(R)-( )-和(S)-(-)-β,β′-联萘酚的制备

手性试剂(R)-( )-和(S)-(—)-β,β′-联萘酚[( )-1和(—)-1]由于能制得高纯度的对映体,光学性质稳定,且具有很强的面不对称性,在不对称合成中易生成高比例 ee 值的产物。已成功地应用于不对称还     

Anti-mycobacterial, cytotoxic activities of Knoevenagel and (E)-α,β-unsaturated esters and ketones from 2-chloronicotinaldehydes

Series of 2-chloronicotinaldehyde Knoevenagel derivatives 3a–r; (E)-α,β-unsaturated esters and ketones 5a–k were prepared and evaluated for their in vitro anti-mycobacterial activity against Mycobacterium tuberculosis H₃₇Rv (Mtb). Compounds 3e, 5b, 5d, 5e, 5g and 5i–k were shown potent to significant activity. Compound 5j is the most potent Mtb inhibitor (MIC: 4.89 μM) when compared to standard drugs Ethambutol (MIC: 7.63 μM) and Ciprofloxacin (MIC: 9.44 μM). Eight compounds displayed potent/significant activity against M. tuberculosis were chosen for the cytotoxicity against three cell lines (Raw 264.7, MCF7, and HeLa). Compound 5j displayed low toxicity with high selective index (15–30) and is an interesting new compound may serve for the development of therapeutics targeted against anti-mycobacterial compounds. This is the first report assigning in vitro anti-mycobacterial inhibitory activity and structure–activity relationship for this class of substituted 2-chloronicotinaldehyde derivatives and presents new family of compounds.     

(2β,3α,16β,17β)-3,17-双乙酰氧基-2,16-双哌啶基-5α-雄甾烷的合成

目的合成泮库溴铵和维库溴铵的中间体(2β,3α,16β,17β)-3,17-双乙酰氧基-2,16-双哌啶基-5α-雄甾烷。方法以表雄酮为原料,经磺酰化、消除、乙酰化、环氧化、取代、乙酰化反应合成目标化合物。结果所得产物及中间体经核磁共振谱确认。结论所设计合成路线可行,总收率30.4%,可用于工业生产。     

麻黄素中间体[(S)-(-)-α-甲胺基苯丙酮]2·(2R,3R)-(-)-二苯甲酰酒石酸的HPLC测定

建立了HPLC法测定合成麻黄素的中间体[(S)-(-)-α-甲胺摹苯丙酮]2(2R,3R)-(-)-二苯甲酰酒石酸中的(S)-(-)-α-甲胺基苯丙酮和(2R,3R)-(-)-二苯甲酰酒石酸.采用C18色谱柱,以0.05 mol/L磷酸二氢钾溶液-甲醇(80:20)为流动相,检测波长238 nm.两者在0.05~0.20 mg/ml和0.06～O.24 mg/ml浓度范围内线性关系良好,回收率为99.8%和99.6%,RSD均为0.6%.     

Microwave-accelerated preparation and analytical characterization of 5-ethoxy-N,N-dialkyl-[α,α,β,β-H(4) ]- and [α,α,β,β-D(4) ]-tryptamines

The increased interest in N,N-dialkyl tryptamines is a reflection of their diverse range of biologically active properties. Deuterated derivatives are of interest for use as internal standards in bioanalytical or pharmacological assays. The present study reports on the synthesis of twelve novel 5-ethoxy-N,N-dialkyl-[α,α,β,β-H(4) ]-tryptamines and their [α,α,β,β-D(4) ]-counterparts following the Speeter and Anthony procedure. The normally time-consuming reduction step was carried out in 5 min under microwave-accelerated conditions. Good yields were obtained using tetrahydrofuran as the solvent at 150 °C. The resulting 24 tryptamines have been characterized by 1D/2D nuclear magnetic resonance spectroscopy and gas chromatography ion trap mass spectrometry. Differential fragmentation of side-chain-related iminium ions has been observed as a key principle. Because many N,N-dialkyltryptamines are available outside of traditional pharmaceutical supply chains as so-called 'research chemicals', the availability, as standards, of these new N,N-dialkyltryptamines will aid in identifiying novel tryptamines arising from these other souces. They should therefore be of immediate value within forensic, research, and public health contexts.     

α7β2 nicotinic acetylcholine receptors assemble, function, and are activated primarily via their α7-α7 interfaces

We investigated assembly and function of nicotinic acetylcholine receptors (nAChRs) composed of α7 and β2 subunits. We measured optical and electrophysiological properties of wild-type and mutant subunits expressed in cell lines and Xenopus laevis oocytes. Laser scanning confocal microscopy indicated that fluorescently tagged α7 and β2 subunits colocalize. F?rster resonance energy transfer between fluorescently tagged subunits strongly suggested that α7 and β2 subunits coassemble. Total internal reflection fluorescence microscopy revealed that assemblies localized to filopodia-like processes of SH-EP1 cells. Gain-of-function α7 and β2 subunits confirmed that these subunits coassemble within functional receptors. Moreover, α7β2 nAChRs composed of wild-type subunits or fluorescently tagged subunits had pharmacological properties similar to those of α7 nAChRs, although amplitudes of α7β2 nAChR-mediated, agonist-evoked currents were generally ~2-fold lower than those for α7 nAChRs. It is noteworthy that α7β2 nAChRs displayed sensitivity to low concentrations of the antagonist dihydro-β-erythroidine that was not observed for α7 nAChRs at comparable concentrations. In addition, cysteine mutants revealed that the α7-β2 subunit interface does not bind ligand in a functionally productive manner, partly explaining lower α7β2 nAChR current amplitudes and challenges in identifying the function of native α7β2 nAChRs. On the basis of our findings, we have constructed a model predicting receptor function that is based on stoichiometry and position of β2 subunits within the α7β2 nAChRs.     

(1R,2S)-(-)-麻黄碱盐酸盐的合成

设计并实现了（1R，2s）-（-）-麻黄碱盐酸盐的一种不对称合成法，以2-溴-1-苯基-1-丙酮为起始原料，经（S’）-α-苯乙胺胺化、分离、KBH4立体选择性还原、Leuckan反应及钯炭脱苄等制得目标物，总收率约25％。     

HPLC法测定(1R,2R)-(-)-1,2-环己二胺中S,S对映异构体

目的建立高效液相色谱法测定(1R,2R)-(-)-1,2-环己二胺中S,S对映异构体含量的方法。方法柱前衍生反相高效液相色谱法,利用间甲基苯甲酰氯为衍生化试剂,采用Chiral-AGP(4.0 mm×150 mm)色谱柱,以异丙醇-磷酸盐缓冲液(pH值=6.1)(15∶85)为流动相、流速0.7 mL.min-1、检测波长为214 nm。结果 1,2-环己二胺的R,R与S,S对映异构体衍生物达到基线分离;S,S-对映异构体的定量限为30.1 ng、检测限12.4 ng;S,S-对映异构体在0.015～0.09μg.mL-1浓度范围内线性良好,平均回收率为98.3%,RSD(n=9)为9.36%。结论建立的间甲基苯甲酰氯柱前衍生高效液相色谱法适用于(1R,2R)-(-)-1,2-环己二胺中S,S对映异构体含量的测定。     

(R,S)-2-氨基丙醇的制备

氯丙酮经乙酸基化、碱性水解、Raney Ni催化还原胺化得到（R，S）-2-氨基丙醇，总收率44％。     

(1R,2S)-(–)-麻黄碱盐酸盐的合成

设计并实现了(1R,2S)-(–)-麻黄碱盐酸盐的一种不对称合成法,以2-溴-1-苯基-1-丙酮为起始原料,经(S)-α-苯乙胺胺化、分离、KBH4立体选择性还原、Leuckart反应及钯炭脱苄等制得目标物,总收率约25%。     

手性(2R,3R)-2,3-环氧丁酸盐的制备

目的用L-苏氨酸制备手性(2R,3R)-2,3-环氧丁酸盐,并对成盐方法、晶型、稳定性进行研究。方法 L-苏氨酸经重氮化、环氧化形成手性(2R,3R)-2,3-环氧丁酸,再与无机或有机碱成盐。研究酸碱度、温度、溶剂、溶液体系等对成盐的影响,XRD、SEM考察盐的晶型和形貌。测试盐与胺的反应,并监测其稳定性。结果得到手性(2R,3R)-2,3-环氧丁酸锂、钠、钾、钙、镁、铵、一甲胺、二甲胺、对甲氧基苯胺盐,IR、1H-NMR、MS确证结构,1年内稳定。液-液或气-液成盐较好,低温下在醇、酮溶剂中钠、钾盐收率超过80%。XRD、SEM显示,溶媒法环氧丁酸盐为晶态,冻干环氧丁酸钠盐为无定形态,粒径小于10μm。环氧丁酸盐与胺反应手性保持,冻干粉反应活性较高。结论环氧丁酸盐稳定,制备工艺简单,质量可控,可用于碳青霉烯类抗生素的制备。     

(2R,4R)-4-甲基-2-哌啶甲酸乙酯的合成工艺改进

目的 优化(2R,4R)-4-甲基-2-哌啶甲酸乙酯的合成工艺.方法 以S-(-)-α-甲基苄胺为原料,与乙醛酸乙酯反应得到[(S)-1-苯乙基亚胺基]乙酸乙酯,与异戊二烯进行环合后,再经不对称氢化和脱保护反应制得(2R,4R)-4-甲基-2-哌啶甲酸乙酯.结果 总收率从17.0％提高至47.6％.结论 本工艺可有效地降低生产成本.     

血吸虫病化学治疗的研究——Ⅳ.β-(5-硝基-2-呋喃)丙酰胺类及其α,β-二溴取代衍生物的合成

本文报道38个β-(5-硝基-2-呋喃)丙酰胺及其α,β-二溴取代衍生物的合成。这类化合物的制备是以相应的β-(5-硝基-2-呋喃)丙烯酰胺类化合物(Ⅰ)进行催化氢化或与溴加成而得。经动物筛选发现β-(5-硝基-2-呋喃)丙烯酰胺类的丙烯双键以氢饱和以后生成丙酰胺类化合物(Ⅱ),对感染日本血吸虫病的小白鼠完全失去治疗或预防作用。而以溴饱和双键的α,β-二溴化合物(Ⅲ)则仍然有较显著的杀虫作用。其中尤以β-(5-硝基-2-呋喃)-α,β-二溴丙酰异丙胺(Ⅲ_(11))和β-(5-硝基-2-呋喃)-α,β-二溴丙酰甘氨酸乙酯(Ⅲ_(24))最为显著,后者曾试用于临床,证明有一定疗效。     

Solute Absorption from the Airways of the Isolated Rat Lung. IV. Mechanisms of Absorption of Fluorophore-Labeled Poly-α,β-[N(2-Hydroxyethyl)-DL-Aspartamide]

The pulmonary absorption kinetics of a single molecular weight distribution (MWD) of fluorophore-labeled poly-,-[N(2-hydroxyethyl)-DL-aspartamide] (F-PHEA), a hydrophilic and biocompatible synthetic polypeptide, were studied in the isolated, perfused rat lung (iprl) as functions of administered polymer concentration, dose, vehicle, and presence and absence of fluorophore. The MWD was characterized before and after absorption by measurement of weight- and number-averaged molecular weights (M _wand M _n, respectively) using high-performance gel-permeation chromatography. Values for M _w and M _n were 8.6 and 5.3 kD before, and 6.7 and 4.7 kD after, absorption into the perfusate; there was no significant metabolism and the MWD of the absorbed polymer was independent of both dose and sampling time over a 3-hr period. F-PHEA failed to show any evidence of aggregation in solution or changes in dose distribution within the airways as functions of increasing polymer concentration and dose. A concentration ranging study indicated the presence of a saturable, carrier-mediated transport process for F-PHEA with a maximum absorption rate, V _max, of approximately 180 µg or 0.027 µmol/hr. Coadministration of fluorophore-free PHEA was capable of depressing the absorption of F-PHEA. The transport process for F-PHEA appeared to have a molecular weight limit of about 7 kD for this hydrophilic polymer.     

用硼酸和(R)-( )-α-甲基苄胺拆分消旋1,1′-二-2-萘酚

消旋 1 ,1′-二 -2 -萘酚、硼酸和 ( R) -( ) -α-甲基苄胺在乙腈中回流 1 2 h,冷至室温 ,过滤得沉淀物和滤液。沉淀物先经乙腈回流处理 ,再经乙酸乙酯与 1 mol/ L盐酸的混合液重结晶 ,得到 ( S) -( -)产物 ,理论收率 70 %。滤液浓缩至干后加 THF回流处理 ,所得沉淀物再同上处理得 ( R) -( )产物 ,理论收率 5 2 %。 ( R) -( ) -α-甲基苄胺可回收用硼酸和(R)-( )-α-甲基苄胺拆分消旋1,1′-二-2-萘酚@庄武     

新头孢烯衍生物(6R,7R)-7-[(2-(2-对氨基苯磺酰胺基噻唑-4-)-Z-2-甲氧基亚胺)-乙酰胺基]—头孢烯酸的合成及体外抑菌试验

氨噻肟类头孢菌素是目前β-内酰胺类抗生素研究中最热门的课题之一,许多研究者们通过氨噻唑头孢菌素的3—位、4—位、6—位取代基及肟基氧上R取代基的改变,制备了一些有很好抑菌活性的衍生物。但是,在氨噻肟的氨基上取代的衍生物尚未见报道。因此,我们设计并合成了(6R、7R)-7-[(-2-(2-对氨基苯磺酰胺基噻唑-4-)-Z-2-甲氧基亚胺)—乙酰胺基]—头孢烯酸[Ⅷ]。并进行了体外抑菌试验。结果如下:     

(1′R,2S,2′S)-2-(2-甲基-2-溴甲基-3-亚甲基)环戊基丙酸的合成

以商业易得的（＋ ）内向３溴莰酮２ 为手性源合成了光学活性的（１′ Ｒ,２ Ｓ,２′ Ｓ）２（２溴甲基２甲基３亚甲基）环戊基丙酸。     

(1R,2R)-1,2-环己烷二甲醇二甲磺酸酯的合成

目的:合成(1R,2R)-1,2-环己烷二甲醇二甲磺酸酯(化合物1)。方法:以(±)-反式-4-环己烯-1,2-二甲酸(化合物2)为原料,经钯碳还原、(R)-1-苯乙胺拆分、在甲醇中与氯化亚砜反应、硼氢化钠-无水氯化锂还原、甲基磺酰氯反应得到目标化合物,并进行核磁共振(1H-NMR)或质谱(MS)表征。以(1R,2R)-1,2-环己烷二甲酸(化合物4)/氯化亚砜的投料比、反应温度和时间对酰化反应进行优化,以化合物4/硼氢化钠/无水氯化锂的投料比、反应温度和时间、溶剂对酯还原反应进行优化,筛选(1R,2R)-1,2-环己烷二甲醇(化合物5)的合成条件。结果:表征确证目标化合物为化合物1,总收率为27.9%,纯度>99%。化合物5的合成中,酰化反应条件为化合物4/氯化亚砜投料比为1.0:2.2,反应温度为65℃,反应时间为2h;酯还原反应条件为化合物4/硼氢化钾/无水氯化锂投料比为1.0:3.0:3.0,反应温度为20～30℃,反应时间为24h,溶剂为四氢呋喃。结论:所建立的反应条件温和、操作简便易行,各步原料价格低廉。     

Unichiral 2-(2'-pyrrolidinyl)-1,4-benzodioxanes: the 2R,2'S diastereomer of the N-methyl-7-hydroxy analogue is a potent α4β2- and α6β2-nicotinic acetylcholine receptor partial agonist

A series of unichiral 7-substituted 2-(1'-methyl-2'-pyrrolidinyl)-1,4-benzodioxanes were synthesized and tested for the affinity for the α4β2 and α7 central nicotinic receptors; the 2R,2'S diastereomer of the 7-OH analogue [(R,S)-7], unique in the series, has a high α4β2 affinity (12nM K(i)). N-Demethylation and configuration inversion of the stereocenters greatly weaken its α4β2 affinity, confirming that such a rigid molecule can be considered a new template for α4β2 ligands. Docking analysis showed how (R,S)-7 is capable of strongly and specifically interacting with the amino acidic counterpart of the α4β2 receptor binding site. Further pharmacological characterization demonstrated that (R,S)-7 also has a high affinity for the α6β2 receptor, and in vitro functional tests indicated that it is a potent α4β2 and α6β2 partial agonist, with modest affinity and potency for the α3β4 receptor. Comparison with varenicline, a well-known nicotinic partial agonist used as a smoking cessation aid, interestingly reveals similar nicotinoid profiles.     

(1R,2S)-2-氨基-1-苯基-1-丙醇的合成

目的：改进（1R，2S）－2－氨基－1－苯基－1－丙醇的合成工艺。方法：以苯丙酮为起始原料，经中间体肟基苯丙酮和Pt-Pd/C催化加氢反 应合成赤式2－氨基－1－苯基－1－丙酮，再用S－羧甲基－L－半胱氨酸作拆分试剂进行拆分，得到目标产物。结果：收率和光学纯度有较大提高，总收率达55．5％。结论：该工艺具有工业应用价值。