匹伐他汀钙及其中间体非对映异构体的合成

目的：为控制匹伐他汀钙的质量,合成匹伐他汀钙及其中间体非对映异构体中的C-5位差向异构体。方法：以（3R,5S,6E）-7-[2-环丙基-4-(4-氟苯基)-3-喹啉基]-3,5-二羟基-3,5-O-亚异丙基庚-6-烯酸叔丁酯（2）为原料经脱缩酮、氧化、反立体选择性还原得（3R,5R,6E）-7-[2-环丙基-4-(4-氟苯基)-3-喹啉基]-3,5-二羟基-6-庚烯酸叔丁酯（5）。5水解成盐得（+）-双-[（3R,5R,6E）-7-[2-环丙基-4-（4-氟苯基）-3-喹啉基]-3,5-二羟基-6-烯庚酸]单钙盐（1）。5与2,2-二甲氧基丙烷形成缩酮得化合物（3R,5R,6E）-7-[2-环丙基-4-（4-氟苯基）-3-喹啉基]-3,5-二羟基-3,5-O-亚异丙基-6-庚烯酸叔丁酯（4）。结果与结论：合成了匹伐他汀钙及其中间体的C-5位差向异构体,并经核磁共振氢谱、碳谱、质谱和比旋光度等确证结构,3个目标化合物5、1和4的总收率分别为70%、68%和56%（以2计）,纯度经HPLC检测均在97.5%以上,可以作为匹伐他汀钙原料药质量控制的对照品。     

盐酸美金刚的合成工艺改进

目的设计一条全新的反应路线,合成阿尔茨海默病治疗药物盐酸美金刚,并对其合成工艺进行改进。方法以1,3-二甲基金刚烷为原料,在催化剂N一羟基邻苯二甲酰亚胺（NHPI）的催化下,经硝酸硝化得1-硝基-3,5-二甲基金刚烷,再在Pd—c的催化下与氢气还原得1-氨基-3,5-二甲基金刚烷,最后与干燥氯化氢反应得盐酸美金刚。对第一步反应采用四因素三水平的正交设计试验优化其反应条件。结果最佳合成工艺条件为温度70℃、时间15h、溶剂乙酸,催化剂量0．2o结论优选出的合成路线反应步骤短、操作简单、经济合理。     

立普妥

[通用名称] atorvastatin calcium ,阿托伐他汀钙 [化学名称] [R-(R,R)]-2-(4-氟苯基)-β-二羟基-5-(1-甲基乙基)-3-苯基-4-[(苯氨基)-羰基]-1H-吡咯-1-庚酸: 钙盐(2∶1)三水化物     

3，5-二氟苯基硝基乙烷的合成工艺研究

3,5-二氟苯基硝基乙烷是常用的药物中间体．目前3,5-二氟苯基硝基乙烷的合成方法还有很多不足。本文以3,5-二氟苯甲醛和硝基甲烷为原料,先经过缩合反应合成中间体1-（3,5-二氟苯基）-2-硝基乙醇,再经过消除反应合成中间体1,3-二氟-5-（2-硝基）-苯乙烯,     

阿立哌唑的合成

目的合成抗精神病药阿立哌唑,并验证所用路线的中间体的螺环季铵盐结构。方法1-（2,3-二氯苯基）哌嗪盐酸盐与1,4-二溴丁烷反应后,再与7-羟基-3,4-2（1H）-喹喏啉酮反应。结果总收率达45%,目标化合物经核磁共振氢谱和红外确证结构,并验证了中间体结构,化学名为5,8-二氮杂螺[4,5]癸烷溴化物。结论此工艺路线生产成本低,反应条件温和、适宜工业化生产。并确证了中间体是5,8-二氮杂螺[4,5]癸烷溴化物,而非1-（4-溴丁基）-4-（2,3-二氯苯基）哌嗪。     

抗肿瘤药米铂的合成工艺改进

目的 改进抗肿瘤药米铂的合成工艺。方法 以顺式-二碘-(1R,2R)-1, 2-环己二胺合铂(II)为起始原料,将顺式-二碘- (1R,2R)-1, 2-环己二胺合铂(II)与硝酸银水解合成含有硝酸根的水合物溶液,然后与阴离子树脂交换生成顺式-二羟基- (1R,2R)-1,2-环己二胺合铂(II)的水溶液,再与正十四碳酸的正丁醇溶液反应合成米铂。采用元素分析、质谱、红外光谱、核磁共振氢谱、热分析和比旋光度对其结构进行表征。结果与结论 合成的化合物结构与标题化合物一致,收率约75%。该方法便于操作,收率高。     

抗肿瘤药米铂的一种新合成方法及结构表征

目的 合成抗肿瘤新药米铂。方法 以顺式- (1R,2R)-1, 2-环己二胺-二碘合铂(II)为起始原料,先将顺式- (1R,2R)-1, 2-环己二胺-二碘合铂(II)与硫酸银水解成含有硫酸根的水合物溶液,然后与八水氢氧化钡反应生成顺式- (1R,2R)-1,2-环己二胺-二羟基合铂(II)的水溶液,最后与正十四碳酸的正丁醇溶液反应合成米铂。采用元素分析、质谱、红外光谱、核磁共振氢谱和热分析对其结构进行表征。结果与结论 合成的化合物结构与标题化合物一致,收率约68%。该方法便于操作,收率高,可做进一步研究。     

(3R,5S)-6-氧代-3,5-二羟基-3,5-O-亚异丙基己酸叔丁酯的合成

目的设计路线合成匹伐他汀钙侧链。方法以(3R,5S)-6-乙酰氧基-3,5-二羟基-3,5-O-亚异丙基己酸叔丁酯为原料经水解、Swern氧化得匹伐他汀钙的重要中间体(3R,5S)-6-氧代-3,5-二羟基-3,5-O-亚异丙基己酸叔丁酯。结果总收率为80.8%。结论经1H-NMR确定为该化合物。     

半合成紫杉醇工艺杂质研究

目的研究半合成紫杉醇工艺杂质,结合合成路线推测工艺杂质的来源。方法利用硅胶柱色谱制备分离了kingston半合成路线中的4个工艺杂质,通过质谱及核磁共振波谱鉴定化学结构。结果4个工艺杂质分别是筇,20-环氧-1,7争二羟基-9-羰基紫杉-11-烯．2a,4,10β,13α-四取代基4,10-二乙酰氧基2-苯甲酰氧基13-[（2R,3S）-3-氨基-2-苯甲酰氧基-3-苯基丙酸酯（1）、7．乙酰基紫杉醇（2）、13．Tes-巴卡亭Ⅲ（3）、7-表紫杉醇（4）。结论杂质（1）尚未被美国药典和欧洲药典收载,研究结果为半合成紫杉醇的质量控制提供了依据。     

帕米膦酸二钠的合成

目的：合成二钠３－氨基－１－羟基－亚丙基－二膦酸盐（帕米膦酸二钠）。方法：有,无溶剂的两种合成路线,并对工艺进行改进,所得产物经元素分析,红外光谱,质谱等分析确证结构。结果;两种路线均可合成目标化合物。路线Ａ收率高于路线Ｂ。结论：溶剂的加入使本反应体系均一,有利于产物生成。     

Isolation and structure determination of oxidative degradation products of atorvastatin

Methods were developed for the preparation and isolation of four oxidative degradation products of atorvastatin. ATV-FX1 was prepared in the alkaline acetonitrile solution of atorvastatin with the addition of hydrogen peroxide. The exposition of aqueous acetonitrile solution of atorvastatin to sunlight for several hours followed by the alkalization of the solution with potassium hydroxide to pH 8–9 gave ATV-FXA. By the acidification of the solution with phosphoric acid to pH 3 ATV-FXA1 and FXA2 were prepared. The isolation of oxidative degradation products was carried out on a reversed-phase chromatographic column Luna prep C18(2) 10 μm applying several separation steps. The liquid chromatography coupled with a mass spectrometer (LC-MS), high resolution MS (HR-MS), 1D and 2D NMR spectroscopy methods were applied for the structure elucidation. All degradants are due to the oxidation of the pyrrole ring. The most probable reaction mechanism is intermediate endoperoxide formation with subsequent rearrangement and nucleophilic attack by the 5-hydroxy group of the heptanoic fragment. ATV-FX1 is 4-[1b-(4-Fluoro-phenyl)-6-hydroxy-6-isopropyl-1a-phenyl-6a-phenylcarbamoyl-hexahydro-1,2-dioxa-5a-aza-cyclopropa[a]inden-3-yl]-3-(R)-hydroxy-butyric acid and has a molecular mass increased by two oxygen atoms with regard to atorvastatin. ATV-FXA is the regioisomeric compound, 4-[6-(4-Fluoro-phenyl)-6-hydroxy-1b-isopropyl-6a-phenyl-1a-phenylcarbamoyl-hexahydro-1,2-dioxa-5a-aza-cyclopropa[a]inden-3-yl]-3-(R)-hydroxy-butyric acid. Its descendants ATV-FXA1 and FXA2 appeared without the atorvastatin heptanoic fragment and are 3-(4-Fluoro-benzoyl)-2-isobutyryl-3-phenyl-oxirane-2-carboxylic acid phenylamide and 4-(4-Fluoro-phenyl)-2,4-dihydroxy-2-isopropyl-5-phenyl-3,6-dioxa-bicyclo[3.1.0]hexane-1-carboxylic acid phenylamide, respectively. Quantitative NMR spectroscopy was employed for the assay determination of isolated oxidative degradation products. The results obtained were used for the determination of the UV response factors relative to atorvastatin.     

吡咯类新衍生物在大鼠胸主动脉的钙拮抗作用

目的　观察 4个吡咯类新化合物是否具有钙拮抗作用。方法　采用4 5Ca跨膜内流动测定技术 ,考查 4个新化合物对大鼠主动脉电压依赖性钙通道的钙拮抗活性。化合物分别为化合物 1:3,5 二甲基 4 (4 甲基 1 甲酰基哌嗪基 ) 1H 吡咯 2 甲酸乙酯 ;化合物 2 :3,5 二甲基 4 [4 (4 硝基苯基 ) 1 甲酰基哌嗪基 ] 1H 吡咯 2 甲酸乙酯 ;化合物 3:3,5 二甲基 4 [4 (3 对甲基苯基丙烯酰基 ) 1 甲酰基哌嗪基 ] 1H 吡咯 2 甲酸乙酯 ;化合物 4 :4 [4 [3 (2 氯苯基 )丙烯酰基 ] 1 甲酰基哌嗪基 ] 3,5 二甲基 1H 吡咯 2 甲酸乙酯。结果　 4个化合物均不同程度降低4 5Ca跨膜内流 ,化合物 1和化合物 2的活性强于阳性对照药硝苯地平。结论　 4个吡咯类化合物有一定的钙拮抗活性     

HPLC法测定阿托伐他汀钙对映异构体

目的：建立阿托伐他汀钙对应异构体的测定方法。方法：采用HPLC法,以阿托伐他汀钙S,S对映异构体对照品为外标进行定性和定量测定。采用AD-H型手性分析柱（4.6mm×250mm,5μm）,以正己烷-乙醇-冰醋酸（92∶8∶0.3）为流动相,流速1.0mL/min,检测波长246nm,柱温25℃。结果：阿托伐他汀钙S,S对映异构体与阿托伐他汀峰及主要杂质峰的分离度均大于1.5;检测限为0.6ng,重复性良好（RSD为1.47,n=6）。结论：本方法经方法学验证,可用于测定阿托伐他汀钙S,S对映异构体。     

Pyrrolnitrin analogues. V. Knorr's pyrrole condensation between N-(4-nitrophenacyl)-3,5-dimethylaniline and ethyl acetoacetate

The reaction between N-(4-nitrophenacyl)-3,5-dimethylaniline and ethyl acetoacetate in boiling ethanol afforded 3-carbethoxy-5-(1-carbethoxyacetonyl)-4,5-dihydro-1-(3,5-dimethylphenyl)-4-hydroxy-2-methyl-4-(4-nitrophenyl)pyrrole and in low yield 3-carbethoxy-1-(3,5-dimethylphenyl)-2-methyl-4-(4-nitrophenyl)pyrrole. Chemical transformation of the former compound into 5-acetonyl-1-(3,5-dimethylphenyl)-2-methyl-4-(4-nitrophenyl)pyrrole is described. The structure of 3-carbethoxy-5-(1-carbethoxyacetonyl)-4,5-dihydro-1-(3,5-dimethylphenyl)-4-hydroxy-2-methyl-4-(4-nitrophenyl)pyrrole has been established by the aid of N.M.R. spectral data. The above reaction, when carried out in boiling ethanol in the presence of a catalytic amount of 3,5-dimethylaniline hydrobromide, led to the formation of 3-carbethoxy-1-(3,5-dimethylphenyl)-2-methyl-4-(4-nitrophenyl)pyrrole and 4,6-dimethyl-2-(4-nitrophenyl)indole, the former formed in a very good yield. Some pyrrolnitrin analogues have been prepared starting from 3-carbethoxy-1-(3,5-dimethylphenyl)-2-methyl-4-(4-nitrophenyl)pyrrole.     

2,4-Dicarboxy-pyrroles as selective non-competitive mGluR1 antagonists: an exploration of the role of the pyrrolic scaffold

Following the disclosure of 3-(1,2,2-trimethylpropyl) 4-[3,5-dimethyl-2-propyloxycarbonyl]pyrrolecarboxylate as a potent and selective mGluR1 non-competitive antagonist, the role and the importance of the pyrrole template were investigated. Different aromatic moieties were investigated as possible bio-isosteric replacement of the original scaffold and some of them were shown to be partially able to mimic the properties of the original pyrrole ring.     

Non-steroidal anti-inflammatory agents. IV. Synthesis and pharmacologic activity of aroylthiopheneacetic acids with a pyrrole group

The synthesis of new antiinflammatory aroylthiopheneacetic acids bearing a pyrrole moiety is described. These compounds can be regarded as analogues of thiaprofen and related isosteres. The antiinflammatory activity of the new pyrryl derivatives has been evaluated in comparison with indomethacin, tolmetin and the unknown 5-(2-chlorobenzoyl)thiophene-2-acetic acid. Among tested derivatives the compounds containing the pyrrole ring were devoid of analgesic-antiinflammatory activities.     

阿托伐他汀钙的合成研究进展

目的介绍了阿托伐他汀钙的研究背景,作用机制以及合成的研究进展。方法综合国内外报道的文献,阐述阿托伐他汀钙的合成方法。结果重点列出了3条阿托伐他汀钙的合成路线,重点分析了Paal-Knorr合成法。结论 Paal-Knorr合成法中,2种重要中间体的各种合成路线为阿托伐他汀钙的高效合成提供了新的思路。     

beta-Oxidation of simvastatin in mouse liver preparations.

All current 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors [simvastatin (SV), lovastatin (LV), atorvastatin, pravastatin, fluvastatin, and cerivastatin] are believed to undergo an atypical beta-oxidation of the dihydroxy heptanoic or heptanoic acid side chain. Metabolites, which are shortened by two- and/or four-carbon units consistent with beta-oxidation products, have been reported exclusively in rodents following LV and SV administration and across species (rodents, dogs, and humans) following the other statins. In this study, in vitro formation of a beta-oxidation product of simvastatin hydroxy acid (SVA) and its intermediates in mouse livers is described. Incubation of SVA with mouse liver preparations fortified with CoASH and ATP led to formation of SV and two major products (P1 and P2). Based on mass spectrometry (MS), tandem mass spectrometry, and/or NMR spectral characteristics, P1 was an alpha,beta-unsaturated metabolite, formed by dehydration of the D,D-dihydroxy heptanoic acid side chain, whereas P2 was probably the L,D-dihydroxy acid isomer of SVA, formed by stereospecific hydration of P1. When NAD(+) was also included in the incubation mixture, there were two additional metabolites with the MS and/or NMR characteristics consistent with a two-carbon shortened product (P3) and its dehydrated derivative (P4). In a complete incubation system with all cofactors (ATP, CoASH, NAD(+), and NADPH) present, there was an additional product with MS spectra and liquid chromatography retention time identical to the beta-oxidized, unsubstituted pentanoic acid metabolite (P5) detected in rats and mice following simvastatin administration. The involvement of CoASH and NAD(+) and the presence of the four metabolic intermediates suggest that SVA (and presumably the other statins) is a substrate for the beta-oxidation enzyme complex in mice. Additionally, the present finding of CoASH-dependent formation of SV substantiates a mechanism proposed previously for the in vivo lactonization of statin hydroxy acids.     

Brominated pyrrole alkaloids from marine Agelas sponges reduce depolarization-induced cellular calcium elevation.

Seven pyrrole alkaloids isolated from Agelas sponges were tested for interactions with the cellular calcium homeostasis. Brominated pyrrole alkaloids reduced voltage dependent calcium elevation in PC12 cells. Dibromosceptrin was the most potent alkaloid with a half maximal concentration of 2.8 microM followed by sceptrin (67.5 microM) and oroidin (75.8 microM). 4,5-Dibromopyrrole-2-carboxylic acid reduced calcium elevation at concentrations exceeding 30 microM but did not eliminate calcium elevation at concentrations up to 1 mM. 4-Bromopyrrole-2-carboxylic acid and pyrrole-2-carboxylic acid were not active in this respect. The aminoimidazole group appeared to have a significant effect on voltage dependent calcium elevation shown by the comparison of oroidin with 4,5-dibromopyrrole-2-carboxylic acid. The degree of bromination of the pyrrole moiety is another important factor, as was shown by the comparison of 4,5-dibromopyrrole-2-carboxylic acid with 4-bromopyrrole-2-carboxylic acid, as well as oroidin with hymenidin and dibromosceptrin with sceptrin. The previously reported feeding deterrent activity of brominated pyrrole alkaloids in Agelas sponges against predatory reef fish may partly be explained by a general interaction of these alkaloids with the cellular calcium homeostasis. The chemoreception of bromopyrrole alkaloids in sea water is shown using sensory neurons in the rhinophore of the sea slug Aplysia punctata.     

Structural elucidation of an unknown Simvastatin by-product in industrial synthesis starting from Lovastatin

Unknown by-product in Simvastatin synthesis from Lovastatin was found. The elucidation of this molecular structure by means of (1)H and (13)C NMR spectroscopy, HPLC/MS, MS/MS and FT-IR was shown. The mentioned by-product, originated during Merck Sharp and Dhome synthesis scheme was isolated in the second-last step replacing butylamine with benzylamine. The spectroscopic results agreed with a molecular formula C(32)H(43)NO(3). The proposed structure of this compound, characterised by the presence of a conjugated dienic system in the heptanoic acid amide residue, was alpha,beta,gamma,delta unsaturated Simvastatin N-benzylamide.