有机化学面对持续的挑战，开发和优化了积极的药物成分（API）的的合成。 These challenges involve a multitude of issues designed to improve yield, purity, stereoselectivity, process conditions (ie, temperature and pressure), scalability, and production economics. 这些挑战涉及众多的旨在提高产量，纯度，立体，工艺条件（即温度和压力），可扩展性，和生产经济学的问题 。 A recent literature review reveals insight into some of these challenges as they relate to organic chemical production overall and pharmaceutical chemical development in particular. 最近的文献回顾揭示洞察到其中的一些挑战，因为这涉及到有机化工生产整体和医药化工的发展，特别是。
O-arylation and O-alkylation O -芳基化和O -烷基化
Patricia Van Arnum 帕特里夏范Arnum
Researchers at Merck & Co. recently reported on a large-scale synthesis of a potent glucokinase inhibitor, MK-0941, through selective O -arylation and O -alkylation. 大型合成的一个强有力的葡萄糖激酶抑制剂，通过选择性O -芳基化和 O -烷基化的MK - 0941，默克公司的研究人员最近报道。 Glucokinase inhibitors are under clinical development for treating Type II diabetes. 葡萄糖激酶抑制剂正在临床开发，用于治疗II型糖尿病 。 MK-0941 is a glucokinase inhibitor that has a differentially substituted 3,5-dihydroxybenzamide structure, and an efficient synthesis that would be suitable for large-scale preparation was required. MK - 0941是一种激酶抑制剂，具有差异取代的3,5 - dihydroxybenzamide结构，高效合成，适合大规模制备需要 。 The researchers reported on several drawbacks of the early-stage synthesis, including multiple recrystallizations to improve enantomeric purity, yield variability, and batch-to-batch variability in the impurity profile of the desired compound. 研究人员报告了早期的合成，包括多个重结晶以提高enantomeric纯度，产量变异，并在所需的化合物的杂质概况一批批变异的几个缺点。 Several factors were key to improving the synthesis: a highly selective mono- O -arylation of methyl 3,5-dihydroxybenzoate with 2-ethanesulfonyl-5-chloropyridine and the selection of a proper protective group for the S N 2 O -alkylation (1). 有几个因素是关键，以提高综合：一种具有高度选择性单- O -芳基化ethanesulfonyl - 2 - 5 -氯甲基3,5 -二羟基苯并选择适当的保护组的 S N 2 O -烷基化（ 1 ）。
One-pot protein synthesis 一锅蛋白质合成
Researchers at the University of Chicago recently developed a one-pot protein synthesis involving a 204-residue covalent-dimer vascular endothelial growth factor (VEGF). 在芝加哥大学的研究人员最近开发出一种一锅煮，涉及204个氨基酸残基共价二聚体血管内皮生长因子（VEGF）的蛋白质的合成。 VEGF is a protein involved in vasculogenesis and angiogenesis and is studied in reference to pharmaceutical compounds, particularly anticancer compounds. 血管内皮生长因子在血管生成和血管生成有关的蛋白质和参考药物化合物，特别是抗癌化合物的研究。 The researchers reported that they prepared a 204-residue covalent dimmer VEGF with full mitogenic activity from three unprotected peptide segments by one-pot native chemical ligations. 研究人员报告说，他们准备一个204个氨基酸残基共价调光器血管内皮生长因子，一锅煮的原生化学结扎完全从3个未受保护的肽段的有丝分裂活动。 The covalent structure of the synthetic VEGF was confirmed through mass measurements, and the three-dimensional structure of the synthetic protein was determined by high-resolution X-ray crystallography (2, 3). 通过大规模的测量证实合成血管内皮生长因子的共价键结构，并合成蛋白质的三维结构是由高分辨率X射线晶体学（2，3）确定。
Chemical protein synthesis is one research area of University of Chicago professor Stephen BH Kent, a co-author of the recently published research on the VEGF synthesis. 化学蛋白质的合成，是芝加哥大学教授斯蒂芬BH肯特，最近公布的血管内皮生长因子的合成研究的共同作者的研究领域之一。 One area of focus is the preparation of long polypeptide chains of protein molecules by the chemoselective reaction (ie chemical ligation) of unprotected protein segments containing mutually reactive functional groups. 一个重点领域是未受保护的蛋白质相互反应的官能团的部分（即化学结扎）的化学选择性反应的蛋白质分子的多肽链的准备。 An example of these ligation chemistries is thioester-mediated, amide-forming ligation or native ligation. 这些结扎化学的一个例子是介导的硫酯，酰胺形成结扎或原生结扎 。 The resulting polypeptide chains are folded with good efficiency to produce high-purity synthetic proteins. 由此产生的多肽链折叠与良好的效率，以生产高纯度合成蛋白质。 The covalent structure of the molecule is confirmed by mass spectrometry, and the three-dimensional fold structure of the synthetic protein is determined by X-ray crystallography. 分子的共价键结构质谱证实，合成蛋白质折叠的三维结构是由X射线晶体学确定。 Another area of research focus is kinetically controlled ligation, a chemistry used for the full convergent synthesis of large protein molecules. 另一个研究的重点领域是结扎，使用完整的大型蛋白质分子的收敛合成化学动力学控制 。 The research group is examining insertion reactions for creating molecular diversity in preformed molecular scaffolds and the use of polymer-supported ligation. 该研究小组正在研究在预制分子支架分子多样性的插入反应和使用聚合物支结扎 。
Suzuki-Miyaura cross couplings in a continuous flow system 铃木- Miyaura交叉偶合器在连续流动系统
Researchers at the Massachusetts Institute of Technology (MIT) reported on the development of a Suzuki–Miyaura cross-coupling reaction in a continuous-flow microreactor system. 在美国麻省理工学院（MIT）的研究人员报告了铃木Miyaura交叉偶联反应的发展，在连续流动微型反应器系统。 Specifically, the researchers reported on a continuous-flow Suzuki–Miyaura cross-coupling reaction that started from phenols and produced various biaryls in good yield using a microfluidic-extraction operation and a packed-bed reactor. 具体来说，研究人员报告了一个连续的流铃木- Miyaura交叉偶联反应，开始在良好的收益率从酚类物质和产生的各种biaryls的操作使用微流体萃取和填充床反应器。 The project used a multidisciplinary approach with the research on microreactor technology developed by a team led by Klaus F. Jensen, department head, Warren K. Lewis professor of chemical engineering, and professor of materials science and engineering at MIT. 该项目采用多学科的方法与沃伦K。刘易斯的化学工程教授，系主任，克劳斯延森楼，并在麻省理工学院材料科学与工程学院教授领导的研究小组开发的微反应器技术的研究。 The organic synthesis portion of the project was developed by a group led by Stephen Buchwald, Camille Dreyfus professor of chemistry at MIT (4, 5). 该项目的有机合成部分是由Stephen布赫瓦尔德，卡米尔德雷福斯的化学教授在麻省理工学院（4，5）领导的小组开发。
Suzuki coupling is a palladium-catalyzed coupling between organoboron compounds and organohalides and is an important reaction in organic chemistry in general and in the development of pharmaceutical compounds specifically. 铃木耦合之间的有机硼化合物和organohalides的钯催化偶联，并在一般和专门的药物化合物的发展是在有机化学的重要反应。 Akira Suzuki, distinguished professor emeritus at Hokkaido University in Sapporo, Japan, was a corecipient of the 2010 Nobel Prize in Chemistry for the development of palladium-catalyzed cross coupling (6). 铃木晃，在日本札幌北海道大学特聘教授名誉，是2010年诺贝尔经济学奖corecipient化学钯催化交叉耦合（6）的发展 。
Although batch manufacturing is the predominant form of manufacturing in the pharmaceutical industry, there is growing interest in microreactor technology. 虽然批量制造，在医药行业是制造业的主要形式，有越来越多的微反应器技术的兴趣。 In general, microstructured devices with small internal volumes and high surface-to-volume ratios offer transport capabilities for rapid mixing, enhanced heat transfer for good temperature control, and intensified mass transfer. 在一般情况下，小的内部体积和高表面体积比的微结构器件提供良好的温度控制快速搅拌，增强传热，传质加剧的运输能力。 Microstructured devices operate in continuous-flow environment, which can offer certain advantages, such as controlled process conditions, high flow rates, and high mass throughput. 微结构器件工作在连续流动的环境，可以提供一定的优势，如控制工艺条件，高流速，高质量的吞吐量，的。 Continuous operations also may allow bulk-chemistry processes to have high production capacities. 连续作战，也可能使散装化学过程，具有很高的生产能力 。 Fluid dynamics determine the characteristics of continuous-flow equipment such as pressure loss, residence time, heat-transfer characteristics, and mixing time (7). 流体动力学确定的压力损失，停留时间，传热特性，并搅拌时间（7）如连续流设备的特点 。
Buchwald is engaged in various research projects involving catalysis, including the creation and study of new ligands, the design of new methods to form carbon–nitrogen bonds through the use of metal catalysts, such as palladium or copper, new methods for the formation of carbon–carbon bonds, including asymmetric transformations, as well as continuous flow chemistry using microreactors and capillary tubing. 布赫瓦尔德是从事各种研究项目，涉及催化，包括创造和新的配体的研究，设计的新方法，通过使用金属催化剂，如钯或铜形成的碳的新方法形成碳-氮键-碳键，包括非对称变换，以及连续流动化学利用微反应器和毛细管。 Buchwald recently reported on the continuous-flow synthesis of 3,3-disubstituted oxindoles by a palladium-catalyzed a-arylation/alkylation sequence. 布赫瓦尔德最近报道了由钯催化a-arylation/alkylation序列合成的3,3 -二取代oxindoles连续流 。 Specifically, he reported on the pallidum-catalyzed a-arylation of oxindoles in continuous flow involving a biphasic system, a precatalyst, and a packed-bed microreactor. 具体来说，他的体催化一个涉及两相体系，precatalyst和填充床微反应器在连续流动oxindoles -芳基化。 The reaction was integrated into a two-step continuous-flow sequence for rapid, modular, and efficient syntheses of 3,3-disubstituted oxindoles (8). 反应是集成到一个两步的连续流动快速，模块化，高效合成3,3 -二取代oxindoles（8）序列。
Jensen's research is focused on understanding and controlling the interaction of reaction and transport processes in realizing and testing functional microstructured and nanostructured materials and devices for chemical, biological, optical, electronic, and energy applications, including the use of microfabricated systems. Jensen的研究重点是了解和控制的实现和测试功能的微结构和纳米结构材料与器件，化学，生物，光学，电子，和能源的应用，包括利用微系统的反应，并在运输过程的交互。 He recently reported on research using an automated microfluidic system for online optimization in chemical synthesis. 他最近有报道使用化学合成的在线优化自动化微流体系统的研究。 He reported that the time and material required for an optimization trial were minimized by performing reactions in an integrated silicon microreactor and incorporating high-performance liquid chromatography for in-line monitoring of the reaction performance. 他报告说，通过在一个集成的硅微反应器的反应并结合高效液相色谱在线监测的反应性能优化试验所需的时间和材料的最小化。 The system was used to optimize two different reactions to understand the potential impact of the system for reaction development. 该系统是用于优化两个不同的反应，以了解该系统的反应发展的潜在影响。 The two reactions studied were a Knoevenagel condensation reaction and a mulitparameter optimization to maximize the yield of benzaldehyde in the oxidation pathway of benzyl alcohol to benzaldehyde to benzoic acid (9). 这两个反应的研究是一个Knoevenagel缩合反应和mulitparameter优化，最大限度地苯甲醛，苯甲醇的氧化途径产量甲醛苯甲酸（ 9）。
In other work, Jensen's team reported on the design and use of a high-pressure and high-temperature microsystem. 在其他工作中，詹森的研究小组报告的设计和使用了高压和高温微 。 Key parameters for the fabrication of the microreactors and modular fluidic packaging were to withstand high pressure and temperature conditions (ie, 30MPa and 400 °C). 关键参数的微反应器的制造和模块化的流体包装以承受较高的压力和温度条件下（即，为30MPa和400℃ ）。 The researchers reported on various applications of the high-pressure/high-temperature plug and play microsystems. 研究人员报告了对high-pressure/high-temperature插件各种应用和发挥微。 These applications included multiphase follow visualization through the transition of liquid–liquid immiscible hexane–water segmented flow to homogeneous supercritical flow, on-chip supercritical water oxidation, and synthesis of iron oxide nanoparticles (10). 这些应用包括多相循混溶正己烷液-液分段流动水的过渡可视化，以均匀的超临界流，芯片上的超临界水氧化和合成的氧化铁纳米粒子（ 10）。
Green-chemistry applications 绿色化学的应用
Green chemistry is an important tool in improving reactions, which may for example, improve production economics through reduced energy requirements, lower solvent use, fewer byproducts, and less waste generation. 绿色化学是提高反应的重要工具，例如通过减少能源需求，降低溶剂使用，副产品少，和减少废物的产生，提高生产经济 。 Bruce H. Lipshutz, professor in the chemistry and biochemistry department at the University of California at Santa Barbara, was recognized in June with a Presidential Green Chemistry Challenge Award, an annual recognition by the US Environmental Protection Agency for advances in green chemistry (11). 布鲁斯H. Lipshutz，在加州大学圣巴巴拉分校化学和生物化学系教授，是在6月承认了总统绿色化学挑战奖“，由美国环境保护署绿色化学的进展的年度表彰（ 11） 。
Nanodispersed surfactant . Lipshutz was recognized for designing a second-generation surfactant, TPGS-750-M, which can be used in industrial processes to replace large amounts of organic solvents with small amounts of the surfactant nanodispersed in water only. Nanodispersed表面活性剂 。Lipshutz确认设计了第二代的表面活性剂，TPGS - 750 - M，可以在工业生产过程中用来代替大量的有机溶剂，少量的表面活性剂在水只 nanodispersed。 TPGS-750-M is composed of TOCopherol (ie, vitamin E), succinic acid, and methoxy polyethylene glycol. TPGS - 750 - M是由生育酚（即维生素E），琥珀酸，和甲氧基聚乙二醇 。 TPGS-750-M forms nanomicelles in water that are lipophilic on the interior and hydrophilic on the exterior. TPGS - 750 - M的形式的内部和外部亲水亲油性水nanomicelles。 A small amount of TPGS-750-M may be used to spontaneously form 50–100-nm diameter micelles in water to serve as nanoreactors. 可以使用一个TPGS - 750 - M的少量自发地在水中形成直径50 - 100纳米胶束作为纳米反应器服务。 The particle size of TPGS-750-M is engineered to facilitate organic reactions, such as cross-couplings. TPGS - 750 - M的粒径是设计，以促进有机反应，如跨接头。 Reactants and catalysts dissolve in the micelles, resulting in high concentrations that lead to increased reaction rates at ambient temperature (11). 反应物和催化剂溶解在胶束，导致高浓度，导致在环境温度（11）反应速率增加 。
Several common organic reactions that are catalyzed by transition metals can take place within TPGS-750-M micelles in water at room temperature and in high isolated yields. 几种常见的过渡金属催化有机反应可以在TPGS - 750 - M在水中的胶束在室温和孤立产量高的地方 。 These reactions include ruthenium-catalyzed olefin metatheses (Grubbs), palladium-catalyzed cross-couplings (Suzuki, Heck, and Sonogashira), unsymmetrical aminations, allylic aminations and silylations, and aryl borylations. 这些反应包括钌催化烯烃metatheses（格拉布斯），钯催化交叉耦合（铃木，哎呀，Sonogashira），非对称aminations，烯丙基aminations和silylations，和芳borylations。 The technology also offers the potential for palladium-catalyzed aromatic carbon–hydrogen bond activation for carbon–carbon bond formation at room temperature. 该技术还提供了钯催化芳香族碳氢键活化碳-碳键的形成在室温的潜力 。 In its awards recognition, EPA cited other advantages to the technology: straightforward product isolation; elimination of frothing and foaming commonly associated with other surfactants; efficient recycling of the surfactant after use; recovery of the insoluble product by extraction; and reuse of the aqueous surfactant with negligible loss of activity. 在它的表彰奖励，EPA列举其他的技术优势：简单的产品隔离;消除通常与其他表面活性剂的发泡和发泡;有效的回收使用后的表面活性剂;提取不溶于水的产品回收;和再利用表面活性剂活动的损失可以忽略不计 。 Future generations of surfactants may include a catalyst tethered to a surfactant to provide both the reaction vessel (ie, the inside of the micelle) and the catalyst to enable the reaction (11). 表面活性剂的后代可能包括拴在表面活性剂的催化剂，同时提供反应釜（即胶束内部）和催化剂，使反应（11） 。
Flow processing . Eli Lilly submitted two entries to EPA's Green Chemistry Presidential Challenge. 流处理 。礼来公司提交了两个条目EPA的绿色化学总统挑战 。 The first involved the commercial production of LY262480undefinedH3PO4, an investigational new drug candidate in Phase II clinical trials and a drug acquired by Lilly with its acquisition of Hypnion. 第一涉及LY2624803 *磷酸的商业化生产，研究在新的候选药物第二期临床试验的药物，由礼来收购收购的Hypnion。 The original synthesis was not amenable to large-scale manufacture and had several environmental and safety issues with the original chemistry. 原合成，不适合大规模生产，并有几个与原来的化学环境和安全问题 。 Among them were: dimethylformamide/sodium hydride in step one of the synthesis; methylene in various steps; a molten step with observed self-heating; an aldehyde purification that would be unsafe at increased scale; phosphoryl chloride in large excess; and chromatographic purification (11). 其中包括：二甲基甲酰胺/氢化钠的合成的步骤之一;在各个步骤甲基;与观察到的自加热熔融一步;醛净化规模的扩大，将不安全;氯化磷大量过剩;和层析纯化 （ 11）。
The company made several improvements to the synthesis using flow processing. 该公司提出了一些改进，使用流处理的合成 。 An efficient carbonylation replaced an inefficient oxidation catalyzed by tetramethyl pentahydropyridine oxide. 一个高效的羰基取代了低效的甲基pentahydropyridine氧化催化氧化 。 Hydrogen replaced sodium triacetoxyborohydride in a reductive amination. 取代氢在还原氨化钠triacetoxyborohydride。 Although both operations required high pressure (ie, 1000 psi), which would be difficult to manage in a batch environment, both operations were amenable to flow processing (11). 虽然这两个操作所需的高压（即1000 PSI），这将是在批处理环境很难管理，这两个操作适合流处理（11）。
Process mass intensity (PMI), a measure of the efficiency of a synthesis, was improved. 过程中的质量强度（PMI），合成效率的措施，进行了改进 。 PMI is the total mass of raw materials (including water) put into a process for every kilogram of product produced. PMI是一个过程，每公斤产品的生产到原材料（包括水）的总质量 。 The original route had a PMI of more than 1000 before chromatography. 色谱原路线收到了超过1000的PMI 。 The new route has a net PMI of 59, representing a 94% reduction in PMI and a 96% percent reduction with chromatography. 新航线，有59个 净采购经理指数，代表了PMI减少94％和，与色谱减少96 ％。 Lilly implemented its new route for LY262480undefinedH 3 PO 4 on a pilot-plant scale in Indianapolis, Indiana, during 2009 and on a commercial scale in Kinsale, Ireland, during 2010, according to the EPA report (11). LY2624803，礼来实施其新航线试点工厂规模_高 3 PO 4在印第安纳波利斯，印第安纳州，在2009年，以商业规模在Kinsale，爱尔兰，在2010年，根据美国环保局的报告（11 ）。
Improved Grignard chemistry. 改进的格氏化学 。 Another entry from Eli Lilly involved the development of Grignard chemistry using a continuous stirred tank reactor. 由美国礼来另一项涉及格氏化学的发展，采用连续搅拌反应釜。 The Grignard reaction is applied to many industrial reactions, including producing intermediates for pharmaceutical compounds. 格氏反应是适用于许多工业的反应，包括生产药物化合物的中间体。 Some commercial-scale problems with the reaction, however, are strongly exothermic activation and reaction steps, heterogeneous reactions with potential problems suspending and mixing the reaction mixture, and operational hazards posed by ethereal solvents, such as diethyl ether (11). 反应有些商业规模的问题，然而，强烈的放热激活和反应步骤，多相反应，暂停和混合反应混合物，和空灵的溶剂，如乙醚（11），造成的业务风险的潜在问题。
本文来自: 医药社区(www.pharmst.cn) 详细出处参考：http://pharmst.web12.mzserver.net/viewthread.php?tid=65007
(责任编辑：大汉昆仑王)
