce(NO3)6 (CAN) 被(NH4)2Ce(NO3)6 (CAN)裂解对甲氧基苄基醚 Cleaved by acids or by hydrogenolysis (Pd/C, H2) 被酸或氢化作用(Pd/C, H2)裂解三苯基甲基醚Protection o