藥物設(shè)計(jì)與合成復(fù)習(xí)-中英對(duì)照版課件

1、關(guān)于考試的說(shuō)明考試內(nèi)容：藥物合成部分75分開(kāi)卷考試，獨(dú)立完成，嚴(yán)禁互相討論、抄襲考試時(shí)間：2012年11月29日，周四上午8點(diǎn)到11點(diǎn)考題形式：完成反應(yīng)問(wèn)答題Advanced Drug Synthesis 張煒程Contents內(nèi)容Organic Synthesis in Pharmaceutical Industry制藥行業(yè)中的有機(jī)合成Chiral Drugs & Asymmetric Synthesis手性藥物&不對(duì)稱(chēng)合成An Introduction to Retrosynthetic Analysis逆合成分析簡(jiǎn)介Alkylation of Enolates烯醇化物的烷基化Reacti

2、on of Carbon Nucleophiles with Carbonyl Derivatives碳親核試劑與羰基衍生物的反應(yīng)ContentsOrganometallic Compounds of Mg & Li Mg & Li的有機(jī)金屬化合物Transition Metals in Drug Synthesis藥物合成中的過(guò)渡金屬Addition Reactions加成反應(yīng)Substitution Reactions取代反應(yīng)Reduction還原反應(yīng)Oxidation氧化反應(yīng)Protecting Groups保護(hù)基團(tuán)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現(xiàn)代藥物開(kāi)發(fā)的流水線(xiàn)The role of organic synthesis in drug discovery & development有機(jī)合成在藥物發(fā)現(xiàn)與開(kāi)發(fā)中的作用Medicinal synthesis vs. Proces

4、s chemistry藥用合成 vs. 過(guò)程/工藝化學(xué)Case study例子MK-4305CI-1008 (Pregabalin)The Pipeline Concept of Drug Development現(xiàn)代藥物開(kāi)發(fā)的流水線(xiàn)Lipinski Rules5 H-bond donors 5個(gè)氫鍵供體10 H-bond acceptors 10個(gè)氫鍵受體MW 500logP 5Poor absorption or permeation are morelikely when以下情況吸收或滲透性差:Preclinical Studies臨床前研究Pharmacodynamics (PD) 藥效

5、學(xué)Pharmacokinetics (PK) 藥代動(dòng)力學(xué)absorption, distribution, metabolism, excretion (ADME) 吸收，分布，代謝，排泄Toxicology 毒理學(xué)Formulations 劑型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藥用合成Employ the most expeditious route to prepare the designed compounds for early drug discovery & development在早期藥物發(fā)現(xiàn)與開(kāi)發(fā)階段使用最迅捷的路線(xiàn)制備所設(shè)計(jì)的化合物Practical factors (yield, number of steps, cost, operational simplicity, waste disposal, environmental impact, etc.) are not major concerns實(shí)

7、際因素 (產(chǎn)量，反應(yīng)步數(shù)，花費(fèi)，操作簡(jiǎn)便性，廢物處理，環(huán)境影響等）都不是主要考慮的Diversity-oriented synthesis多樣性導(dǎo)向合成Process Chemistry過(guò)程/工藝化學(xué)An efficient route for the large-scale (or commercial) manufacture of the active pharmaceutical ingredient (API)大量（或商業(yè)化）制備藥物活性成分 (API)的高效路線(xiàn)Progressively optimized with respect to all practical factors

8、有關(guān)所有實(shí)際因素的逐步優(yōu)化It may differ significantly from the original medicinal synthesis可能與初始藥物合成有顯著不同Target-oriented synthesis靶點(diǎn)導(dǎo)向合成Outline 概述Stereochemistry & conformational analysis立體化學(xué) & 構(gòu)象分析Molecular chirality & chiral drugs手性分子 & 手性藥物Asymmetric synthesis不對(duì)稱(chēng)合成 Stereochemistry立體化學(xué)異構(gòu)體結(jié)構(gòu)異構(gòu)體立體異構(gòu)體順-反異構(gòu)體有手性中心的

9、異構(gòu)體“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.”“當(dāng)且僅當(dāng)一個(gè)

10、物體與其鏡像不能重疊時(shí)，它具有手性，否則，則為非手性”- K. MislowCahn-Ingold-Prelog (CIP) Priority RulesPriority優(yōu)先性: 1 2 3 4(based on atomic number根據(jù)原子數(shù))clockwise順時(shí)針 Rcounterclockwise逆時(shí)針 SSome Chiral MoleculesThe Lock and Key Model鎖鑰模型Pharmaceutical Significance of Chirality手性在制藥中的意義Pharmaceutical Significance of ChiralityPha

11、rmaceutical Significance of Chirality手性在制藥中的意義鎮(zhèn)靜致畸Axial Chirality 軸手性Chiral Environment of Ru(S)-BINAPComplex Ru(S)-BINAP 復(fù)合物的手性環(huán)境Planar Chirality平面手性JosiPhosEnantiomeric Excess (ee)對(duì)映體過(guò)量百分?jǐn)?shù)100% ee optically pure (single) enantiomer光學(xué)純 (一種) 對(duì)映異構(gòu)體0% ee racemic mixture (1:1 enantiomers)外消旋混合物 (1:1 對(duì)映異

12、構(gòu)體)Diastereomeric Excess (de)非對(duì)映體過(guò)量百分?jǐn)?shù)100% de pure (single) diastereomer純 (一種) 非對(duì)映異構(gòu)體0% de 1:1 diastereomeric mixture1:1 非對(duì)映異構(gòu)體混合物Asymmetric Synthesis不對(duì)稱(chēng)合成Resolution拆分Chromatography separation色譜分離Chiral pool synthesis手性池合成Chiral auxiliary based synthesis基于手性輔助基團(tuán)的合成Asymmetric catalysis不對(duì)稱(chēng)催化Classic Re

13、solution 經(jīng)典拆分Acid (racemic) + Amine (chiral resolving reagent)酸 (外消旋) + 胺 (手性分離試劑)Amine (racemic) + Acid (chiral resolving reagent)胺 (外消旋) + 酸 (手性分離試劑)Kinetic Resolution動(dòng)力學(xué)拆分Maximum yield 50%(like classic resolution)Dynamic Kinetic Resolution動(dòng)態(tài)動(dòng)力學(xué)拆分Maximum yield 100%Chiral Auxiliary手性輔助基團(tuán)Asymmetric

14、Catalysis不對(duì)稱(chēng)催化Lecture 04Alkylation of Enolates烯醇化物的烷基化張煒程2012Asymmetric Alkylation of Enolates烯醇化物的不對(duì)稱(chēng)烷基化N-AcyloxazolidinonesDavid A. Evans(Harvard University)Origin of Diastereoselectivity非對(duì)映異構(gòu)選擇性的來(lái)源Further Transformations進(jìn)一步轉(zhuǎn)化Pfizers Synthesis of PregabalinLecture 05Reaction of Carbon Nucleophiles

15、 with Carbonyl Derivatives碳親核試劑與羰基衍生物的反應(yīng)張煒程2012Mannich ReactionDuloxetineWittig Reaction Nonstabilized YlidesWittig Reaction 不穩(wěn)定的Ylide試劑Devoid of electron-withdrawing groups at the anionic center在陰離子中心缺乏吸電子基Generated through deprotonation with strong bases通過(guò)用強(qiáng)堿脫質(zhì)子制得Highly reactive & must be handled

16、in inert atmosphere高反應(yīng)性，必須在惰性氣體中操作(Z)-alkenes are preferred product(Z)-烯烴為主要產(chǎn)物L(fēng)ecture 06Organometallic Compounds of Mg & LiMg & Li的有機(jī)金屬化合物張煒程2012Retrosynthetic Disconnection using RLi (A) & RMgX (B) Reagents使用RLi (A) & RMgX (B) 試劑逆合成切斷CetirizineSteven Weinreb(Penn State University)Weinreb AmideLectu

17、re 07Transition Metals in Drug Synthesis藥物合成中的過(guò)渡金屬?gòu)垷槼?0122010 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、芐基R：烷基、烯基、芳基、CO2R、OR堿：Et3N、NaOAc、Na2CO3水溶液Catalytic Cycle 催化循環(huán)Suzuki Cross-Coupling鈴

18、木交叉偶合反應(yīng)LosartanLosartan (Cozaar)treatment of hypertensionLecture 08Addition Reactions加成反應(yīng)張煒程2012Hydroboration-oxidation硼氫化-氧化反應(yīng)anti Markovnikov addition反馬氏加成Hydroboration 硼氫化反應(yīng) 4-Membered ring transition state四元環(huán)過(guò)渡態(tài) Regioselectivity: B is added to the less substituted side of a C=C bond 區(qū)域選擇性: B加在 C

19、=C鍵取代基少的那一端 Stereoselectivity: B-H cis addition from the less hindered side 立體選擇性: B-H與位阻小的一端順式加成9-BBNCarboxylic Acid Derivatives羧酸衍生物Preparation of Carboxylic Acid Esters羧酸酯的制備 Catalyzed by strong acid (H2SO4, HCl, etc.)強(qiáng)酸催化 (H2SO4, HCl, etc.) Shift the equilibrium to right for better yield 平衡向右端移動(dòng)

20、產(chǎn)量更高Preparation of Carboxylic Acid Esters羧酸酯的制備高活性中間體Preparation of Carboxylic Acid Esters羧酸酯的制備DMAPPreparation of Carboxylic Acid Esters羧酸酯的制備DCCLecture 10Reduction還原反應(yīng)張煒程2012Homogeneous Catalytic Hydrogenation syn addition of H2 H2同步加成 cis double bonds are hydrogenated faster than trans double bon

21、ds順式雙鍵比反式雙鍵氫化速度快 terminal double bonds are hydrogenated faster than internal double bonds末端雙鍵比鏈內(nèi)雙鍵氫化速度快 little isomerization of double bonds雙鍵幾乎沒(méi)有異構(gòu)化 RCN, RNO2, RCl, RCOOH, RCOOR, RC(O)R are not reduced 不被還原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)穩(wěn)定 RCONH2, CN, NO2 不被還原Reductive Amination還原胺化反應(yīng)Lecture 12Protecting Groups保護(hù)基團(tuán)張煒程2012Basic Requirements of Protecting Groups保護(hù)基團(tuán)的基本要求Stable to & non-interfering with the projected reactions對(duì)主反應(yīng)穩(wěn)定，不干擾主反應(yīng)Easily attached (easy

23、 on)容易連接Easily removed after its task is done (easy off)任務(wù)完成后容易去掉Protection of OH with Ethers醚化保護(hù)OH Mask the acidic proton of OH掩飾OH的酸性質(zhì)子Protect OH from being oxidized保護(hù)OH不被氧化Stable to basic reaction conditions對(duì)堿性條件穩(wěn)定親核還原試劑氧化劑甲基醚正丁基醚 Stable under both acidic & basic conditions在酸性和堿性條件下都穩(wěn)定芐基醚 Also cleaved by (NH4)2Ce(NO3)6 (CAN) 被(NH4)2Ce(NO3)6 (CAN)裂解對(duì)甲氧基芐基醚 Cleaved by acids or by hydrogenolysis (Pd/C, H2) 被酸或氫化作用(Pd/C, H2)裂解三苯基甲基醚Protection o