4-甲基-2-正丙基-6-甲氧羰基苯并咪唑的合成

目的：合成抗高血压药替米沙坦的重要中间体4-甲基-2-正丙基-6-甲氧羰基苯并咪唑.方法：以3-甲基-4-氨基苯甲酸甲酯为原料,经酰化、硝化、还原、环合4步反应制得目标化合物.结果：文献报道的相应各步反应条件得以优化,产率由39.6%提高到62.54%.结论：本方法简化了操作步骤,优化了反应条件,降低了成本,提高了收率.     

4-[[1-[(4-氟苯基)甲基]-1H-2-苯并咪唑基]氨基]-1-哌啶甲酸乙酯的合成

以邻苯二胺为起始原料，经过缩合、氯代、烷基化和取代反应来合成4-[[1-[（4-氟苯基）甲基]-1H-2-苯并咪唑基]氨基]-1-哌啶甲酸乙酯。该合成方法操作简单，总收率达到30．7％。     

2-(4-甲氧基苯基)苯并咪唑的合成方法的研究

目的本文对2-(4-甲氧基苯基)苯并咪唑的合成方法进行了研究,并探索了其合成的最优工艺条件.方法本课题以邻苯二胺和对甲氧基苯甲醛为原料,在甲醇为溶剂,磷酸为催化剂的酸性条件下,一步反应制得2-(4-甲氧基苯基)苯并咪唑.结果考察了催化剂、催化剂的量、反应物料摩尔比、溶剂四个因素对反应产率的影响.反应产物烘干后,通过测熔点,红外光谱进行分析.结论通过对实验数据的处理得出了最优化工艺合成条件:以磷酸作催化剂,甲醇为溶剂物料摩尔比为N(邻苯二胺):N(对甲氧基苯甲醛):N(磷酸)为1:1.2:3.8,的条件下,2-(4-甲氧基苯基)苯并咪唑收率可以达到75%以上。     

α,ω-双(2-苯并咪唑)二硫化合物合成工艺的优化

目的 优化α,ω-双(2-苯并咪唑)二硫化合物的合成条件.方法 以邻苯二胺、二硫化碳为原料,加入四丁基溴化铵作催化剂,在氢氧化钠的碱性条件和氮气保护下经缩合反应和加热闭环生成2-苯并咪唑硫醇钠;然后经氯化制得α,ω双(2-苯并咪唑)二硫化合物.结果 经波谱确证为目标物,总收率90%以上.结论 该工艺原料易得,条件温和,...     

4-氟-5-羟基-2-甲基吲哚的合成

2,3,4-三氟硝基苯在NaH作用下与乙酰乙酸乙酯进行芳环亲核取代,然后在酸性条件下水解脱羧制得1-(2,3-二氟-6-硝基苯基)丙-2-酮,再经羟基化、甲酸铵/钯炭还原闭环制得4-氟-5-羟基-2-甲基吲哚,总收率约38％.     

4-氟-3-甲基吡啶-2-甲酸甲酯的合成

3-甲基吡啶-2-甲酸甲酯(2)经氧化、硝化和还原反应制得4-氨基-3-甲基吡啶-2-甲酸甲酯(5),然后经改进的Balz-Schiemann反应制得4-氟-3-甲基吡啶-2-甲酸甲酯(1),以2计总收率约18%。     

4-甲基-香豆素及4-甲基喹啉-2(1H)-酮的7位羟基、巯基与炔丙基卤代物的不同反应性

目的合成具有抗HIV活性的三环杂环化合物的关键中间体.方法 7-羟基-4-甲基-香豆素、7-羟基-4-甲基喹啉-2(1H)-酮、7-巯基-4-甲基-香豆素分别与3-氯-3-甲基-1-丁炔、3-溴丙炔反应得到相应产物,其结构经波谱确证.结果 4-甲基-香豆素的7位羟基发生正常的双分子亲核取代反应(SN2),得到炔丙基醚产物4、7和10,进一步热环合得到三环杂环化合物5、8和11;7-巯基-4-甲基-香豆素、7-巯基-4-甲基喹啉-2(1H)-酮与3-氯-3-甲基-1-丁炔反应分别得丙二烯醚双分子亲核取代反应(SN2′)产物聚集双键硫醚化合物12和14,且不能进一步热环合成三环杂环.结论 4-甲基-香豆素及4-甲基喹啉-2(1H)-酮的7位羟基、巯基与炔丙基卤代物表现出不同的反应性.     

2-巯基-5-甲氧基苯并咪唑合成工艺的研究

目的改进2-巯基-5-甲氧基苯并咪唑的合成工艺。方法以对氨基苯甲醚为起始原料,采用醋酸硝酰作硝化剂进行硝化;采用雷尼镍催化加氢法进行还原。结果制得了奥美拉唑中间体2-巯基-5-甲氧基苯并咪唑,总收率78.5%。结论值得推广到工业化生产。     

2-巯基-5-甲氧基苯并咪唑合成工艺的研究

目的改进2-巯基-5-甲氧基苯并咪唑的合成工艺。方法以对氨基苯甲醚为起始原料,采用醋酸硝酰作硝化剂进行硝化;采用雷尼镍催化加氢法进行还原。结果制得了奥美拉唑中间体2-巯基-5-甲氧基苯并咪唑,总收率78.5%。结论值得推广到工业化生产。     

5-三氟甲基-3-(4-甲基-1H-咪唑-1-基)苯胺的合成

3,5-二硝基三氟甲苯(2)与氟化四甲铵进行氟代反应,所得单氟中间体再与4-甲基-1H-咪唑进行取代反应得到5-三氟甲基-3-(4-甲基-1H-咪唑-1-基)-硝基苯(3),然后在Pd/C催化下氢化还原制得抗肿瘤药尼罗替尼的中间体5-三氟甲基-3-(4-甲基-1H-眯唑-1-基)-苯胺(1),总收率约50％(以2计).     

Contribution of CYP2C9, CYP2A6, and CYP2B6 to valproic acid metabolism in hepatic microsomes from individuals with the CYP2C9*1/*1 genotype.

The present study investigated the role of specific human cytochrome P450 (CYP) enzymes in the in vitro metabolism of valproic acid (VPA) by a complementary approach that used individual cDNA-expressed CYP enzymes, chemical inhibitors of specific CYP enzymes, CYP-specific inhibitory monoclonal antibodies (MAbs), individual human hepatic microsomes, and correlational analysis. cDNA-expressed CYP2C9*1, CYP2A6, and CYP2B6 were the most active catalysts of 4-ene-VPA, 4-OH-VPA, and 5-OH-VPA formation. The extent of 4-OH-VPA and 5-OH-VPA formation by CYP1A1, CYP1A2, CYP1B1, CYP2C8, CYP2C19, CYP2D6, CYP2E1, CYP4A11, CYP4F2, CYP4F3A, and CYP4F3B was only 1-8% of the levels by CYP2C9*1. CYP2A6 was the most active in catalyzing VPA 3-hydroxylation, whereas CYP1A1, CYP2B6, CYP4F2, and CYP4F3B were less active. Correlational analyses of VPA metabolism with CYP enzyme-selective activities suggested a potential role for hepatic microsomal CYP2A6 and CYP2C9. Chemical inhibition experiments with coumarin (CYP2A6 inhibitor), triethylenethiophosphoramide (CYP2B6 inhibitor), and sulfaphenazole (CYP2C9 inhibitor) and immunoinhibition experiments (including combinatorial analysis) with MAb-2A6, MAb-2B6, and MAb-2C9 indicated that the CYP2C9 inhibitors reduced the formation of 4-ene-VPA, 4-OH-VPA, and 5-OH-VPA by 75-80% in a panel of hepatic microsomes from donors with the CYP2C9*1/*1 genotype, whereas the CYP2A6 and CYP2B6 inhibitors had a small effect. Only the CYP2A6 inhibitors reduced VPA 3-hydroxylation (by approximately 50%). The extent of inhibition correlated with the catalytic capacity of these enzymes in each microsome sample. Overall, our novel findings indicate that in human hepatic microsomes, CYP2C9*1 is the predominant catalyst in the formation of 4-ene-VPA, 4-OH-VPA, and 5-OH-VPA, whereas CYP2A6 contributes partially to 3-OH-VPA formation.     

2-甲基-4-(2,6,6-三甲基-1-环己烯-1-基)-2-丁烯醛的合成

2,6,6-三甲基-1-环己烯-1-甲醛与(3-甲氧基-2-甲基烯丙基)膦酸二乙酯经Wittig-Homer缩合制得1-甲氧基-2-甲基-4-(2,6,6-三甲基-1-环己烯-1-基)-1,3-丁二烯,然后经酸催化水解得到维生素A的关键中间体2-甲基-4-(2,6,6-三甲基-1-环己烯-1-基)-2-丁烯醛,总收率约47%.     

1-氯-2-甲基-4-乙酰氧基-2-丁烯的制备

异戊二烯与三氯异氰脲酸和水进行氯醇化反应,得1-氯-2-甲基-3-丁烯-2-醇和4-氯-3-甲基-2-丁烯醇,该混合物在对甲苯磺酸催化下与乙酐反应,得1-氯-2-甲基-4-乙酰氧基-2-丁烯,总收率约为61%,纯度93.5%。     

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。     

软珊瑚共附生真菌Schizophyllum sp. CGF9-1-2次生代谢产物研究

目的 首次对软珊瑚来源共附生裂褶菌属真菌Schizophyllum sp. CGF9-1-2次生代谢产物的化学成分进行研究,以期获得结构新颖、生理活性好的次生代谢产物。方法 以PDA及真4培养基发酵软珊瑚共附生真菌Schizophyllum CGF9-1-2;采用硅胶、凝胶、ODS等柱层析、高效液相色谱法（HPLC）等方法对其菌丝体的乙酸乙酯部位进行分离纯化;采用核磁共振（NMR）、（高分辨）质谱（（HR）MS）和旋光（ORD）等现代波谱解析手段,并与文献数据对照方法确定化合物结构。结果 从其乙酸乙酯部位共分离鉴定10个化合物,依次为7, 8-二甲基四氧嘧啶（1）、杂色曲霉素（2）、Arugosin C（3）、酒酵母甾醇（4）、（22e,24r）-3β, 5α, 9α-三乙烯基麦角甾-7, 22-二乙烯-6酮（5）、1-亚油酸甘油酯（6）、10-十七烯酸甲酯（7）,2-辛烷烯酸甲酯（8）、十八烷酸（9）和十四烷酸（10）。结论 首次从裂褶菌属真菌CGF9-1-2中分离鉴定10个化合物,结构类型涉及吡嗪类、芳香酚酸类和长链脂肪酸及酯类。丰富了宿主软珊瑚中海洋微生物的种类,确定其次生代谢产物的多样性,为进一步药理活性实验奠定了基础。     

2-〔4(s)-4-酚胺基-3-氧代-2-异噁唑烷基〕-5-氧代-2-四氢呋喃甲酸钠类化合物的合成

以L-丝氨酸和α-酮戊二酸为原料,采用三条合成路线,经6～8步反应,合成8个目标化合物。其部份中间体的结构经IR,PMR,MS及元素分析证实。产物的结构也经IR及PMR证实。体外抑菌试验表明,TM7和TM8显示较强的广谱抑菌活性,TM6则具有中等强度。TM2和TM3对金葡菌也有一定活性。     

N~2-芳基三嗪青霉素和N~2-苯基-N~4-烷基(芳基)三嗪青霉素的合成及其抗菌活性

设计合成了十个N~2-芳基三嗪青霉素和六个N~2-苯基-N~4-烷基(芳基)三嗪青霉素,这十六个化合物均为未见文献报道的新化合物,元素分析数据和光谱数据证实了它们的结构。初步体外抑菌试验表明,十六个化合物对G( )菌和G(-)菌均有一定的活性,其中的五个化合物具有一定程度的广谱特征。     

Visual monitoring of solid-phase extraction using chromogenic fluorous synthesis supports

Reductive aminations and further transformations of an azo dye and fluorous tagged aldehyde are described. The intensely colored 2,4-dialkoxybenzyl protected amines undergo Fmoc-based peptide coupling, Suzuki reactions, and sulfonamide formation with product isolation facilitated by visual monitoring of fluorous solid phase extraction. Target compounds are released from the supports in high yields and purities by treatment with trifluoroacetic acid (TFA).     

In vitro evaluation of valproic acid as an inhibitor of human cytochrome P450 isoforms: preferential inhibition of cytochrome P450 2C9 (CYP2C9)

AIMS: To evaluate the potency and specificity of valproic acid as an inhibitor of the activity of different human CYP isoforms in liver microsomes. METHODS: Using pooled human liver microsomes, the effects of valproic acid on seven CYP isoform specific marker reactions were measured: phenacetin O-deethylase (CYP1A2), coumarin 7-hydroxylase (CYP2A6), tolbutamide hydroxylase (CYP2C9), S-mephenytoin 4'-hydroxylase (CYP2C19), dextromethorphan O-demethylase (CYP2D6), chlorzoxazone 6-hydroxylase (CYP2E1) and midazolam 1'-hydroxylase (CYP3A4). RESULTS: Valproic acid competitively inhibited CYP2C9 activity with a Ki value of 600 microM. In addition, valproic acid slightly inhibited CYP2C19 activity (Ki = 8553 microM, mixed inhibition) and CYP3A4 activity (Ki = 7975 microM, competitive inhibition). The inhibition of CYP2A6 activity by valproic acid was time-, concentration- and NADPH-dependent (KI = 9150 microM, Kinact=0.048 min(-1)), consistent with mechanism-based inhibition of CYP2A6. However, minimal inhibition of CYP1A2, CYP2D6 and CYP2E1 activities was observed. CONCLUSIONS: Valproic acid inhibits the activity of CYP2C9 at clinically relevant concentrations in human liver microsomes. Inhibition of CYP2C9 can explain some of the effects of valproic acid on the pharmacokinetics of other drugs, such as phenytoin. Co-administration of high doses of valproic acid with drugs that are primarily metabolized by CYP2C9 may result in significant drug interactions.     

Synthesis of biologically active 1'-(2-oxo-2H-benzopyran-6-yl)- 5'-hydroxy-2'-methylindole-3'-amido-2"-phenyl-thiazolidene-4"-ones

6-Aminocoumarins on refluxing with ethyl acetoacetate in 1,2-dichloroethane gave two products: 3'-(2-oxo-2H-benzopyran-6-yl-amino)-but-2'-enoic acid ethyl ester 2a-c and N-(-2-oxo-2H-benzopyran-6-yl)-3'-oxo-butyramide 3a-c. Compounds 2a-c on treatment with 1,4-benzoquinone in N2-atmosphere yielded 1'-( 2-oxo-2H-benzopyran-6-yl)-5'-hydroxy-2'-methyl-3'-carbethoxyindoles 4a-c, which on further treatment with hydrazine hydrate gave 1'-(2-oxo-2H-benzopyran-6-yl)-5'-hydroxy-2'-methylindole-3'-acid hydrazides 5a-c. These acid hydrazides were treated with benzaldehyde to give 1'-(2-oxo-2H-benzopyran-6-yl)-5'-hydroxy-2'-methylindole-3'-benzylidene hydrazides 6a-c, which on further treatment with mercaptoacetic acid in 1,4-dioxane yielded 1'-(2-oxo-2H-benzopyran-6-yl)-5'-hydroxy-2'-methylindole-3'-amido-2"-phenylthiazolidene-4"-ones 7a-c. The structures of the compounds have been established on the basis of spectral and analytical data. All compounds have been screened for their antimicrobial activity and have been found to exhibit significant antibacterial and antifungal activities.