如何提高原料藥合成的效率（中英對照）
有機化學面對持續(xù)的挑戰(zhàn)，開發(fā)和優(yōu)化了積極的藥物成分（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. 這些挑戰(zhàn)涉及眾多的旨在提高產(chǎn)量，純度，立體，工藝條件（即溫度和壓力），可擴展性，和生產(chǎn)經(jīng)濟學的問題 。
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. 最近的文獻回顧揭示洞察到其中的一些挑戰(zhàn)，因為這涉及到有機化工生產(chǎn)整體和醫(yī)藥化工的發(fā)展，特別是。
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. 大型合成的一個強有力的葡萄糖激酶抑制劑，通過選擇性O(shè) -芳基化和 O -烷基化的MK - 0941，默克公司的研究人員最近報道。
Glucokinase inhibitors are under clinical development for treating Type II diabetes. 葡萄糖激酶抑制劑正在臨床開發(fā)，用于治療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是一種激酶抑制劑，具有差異取代的3,5 - dihydroxybenzamide結(jié)構(gòu)，高效合成，適合大規(guī)模制備需要 。
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. 研究人員報告了早期的合成，包括多個重結(jié)晶以提高enantomeric純度，產(chǎn)量變異，并在所需的化合物的雜質(zhì)概況一批批變異的幾個缺點。
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). 有幾個因素是關(guān)鍵，以提高綜合：一種具有高度選擇性單- O -芳基化ethanesulfonyl - 2 - 5 -氯甲基3,5 -二羥基苯并選擇適當?shù)谋Ｗo組的 S N 2 O -烷基化（ 1 ）。
One-pot protein synthesis 一鍋蛋白質(zhì)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). 在芝加哥大學的研究人員最近開發(fā)出一種一鍋煮，涉及204個氨基酸殘基共價二聚體血管內(nèi)皮生長因子（VEGF）的蛋白質(zhì)的合成。
VEGF is a protein involved in vasculogenesis and angiogenesis and is studied in reference to pharmaceutical compounds, particularly anticancer compounds. 血管內(nèi)皮生長因子在血管生成和血管生成有關(guān)的蛋白質(zhì)和參考藥物化合物，特別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. 研究人員報告說，他們準備一個204個氨基酸殘基共價調(diào)光器血管內(nèi)皮生長因子，一鍋煮的原生化學結(jié)扎完全從3個未受保護的肽段的有絲分裂活動。
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). 通過大規(guī)模的測量證實合成血管內(nèi)皮生長因子的共價鍵結(jié)構(gòu)，并合成蛋白質(zhì)的三維結(jié)構(gòu)是由高分辨率X射線晶體學（2，3）確定。
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. 化學蛋白質(zhì)的合成，是芝加哥大學教授斯蒂芬BH肯特，最近公布的血管內(nèi)皮生長因子的合成研究的共同作者的研究領(lǐng)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. 一個重點領(lǐng)域是未受保護的蛋白質(zhì)相互反應(yīng)的官能團的部分（即化學結(jié)扎）的化學選擇性反應(yīng)的蛋白質(zhì)分子的多肽鏈的準備。 An example of these ligation chemistries is thioester-mediated, amide-forming ligation or native ligation. 這些結(jié)扎化學的一個例子是介導的硫酯，酰胺形成結(jié)扎或原生結(jié)扎 。
The resulting polypeptide chains are folded with good efficiency to produce high-purity synthetic proteins. 由此產(chǎn)生的多肽鏈折疊與良好的效率，以生產(chǎn)高純度合成蛋白質(zhì)。
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. 分子的共價鍵結(jié)構(gòu)質(zhì)譜證實，合成蛋白質(zhì)折疊的三維結(jié)構(gòu)是由X射線晶體學確定。
Another area of research focus is kinetically controlled ligation, a chemistry used for the full convergent synthesis of large protein molecules. 另一個研究的重點領(lǐng)域是結(jié)扎，使用完整的大型蛋白質(zhì)分子的收斂合成化學動力學控制 。
The research group is examining insertion reactions for creating molecular diversity in preformed molecular scaffolds and the use of polymer-supported ligation. 該研究小組正在研究在預制分子支架分子多樣性的插入反應(yīng)和使用聚合物支結(jié)扎 。
Suzuki-Miyaura cross couplings in a continuous flow system 鈴木- Miyaura交叉偶合器在連續(xù)流動系統(tǒng)
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. 在美國麻省理工學院（MIT）的研究人員報告了鈴木Miyaura交叉偶聯(lián)反應(yīng)的發(fā)展，在連續(xù)流動微型反應(yīng)器系統(tǒng)。
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. 具體來說，研究人員報告了一個連續(xù)的流鈴木- Miyaura交叉偶聯(lián)反應(yīng)，開始在良好的收益率從酚類物質(zhì)和產(chǎn)生的各種biaryls的操作使用微流體萃取和填充床反應(yīng)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. 該項目采用多學科的方法與沃倫K。劉易斯的化學工程教授，系主任，克勞斯延森樓，并在麻省理工學院材料科學與工程學院教授領(lǐng)導的研究小組開發(fā)的微反應(yīng)器技術(shù)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). 該項目的有機合成部分是由Stephen布赫瓦爾德，卡米爾德雷福斯的化學教授在麻省理工學院（4，5）領(lǐng)導的小組開發(fā)。
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. 鈴木耦合之間的有機硼化合物和organohalides的鈀催化偶聯(lián)，并在一般和專門的藥物化合物的發(fā)展是在有機化學的重要反應(yīng)。
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). 鈴木晃，在日本札幌北海道大學特聘教授名譽，是2010年諾貝爾經(jīng)濟學獎corecipient化學鈀催化交叉耦合（6）的發(fā)展 。
Although batch manufacturing is the predominant form of manufacturing in the pharmaceutical industry, there is growing interest in microreactor technology. 雖然批量制造，在醫(yī)藥行業(yè)是制造業(yè)的主要形式，有越來越多的微反應(yīng)器技術(shù)的興趣。
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. 在一般情況下，小的內(nèi)部體積和高表面體積比的微結(jié)構(gòu)器件提供良好的溫度控制快速攪拌，增強傳熱，傳質(zhì)加劇的運輸能力。
Microstructured devices operate in continuous-flow environment, which can offer certain advantages, such as controlled process conditions, high flow rates, and high mass throughput. 微結(jié)構(gòu)器件工作在連續(xù)流動的環(huán)境，可以提供一定的優(yōu)勢，如控制工藝條件，高流速，高質(zhì)量的吞吐量，的。
Continuous operations also may allow bulk-chemistry processes to have high production capacities. 連續(xù)作戰(zhàn)，也可能使散裝化學過程，具有很高的生產(chǎn)能力 。
Fluid dynamics determine the characteristics of continuous-flow equipment such as pressure loss, residence time, heat-transfer characteristics, and mixing time (7). 流體動力學確定的壓力損失，停留時間，傳熱特性，并攪拌時間（7）如連續(xù)流設(shè)備的特點 。
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. 布赫瓦爾德是從事各種研究項目，涉及催化，包括創(chuàng)造和新的配體的研究，設(shè)計的新方法，通過使用金屬催化劑，如鈀或銅形成的碳的新方法形成碳-氮鍵-碳鍵，包括非對稱變換，以及連續(xù)流動化學利用微反應(yīng)器和毛細管。
Buchwald recently reported on the continuous-flow synthesis of 3,3-disubstituted oxindoles by a palladium-catalyzed a-arylation/alkylation sequence. 布赫瓦爾德最近報道了由鈀催化
a-arylation/alkylation序列合成的3,3 -二取代
oxindoles連續(xù)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. 具體來說，他的體催化一個涉及兩相體系，precatalyst和填充床微反應(yīng)器在連續(xù)流動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). 反應(yīng)是集成到一個兩步的連續(xù)流動快速，模塊化，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的研究重點是了解和控制的實現(xiàn)和測試功能的微結(jié)構(gòu)和納米結(jié)構(gòu)材料與器件，化學，生物，光學，電子，和能源的應(yīng)用，包括利用微系統(tǒng)的反應(yīng)，并在運輸過程的交互。
He recently reported on research using an automated microfluidic system for online optimization in chemical synthesis. 他最近有報道使用化學合成的在線優(yōu)化自動化微流體系統(tǒng)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. 他報告說，通過在一個集成的硅微反應(yīng)器的反應(yīng)并結(jié)合高效液相色譜在線監(jiān)測的反應(yīng)性能優(yōu)化試驗所需的時間和材料的最小化。
The system was used to optimize two different reactions to understand the potential impact of the system for reaction development. 該系統(tǒng)是用于優(yōu)化兩個不同的反應(yīng)，以了解該系統(tǒng)的反應(yīng)發(fā)展的潛在影響。
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). 這兩個反應(yīng)的研究是一個Knoevenagel縮合反應(yīng)和mulitparameter優(yōu)化，最大限度地苯甲醛，苯甲醇的氧化途徑產(chǎn)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，詹森的研究小組報告的設(shè)計和使用了高壓和高溫微 。
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). 關(guān)鍵參數(shù)的微反應(yīng)器的制造和模塊化的流體包裝以承受較高的壓力和溫度條件下（即，為30MPa和400℃ ）。
The researchers reported on various applications of the high-pressure/high-temperature plug and play microsystems. 研究人員報告了對high-pressure/high-temperature插件各種應(yīng)用和發(fā)揮微。
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). 這些應(yīng)用包括多相循混溶正己烷液-液分段流動水的過渡可視化，以均勻的超臨界流，芯片上的超臨界水氧化和合成的氧化鐵納米粒子（ 10）。
Green-chemistry applications 綠色化學的應(yīng)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. 綠色化學是提高反應(yīng)的重要工具，例如通過減少能源需求，降低溶劑使用，副產(chǎn)品少，和減少廢物的產(chǎn)生，提高生產(chǎn)經(jīng)濟 。
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). 布魯斯H. Lipshutz，在加州大學圣巴巴拉分?；瘜W和生物化學系教授，是在6月承認了總統(tǒng)綠色化學挑戰(zhàn)獎“，由美國環(huán)境保護署綠色化學的進展的年度表彰（ 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表面活性劑 。Lipshutz確認設(shè)計了第二代的表面活性劑，TPGS - 750 - M，可以在工業(yè)生產(chǎn)過程中用來代替大量的有機溶劑，少量的表面活性劑在水只 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（即維生素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的形式的內(nèi)部和外部親水親油性水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. 可以使用一個TPGS - 750 - M的少量自發(fā)地在水中形成直徑50 - 100納米膠束作為納米反應(yīng)器服務(wù)。 The particle size of TPGS-750-M is engineered to facilitate organic reactions, such as cross-couplings. TPGS - 750 - M的粒徑是設(shè)計，以促進有機反應(yīng)，如跨接頭。 Reactants and catalysts dissolve in the micelles, resulting in high concentrations that lead to increased reaction rates at ambient temperature (11). 反應(yīng)物和催化劑溶解在膠束，導致高濃度，導致在環(huán)境溫度（11）反應(yīng)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. 幾種常見的過渡金屬催化有機反應(yīng)可以在TPGS - 750 - M在水中的膠束在室溫和孤立產(chǎn)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. 這些反應(yīng)包括釕催化烯烴metatheses（格拉布斯），鈀催化交叉耦合（鈴木，哎呀，Sonogashira），非對稱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. 該技術(shù)還提供了鈀催化芳香族碳氫鍵活化碳-碳鍵的形成在室溫的潛力 。 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. 在它的表彰獎勵，EPA列舉其他的技術(shù)優(yōu)勢：簡單的產(chǎn)品隔離;消除通常與其他表面活性劑的發(fā)泡和發(fā)泡;有效的回收使用后的表面活性劑;提取不溶于水的產(chǎn)品回收;和再利用表面活性劑活動的損失可以忽略不計 。 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). 表面活性劑的后代可能包括拴在表面活性劑的催化劑，同時提供反應(yīng)釜（即膠束內(nèi)部）和催化劑，使反應(yīng)（11） 。
Flow processing . Eli Lilly submitted two entries to EPA's Green Chemistry Presidential Challenge. 流處理 。禮來公司提交了兩個條目EPA的綠色化學總統(tǒng)挑戰(zhàn) 。 The first involved the commercial production of LY2624803*H3PO4, 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 *磷酸的商業(yè)化生產(chǎn)，研究在新的候選藥物第二期臨床試驗的藥物，由禮來收購收購的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，不適合大規(guī)模生產(chǎn)，并有幾個與原來的化學環(huán)境和安全問題 。 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/氫化鈉的合成的步驟之一;在各個步驟甲基;與觀察到的自加熱熔融一步;醛凈化規(guī)模的擴大，將不安全;氯化磷大量過剩;和層析純化 （ 11）。
The company made several improvements to the synthesis using flow processing. 該公司提出了一些改進，使用流處理的合成 。 An efficient carbonylation replaced an inefficient oxidation catalyzed by tetramethyl pentahydropyridine oxide. 一個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. 取代氫在還原氨化鈉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). 雖然這兩個操作所需的高壓（即1000 PSI），這將是在批處理環(huán)境很難管理，這兩個操作適合流處理（11）。
Process mass intensity (PMI), a measure of the efficiency of a synthesis, was improved. 過程中的質(zhì)量強度（PMI），合成效率的措施，進行了改進 。 PMI is the total mass of raw materials (including water) put into a process for every kilogram of product produced. PMI是一個過程，每公斤產(chǎn)品的生產(chǎn)到原材料（包括水）的總質(zhì)量 。 The original route had a PMI of more than 1000 before chromatography. 色譜原路線收到了超過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. 新航線，有59個 凈采購經(jīng)理指數(shù)，代表了PMI減少94％和，與色譜減少96 ％。 Lilly implemented its new route for LY2624803*H 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，禮來實施其新航線試點工廠規(guī)模* 高 3 PO 4在印第安納波利斯，印第安納州，在2009年，以商業(yè)規(guī)模在Kinsale，愛爾蘭，在2010年，根據(jù)美國環(huán)保局的報告（11 ）。
Improved Grignard chemistry. 改進的格氏化學 。 Another entry from Eli Lilly involved the development of Grignard chemistry using a continuous stirred tank reactor. 由美國禮來另一項涉及格氏化學的發(fā)展，采用連續(xù)攪拌反應(yīng)釜。 The Grignard reaction is applied to many industrial reactions, including producing intermediates for pharmaceutical compounds. 格氏反應(yīng)是適用于許多工業(yè)的反應(yīng)，包括生產(chǎn)藥物化合物的中間體。 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). 反應(yīng)有些商業(yè)規(guī)模的問題，然而，強烈的放熱激活和反應(yīng)步驟，多相反應(yīng)，暫停和混合反應(yīng)混合物，和空靈的溶劑，如乙醚（11），造成的業(yè)務(wù)風險的潛在問題。
北京天優(yōu)福康生物科技有限公司
官網(wǎng)：http://www.jyzjsd.com/
服務(wù)熱線：400-860-6160
聯(lián)系電話/微信：13718308763
QQ:2136615612 3317607072
E-mail：Tianyoubzwz@163.com
