2,N-二甲基-N-(3,3-二苯基丙基)-1-氨基-2-丙醇的合成

目的研究2,N-二甲基-N-(3,3-二苯基丙基)-1-氨基-2-丙醇(1)的合成方法.方法以肉桂酸、氯化亚砜、甲胺等为原料,经烃化、氯化、酰化和还原反应得到N-甲基-3,3-二苯基丙胺(5);以3-氯异丁烯为原料,经加成、水解、环合反应得到环氧异丁烷(7),化合物5与7经烃化反应得到目标产物.结果与结论设计的合成路线以肉桂酸计,5步反应总收率为62.7%,合成路线简便易行,适于大规模制备.所合成的目标产物经ESI-MS和1H-NMR确证.     

瑞戈非尼的合成工艺改进

改进抗癌新药瑞戈非尼的合成工艺,以2-吡啶甲酸为原料通过卤化,酰胺化,得到4-氯-N-甲基吡啶-2-甲酰胺,成盐酸盐得到4-氯-N-甲基吡啶-2-甲酰胺盐酸盐,与3-氟-4-氨基苯酚亲核取代反应得到4-(4-氨基-3-氟苯氧基)-N-甲基吡啶-2-甲酰胺,然后和4-氯-3-三氟甲基苯异氰酸酯缩合反应得到瑞戈非尼,总收率为47%。     

非布索坦的合成

设计完成两条非布索坦(1)的合成路线.以对羟基苯甲酸甲酯为原料,经过溴化、醚化得到关键中间体3-溴-4-(2-甲基丙氧基)苯甲酸甲酯(9).第一条合成路线将9与氰化亚铜反应引入氰基,然后合成噻唑环,最后经水解得到1,总收率为35%;第二条合成路线将9合成噻唑环,然后引入氰基,水解后得到1,总收率为38%.     

人血浆中非索非那定的LC-MS/MS法测定及药动学

建立了LC-MS/MS法测定人血浆中的非索非那定浓度.以格列美脲为内标,采用C18柱,流动相为甲醇-水(含15 mmol/L乙酸铵和0.05%甲酸)(68∶32),电喷雾离子化源,选择性正离子反应监测,检测离子为m/z 502.1→466.2(非索非那定),m/z 491.2→352.0(格列美脲),并用于人体药动学研究.20名健康志愿者单剂量口服非索伪麻缓释胶囊(非索非那定60、120 mg)后非索非那定的主要药动学参数为:t1/2β(11.34±4.59)和(11.09±3.27)h,tmax(4.20±0.98)和(3.72±1.21)h,cmax(159.28±76.81)和(368.89±165.21)ng/ml,AUC0-48h(997.87±421.12)和(2 386.3±867.5)ng·h·ml-1;多剂量口服非索伪麻缓释胶囊(60 mg,bid)后非索非那定的主要药动学参数为:Cmin(35.45±21.56)ng/ml,Cav(97.88±57.12)ng/ml,DF(1.78±0.32),AUCss(1 196.26±665.06)ng·h·ml-1.     

氢溴酸达非那新合成方法研究

目的合成氢溴酸达非那新。方法以R-(+)-3-羟基吡咯烷盐酸盐为原料,经氯代、氨基保护、缩合、脱N-保护基、氰基水解,与L-(+)-酒石酸成盐,再经皂化游离等反应,制得3-(S)-(-)-(1-氨甲酰基-1,1-二苯基甲基)四氢吡咯,与5-(2-溴乙基)-2,3-二氢苯并呋喃缩合、成盐,制得氢溴酸达非那新。结果与结论氢溴酸达非那新的总收率为23%,产物结构经1H-NMR和MS进行了确认。     

非索非那定的合成

α,α-二甲基苯乙酸经硅胶负载磷钨酸(PW/SiO2)固体酸催化酯化、与4-氯丁酰氯反应生成α,α-二甲基-4-(4-氯-1-氧代丁基)苯乙酸乙酯,用硼氢化钠还原后与α,α-二苯基-4-哌啶甲醇反应、碱性水解制得抗组胺药非索非那定,总收率约48%.     

替比培南匹伏酯侧链的合成

目的:合成替比培南匹伏酯侧链1-(4,5-二氢-2-噻唑啉基)-3-巯基吖丁啶盐酸盐。方法:以2-甲硫基-2-噻唑啉为原料,经与3-羟基吖丁啶盐酸盐,甲烷磺酰氯,硫代乙酸钾以及水解4步反应合成1-(4,5-二氢-2-噻唑啉基)-3-巯基吖丁啶盐酸盐。结果:合成了1-(4,5-二氢-2-噻唑啉基)-3-巯基吖丁啶盐酸盐,总收率42%。结论:本方法可以方便地得到替比培南匹伏酯侧链1-(4,5-二氢-2-噻唑啉基)-3-巯基吖丁啶盐酸盐,提高了反应收率,简化了操作,降低了成本。     

千金藤素对非索非那定肠吸收的影响

目的 研究千金藤素对非索非那定大鼠肠吸收的影响.方法 采用大鼠肠外翻模型,以维拉帕米为阳性对照,研究千金藤素对非索非那定肠吸收的影响,并用反相高效液相色谱法测定大鼠肠黏膜内外两测的非索非那定浓度.结果 非索非那定在大鼠十二指肠有吸收,千金藤素能增加非索非那定的吸收.结论 千金藤素能增加非索非那定吸收,机制可能是抑制了P...     

非索那定的合成

目的:合成非索那定.方法:以苯乙酸乙酯为起始原料,经甲基化、F-C酰化、N-烷基化、还原和水解等反应制得非镇静抗组胺药 (NSA) 非索那定.结果:N-烷基化反应中改用乙腈为溶剂,提高了溶解性,加快了反应速度,提高了产物的纯度与收率;羰基还原反应由催化加氢改为硼氢化钠还原,方便了操作,便于今后的大批量制备.结论:该方法原料易得、操作简便,总收率40.7%.     

N-取代-5-羟基-1H吲哚-3-羧酸酯类衍生物的合成

目的:以阿比朵尔为先导化合物,设计并合成一系列4-取代胺甲基-5-羟基-1-烃基-2-苯硫基甲基-1H吲哚-3-羧酸乙酯盐酸盐.方法:以4-氯代乙酰乙酸乙酯为起始原料通过硫代、胺化、Nenitzescu反应、Mannich反应、成盐反应共5步反应制得目标产物.由薄层色谱(TLC)确定每步反应终点.结果:目标化合物结构经红外光谱、核磁共振光谱及质谱确证.结论:通过该合成方法合成了9个未见报道的新化合物.     

Discriminated taste aversion with chlordiazepoxide.

Discriminative stimulus effects have been studied extensively with the two-response, food-reinforced operant procedure and more recently also with discriminated taste aversion (DTA) procedures. DTA procedures have the advantage of a more rapid discrimination training. However, the test phase, i.e., drug substitution, of the DTA procedure is more time consuming (1 test per 4 days) than the test phase of the two-response procedure (2 tests per 5 days). The present study investigated whether a DTA procedure with 2 tests per 5 days could be implemented. In addition, the specificity of the DTA procedure was investigated. Rats were trained to discriminate chlordiazepoxide (CDP, 20 mg/kg, IP) from vehicle using a discriminated taste aversion procedure. Selective suppression of saccharin consumption after CDP injections was maximal after seven CDP-LiCl pairings. In subsequent substitution tests, with 2 tests per 5 days, CDP-mimicking effects were found only for another benzodiazepine, diazepam, and for a barbiturate, pentobarbital. The results indicate that rats can be rapidly trained to discriminate CDP from vehicle in the discriminated taste aversion procedure and that the CDP-cue so produced has the same specificity as in a two-response, food-reinforced operant procedure. However, the DTA procedure has a number of drawbacks that make its advantage over the two-response procedure questionable.     

(+)-氯吡格雷的合成工艺改进

目的改进抗血栓药物氯吡格雷硫酸氢盐的合成工艺。方法以(±)-邻氯苯甘氨酸为原料,经拆分、酯化,得到( )-邻氯苯甘氨酸甲酯,再与2-(2-噻吩基)乙醇对甲苯磺酸酯经SN2取代,生成α-2-噻吩乙氨基-2-氯苯基乙酸甲酯,后者在甲醛存在下环合制得( )-氯吡格雷游离碱,最后与硫酸成盐,经重结晶得目标产物氯吡格雷硫酸氢盐。结果与结论以26.9%的收率合成了目标产物,较大幅度地降低了生产成本,优化了反应条件,简化了后处理过程,适合于工业化生产。     

5-氯吲哚酮的合成

目的 优化5--氯吲哚酮合成工艺，提高其收率。方法 以对氯苯胺为起始原料，与水合氯醛及盐酸羟胺反应生成对氯异亚硝基乙酰苯胺，然后在浓硫酸作用下经环合、水解得到5—氯靛红，再经Wolff—Kishner—黄鸣龙反应得到5—氯吲哚酮。结果与结论 总收率可达71％。本法具有原料价廉易得，反应条件温和，操作简便，收率高等优点。     

2-氰基嘧啶的合成工艺改进

以氯化三甲基嘧啶-2-铵为原料，在氯化铵存在下与氰化钾经亲核取代反应合成波生坦的关键中间体——2-氰基嘧啶，并对其工艺进行改进。改进后的工艺操作简单，反应条件温和，收率高于文献报道水平。     

(+)-氯吡格雷硫酸氢盐的合成研究

目的改进抗血栓药物氯吡格雷硫酸氢盐的合成工艺。方法以邻氯苯乙腈为原料,经溴代、缩合、水解、酯化、拆分,最后与硫酸成盐,经重结晶得目标产物氯吡格雷硫酸氢盐。结果与结论以16%的收率合成了目标产物,较大幅度地降低了生产成本,优化了反应条件,简化了后处理过程,适合于工业化生产。     

The estimation of parameters from bulked samples.

An estimation procedure has been developed for the estimation of parameters from bulked sample using the parametric bootstrap and density estimation in conjunction with the one-step maximum-likelihood estimator. It is shown that the proposed estimation procedure provides an asymptotically efficient estimator for parameters of interest when the density for the mean of the bulked samples has a certain form. The lognormal density (with sigma 2 assumed known) is an important distribution with the proper form. The finite sample performance for bulked samples based on underlying lognormal observations was examined by Monte Carlo study. The results indicate that the proposed procedure leads to a reduction in mean squared error compared to known procedures.     

Metallation of heteroaryls and its application to isotopic labelling

The recently published procedure for the metallation of heteroaromatics and their subsequent reaction with iodine has been applied to the synthesis of deuterium‐labelled compounds. The mixed magnesium/lithium base (2) has been prepared and reacted with a range of heteroaromatics. The metallated compounds were iodolyzed with molecular iodine and the resulting iodo compounds were reductively dehalogenated with deuterium gas. This allowed confirmation of the regiochemistry of the metallation and the use of the procedure as a labelling method. Copyright © 2009 John Wiley & Sons, Ltd.     

Urinary excretion of xanthurenic acid and zinc in diabetes: 1) Separation of xanthurenic acid-Zn2+ complex by ion-exchange chromatography

In view of the relevance of urinary xanthurenic acid (XA) and zinc in diabetes, a chromatographic procedure has been devised which allows separation of XA from its complex with Zn2+. The procedure involves chromatography on DEAE-Sepharose CL-6B at pH 7.2 with a stepwise Tris-HCl concentration gradient. The ultraviolet absorption difference spectra due to formation of the XA-Zn2+ complex allowed the estimate of the binding molar ratio in the XA-Zn2+ complex. This corresponds to a 1:1 as estimated on the basis of the Hill plot of the experimental data.     

Spectrophotometric determination of fenoterol hydrobromide in pure form and dosage forms

A sensitive and rapid spectrophotometric procedure has been investigated for the determination of fenoterol either per se or in pharmaceutical preparations. The proposed procedure is based on the reaction between the drug and 4-chloro-7-nitrobenzo-2-oxa-1,3-diazole (NBD-Cl) at pH 7.2, using borate buffer, to produce a yellow adduct. The latter has maximum absorbance at 400 nm and obeys Beer's law within the concentration range 5-30 microg/ml. Regression analysis of the calibration data showed a good correlation coefficient (r=0.9996) with minimum detection limit of 0.24 microg/ml (6.2 x 10(-8) M). The proposed procedure has been successfully applied to the determination of this drug in its tablets and in syrup, the mean percent recoveries were 97.45+/-0.59 and 98.7+/-0.64%, respectively. The results obtained are in good agreement with those given using a reference method. The pharmaceutical additives other than active ingredient did not interfere. A proposal of the reaction pathway has been postulated.     

Determination of verapamil and norverapamil in human plasma by liquid chromatography: Comparison between a liquid—liquid extraction procedure and an automated liquid—solid extraction method for sample preparation

A conventional liquid-liquid extraction (LLE) procedure with high-performance liquid chromatography (HPLC) has been developed for the determination of verapamil and its main metabolite, norverapamil, in plasma. After addition of the internal standard, plasma samples were basified with phosphate buffer (pH 9.0) and extracted with a mixture of cyclohexane-dichloromethane. After centrifugation, the organic layer was separated and the analytes were extracted back into a 0.1 N sulphuric acid solution containing 2-aminoheptane. An aliquot of this aqueous phase was then injected directly onto the HPLC column. This LLE procedure has been compared with an automated liquid-solid extraction (LSE) method that has been developed in parallel. Good linearity was obtained using both extraction methods. The absolute recoveries for the two analytes were ca 95% with the automated LSE procedure and slightly lower (ca 84%) for the LLE method. The automated method gives better results with respect to detectability and precision, but the LLE procedure is simpler to develop, requires much less expensive equipment, and remains a useful alternative when the number of samples to be analysed is limited.