盐酸文拉法辛的合成

4-甲氧基苯乙腈和环己酮在KH、甲苯中缩合得到α-（1-羟基环己基）-对甲氧基苯乙腈,再在相转移催化剂溴化四丁铵作用下经NaBH4、CH3I、CH2Cl2体系还原及甲基化等反应制得盐酸文拉法辛,总收率67%.     

盐酸文拉法辛光降解杂质的合成

目的 合成盐酸文拉法辛的光降解杂质1-[2-(二甲胺基)-1-(4-甲氧苯基)乙烯基]-1-环己烷(杂质Ⅰ),加强对二环类非典型抗抑郁药盐酸文拉法辛原料药的质量控制.方法 对甲氧基苯乙腈与环己酮经缩合反应,LiAlH4还原反应,甲酸/甲醛双甲基化反应得到光降解杂质Ⅰ.结果 杂质Ⅰ的结构经1H-NMR、13C-NMR和M...     

微波法合成维拉帕米中间体-2-（3，4-二甲氧基苯基）-3-甲基苯丁腈

目的采用微波法合成2-（3，4-二甲氧基苯基）-3-甲基苯丁腈。方法以3，4-二甲氧基苯乙腈和2-溴丙烷为原料，加入相转移催化剂苄基三乙基氯化铵，利用微波反应器进行烃化反应得到目标物。结果在电流30mA下辐射6min时，反应收率最高，可达64.5%。产物结构经液相色谱和核磁共振氢谱确认。结论此合成方法操作简便，反应时间短，明显提高反应效率。     

盐酸文拉法辛合成工艺改进

目的：改进盐酸文拉法辛的合成工艺。方法：以对甲氧基苯乙腈和环己酮为原料，经缩合得α-（1-羟基环己基）-对甲氧基苯乙腈，再经还原，最后甲基化制备盐酸文法拉辛。以甲醇钠代替氢化钾作为缩合剂，以盐酸乙醇代替氯化氢气体，以甲苯代替乙醚，对此工艺进行了改进。结果：得到较好的工艺条件。总收率达到47．4％。结论：改进后的工艺降低了生产成本，易于工业化生产。     

白藜芦醇的合成

3,5-二羟基苄醇经氯代、氰化和羟基保护制得3,5-二(甲氧甲氧基)苯乙腈(5),5和4-甲氧甲氧基苯甲醛(6)在微波辐照下经缩合、水解及脱羧,然后脱保护基得到白藜芦醇,总收率约56%(以3,5-二羟基苄醇计)。     

国外关于合成药及其中间体工艺简讯

心血管药物异搏定(戊脉安)(Ⅰ)可由3,4-二甲氧基苯乙腈(Ⅱ)经烃化制成Ⅲ。反应可用NaH、NaNH_2或叔丁醇钾(KOCMe_3)为缩合剂,在二甲亚砜(DMSO)中进行。Ⅲ经水解后可得Ⅳ,然后Ⅳ与Ⅴ反应并经催化氢化即得成品Ⅰ。     

3,4-二甲氧基苯乙酸的合成新工艺

3,4-二甲氧基苯乙酸(1)又名高藜芦酸,可用于合成β受体阻滞药贝凡洛尔(bevantolol)和抗心律失常药维拉帕米(verapamil)等,也是合成异喹啉类生物碱的关键中间体[1].传统合成方法是用3,4-二甲氧基氯苄和氰化物反应得到3,4-二甲氧基苯乙腈,再经水解制得1[2,3],该路线需使用剧毒的氰化物.另一合成路线是以3,4-二甲氧基苯甲醛为原料,经硝基甲烷缩合生成3,4-二甲氧基-β-硝基苯乙烯,再经硼氢化钾还原、DMSO氧化制得[4].该路线的原料和还原试剂价格较高,生产成本较高.     

2-苯基-1-丁醇与2-二甲氨基-2-苯基丁腈的合成

目的为马来酸曲美布汀的重要中间体2-二甲氨基-2-苯基-1-丁醇的合成奠定基础。方法苯乙腈与溴乙烷进行烃化反应得2-苯基-1-丁腈,所得产物经水解得2-苯基-1-丁酸,然后通过硼氢化钠-碘体系还原得2-苯基-1-丁醇;苯乙腈与N-溴代丁二酰亚胺进行卤代反应得溴代苯乙腈,所得产物与二甲胺进行烃化反应得2-二甲氨基苯乙腈,然后与溴乙烷进行烃化反应得2-二甲氨基-2-苯基丁腈。结果合成了2-苯基-1-丁醇和2-二甲氨基-2-苯基丁腈,总收率为分别为51%和59.4%。目标产物的结构经核磁共振氢谱、质谱确证。结论本合成方法原料易得,操作简单,收率较高,适合于工业化生产。     

盐酸洛哌丁胺的合成

苯乙腈经溴化、傅-克反应得到二苯基乙腈(2)。2经与环氧乙烷反应,以36%溴化氢冰醋酸溶液开环得4-溴-2,2-二苯基丁酸(4)。后者的酰氯与二甲胺反应,续与4-对氯苯基-4-羟基哌啶(7)缩合以及成盐,得盐酸洛哌丁胺。收率58%(以7计)。     

相转移催化反应合成咳必清中间体

咳必清生产中的重要中间体1-苯基环戊烷羧酸系用苯乙腈为原料,经烷基化-环合、水解制得。烷基化和环合反应激烈,需严格控制无水。生产中操作不当常会发生冲料、固罐。苯乙腈α-碳原子的烷基化 Makosza 作过很多报道。我们采用相转移催化反应对苯乙腈烷基化-环合工艺进行试验,对反应条件、加料次序、催化剂用量作了摸索。新工艺不需要无水操作,环合物可免去减压分馏,消除了冲料、固罐等事故,并具有反应条件温和、操作便利、收率高     

Efficacy of gut lavage,hemodialysis, and hemoperfusion in the therapy of paraquat or diquat intoxication

Clinical and in vitro investigations were carried out to test the efficacy of gut lavage, hemodialysis, and hemoperfusion in the treatment of poisoning with paraquat or diquat. In a patient suffering from diquat intoxication 130 times more diquat was removed by gut lavage 30 h after ingestion than was removed by complete aspiration of the gastric contents.Determination of in vitro clearances for paraquat and diquat by hemodialysis showed that, at serum concentrations of 1–2 ppm, such as are frequently encountered in poisoning in man, toxicologically relevant quantities of herbicide cannot be removed from the body. At a concentration of 20 ppm, on the other hand, hemodialysis proved to be effective, the clearance being 70 ml/min at a blood flow rate of 100 ml/min. The efficacy of hemoperfusion with coated activated charcoal was on the whole better. Especially at concentrations around 1–2 ppm, the clearance values for hemoperfusion were some 5–7 times higher than those for hemodialysis.In a patient suffering from paraquat poisoning, both hemodialysis as well as hemoperfusion were carried out. The in vitro results could be confirmed: At serum concentrations of paraquat less than 1 ppm no clearance could be obtained by hemodialysis while by hemoperfusion with activated charcoal quite high clearance values were measured and the serum level dropped down to zero.

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Zusammenfassung Klinische Untersuchungen und Laboratoriumsversuche wurden durchgeführt, um die Wirksamkeit von Darmspülung, Hämodialyse und Hämoperfusion bei Paraquat- und Deiquat-Vergiftungen zu prüfen.Bei einem Patienten wurde 30 Std nach Deiquat-Aufnahme durch Darmspülung 130mal mehr Deiquat entfernt als durch vollständige Aspiration des Mageninhaltes. In vitro-Versuche ergaben, daß bei Blutserumkonzentrationen von 1–2 ppm, die bei Vergiftungen oft gemessen werden, durch Hämodialyse keine toxikologisch relevanten Paraquat- oder Deiquat-Mengen entfernt werden können. Dagegen erwies sich die Hämodialyse bei 20 ppm und einer Blutumlaufgeschwindigkeit von 100 ml/min mit einer Clearance von 70 ml/min als wirksam. Die Hämoperfusion mit beschicheter Aktivkohle war in diesen Versuchen aber eindeutig überlegen, denn insbesondere bei Konzentrationen um 1–2 ppm waren die Clearance-Werte 5–7mal höher als bei der Hämodialyse.Die in vitro-Ergebnisse wurden bei einem Patienten mit einer Paraquat-Vergiftung bestätigt: Bei Konzentrationen unter 1 ppm war die Hämodialyse wirkungslos, während durch Hämoperfusion relativ hohe Clearance-Werte erreicht wurden, so daß der Serumspiegel rasch unter die Nachweisgrenze abfiel.

     

In vitro studies on sterically stabilized liposomes (SL) as enzyme carriers in organophosphorus (OP) antagonism

This study describes a new approach for organophosphorous (OP) antidotal treatment by encapsulating an OP hydrolyzing enzyme, OPA anhydrolase (OPAA), within sterically stabilized liposomes. The recombinant OPAA enzyme was derived from Alteromonas strain JD6. It has broad substrate specificity to a wide range of OP compounds: DFP and the nerve agents, soman and sarin. Liposomes encapsulating OPAA (SL)* were made by mechanical dispersion method. Hydrolysis of DFP by (SL)* was measured by following an increase of fluoride ion concentration using a fluoride ion selective electrode. OPAA entrapped in the carrier liposomes rapidly hydrolyze DFP, with the rate of DFP hydrolysis directly proportional to the amount of (SL)* added to the solution. Liposomal carriers containing no enzyme did not hydrolyze DFP. The reaction was linear and the rate of hydrolysis was first order in the substrate. This enzyme carrier system serves as a biodegradable protective environment for the recombinant OP-metabolizing enzyme, OPAA, resulting in prolongation of enzymatic concentration in the body. These studies suggest that the protection of OP intoxication can be strikingly enhanced by adding OPAA encapsulated within (SL)* to pralidoxime and atropine.     

Aquatic Insects and Trace Metals: Bioavailability,Bioaccumulation, and Toxicity

Abstract

The uptake of metals from food and water sources by insects is thought to be additive. For a given metal, the proportions taken up from water and food will depend both on the bioavailable concentration of the metal associated with each source and the mechanism and rate by which the metal enters the insect. Attempts to correlate insect trace metal concentrations with the trophic level of insects should be made with a knowledge of the feeding relationships of the individual taxa concerned. Pathways for the uptake of essential metals, such as copper and zinc, exist at the cellular level, and other nonessential metals, such as cadmium, also appear to enter via these routes. Within cells, trace metals can be bound to proteins or stored in granules. The internal distribution of metals among body tissues is very heterogeneous, and distribution patterns tend to be both metal and taxon specific. Trace metals associated with insects can be both bound on the surface of their chitinous exoskeleton and incorporated into body tissues. The quantities of trace meals accumulated by an individual reflect the net balance between the rate of metal influx from both dissolved and particulate sources and the rate of metal efflux from the organism. The toxicity of metals has been demonstrated at all levels of biological organization: cell, tissue, individual, population, and community. Much of the literature pertaining to the toxic effects of metals on aquatic insects is based on laboratory observations and, as such, it is difficult to extrapolate the data to insects in nature. The few experimental studies in nature suggest that trace metal contaminants can affect both the distribution and the abundance of aquatic insects. Insects have a largely unexploited potential as biomonitors of metal contamination in nature. A better understanding of the physico-chemical and biological mechanisms mediating trace metal bioavailability and exchange will facilitate the development of general predictive models relating trace metal concentrations in insects to those in their environment. Such models will facilitate the use of insects as contaminant biomonitors.     

Pharmacological treatment of COVID-19: an opinion paper

The precocity and efficacy of the vaccines developed so far against COVID-19 has been the most significant and saving advance against the pandemic. The development of vaccines has not prevented, during the whole period of the pandemic, the constant search for therapeutic medicines, both among existing drugs with different indications and in the development of new drugs. The Scientific Committee of the COVID-19 of the Illustrious College of Physicians of Madrid wanted to offer an early, simplified and critical approach to these new drugs, to new developments in immunotherapy and to what has been learned from the immune response modulators already known and which have proven effective against the virus, in order to help understand the current situation.     

Alzheimer’s disease – current trends in basic and clinical research. Highlights from the 16th ECNP

Advances in the molecular biological knowledge of neuronal nicotinic acetylcholine receptors (nAChRs) have led to a growing interest by the pharmaceutical industry in the development of novel compounds that selectively modulate nAChR function. The ability of (-)-nicotine, an activator of nAChRs, to enhance attentional aspects of cognition in animals and humans, to exert neuroprotective and anxiolytic-like effects, and presumably to mediate the negative correlation between smoking and Alzheimer's (and Parkinson's) Disease, has focused interest on the potential therapeutic utility of modulators of nAChR function for treatment of some of the deficits associated with these progressive, neurodegenerative conditions. Numerous compounds are known which activate nAChRs and which might serve as lead compounds toward the development of such agents. The pharmacologic diversity of neuronal nAChR subtypes suggests the possibility of developing selective compounds which would have more favourable side-effect profiles than existing agents. This broader class of agents, collectively called cholinergic channel modulators (ChCMs), is anticipated to encompass compounds which would have more favourable side-effect profiles than existing agents, which generally exhibit low selectivity. This selectivity may be achieved by preferentially activating some subtypes of nAChRs (i.e., Cholinergic Channel Activators, ChCAs) or inhibiting the function of other subtypes (Cholinergic Channel Inhibitors, ChCIs). An overview of the biology of nAChRs and the rationale for the use of ChCMs for the treatment of dementia related to neurodegenerative diseases are presented, followed by a discussion of lead compounds and compounds under consideration for clinical evaluation.     

Steroidal sapogenin contents in some domestic plants

In order to find out the values of the steroid resources for the future use. the compositions and contents of steroidal sapogenins from 13 domestic plants have been investigated. As a result,Dioscorea nipponica, D. quinqueloba andSmilax china were found to have large amount of diosgenin. And pennogenin inTrillium kamtschaticum andParis verticillata, yuccagenin inAllium fistulosum, hecogenin inAgave americana and neochlorogenin inSolanum nigum were appeared to be major steroidal sapogenins.