氯化亚砜在有机合成中的应用

综述了近年来氯化亚砜在有机合成中的应用进展，主要涉及氯代化合物、烯烃、酯及酰胺、腈、环式亚硫酸酯、亚磺酰氯等化合物的制备。     

钯催化合成反应的最新进展

五十年代中,应用钯催化剂氧化乙烯制备乙醛的工业方法,称为Wacker 法。在该法问世以前,钯催化剂在有机合成中主要用于部份氢化和氧化。嗣后,对该法的研究,开辟了钯络合物在有机合成研究领域中的应用,激起有机钯化学的热潮。钯催化剂不仅应用于部份氢化和氧化,且陆续应用于烃化、偶合、环合、加成、重排、胺化、氯化、消除和脱保护基等反应。反应     

有机硅试剂在药物合成中的应用

由于有机硅试剂在有机合成中显示出良好的反应性能及高度的区域专一性和立体选择性,现已成为有机合成中不可缺少的重要试剂~[1～3]。对某些有机硅试剂及其在药物合成中的应用亦曾有介绍~[4],近几年来进展很快,在药物合成中的应用也愈加普遍。现择要介绍如下:     

烯醇硅醚(Silyl Enol Ethers)在药物合成中的应用

近年来,有机硅化合物的应用得到迅速发展。它不仅作为一类有效的保护试剂应用于有机合成,而且已成为一类非常有用的合成中间体,广泛应用于天然化合物和药物的合成。本文仅就目前在合成中应用较广泛而又易于在一般实验室中制备的烯醇硅醚的制备及反应性能,结合在药物合成中的应用实例作一介绍。一、烯醇硅醚的性质和制备方法如图1所示,由于烯醇硅醚中有C=C键存在,Si—O键强度削弱,烯醇硅醚以负碳离子进行亲核反应,亲电试剂E~+进攻O—C键的α位:     

使用OprF作为锚定蛋白在大肠杆菌表面展示脂肪酶及在有机溶剂中筛选对映异构体的应用

开发了一种新的细胞表面展示系统，使用铜绿假单孢菌的一种主要外膜蛋白OprF作为锚定位点。荧光假单孢菌SIK W1脂肪酶基因通过C端删除融合技术与截短的oprF基因融合。在大肠杆菌表面成功展示了截短的OprF-脂肪酶融合蛋白。通过蛋白杂交分析、免疫荧光显微术和整个细胞的脂肪酶活性确定了截短的OprF-脂肪酶融合蛋白在膜上的定位。为了检测细胞表面展示脂肪酶的酶学特征，在各种条件下考查了细胞整体酶活力和稳定性。细胞表面展示脂肪酶在37℃、pH 8．0时酶活力最高。在水溶液和有机溶液中温育一周后，酶活力还可保留80％以上。将展示脂肪酶的大肠杆菌用于外消旋1-苯基乙醇在正己烷中的对映异构体选择，经36h反应成功获得了对映体超过96％的（R）-苯乙酸乙酯。结果表明OprF作锚定蛋白展示脂肪酶的大肠杆菌可用于各种水相、非水相的生物技术应用。     

对甲苯丙醚相转移催化法合成

对甲苯丙醚是农药、医药等合成的有机中间体。以往用 Williamson 法,即酚钠与卤代烷或草酸酯反应制备,但产率低,条件苛刻,操作繁琐。随着相转移催化技术在有机合成中的应用,Rowe 和王梦如报道了以溴化或氯化四丁基铵为相转移催化剂,用对甲苯酚和溴代正丙烷反应来制备。但这类季     

脂肪酶在普瑞巴林制备中的应用进展

目的 对脂肪酶在普瑞巴林化学-酶法合成中的应用进行综述及探讨。方法 通过文献检索及整理,综述了近年来在化学合成普瑞巴林的基础上引入脂肪酶拆分得到普瑞巴林手性中间体的应用进展,按脂肪酶的反应类型进行了分类,并对拆分2-乙氧羰基-3-氰基-5-甲基己酸乙酯得到普瑞巴林中间体的催化剂进行了阐述。结果 脂肪酶催化拆分普瑞巴林中间体专一性强、产率高、环境友好。结论 与单纯的化学法合成普瑞巴林相比,脂肪酶在普瑞巴林制备工艺中有明显的优势,具有良好的应用前景。     

胰酶制备中三酶活性的相互关系及其主要影响因素的研究

作者对猪胰酶制备过程中胰蛋白酶、脂肪酶、淀粉酶等三酶活性间的相互关系,主要影响因素及如何提高胰酶产品的三酶活性等方面进行了研究。结果表明,三酶中起主导作用的是胰蛋白酶,最不稳定的是胰脂肪酶;三酶活性可通过温度、时间、激活剂等因素控制,适当的工艺条件可使产品在脂肪酶、淀粉酶活性较高的前提下,其蛋白酶活性提高。     

手性噁唑硼烷催化酮的不对称还原反应

唑硼烷催化酮的不对称还原反应是最成功的催化不对称反应之一，本文介绍这一反应，并着重论述各种唑硼烷的催化活性以及这一反应在有机合成中的应用。     

甲基锂试剂的改良制备法

甲基锂是有机合成中的重要试剂。其质量高低直接影响到反应的成功与否。在已报道的甲基锂制备方法中,有的方法难以除尽细微的锂屑和碘化锂,这样会影响某些有机反应的进行或产生副反应。有的方法制备的甲基锂溶液,浓度可能受空气中的 O_2和水份、容器吸附的水份等影响,使甲基锂含量变低,引入杂质。且滴定时所用的     

Microbial/enzymatic synthesis of chiral pharmaceutical intermediates

Chirality is a key factor in the efficacy of many drugs; thus, the production of single enantiomers of drug intermediates has become increasingly important in the pharmaceutical industry. Chiral intermediates and fine chemicals are in high demand from the pharmaceutical and agrochemical industries for the preparation of bulk drug substances and agricultural products. There has been an increasing awareness of the enormous potential of microorganisms and enzymes for the transformation of synthetic chemicals with high chemo-, regio- and enantioselectivity. In this article, biocatalytic processes for the synthesis of chiral pharmaceutical intermediates are described.     

Hydroformylation and carbonylation processes: new trends in the synthesis of pharmaceuticals

The synthesis of complex organic molecules by catalytic transformations has made a significant impact on the development of new routes to a variety of pharmaceutical intermediates and optically active drugs. Carbonylation and hydroformylation reactions using metal complex catalysts are particularly attractive in this context as they provide clean, atom-efficient routes for the synthesis of molecules with carboxylic acid, aldehyde and amide functional groups to replace stoichiometric, multi-step routes using toxic and hazardous reagents. This review presents an update of recent research demonstrating the novel features of catalytic carbonylation and hydroformylation reactions and the current state of their development. Besides the expanding applications of carbonylation reactions, their unique features, such as high regioselectivity, high enantioselectivity (using appropriate chiral ligands) and their combination with other reactions to facilitate tandem (one-pot) synthesis, are highly promising. Clearly, the future direction is toward the synthesis of enantiomerically pure drug molecules and intermediates by asymmetric catalysis if the challenges of catalyst-product separation and the development of chiral ligands at a lower cost can be met.     

Scalable enantioselective processes for chiral pharmaceutical intermediates

The importance and practicality of asymmetric synthesis to obtain enantiomerically pure drug substances has been fully recognized by process chemists of the pharmaceutical industry. Catalytic enantioselective processes would be particularly advantageous, compared to processes requiring stoichiometric amounts of chiral initiators, and would also be of interest from an environmental perspective. Since the commercialization of the Monsanto process for the manufacturing of L-DOPA in the early 1970s, catalytic asymmetric reactions have often been utilized in the commercial production of active pharmaceutical ingredients. This review will focus on recent advances in the development of scalable enantioselective processes for chiral pharmaceutical intermediates.     

Biocatalysis: synthesis of chiral intermediates for drugs

Chirality is a key factor in the safety and efficacy of many drug products and thus the production of single enantiomers of drug intermediates has become increasingly important in the pharmaceutical industry. Chiral intermediates and fine chemicals are in high demand for the bulk preparation of drug substances and agricultural products. There has been an increasing awareness of the enormous potential of the use of microorganisms and microorganism-derived enzymes for the transformation of synthetic chemicals with high chemo-, regio- and enantioselectivities. In this article, biocatalytic processes are described for the synthesis of chiral intermediates for drugs.     

手性叔丁基亚磺酰胺的制备方法及其在药物合成中的应用

手性叔丁基亚磺酰胺是近年来发展起来的一种新型医药中间体,也是合成手性胺类药物及其中间体的关键手性源,其相关研究受到研究人员的广泛关注。综述手性叔丁基亚磺酰胺的制备方法以及该化合物在药物合成领域中的应用情况。     

微生物转化技术在现代医药工业中的应用

对微生物转化技术在现代医药工业应用上的独特优势。特别是在手性药物或药物中间体制备、借助微生物转化手段实施组合生物催化在新药筛选方面发挥的积极作用进行了阐述分析，并结合作者自身近年来在该技术领域的实践和收获对数个相关课题作了介绍。     

专利视角下我国医药中间体应用技术发展态势研究

目的:协助企业了解医药中间体行业相关的技术点和发展趋势,为医药中间体应用技术提供新的发展思路和技术支持。方法:将医药中间体涉及的核心技术列为研究对象并分为四级,检索国家知识产权局专利检索系统(SIPO)及合享(INCOPAT)、智慧芽(PatSnap)专利数据库中2020年2月2日之前公开/公告的医药中间体专利数据。运用专利分析方法分析医药中间体专利申请趋势以及专利申请人,同时对医药中间体二、三级技术进行详细分析。最后运用SPSS 24.0软件对我国医药中间体专利的申请数量进行曲线拟合预测分析。结果:共检索出相关专利12103条;二级技术分类下,抗生素类药物中间体专利有331条,解热镇痛药物中间体专利有474条,心血管药物中间体专利有1227条,抗癌用医药中间体专利有1550条。全球与我国医药中间体专利申请数量均逐年递增,中国大陆的专利申请数量是最多的,其中江苏、上海、山东等省份专利申请数量排名前3位;排在前10位的专利申请人中有8家为我国国内企业或高校,他们也在我国医药中间体专利申请人构成中排名前2位。医药中间体二级技术中,心血管药物中间体专利申请数量占比最大(占32%),其次是抗癌用医药中间体技术(占30%);三级技术中,医药中间体在产品(占35%)、方法(占35%)和用途(占28%)上均有专利申请。我国医药中间体专利申请数量的曲线拟合显示,当前申请趋势与三次曲线模型拟合程度最高,并预测我国2020、2021年的专利申请数量分别为688、781件。结论:医药中间体技术在我国发展迅速,高校与企业都具备相当的研发实力;企业除了在技术创新上有所发展外,还可以考虑校企合作的发展思路以及企业间的专利交叉许可,助力我国医药中间体产业更好发展。     

Separation processes for organic molecules using SCF Technologies

Supercritical fluids have been applied for many years for the separation of solutes from solids or solute mixtures in both exploratory and industrial applications. In the pharmaceutical industry the generation of pure solid states without impurities is important as the presence of impurities can result in a change in chemical properties or lead to physical instability. The literature on the separation and purification of solutes from solid matrices and solute mixtures using supercritical fluids, with the main emphasis on pharmaceutically important molecules, is reviewed in this article. Also discussed is the application of supercritical fluids in the control of process impurities such as chemical intermediates and residual solvent and in polymorphic control and chiral resolution. As the generation of organic molecules of pharmaceutical interest with high purity is important in pharmaceuticals this review additionally provides a brief overview of highly selective chemical reactions in supercritical fluids.     

Solid-phase and combinatorial synthesis in beta-lactam chemistry.

Combinatorial chemistry has became a core technology for the rapid development of novel lead compounds in the pharmaceutical industry and for the optimization of therapeutic efficacy. The effort to prepare libraries of compounds by combinatorial chemistry has led to an unprecedented growth in solid phase organic synthesis (SPOS), particularly for the preparation of non-oligomeric small molecules. In this context, the clinically valuable b-lactam compounds are very attractive targets for research using these new techniques. In recent years, b-lactam compounds have been recognized not only as unique antibacterial agents but also as potent enzyme inhibitors, drug delivery agents, and versatile synthetic intermediates. This review gives a comprehensive up-date for the application of solid-phase and combinatorial synthesis to b-lactam compounds.     

Setting occupational exposure limits for unstudied pharmaceutical intermediates using an in vitro parallelogram approach

Occupational exposure limits for unstudied pharmaceutical synthetic intermediates are often established under the assumption that penultimate and near-ultimate intermediates have the same structure-activity and dose-response as the ultimate active pharmaceutical ingredient (API). This is seldom the case because moieties that render biological activity to the API are often protected or modified for synthetic purposes. Incorrectly assuming that intermediates have biological activity similar to the API may lead to excessive exposure controls that in turn impose unnecessary ergonomic hazards on workers and greatly reduces the scale and efficiency of production. Instead of assuming intermediates have the same toxicity profile as the API, it is feasible to use a parallelogram approach to establish exposure limits for synthetic intermediates using low-cost in vitro data. By comparing in vitro responses of intermediates to structurally similar data-rich molecules such as the API, occupational exposure categories can be established for unstudied intermediates. In this contribution (1) methods for setting occupational exposure limits for data-poor compounds are reviewed; (2) applications and limitations of in vitro assays are discussed; (3) two exposure categorization examples are presented that rely on an in vitro parallelogram approach; and (4) inherent safeguards for uncertainties in pharmaceutical risk assessment are identified. In vitro hazard and dose-response information for unstudied intermediates that are structurally similar to well-studied APIs can greatly enhance the basis for setting occupational exposure limits for unstudied synthetic intermediates.