马来酸氟伏沙明-D3的合成

以4-苄氧基-1-丁醇（2）为起始原料,氘代碘甲烷为氘代试剂,经氘代甲基化、氢化脱苄、溴化、格氏反应、戴斯-马丁氧化、缩合、取代、成盐等反应,以51.7%总收率合成了稳定同位素标记的马来酸氟伏沙明-D₃（1）。该合成方法原料易得、操作简单、重现性好。目标化合物的结构经核磁共振和高分辨质谱确认,可用于药代动力学研究     

氘代苯胺类化合物的合成

报道了一种合成氘代苯胺类化合物的新方法。在SOCl₂介导下,以碘代苯胺类化合物和重水为原料,经碘-氘交换反应合成了一系列氘代苯胺类化合物,收率62%～95%,氘同位素丰度>97 atom%,其结构经¹H NMR, ¹³C NMR, IR和HR-MS(EI)表征。并初步探讨了反应机理。     

氘代甲基萤火虫荧光素的全合成

以2-氰基-6-甲氧基苯并噻唑为原料,经脱甲基、氘甲基化,与D-半胱氨酸盐酸盐水合物反应合成了新化合物——氘代甲基萤火虫荧光素,总收率46%,对映选择性100%,其结构经1H NMR,FT-IR和MS表征。     

光、电催化合成氘代化学品和药物分子研究综述

稳定氘同位素因其安全、易控制、廉价易得等优势而被广泛应用于探究有机反应机理和揭示药物及其代谢物的吸收、分布、代谢和排泄过程.此外,氘标记药物也被称为重氢药、重药,即把药物分子上处于代谢位点的一个或多个碳氢键(C-H)用碳氘键(C-D)替代获得的新药,以延长药物代谢周期、减少进入血液前的代谢、减少有毒代谢物产生,从而降低给药剂量、提高安全性以及获得更佳的疗效.2017年4月,第一例氘代新药,氘代四苯喹嗪(海外商品名Austedo,国内商品名:安泰坦)被美国食品药品监督管理局批准,氘代新药市场被彻底激活.临床数据显示,丁苯那嗪原药具有严重的毒副作用,19%的病人使用后表现出抑郁病症,严重者甚至有自杀倾向;氘代丁苯那嗪相对于原药,代谢动力学特征明显改善,毒副作用显著降低.目前,国内外已有多家知名药企(如BMS,Concert,Teva,苏州泽璟生物制药以及成都海创等)布局氘代新药研发.2021年6月,中国国家药品监督管理局正式批准苯磺酸多纳非尼片(商品名:泽普生),用于治疗既往未接受过全身系统性治疗的不可切除肝细胞癌患者.氘代药物的蓬勃发展使得对其精准合成提出了更高的要求和更强烈的需求.氢氘交换等传统方法由于反应条件苛刻、氘源昂贵、氘代个数和位点难以精准控制等限制,难以满足新时代氘代药物的发展需要.近年,化学家开始致力于开发温和、精准氘代新方法,其中,光或电驱动的温和、精准氘标记方法引起了广泛关注.本综述着重总结近五年光/电驱动的温和、精准的氘代方法的研究进展.基于氘原子引入的反应模式分为以下三种类型.(1)氘原子转移策略:以光/电催化单电子转移或者氢原子转移方式生成自由基中间体R^?;随后,R^?与氘原子转移试剂(由硫醇和重水原位制得)反应,得到相应的氘代产物R-D.利用该策略,目前已发展了羧酸、卤代烃、硫醚(醇)等的去官能化氘代反应以及硅烷、叔胺、醛基等的氢氘交换反应.(2)氘原子攫取策略:以光/电催化单电子转移、氢原子转移或者能量转移方式生成自由基R^?中间体,一方面,以产物碳氘键键能大于溶剂碳氘键键能为驱动力,使R^?直接从氘代溶剂中攫取氘原子制得相应的氘代产物R-D;另一方面,利用光/电催化强驱动力,使R^?再次获得一个电子形成相应负离子,从而顺利从重水中攫氘,制得相应的氘代产物R-D.利用该策略,目前已开发了羧酸、重氮、卤代物等的去官能化氘代反应,以及亚胺的加氘还原反应.(3)重水分解策略:基于光/电催化水分解制氢原理,以光或电为驱动力分解重水,使其产生高活性氘物种,原位耦合还原氘代反应.利用该策略,目前已开发了以重水为氘源的卤代物,不饱和官能团(包括烯烃、炔烃、亚胺和芳基酮等)等的氘代还原反应以及伯、仲胺的氘甲基化反应.本综述归纳了近年来光或电催化驱动的温和、精准氘代方法研究进展.在此基础上结合课题组在该领域的研究经历,分析了药物和精细化学品精准氘代面临的关键挑战和重要机遇,包括:发展温和、精准的不对称催化氘代方法用于制备手性氘代药物;针对复杂药物多个代谢位点,实现精准、可控氘代,从而更有效调节药物代谢动力学和代谢产物.此外,光合成、电合成迅猛发展也将为氘代精细化学品和药物光、电催化合成带来新的机遇.     

三乙胺催化的双环氮杂锡氧烷配合物氘代反应研究

全面研究了三乙胺催化下双环氮杂锡氧烷配合物α 氢的氘代反应 .首先考察了三乙胺催化下双环氮杂锡氧烷配合物α 氢的氘代反应的核磁共振谱 ,研究发现 :在三乙胺存在下 ,有机锡配合物α 氢可以与CD3 OD溶剂发生氘代反应 ,其核磁共振峰强度随着时间而衰减 ,且氘代反应速率与三乙胺的浓度有关 .其次 ,利用核磁共振技术测定氘代反应速率 ,其反应表观速率常数为 2 .0× 1 0 -4 ～ 1 0 .0× 1 0 -4 s-1,推导了其动力学机理并讨论了取代基对氘代反应速率的影响 .     

氘代Rigosertib类似物的合成

以2,4,6-三羟基苯甲醛为原料制得中间体2,4,6-三甲氧基苯甲醛(2a)和2,4,6-三三氘甲氧基苯甲醛(2b);以4-烷氧基-3-硝基苄硫基乙酸为原料,经氧化、缩合-脱羧、还原、取代和水解5步反应合成了氘代Rigosertib类似物,收率80%~86%,其结构经1H NMR和MS表征。     

氘代苯乙酮-d8的合成与还原反应

氘代苯乙酮ｄ８及其还原产物氘代α苯乙醇ｄ１０是合成众多氘标记化合物及全氘代化合物的重要中间体．以氘代苯ｄ６和氘代醋酸ｄ４为原料制得氘代苯乙酮ｄ８,经ＬｉＡｌＤ４还原可得氘代α苯乙醇ｄ１０［１］．其缺点是ＬｉＡｌＤ４价格昂贵且不易获得,...     

NMR对MDI在稀溶液中水解反应机理的表征

采用核磁共振波谱(NMR)研究了二苯基甲烷二异氰酸酯(MDI)在稀溶液中的水解反应机理.将同一MDI样品分别溶解在氘代氯仿、氘代丙酮和加入少量水分的氘代二甲基亚砜溶剂(DMSO)中,进行核磁共振氢谱(1H NMR)、核磁共振碳谱(13C NMR)测试.结果显示,MDI在含水的DMSO溶剂中测得的谱图与氘代氯仿、氘代丙酮中的差别显著.对该溶液进行了13C-1H异核近程相关(HMQC)、13C-1H异核远程相关(HMBC)及碳原子级数(DEPT 135)测试,并利用经验公式对其进行了详细归属,确认了反应产物的结构.分析得知MDI在含水溶剂中迅速反应,异氰酸酯基转化为脲基和氨基基团.异氰酸酯与水反应生成氨基基团,其与异氰酸酯反应活性比水高,对位取代氨基与水的竞聚率比值为7.1,邻位为1.4,对位取代氨基活性约是邻位的5倍.     

地西泮-D_5中间体的简便合成

报道了一种合成氘代地西泮中间体的新方法。以2-氨基-5-氯苯甲酸为原料,经环化、格氏反应、水解、酰化、环合等反应合成了氘代地西泮中间体7-氯-1,3-二氢-5-(苯基-d_5)-2H-1,4-苯并二氮杂-2-酮(1),其结构经~1H NMR和HR-MS(ESI)确证。1只需经一步甲基化反应即可合成地西泮-D_5。     

LC-MS/MS法快速高效检测尿液中尼古丁及其9种代谢物

以氘代尼古丁、氘代可的宁、3-OH-氘代可的宁、氘代尼古丁葡萄糖醛酸复合物、氘代可的宁葡萄糖醛酸复合物、3-OH-氘代可的宁葡萄糖醛酸复合物作内标, 在LC-MS/MS的大气压化学电离(APCI)离子化模式下, 建立了快速检测吸烟者尿液中尼古丁及其9种代谢物的方法, 并对19个实际样品进行了测试和判别分析(DA). 实验前处理简单, 色谱运行时间仅为3.8 min. 结果表明, 尼古丁及其代谢物的精密度在0.5%～5.5%之间, 回收率在94%～109%之间, 线性相关系数均大于0.995. DA分析充分区别开了不同量的吸烟者, 进一步的相关性分析表明吸烟者24 h尿液中的尼古丁及其9种代谢物含量与卷烟抽吸量的分析因子之间均有较强正相关性.     

二氧化碳和丙烯直接合成甲基丙烯酸的NiPMo/TiO2催化剂的研究

用溶胶-凝胶法以磷钼酸(MPA)的镍盐溶液水解钛酸四丁酯制备了NiPMo/TiO2催化剂.使用ICP、 XRD、 TG-DTA、 IR、 TPD-MS和微反应技术研究了催化剂的化学组成、热稳定性、化学吸附性质和催化反应性能.杂多钼酸盐与TiO2通过O2-在TiO2表面发生了键合.在623 K下,杂多阴离子仍保持原有的Keggin结构.CO2在Lewis酸位Ni(Ⅱ)和Lewis碱位Ni-O-Mo的桥氧协同作用下生成CO2卧式吸附态Ni(Ⅱ)←O-(CO)←(O--Ni).丙烯有多种吸附态在催化剂上吸附.在563 K、 1 MPa和空速1500 h-1的反应条件下,丙烯的摩尔转化率为3.2%,产物MAA选择性为95%.     

Synthesis of 1-benzyloxypyrazin-2(1H)-one derivatives

Different approaches for the synthesis of 1-benzyloxypyrazin-2(1H)-one derivatives from simple amino acids have been investigated. A library of 33 precursors for the preparation of N-hydroxy pyrazinones was obtained in moderate to good yields.     

Toward new camptothecins. Part 6: Synthesis of crucial ketones and their use in Friedländer reaction

In the context of the preparation of camptothecin and luotonin A analogs, the synthesis of some key keto-precursors and their use in Friedländer condensation are described. This paper also focuses on the stability of these keto intermediates and emphasizes the major differences between indolizinones and pyrroloquinazolinones series. Noteworthy is also the report of some original structures isolated as by-products of some experiments.     

CoFe2O4自形成磁性液体场致结构化对磁化的影响

The Langevin paramagnetic theory can’t describe the relation between magnetization of ferrofluids and applied magnetic field. The structuralization of ferrofluids, which is considered the main influence factor of the magnetization, is regarded. The part of magnetization works is deposited when the structure is forming. This action influences the magnetization of ferrofluids directly or indirectly. On the base of the “compressing” model, the Langevin function that usually describes the magnetization of ferrofluid is modified, and a well-fitted curve is obtained. An equation of the relation between the equivalent volume fraction after being “compressed” and the intensity of magnetic field is discovered, which approximately describes the process of magnetization. The relation between the approximate initial susceptibility and the volume fraction can be obtained from modified formula.     

Highly regioselective Buchwald–Hartwig amination at C-2 of 2,4-dichloropyridine enabling a novel approach to 2,4-bisanilinopyridine (BAPyd) libraries

The highly regioselective Buchwald–Hartwig amination at C-2 of the cheap and readily accessible reagent, 2,4-dichloropyridine with a range of anilines and heterocyclic amines is described. This new methodology is robust and provides a facile access to 4-chloro-N-phenylpyridin-2-amines on 0.25 mol scale. These intermediates undergo a further Buchwald–Hartwig amination at higher temperature to enable rapid exploration of the chemical space at C-4 and to provide a library of 2,4-bisaminopyridines.     

KMnO4-mediated oxidative CN bond cleavage of tertiary amines: Synthesis of amides and sulfonamides

KMnO₄-mediated oxidative CN bond cleavage of tertiary amines producing secondary amine was introduced, which was trapped by electrophiles (acyl chloride and sulfonyl chloride) to form amides and sulfonamides. The reaction could take place at mild condition, tolerating a wide range of function groups and affording products in moderate to excellent yields.     

Chemistry of heterocyclic compounds at the A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch of the Russian Academy of Sciences, over 50 years (Review)

The review contains a concise historical account and information on the most significant researches undertaken by the staff at the A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch of the Russian Academy of Sciences on the Chemistry of Heterocyclic Compounds. Dedicated to Academician of the Russian Academy of Sciences B. A. Trofimov on his 70th jubilee. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1443–1502, October, 2008.     

Sulfur-directed metal-free and regiospecific methyl C(sp3)–H imidation of thioanisoles

Regiospecific and direct imidation of the methyl C(sp³)–H bond of thioanisoles is realized under mild and metal-free conditions with N-fluorobis(benzenesulfonyl)imide as an oxidant and nitrogen source. Proposed mechanism suggests that thionium ion intermediates and a Pummerer-type reaction are involved. The imidation has advantages such as high step-economy, excellent functionality tolerance, and regiospecificity, giving structurally diverse imidation products.     

A general and convenient synthesis of 4-(tosylmethyl)semicarbazones and their use in amidoalkylation of hydrogen,heteroatom, and carbon nucleophiles

A general synthesis of previously unknown semicarbazone-based α-amidoalkylating reagents, 4-(tosylmethyl)semicarbazones, has been developed. The synthesis involved three-component condensation of semicarbazones of aliphatic or aromatic aldehydes with the same or other aldehydes and p-toluenesulfinic acid. The scope and limitations of this reaction were investigated. The compounds obtained were demonstrated to be an efficient α-(4-semicarbazono)alkylating agents. They were reacted with H- (sodium borohydride), O- (sodium methylate), S- (sodium phenylthiolate), N- (pyrrolidine, sodium succinimide), P- (trialkyl phosphites), and C-nucleophiles (sodium diethyl malonate) to give the corresponding products of the tosyl group substitution, 4-substituted semicarbazones, including analogues of nitrofurazone. Among the prepared compounds tested in vitro for antibacterial and antifungal activity, three nitrofuryl-containing semicarbazones exhibited high biological activities with minimum inhibitory concentration (MIC) values of 8–32 μg/mL.     

Synthesis of novel chiral bidentate hydroxyalkyl-N-heterocyclic carbene ligands and their application in palladium-catalyzed Mizoroki–Heck couplings and asymmetric addition of diethylzinc to benzaldehyde

A small library of new chiral bidentate hydroxyalkyl-imidazolium salts 1 is conveniently synthesized on multi-gram scale from inexpensive and commercially available chiral pool amino acids. The corresponding carbenes, generated by deprotonation of imidazolium salts 1, in combination with palladium(II) chloride were tested in the Mizoroki–Heck coupling reaction. The most significant results in terms of yields and reactivities were achieved with low catalyst loading. The catalytic activities of these imidazolium salts were also investigated in the asymmetric addition of diethylzinc to benzaldehyde. The use of MgO nanoparticles as an additive in conjunction with these ligands played a crucial role in increasing the efficiency of these reactions.