洛索洛芬钠合成工艺研究Ⅱ.高区域选择性烷基化合成法

在叔丁醇钠和二甲基亚砜的存在下,2-(对溴甲基苯基)丙酸对2-乙氧羰基环戊酮进行C-烷基化,再经水解脱羧,成盐即得洛索洛芬钠,以2-(对溴甲基苯基)丙酸计算,总收率为72%。探索了不同溶剂和反应温度对烷基化收率的影响。     

Effect of alkylation with different sized substituents on thermal stability of lysozyme

The amino groups of hen egg white lysozyme were reductively alkylated by the reaction with aliphatic aldehydes of various chain lengths and with two aldehydes of different steric hindrance at pH 7.5 and 4° for 3 h. About four of the original six lysine residues were modified by the reaction with acetaldehyde, n-butylaldehyde or n-hexylaldehyde. About three lysine residues were 2, 2-dimethylpropylated with trimethy-lacetaldehyde while a single residue was modified with benzaldehyde. The thermal stabilities of these alkylated lysozymes were investigated by differential scanning calorimetry (DSC) at different acidic pH values. Alkylation thermally destabilized the proteins, depending not only on the extent of modification but also on the size of the substituent. The alkylated derivatives were 8–19kJ/mol less stable than native lysozyme at 25° and pH 3.0. The temperature dependences of the activities of the alkylated lysozymes against ethylene glycol chitin indicated that the orders of the optimum temperatures and the maximum activities were exactly the same as the order of the thermal stabilities.     

Alkylation of histidine with maleimido-compounds

Introduction of the maleimide function via a spacer into histidine-containing peptides was found to produce ring closure by nucleophilic addition of the N^im-imino function of the histidine side-chain to the activated double bond of the maleimide. As an intramolecular cyciization reaction it proceeds at remarkably higher rates than the bimolecular alkylation of histidine derivatives with N-ethyl-maleimide. Correspondingly, in the case of the histidine-peptides examined only mixtures of the cyclic isomeric compounds were isolated and structurally characterized by ¹H-NMR analysis. As expected, prevention of this reaction in histidine-containing maleoyl-peptides can be achieved by N^im-protection of the imidazole group. However, upon removal of this protection, the reaction takes place again, thus remarkably hampering the usefulness of the maleimide/thiol addition principle in conjugate chemistry for peptides. On the other hand this reaction could represent an interesting new approach for the design of cyclic peptidomimetic analogs.     

One‐step reductive etherification of 4‐[18F]fluoro‐benzaldehyde with decaborane

Reductive coupling reactions between 4‐[¹⁸F]fluoro‐benzaldehyde ([¹⁸F] 1 ) and different alcohols by use of decaborane (B₁₀H₁₄) as reducing agent have the potential to synthesize 4‐[¹⁸F]fluoro‐benzylethers in one step. [¹⁸F] 1 was synthesized from 4‐trimethylammonium benzaldehyde (triflate salt) via a standard fluorination procedure (K[¹⁸F]F/Kryptofix^® 222) in dimethylformamide at 90°C for 25 min and purified by solid‐phase extraction. Subsequently, reductive etherifications of [¹⁸F] 1 were performed as one‐step reactions with primary and secondary alcohols, mediated by B₁₀H₁₄ in acetonitrile at 60°C. Various 4‐[¹⁸F]fluorobenzyl ethers (6 examples are shown) were obtained within 1–2 h reaction time in decay‐corrected radiochemical yields of 12–45%. Copyright © 2006 John Wiley & Sons, Ltd.     

KF／Al2O3催化烃化合成止咳酮的研究

目的通过催化烃基化反应最终合成止咳酮。方法在无溶剂条件下，以固体碱KF／Al2O3为催化剂．乙酰乙酸乙酯和苄氯进行固-液相烃化反应。结果烃化反应温度为60。C，总反应物与催化剂的摩尔比是1．18：1，烃化反应时间为1．5h。止咳酮总收率60％～65％。结论固体碱KF／Al2O3能有效催化止咳酮的烃基化反应。     

Synthesis of novel protected Nα(ω‐thioalkyl) amino acid building units and their incorporation in backbone cyclic disulfide and thioetheric bridged peptides

Abstract: General methods for the preparation of protected N^α(ω‐thioalkyl) amino acids building units for backbone cyclization using reductive alkylation and on‐resin preparation are described. The synthesis of non‐Gly Fmoc‐protected S‐functionalized N‐alkylated amino acids is based on the reaction of readily prepared protected ω‐thio aldehyde with the appropriate amino acid. Preparation of Fmoc‐protected S‐functionalized N‐alkylated Gly building units was carried out using two methods: reaction of glyoxylic acid with Acm‐thioalkylamine and an on‐resin reaction of bromoacetyl resin with Trt‐thioalkylamines. Three model peptides were prepared using these building units. The GlyS2 building unit was incorporated into a backbone cyclic analog of somatostatin that contains a disulfide bridge. Formation of the disulfide bridge was performed by on‐resin oxidation using I₂ or Tl(CF₃COO^–)₃. Both methods resulted in the desired product in a high degree of purity in the crude. The AspS3 building unit was also successfully incorporated into a model peptide. In addition, the in situ generation of sulfur containing Gly building units was demonstrated on a Substance P backbone cyclic analog containing a thioether bridge.     

马兜铃酸体内毒性的产生及防治研究进展

马兜铃酸广泛存在于马兜铃科马兜铃属中草药中,具有。肾毒性和致癌致突变性。其在体内经一系列硝基还原酶代谢活化后与DNA共价结合形成加合物而诱发癌变,并通过诱导肾小管上皮细胞凋亡及间质纤维化而导致马兜铃酸肾病。综述马兜铃酸体内毒性产生的分子机制和防治研究进展,探讨相关药物的研发,为马兜铃酸肾病的治疗提供新思路。     

电位水杀菌作用的研究

目的 采用酸性氧化电位水(EOW)和碱性还原电位水(ERW)研究对枯草杆菌黑色变种芽胞(ATCC9372)和大肠杆菌(8099)的杀菌效率和杀菌机制.方法 利用离子膜电解法制备EOW和ERW.采用悬液定量杀菌实验.结果 当杀菌时间为30 min时,EOW对枯草杆菌黑色变种芽胞杀菌率为99.59%,杀灭对数值为2.38 log cfu/ml;当杀菌时间为60 min时,ERW对枯草杆菌黑色变种芽胞杀菌率为94.62%,杀灭对数值为1.27 log cfu/ml;当杀菌时间为30 min时,ERW对大肠杆菌杀菌率达到100%,杀灭对数值为8.26 log cfu/nd.当EOW中有效氯(ACC)值为74.90 ms/L时,对枯草杆菌黑色变种芽胞杀菌率为99.89%,杀灭对数值2.67 log cfu/ml;而当ACC值降为6.82 mg/L时,其杀菌率仅为83.30%,杀灭对数值仅为0.78 log cfu/ml.另外,当高氧化还原电位值(ORP)值为1138 mV,pH值为2.24时,EOW对枯草杆菌黑色变种芽胞杀菌率为99.99%;当ORP值变化为883mV,pH值为5.43时,其杀菌率降为99.73%;两者差距不大,但两者杀灭对数值相差1.30 log cfu/ml.此外,当ORP值为-918 mV时,ERW对枯草杆菌黑色变种芽胞杀菌率为94.62%,杀灭对数值为1.27 log cfu/ml;而当ORP值为-155 mV时,其杀菌率降为40.19%,杀灭对数值降为0.13 log cfu/ml.结论 通过考察,我们得出EOW杀菌机制是以化学因素(ACC)杀菌为主,物理杀菌为辅.ERW杀菌是物理杀菌,ORP值对杀菌效果影响很大.     

Improved synthesis and application of [11C]benzyl iodide in positron emission tomography radiotracer production

Positron emission tomography has increased the demand for new carbon‐11 radiolabeled tracers and building blocks. A promising radiolabeling synthon is [¹¹C]benzyl iodide ([¹¹C]BnI), because the benzyl group is a widely present functionality in biologically active compounds. Unfortunately, synthesis of [¹¹C]BnI has received little attention, resulting in limited application. Therefore, we investigated the synthesis in order to significantly improve, automate, and apply it for labeling of the dopamine D₂ antagonist [¹¹C]clebopride as a proof of concept. [¹¹C]BnI was synthesized from [¹¹C]CO₂ via a Grignard reaction and purified prior the reaction with desbenzyl clebopride. According to a one‐pot procedure, [¹¹C]BnI was synthesized in 11 min from [¹¹C]CO₂ with high yield, purity, and specific activity, 52 ± 3% (end of the cyclotron bombardment), 95 ± 3%, and 123 ± 17 GBq/µmol (end of the synthesis), respectively. Changes in the [¹¹C]BnI synthesis are reduced amounts of reagents, a lower temperature in the Grignard reaction, and the introduction of a solid‐phase intermediate purification. [¹¹C]Clebopride was synthesized within 28 min from [¹¹C]CO₂ in an isolated decay‐corrected yield of 11 ± 3% (end of the cyclotron bombardment) with a purity of >98% and specific activity (SA) of 54 ± 4 GBq/µmol (n = 3) at the end of the synthesis. Conversion of [¹¹C]BnI to product was 82 ± 11%. The reliable synthesis of [¹¹C]BnI allows the broad application of this synthon in positron emission tomography radiopharmaceutical development. Copyright © 2015 John Wiley & Sons, Ltd.