Asymmetric synthesis of 4-deoxyverrucarol via two types of ring expansion reactions

Asymmetric synthesis of a trichothecane analogue, 4-deoxyverrucarol (2), was carried out through two types of ring expansion reactions. First, synthesis of the racemate of 2 was investigated. Thus, 1-[1-(tert-butyldimethylsiloxy)-ethyl]-1-methoxycarbonyl-2-hexen-4-on e (10), prepared by Diels-Alder reaction, was converted into the cyclopropylidene 15. The cyclobutanone (+/-)-18 was obtained from 15 via dihydroxylation, followed by successive treatments with SO(2)Cl(2) in the presence of imidazole and Florisil. After transformation of (+/-)-18 into the vinylcyclobutanol (+/-)-19, the second ring expansion reaction was performed with Pd(OAc)(2) to provide the cyclopentanone (+/-)-20. The product was converted into the racemate of 4-deoxyverrucarol (2) through the cyclohexenone (+/-)-22, but the diastereoselectivity during the introduction of the double bond was unsatisfactory. The selectivity was improved in the case of the asymmetric synthesis. The optically active cyclobutanone (+)-18 was prepared via AD reaction of 15 with 73% ee. After the transformation of (+)-18 into the cyclohexanone (-)-30 through the palladium-mediated ring expansion reaction, (-)-30 was subjected to the diastereoselective deprotonation reaction using the chiral amide. The key synthetic intermediate (-)-25 of 4-deoxyverrucarol (2) was synthesized in an optically pure form by taking advantage of a kind of kinetic resolution that occurred during the deprotonation step.     

Mechanism of antioxidative activity of fluvastatin-determination of the active position

In order to clarify the mechanism of action for the antioxidative activity of fluvastatin sodium (FLV, (+/-)-sodium (3RS, 5RS, 6E)-7-[3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indol-2-yl]-3, 5-dihydroxy-6-heptanoate) and its derivatives, reaction of the corresponding methyl ester of FLV with di-tert-butyl diperoxyoxalate was examined, and the corresponding keto derivative was isolated from the reaction mixture. On the basis of this result, it was concluded that the active site is the allylic carbon conjugated with the indole ring.     

Isolation of highly pure erlotinib hydrochloride by recrystallization after nucleophilic substitution of an impurity with piperazine

Optimized synthesis and purification of erlotinib hydrochloride (N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazoline-4-amine hydrochloride) were studied. Highly polar piperazine was used in a nucleophilic substitution reaction with the chlorinated intermediate byproduct N-(3-ethynylphenyl)-6(2-chloroethoxy)-7-(2-methoxyethoxy)quinazolin-4-amine hydrochloride. As a result, N-(3-ethynylphenyl)-6(2-chloroethoxy)-7-(2-methoxyethoxy)quinazolin-4-amine hydrochloride was completely transformed to N-(3-ethynylphenyl)-6(2-piperzinoethoxy)-7-(2-methoxyethoxy)quinazolin-4-amine hydrochloride. The polarity of N-(3-ethynylphenyl)-6(2-piperzinoethoxy)-7-(2-methoxyethoxy)quinazolin-4-amine hydrochloride was changed, and its molecule was enlarged. It was easy to remove this larger, more polar, compound by recrystallization. Highly pure erlotinib hydrochloride was obtained with low impurity content (<1 %). The purity of erlotinib hydrochloride was >99.9 %.     

丁酸氯维地平降解杂质的合成

以4-(2,3-二氯苯基)-1,4-二氢-2,6-二甲基-3,5-吡啶二羧酸(2-氰基乙基)（甲基）酯(5)为起始原料,合成了丁酸氯维地平的5种降解杂质：4-(2,3-二氯苯基)-1,4-二氢-2,6-二甲基-3,5-吡啶二羧酸单甲酯(A), 4-(2,3-二氯苯基)-1,4-二氢-2,6-二甲基-3-吡啶羧酸甲酯(B), 4-(2,3-二氯苯基)-2,6-二甲基-3,5-吡啶二羧酸单甲酯(C), 4-(2,3-二氯苯基)-2,6-二甲基-3,5-吡啶二羧酸（丁酰氧基甲基）（甲基）酯(D)和4-(2,3-二氯苯基)-2,6-二甲基-3-吡啶羧酸甲酯(E)。其中A由5水解制得;B由A脱羧制得;C由5氧化后再经水解制得;D由C和丁酸氯甲酯缩合制得;E由C脱羧制得,化合物结构经¹H NMR和MS（ESI）确证。     

一种新的质子泵抑制剂苯并咪唑衍生物的合成与表征

以2-巯基苯并咪唑为原料,在碱性条件下与自制的盐酸2-氯甲基-4-(3-甲氧基丙氧基)-3-甲基吡啶缩合得2-{[4-(3-甲氧基丙氧基)-3-甲基吡啶-2-基]甲基硫}-1H-苯并咪唑,再经氧化、成盐反应生成产物2-{[4-(3-甲氧基丙氧基)-3-甲基吡啶-2-基]甲基亚硫酰基}-1H-苯并咪唑钠,总收率66%.此产物通过红外光谱、核磁共振、质谱表征加以确认.     

离子色谱法测定火场爆炸残留物中7种阴离子

建立了离子色谱法测定爆炸残留物中F,Cl,NO_2,SO_4,Br,NO_3,PO_47种阴离子的方法。采用抑制电导检测器,以DIONEX Ion Pac~?AS11–HC型阴离子交换柱为分离柱,柱箱温度为40℃,以22 mmol/L KOH溶液为淋洗液,流量为1.20 m L/min。F~–,Cl~–,NO_2~–,SO_4~(2–),Br~–,NO_3~–,PO_4~(3–)在各自范围内均呈良好的线性关系,相关系数均大于0.999,检出限在0.06~0.15 mg/L之间,加标回收率为92.5%~101.3%,测定结果的相对标准偏差为1.86%~2.79%(n=7)。该方法简便、快捷,选择性好,灵敏度高,可满足分析要求。     

Chemical composition and in vitro antimicrobial activity of the essential oil of the flowers of Tridax procumbens

The essential oil of the flowers of Tridax procumbens L. was obtained by hydro-distillation and analyzed by gas chromatography equipped with a flame ionization detector (GC-FID) and gas chromatography coupled with mass spectrometry (GC/MS). Twenty-six compounds were identified, which comprised 90.6% of the total constituents. The most abundant compound was (Z)-falcarinol (25.9%), followed by alpha-selinene (15.3%), limonene (8.3%) and zerumbone (4.3%). Antimicrobial activity was tested against six Gram-positive and eight Gram-negative bacteria, and three fungi. The oil was active against the tested Gram-positive bacteria at a concentration range of 0.14 +/- 0.03 - 0.57 +/- 0.05 mg/mL, while 0.67 +/- 0.12 - 4.58 +/- 0.41 mg/mL was effective against the studied Gram-negative bacteria. Remarkable antifungal activity was found against the tested fungi at a concentration range of 0.06 +/- 0.008 - 0.10 +/- 0.01 mg/mL.     

一个取代的1,5-苯并二氮杂的晶体结构及构象研究

用X射线衍射方法测定了4-苯甲酰基-3-(邻氯苯基)-1-乙酸乙酯基-1a-苯基-1,1a,2,3-四氢化-4H-环丙胺-[1,2-a][1,5」-苯并二氯化合物的晶体结构,晶体结构测定结果表明分子核心骨架二氮杂为类船式构象.用动力学模拟退火(Simulated Annealing)方法对分子进行了构象分析,结果表明分子中的二氮杂七元环具有三种较稳定的构象,其中以船式构象为最稳定,并存在着明显的芳环堆积作用.分子中七元环同时并接苯环和三元环,且环中的N(2)—C(12)—C(11)—N(1)有π键成分,大大限制了七元环构象的相互转换.     

1,4,5,8-四甲氧基萘-2-甲醛的合成工艺研究

紫草素（shikonin）为中药紫草中的有效成分，具有多种生物学活性，如抗菌、抗炎、抗病毒、抗肿瘤、抗生育、抗甲状腺亢进、抗免疫低下、降血糖、保肝扩肝等多种作用，引起人们对其合成的重视，有许多紫草素的全合成研究报道。多数以1，4，5，8-四甲氧基萘-2-甲醛（1）为起始原料，但收率均不高。     

Development and validation of a capillary electrophoresis assay for the determination of the stereoisomeric purity of chloroquine enantiomers

A stereoselective CE assay for the determination of the enantiomeric purity of (R)-(-)-chloroquine and (S)-(+)-chloroquine was developed and validated. The separations were performed in a 50.2/40 cm uncoated fused silica capillary at 20°C using a 100 mM sodium phosphate buffer, pH 2.5, containing 30 mg/mL sulfobutylether(VII)-β-cyclodextrin as background electrolyte operated at an applied voltage of -25 kV and 20°C. The detection wavelength was 225 nm. Carbamazepine was used as internal standard. The assay was validated in the range of 0.05-1.0% for the respective minor chloroquine enantiomer based on a concentration of 3 mg/mL of the major enantiomer, either (R)-(-)-chloroquine or (S)-(+)-chloroquine. The method was applied to analyze the stereoisomeric purity of synthetic samples of the chloroquine enantiomers.     

氘代AZD9291的合成

吲哚和2,4-二氯嘧啶经偶联反应制得3-(2-氯嘧啶-4-基)-1H-吲哚(1); 1与CD₃I 经取代反应制得3-(2-氯嘧啶-4-基)-1-(甲基-d₃)-吲哚(2); 2经两步亲核取代反应制得N′-(2-二甲基氨基乙基)-2-甲氧基-N′-甲基-N-{［4-(1-(甲基-d₃)吲哚-3-基)］嘧啶-2-基}-5-硝基苯-1,4-二胺(4); 4经还原反应后,与氯丙酰氯发生缩合反应合成了氘代AZD9291,总收率8.5%,其结构经¹H NMR, ¹³C NMR和ESI-MS表征。     

含氧阴离子的离子色谱法研究

 在含有阴、阳离子双官能团的色谱柱上 ,用两种浓度的Na2 HPO4洗脱液分别同时分离了 5种和 7种含氧阴离子 ,并且实现了元素不同价态的分析。 7.5mmol/LNa2 HPO4( pH 9.3)适于同时分离SeO32 - ,HAsO42 - ,SeO42 - ,WO42 - ,MoO42 - ,GeO32 - 和CrO42 - ;0 .75mmol/LNa2 HPO4(pH 9.3)适于同时分离IO3- ,H2 AsO3- ,BrO3- ,NO2 - 和NO3- ;检测波长为 2 0 4nm。另外 ,选择其它 4种阴离子色谱柱进行比较 ,对分离机理进行了初步的研究。     

从中药繁缕中几个黄酮碳苷成分的分离和分析看LC-MS-MS技术的优势与不足

繁缕[Stellariamedia(L.)Cyr.]为石竹科植物繁缕的茎、叶,具有活血、去瘀、下乳、催生作用,主要含皂苷、黄酮、酚酸、氨基酸等成分。贵州民间作为降血脂药物应用,效果很好。文献调研表明,其活性成分可能为黄酮苷类化合物。我们采用大孔吸附树脂技术,得到了其主要活性部位,并采用液相色谱-质谱技术,初步分析了其中的主要成分。它们主要是黄酮碳苷类化合物,其中3个成分的相对分子质量均为594,分别以不同方式与两个六碳糖相连接;另外3个成分的相对分子质量为564,分别也以不同方式与1个六碳糖和1个五碳糖相连接。本文报道对相对分子质量为594的主要成分的分离和LC-MS-MS分析,结果显示了该技术在中药分离和分析中的巨大优势,同时也显露出它在分析异构体时的局限性。我们采用1D-HOHAHA技术分析出了该成分两个异构体的结构特征。     

The synthesis of peptides containing purine and pyrimidine derivatives of DL-alanine

The incorporation of the “base-bearing amino acids”, DL - β - (uracil - 1 - yl)alanine 1 (Uala), DL - β - (thymin - 1 - yl)alanine 2 (Tala), DL - β - (cytosin - 1 - yl)alanine 3 (Cala) and DL - β - (adenin - 9 - yl 4 (Aala) into peptides has been studied. The carboxyl group of each of these compounds was protected by the formation of the ethyl ester. The t - butoxycarbonyl (t-BOC) group was suitable for the protection of the α-amino group of 1 but not that of 2, 3 and 4 because of the formation of ring substituted compounds. Peptides containing the amino acids 1–4 and L-serine were synthesised, however, by the mixed anhydride method; uracil, thymine and adenine residues needed no protection, neither did the cytosine residue provided that it was not present in the intermediate which was treated with ethyl chloroformate to produce the mixed anhydride. In this case reaction with the cytosine residue occurred. By these procedures, four protected dipeptides, namely α - N - t - BOC - L - seryl derivatives of 1–4 and three protected tetrapeptides, namely α - N - t - BOC - L - seryl - DL - β - (thymin - 1 - yl)alanyl - L - ethyl ester (t - BOC - Ser - Tala - Ser - Tala - OEt), t - BOC - Ser - Aala - Ser - Aala - OEt and t - BOC - Ser - Uala - Ser - Uala - OEt were obtained. For the protection of the α-amino group of 2 or 3 the formyl group was found to be satisfactory.     

新型P,N配体及基1,4-共轭加成反应

以2-萘酚为起始原料,经过氧化偶联,消旋体的拆分得到手性骨架2-氨基-2'-羟基-1,1'-联萘(NOBIN),并以S-NOBIN为原料,经过六步反应合成了两个新型配体S-(+)-2-(2-吡啶酰胺基)-2'-二苯基膦基-1,1'-联萘(1a)和S-(+)-2-(6-甲基-2-吡啶酰胺基)-2'-二苯基膦基-1,1'-联萘(1b)。并进行了铜配合物催化的二乙基锌对2-环己烯酮的1,4-共轭加成反应的研究。反应产物3-乙基环己酮(13)的e.e.值高达92%。     

Kinetics and mechanism of the oxidation of amaranth with hypochlorite

The reaction mechanism of the oxidation of Amaranth dye (2-hydroxy-1-(4-sulfonato-1-naphthylazo) naphthalene-3,6-disulfonate) with hypochlorite under varied pH conditions was elucidated by a kinetic approach. Under excess concentration of oxidant, the reaction followed pseudo-first-order kinetics with respect to Amaranth, and the oxidation was found to occur through two competitive reactions, initiated by hypochlorite and hypochlorous acid. The reaction order with respect to both OCl(-) ion and HOCl was unity. While the latter reaction was fast, the significance of the oxidation paths depended on the relative concentration of the two oxidizing species, which was dictated by the reaction pH. The role of the H(+) ion in the reaction was established. For the hypochlorite ion and hypochlorous acid facilitated reactions, the second-order rate coefficients were 1.9 and 23.2 M(-1) s(-1), respectively. The energy parameters were E(a) = 33.7 kJ mol(-1), ΔH(?) = 31.2 kJ mol(-1) and ΔS(?) = -190.6 J K(-1) mol(-1) for the OCl(-) ion-driven oxidation, and E(a) = 26.9 kJ mol(-1), ΔH(?) = 24.3 kJ mol(-1) and ΔS(?) = -222.8 J K(-1) mol(-1) for the reaction with HOCl-initiated oxidation. The major oxidation products for both the pathways were 3,4-dihydroxy naphthalene-2,7-disulfonic sodium salt (P(1)), dichloro-1,4-naphthoquione (P(2)) and naphtha(2,3)oxirene-2, 3-dione (P(3)). On the basis of the primary salt effect and other kinetic data, the rate law for the overall reaction and probable reaction mechanism was elucidated. The proposed mechanism was validated by simulations using Simkine-2.     

阴极铜化学标准样品的研制

经成分设计、原料选取、熔铸加工、均匀性检验等研制了阴极铜化学标准样品。以高纯铜为主原料,加入Si,Zn,S,Se等18种杂质元素制备而成,各定值元素含量呈梯度上升分布。经检验该标准样品成分均匀,稳定性好,18种杂质元素的定值结果分别为Se 0.000 02%~0.000 87%,Te 0.000 03%~0.001 1%,Bi 0.000 02%~0.001 2%,Cr 0.000 02%~0.003 2%,Mn 0.000 03%~0.002 7%,Sb 0.000 02%~0.003 1%,Cd 0.000 01%~0.003 0%,As0.000 01%~0.003 8%,P 0.000 05%~0.005 6%,Pb 0.000 03%~0.004 4%,S 0.000 15%~0.008 2%,Sn 0.000 01%~0.002 6%,Ni0.000 09%~0.006 0%,Fe 0.000 16%~0.005 4%,Si 0.000 15%~0.003 4%,Zn 0.000 04%~0.005 2%,Co 0.000 01%~0.003 5%,Ag 0.000 07%~0.007 2之间。定值结果的扩展不确定度为0.000 01%~0.000 3%(k=2)。研制的阴极铜化学标准样品已被批准为国家级标准样品,标准编号为GSB 04–2554–2010。该标准样品成分设计合理、涵盖范围广,可用于阴极铜及部分铜合金的分析检测。     

盐酸奈法唑酮的合成

盐酸奈法唑酮是一类新型抗抑郁药.先用间氯苯胺与二乙醇胺环化合成1-(3-氯苯基)哌嗪,再与1-溴-3-氯丙烷反应制得1-(3-氯丙基)-4-(3-氯苯基)哌嗪盐酸盐,最后与5-乙基-4-(2-苯氧乙基)-1,2,4-三唑-3-酮反应得到盐酸奈法唑酮.产物结构经IR,MS,1H NMR及13C NMR确证.     

2 - 芳基 -4- 苯基 -2, 3- 二氢 -1, 5- 苯并二氮杂卓与重氮乙酸乙酯反应机 理和 立体化学的研究

2-芳基-4-苯基-2,3-二氢-1,5-苯并二氮杂卓与重氮乙酸乙酯在铜粉催化下反应,得到环加成产物吖丙啶并苯并二氮杂卓I外,还得到一个非预期的五员环产物吡咯并苯并二氮杂卓II。改变反应条件可以使化合物II的收率达到50%。通过研究反应过程中分离出的副产物反丁烯酸二乙酯III和4,5-二氢吡唑-3,4,5-三羧酸乙酯IV,初步提出了反应经过乙氧羰基甲基化苯并二氮杂卓翁中间体V再发生环加成反应的机制。通过X-射线单晶衍射分析和NMR分析研究了它们的立体化学,发现为立体专一性反应。     

Dorsomorphin的合成

以2-氯甲基吡啶盐酸盐为原料,经氰基化、缩合和环合反应制得4-（4-吡啶基）-1H-吡唑-5-胺（5）; 5与2-（4-甲氧基苯基）丙二醛经缩合反应制得化合物6-（4-甲氧基苯基）-3-（4-吡啶基)吡唑并［1,5-a］嘧啶（9）; 9经脱甲基和成醚反应合成了骨形态生成蛋白受体及腺苷酸活化蛋白激酶抑制剂Dorsomorphin,总收率24%,其结构经¹H NMR和MS(ESI)确证。