An efficient synthesis of LY544344·HCl: a prodrug of mGluR2 agonist LY354740

LY544344·HCl was efficiently prepared in two steps from LY354740. The key step highlighted the in situ masking of the carboxylic acid groups as trimethylsilyl esters to facilitate an effective acylation reaction.     

γ-分泌酶抑制剂(LY411575)的合成工艺研究

对γ-分泌酶抑制剂(LY411575)的合成路线进行改进,新合成路线下该化合物的总收率为35%,比文献方法提高了16%;对关键中间体提前进行了手性拆分,从而使在制备最终产品的后3步反应中用到的原料减少了50%,降低了反应成本和最终产品的纯化难度.另外,对拆分过程中的主要因子进行了单因素实验,考察了各因素对产品的e.e.值和反应收率的影响.获得了最佳反应条件:D-(+)-二对甲基苯甲酰酒石酸为拆分试剂,甲醇作溶剂,加热到回流溶解,加入的溶剂量为每g底物12 m L,从回流降到室温所用时间控制在120 min,拆分的收率为40%,e.e.值为99%.     

Selective methylphosphonylation of an echinocandin B analog derived from LY303366

Echinocandin B (ECB) analog 1c was methylphosphonylated with the new reagent dimethyldiphosphonate 7. Selective functionalization of the phenol group was achieved in the presence of 11 other reactive alcohol and amide groups. The phosphonylation was best conducted in a mixture of THF and DMF using lithium t-butoxide as base. Methylphosphonate diester 1d was deprotected by hydrogenolysis to afford methylphosphonate monoester 1e, a potential prodrug for ECB analog 1c.     

环氧树脂涂覆LY12铝合金在NaCl溶液中的阻抗模型

分别研究了裸LY12铝合金及涂覆环氧树脂涂层后合金在3.5％NaCl溶液中的电化学阻抗谱（EIS）.结果表明,LY12铝合金在点蚀电位以下阻抗谱上出现两个容抗弧,高频段对应Cl－参与的成膜阻抗,低频段对应铝阳极溶解的电化学反应阻抗.合金发生点蚀后出现低频感抗弧.合金/电极在NaCl溶液中先发生涂层吸水,当水及O2抵达基体后建立起电化学反应界面,合金遭受腐蚀；受涂层阻挡的影响,腐蚀产物的扩散逐渐成为控制步骤；当扩散速度较慢的Cl－抵达涂层/金属界面后,与界面处聚集的腐蚀产物间发生化学反应,完成成膜过程,阻抗谱上出现盐膜的阻抗,而扩散阻抗消失.提出了不同浸泡失效阶段涂层电极体系的阻抗模型.     

LY12铝合金表面稀土转化膜腐蚀行为的研究

通过金相观察和Ｘ射线射能谱分析研究了ＬＹ１２铝合金表面两种稀土转化膜的腐蚀行为,在ＮａＣｌ溶液中稀土转化膜的腐蚀以点腐蚀开始,点蚀处基体含Ｃｕ量高。根据Ｍａｎｓｆｅｌｄ点腐蚀模型等效电路提出了利用电化学阻抗谱研究稀土转化膜在ＮａＣｌ溶液中腐蚀程度的新方法,转化膜在ＮａＣｌ淀粉 中浸泡时间较短、腐蚀不太严重的情况下,等效电路中的Ｗａｒｂｕｒｇ阻抗Ｗ可以忽略,简化等效电路得出了计算转化膜表面点腐蚀百分     

铈纳米膜对LY12铝合金表面耐蚀性能的影响

铝合金表面在使用环境中发生的腐蚀破坏限制了它的应用。采用Sol-gel提拉法在LYl2铝合金表面制备的铈纳米膜具有无毒、无污染和明显的防腐作用。表面分析测试结果表明，膜的主要成分为铈的氧化物；用XRD测试结果估算出膜中铈的粒径为10nm。盐水浸渍法试验结果证明了成膜后LYl2铝合金表面的腐蚀速率明显降低；成膜后试样的Tafel曲线腐蚀电势正移；EIS分析结果表明铈纳米膜具有明显的电容特征，该膜阻碍了铝合金表面腐蚀反应的发生；初步提出了铈纳米膜改善LYl2铝合金腐蚀性能的机制。     

An enantioselective strategy to macrocyclic bisindolylmaleimides. An efficient formal synthesis of LY 333531

[reaction: see text]. The ability to employ a bromo alcohol as a nucleophile in a palladium-catalyzed dynamic kinetic asymmetric transformation leads to an efficient synthesis of a selective PKC inhibitor under clinical development.     

Enantioselective synthesis of (+)-cryptophycin 52 (LY355703), a potent antimitotic antitumor agent

A highly enantioselective and convergent synthesis of cryptophycin 52 (2), an exceedingly potent cytotoxic agent, is described. Cryptophycin 52, a synthetic variant of the cryptophycin family, is currently undergoing clinical trials. The synthesis is convergent and involves assembly of three fragments, phenyl hexenal 3, d-tyrosine phosphonate 4, and protected beta-amino acid derivative 5. The synthesis of fragment 3 involves an efficient and stereocontrolled construction of both stereogenic centers at C-3 and C-4 by cleavage of a substituted tetrahydrofuran ring via an acyloxycarbenium ion intermediate. Both of these stereogenic centers were derived from optically active 4-phenylbutyrolactone, synthesized enantioselectively by Corey-Bakshi-Shibata reduction.     

Asymmetric Sulfonium Ylide Mediated Cyclopropanation: Stereocontrolled Synthesis of (+)‐LY354740

The reaction of ester‐stabilized sulfonium ylides with cyclopentenone to give (+)‐ 5 ((1S,5R,6S)‐ethyl 2‐oxobicyclo[3.1.0]hexane‐6‐carboxylate), an important precursor to the pharmacologically important compound (+)‐LY354740, has been studied using chiral sulfides operating in both catalytic (sulfide, Cu(acac)₂, ethyl diazoacetate, 60 °C) and stoichiometric modes (sulfonium salt, base, room temperature). It was found that the reaction conditions employed had a major influence over both diastereo‐ and enantioselectivity. Under catalytic conditions, good enantioselectivity with low diastereoselectivity was observed, but under stoichiometric conditions low enantioselectivity with high diastereoselectivity was observed. When the stoichiometric reactions were conducted at high dilution, diastereoselectivity was reduced. This indicated that base‐mediated betaine equilibration was occurring (which is slow relative to ring closure at high dilution). Based on this model, conditions for achieving high enantioselectivity were established as follows: use of a preformed ylide, absence of base, hindered ester (to reduce ylide‐mediated betaine equilibration), and low concentration. Under these conditions high enantioselectivity (95 % ee) was achieved, albeit with low diastereocontrol. Our model for selectivity has been applied to other sulfonium ylide mediated cyclopropanation reactions and successfully accounts for the diastereoselectivity observed in all such reported reactions to date.     

Determination of Dirithromycin,LY281389 and Other Macrolide Antibiotics by HPLC with Electrochemical Detection

Abstract

Sensitive and rapid assays have been developed for the determination of the macrolide antibotics dirithromycin, erythromycylamine, and LY281389 in plasma. The methods utilize dichloromethane extraction of alkalinized plasma and isocratic reverse phase HPLC with electrochemical detection. The lower limit of detection is 10 ng/ml. Calibration curves are linear and highly reproducible over the range of 20–500 ng/ml. Precision of the calibration curves is very good having relative standard deviations of 5% or less over the dynamic range. These methods can be used for other macrolide antibiotics with minor modifications to the mobile phase. The electrochemical response of various macrolides was found to be dependent upon the functionality at C-9 of the macrolide ring.     

LY12铝合金表面电化学沉积制备DTMS硅烷膜及其耐蚀性研究

采用电化学技术在LY12铝合金表面沉积制备了十二烷基三甲氧基硅烷(DTMS)膜. 反射吸收红外光谱表明, DTMS硅烷试剂与铝合金基体表面发生了化学键合作用, 生成—SiOAl键实现成膜. 通过对膜覆盖电极在质量分数为3.5%的NaCl溶液中的电化学阻抗谱(EIS)测试结果表明, 与开路电位下相比, 采用阴极电位沉积方法得到硅烷膜的耐蚀性能有明显提高, 且存在一个最佳“临界电位”, 在此电位下沉积得到的硅烷膜具有最高的耐蚀性. 扫描电镜观察结果表明, 在“临界电位”下制备得到的硅烷膜的结构最致密. 给出了硅烷膜覆盖电极的阻抗模型及相关参数的拟合结果.     

Design and synthesis of novel 5,6-bisindolylpyrimidin-4-ones structurally related to ruboxistaurin (LY333531)

2,3-Bis(1-methyl-1H-indol-3-yl) methyl-3-oxopropionate is a key intermediate in the synthesis of a new family of LY333531 analogues. Base-mediated cyclocondensation with thiourea afforded novel 5,6-bis(1-methyl-1H-indol-3-yl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one, which was efficiently converted to the pyrimidin-2,4(1H,3H)-dione congener. Synthesis of a six-membered K-252c analogue, 5,6-bis(1-methyl-1H-indol-3-yl)pyrimidin-4(3H)-one, is also described.     

稀土铈对铝合金LY12CZ微生物腐蚀行为的影响

采用紫外分光光度法（UVS）、最大可能数法（MPN）、循环阳极极化法、电化学阻抗谱（EIS）和表面荧光显微法（EFM）研究了不同含量稀土Ce³⁺离子对硫酸盐还原菌（SRB）生长及LY12CZ铝合金微生物腐蚀行为的影响.结果表明:低浓度的Ce³⁺离子能够促进SRB生长,而高浓度时则抑制其生长;循环阳极极化曲线表明,稀土Ce³⁺离子的加入使铝合金LY12CZ的点蚀敏感性降低;电化学阻抗谱表明,在纯培养基中,随稀土Ce³⁺离子浓度的增大,铝合金耐蚀性增大.而在接种1%SRB的培养基中,当Ce³⁺浓度为0.376 mg·L^-1时,生长旺盛的生物膜与Ce³⁺间产生协同作用,增加了基体铝合金耐腐蚀性能.随着Ce³⁺浓度的增加,SRB生长受到抑制,不能形成致密的生物膜.此时SRB的存在促进铝合金腐蚀,显著减弱Ce³⁺对基体铝合金的保护作用.     

Asymmetric construction of quaternary centers by enantioselective allylation: application to the synthesis of the serotonin antagonist LY426965

[reaction: see text] Catalytic enantioselective allylation with a chiral bisphosphoramide was applied to the synthesis of LY426965, a serotonin antagonist. The key step, addition of a 3,3-disubstituted allyltrichlorosilane to benzaldehyde, provided the adduct containing a stereogenic quaternary center with excellent diastereoselectivity and enantioselectivity.     

Kinetic models for the SR1500 and LY556 epoxies under manufacturer’s recommended cure cycles

The kinetic behaviours of two commercial epoxy resin systems subjected to manufacturer’s recommended cure cycles (MRCC) were studied in detail. The two systems were characterized through differential scanning calorimetry (DSC) using both isothermal and dynamic test conditions. The kinetic parameters were determined and two original kinetic models were established for these resin systems subjected to the “real” processing conditions. In this paper the experimental procedure is described, together with its results and the original kinetic models developed.     

The putative endocannabinoid transport blocker LY2183240 is a potent inhibitor of FAAH and several other brain serine hydrolases

How lipid transmitters move within and between cells to communicate signals remains an important and largely unanswered question. Integral membrane transporters, soluble lipid-binding proteins, and metabolic enzymes have all been proposed to collaboratively regulate lipid signaling dynamics in vivo. Assignment of the relative contributions made by each of these classes of proteins requires selective pharmacological agents to perturb their individual functions. Recently, LY2183240, a heterocyclic urea inhibitor of the putative endocannabinoid (EC) transporter, was shown to disrupt the cellular uptake of the lipid EC anandamide and promote analgesia in vivo. Here, we show that LY2183240 is a potent, covalent inhibitor of the EC-degrading enzyme fatty acid amide hydrolase (FAAH). LY2183240 inactivates FAAH by carbamylation of the enzyme's serine nucleophile. More global screens using activity-based proteomic probes identified several additional serine hydrolases that are also inhibited by LY2183240. These results indicate that the blockade of anandamide uptake observed with LY2183240 may be due primarily to the inactivation of FAAH, providing further evidence that this enzyme serves as a metabolic driving force that promotes the diffusion of anandamide into cells. More generally, the proteome-wide target promiscuity of LY2183240 designates the heterocyclic urea as a chemotype with potentially excessive protein reactivity for drug design.     

Stereochemistry of C-6 nucleophilic displacements on 1,1-difluorocyclopropyldibenzosuberanyl substrates. An improved synthesis of multidrug resistance modulator LY335979 trihydrochloride

Studies of the displacement chemistry of 1,1-difluorocyclopropyldibenzosuberanyl alcohol 4 and its activated bromide derivative 6 have led to an improved approach to anti-2, a key precursor to LY335979 3HCl (1). Bromination of either syn-4 or anti-4 gave anti-oriented 6, indicating thermodynamically controlled product stereochemistry via a stabilized 1,1-difluorohomotropylium ion intermediate. Reaction of 6 with piperazine proceeded irreversibly to provide an isomeric mixture of piperazine products, with the syn:anti product ratio increased by solvent effects. Reaction of 6 with pyridine and pyrazine, on the other hand, gave anti-pyridinium and pyrazinium salts, respectively, apparently via equilibration of initially formed syn products. Reduction of pyrazinium salt 11 with lithium borohydride/TFA provided anti-2 unaccompanied by its syn isomer. A practical and expeditious approach to 1 was derived from these new results.     

Determination of LY217332, A New 3'-Quaternary Ammonium Cephalosporin,In Plasma by Solid Phase Column Extraction and HPLC

Abstract

A sensitive and rapid assay has been developed for the determination of LY217332, a 3'-imidazolo[4,5-c]pyridinium cephalosporin, in plasma. The method utilizes cyano solid phase column extraction and HPLC with ultraviolet detection. The lower limit of detection is 5 ng/ml plasma and the relative standard deviation for precision and accuracy was 5% or less from 50–500 ng/ml. The method is applicable to the assay of ceftazidime, cephaloridine, cefpirome and BMY-28142 with minor modification of the mobile phase and the detection wavelength.