4-溴-2-甲氧基苯甲酸甲酯的合成

4-溴-2-氟甲苯经溴代、水解得4-溴-2-氟苯甲醛，再经氰化、甲氧基化、水解和酯化等反应制得4-溴-2-甲氧基苯甲酸甲酯，总收率约47％，纯度99．8％（GC法）。     

金刚乙胺盐酸盐的制备工艺改进

报道了以金刚烷为起始原料，经1－溴代金刚烷、1－金刚烷甲基酮等中间体，再与盐酸羟胺反应，然后催化加氢反应，制得金刚乙胺盐酸盐，总收率为53．6％。     

4′-溴甲基-2-联苯甲酸叔丁酯的合成

4′-溴甲基-2-联苯甲酸叔丁酯（1）是降压药替米沙坦（telmisartan）的合成中间体。本研究参考文献，用4′-甲基-2-氰基联苯（2）经水解、酯化、溴代制得1（图1），并进行了改进。2在乙醇-水（5：1）中于80℃反应16h，得粗品纯度99％，可直接用于下步反应。酯化时，文献用浓硫酸催化或直接通入异丁烯制取，用HPLC跟踪反应进程，经试验结果不理想。现改在0℃用叔丁醇加DCC酯化，收率90％（文献：86．1％）。溴化时用氯仿代替四氯化碳㈨作溶剂。改进后的1总收率61％。     

4-氟-α-(2-甲基-1-氧丙基)-γ-氧-N,β-二苯基-苯丁酰胺的合成

目的合成阿伐他汀的关键中间体4-氟-α-(2-甲基-1-氧丙基)-γ-氧-N,β-二苯基-苯丁酰胺(1).方法以异丁酸、苯甲酰氯、Meldrum酸、苯胺等为原料,经氯化、缩合和胺解反应得到异丁酰乙酰苯胺(4);以苯乙酸、氯化亚砜、氟苯、溴等为原料,经氯化、烃化和溴化反应得到2-溴-1-(4-氟苯基)-苯乙酮(7),化合物4与7经烃化反应得到目标产物1.结果与结论合成路线原料易得,操作简便,收率较高,各主要化合物结构经质谱、核磁共振氢谱确证.     

硫酸特布他林及其B晶型的合成新工艺

用3,5-二苄氧基苯乙酮(2)与溴化铜发生溴化反应生成α-溴代-3,5-二苄氧基苯乙酮(3),3无需分离纯化，直接经硼氢化钾还原得到1-(3,5-二苄氧基苯基)-2-溴乙醇(4),4与叔丁胺经取代反应得到1-(3,5-二苄氧基苯基)-2-叔丁基氨基乙醇(5),5经纯化后通过催化加氢脱除苄基并与硫酸成盐得到硫酸特布他林(1),1在丙酮和水的混合体系中析晶得到药用的B晶型结晶，总收率约42%。该工艺已完成中试放大，原料价廉易得，操作简便，适合工业化生产。     

4-(2-溴乙酰基)-3-氟苯硼酸的制备

4-溴-2-氟苯基氰经格氏反应得到4-溴-2-氟苯乙酮,先保护羰基,再经格氏反应和二羟硼基取代、溴代制得4-(2-溴乙酰基)-3-氟苯硼酸,总收率54%.     

盐酸卡替洛尔的合成

1，3-环己二酮和乙酸铵反应得到的3-氨基-2-环己烯酮，与丙烯酸反应后经溴脱氢芳构化得到5-羟基-3，4-二氢-2（1H）-喹诺酮，与环氧氯内烷缩合后经叔丁胺开环、成盐得到盐酸卡替洛尔，总收率约32％。     

阿立哌唑的合成

4-（2，3-二氯苯基）-1-哌嗪盐酸盐与1，4-二溴丁烷缩合得到1-（4-溴丁基）-4-（2，3-二氯苯基）哌嗪，再与3-氯-N-（3-羟基苯基）丙酰胺反应得3-氯-N-[3-[4-[4-（2，3-二氯苯基）]-1-哌嗪基]丁氧基]苯丙酰胺，最后经闭环制得阿立哌唑，总收率25％。     

4-溴-2-氯甲苯的合成

4-溴-2-氯甲苯（1）是一种常用的医药、农药中间体。本研究参考相关文献，用4-溴-2-硝基甲苯（2）经铁粉还原制得5-溴-2-甲基苯胺（3），经实验发现2、铁粉和乙酸的投料比为1：3：0．4系最佳反应条件，3收率可达84．7％，纯度97．8％（GC法）。3再同时进行重氮化和Sandmeyer反应制得1。按照传统的方法（即先重氮化，后加CuCl氯代）在0～5℃反应得到的1粗品含量为98．5％（GC法），收率83．4％，但低温操作对设备要求较高，操作也不易控制。研究发现适当改变投料顺序（先加CuCl，再慢慢加入亚硝酸钠，重氮化和Sandmeyer反应同时进行）及投料量（3、CuCl和亚硝酸钠的投料比为1：0．5：1．55，控制滴加亚硝酸钠水溶液的量直至反应体系无大量悬浮物），     

1,2,6,7-四甲氧基-9H-咔唑和2,3,6,7-四甲氧基-9H-咔唑的合成方法研究

目的 研究1，2，6，7-四甲氧基-9H-咔唑和2，3，6，7-四甲氧基-9H-咔唑的合成方法。方法 以4,5-二甲氧基-2-溴硝基苯和4-碘-1，2．二甲氧基苯为原料，经Ullmann反应得2-(3，4-二甲氧基苯基)-4．5．二甲氧基硝基苯(3)，再经亚磷酸三乙酯还原环合得1，2，6，7-四甲氧基-9H-咔唑(1)和2，3，6，7-四甲氧基-9H-咔唑(2)。结果 以4，5-二甲氧基-2-溴硝基苯和4-碘-1，2-二甲氧基苯为原料，制得3的收率为42％，3经环合制备l和2的收率分别为38％和39％。结论 化合物3经亚磷酸三乙酯还原环合时。等量得到l和2。研究发现化合物2还可由Ullmann反应的副产物4，4′，5，5′-四甲氧基-2，2′-二硝基联苯4经亚磷酸三乙酯还原环合制得。     

聚乙二醇（帕布昔利布、SB-743921）联体的化学合成

目的合成聚乙二醇双抗癌药偶联体并进行结构表征。方法以小分子抗癌药帕布昔利布为原料药,以可生物降解的GLG肽链作为连接链,经过酰胺化反应,去Boc保护反应等反应,得到Fmoc-E(GLG-PCB)(OH);再以类似方法得到H2N-GLG-SB743921后,使其与Fmoc-E(GLGPCB)(OH)进行反应,得到E(GLG-SB743921)(GLG-PCB),再与Boc-Gly-OH进行反应,分离纯化后得到G-E(GLG-SB743921)(GLG-PCB),将其与PEG-10K在N,N-二甲基甲酰胺作溶剂的条件下,低速、避光在室温下搅拌反应一周,经分离纯化得到目标产物PEG-10K-G-E(GLGSB743921)(GLG-PCB)。结果与结论首次合成了聚乙二醇偶联双抗癌药PEG-10K-G-E(GLG-SB743921)(GLG-PCB),重要中间体和目标产物的结构经1H-NMR、MS谱确证,均为未见文献报道的新化合物。利用该方法可合成聚乙二醇偶联双抗癌药,为高分子偶联抗癌药提供新的合成路线。     

Rodgersinine A和B的全合成

目的合成苯并二氧六环类新木脂素。方法综合使用多种有机合成反应来合成 Rodgersinine A,4-（3-甲基-7-（E）-1-丙烯基-2,3-二氢-1,4-二氧六环）-1,2-苯二酚和Rodgersinine B,4-（3-甲基-7-（1-丙炔基）-2,3-二氢-1,4-二氧六环）-1,2-苯二酚。结果首次合成了目标分子 Rodgersinine A和B。结论本文建立的合成方法可用于苯并二氧六环类新木脂素的合成。     

Synthesis and biological activity of functionalized indole-2-carboxylates, triazino- and pyridazino-indoles

Condensation of aryl hydrazines with ethyl pyruvate gave the respective hydrazones 4-6; Fischer indolization led to substituted-1H-indole-2-carboxylic acid ethyl esters 7-9. The Mannich reaction of these compounds with formaldehyde and morpholine yielded ethyl 3-(morpholinomethyl)-substituted-1H-indole-2-carboxylates 10-12. The 5,7-dichloro-1H-indole-2-carbohydrazide 13 was cyclized with methyl orthoformate in DMF to give 6,8-dichloro[1,2,4]triazino[4,5-a]indol-1(2H)-one 14. Vilsmeier-Haack formylation of 7-9 gave ethyl 3-formyl-substituted-1H-indole-2-carboxylates 15-17 whose 2,2'-((5-chloro-2-(ethoxycarbonyl)-1H-indol-3-yl)methylene)bis-(sulfanediyl) diacetic acid 18 was prepared. The reaction of 15 and 16 with substituted anilines by conventional and microwave methods gave ethyl 3-(N-aryliminomethyl)-5-halo-1H-indole-2-carboxylates 19-29. In a cyclocondensation reaction of 19-25 with thiolactic acid or thioglycolic acid substituted indolylthiazolidinones 30-33 were prepared. Reaction of hydrazine hydrate with 15-17 did not give the respective hydrazones but directly led to the cyclized products substituted-3H-pyridazino[4,5-b]indol-4(5H)-ones 34-36, while a reaction with 2,4-dichlorophenylhydrazine yielded the uncyclized hydrazones. The chlorination of 35 and 36 with POCl3 gave pyridazino[4,5-b]indoles 39 and 40, respectively; reaction of the latter compounds with morpholine gave 4-(substituted-5H-pyridazino[4,5-b]indol-4-yl)morpholine 41 and 42. Mannich reaction of 34 with formaldehyde and N-ethylpiperazine gave 8-chloro-3-((4-ethylpiperazin-1-yl)methyl)-3H-pyridazino[4,5-b]indol-4(5H)-one 43. The microwave assistance of selected reactions has a profound effect on the reaction speed. The structures of the new compounds were confirmed by both analytical and spectral data. Some compounds were subjected to investigations concerning their antimicrobial, tranquilizing, and anticonvulsant activities.     

Synthesis and antimicrobial activities of some new nitroimidazole derivatives

In this study, some new nitroimidazole derivatives were obtained from 2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethylamine dihydrochloride (4) and 1-(2-bromoethyl)-2-methyl-5-nitroimidazole (5), which were prepared using metronidazole. Compound 4 was reacted with arylisothiocyanates (6) to obtain 1-[2-(2-methyl-5-nitroimidazol-1-yl)ethyl]-3-arylthioureas (7) and the latter with alpha-bromoacetophenones (8) to give 3-[2-(2-methyl-5-nitroimidazol-1-yl)ethyl]-2-arylimino-4-aryl-4-thiazolines (9). Also 1-[2-(2-methyl-5-nitroimidazol-1-yl)ethyl]-2-phenyl-4-arylideneimidazolin-5-ones (11) were prepared by reaction of 4 with 2-phenyl-4-arylidene-5-oxazolones (10). The reaction of the other starting material 5 with 5-arylidenethiazolidin-2,4-dione (12) gave 3-[2-(2-methyl-5-nitroimidazol-1-yl)ethyl]-5-arylidenethiazolidin-2,4-dione (13) derivatives. Structural elucidation of the compounds was performed by IR, 1H-NMR and MASS spectroscopic data and elemental analysis results. Antimicrobial activities of the compounds were examined and moderate activity was obtained.     

N-[4-(苯并咪唑-2-硫基)苯基]-N'-烷基胍类衍生物的合成和生物活性

为了寻找对诱生型一氧化氮合酶(inducible nitric oxide synthase，iNOS)有抑制活性的新型化合物，设计合成了一系列N-［4-(苯并咪唑-2-硫基)苯基］-N′-烷基胍类衍生物(I₁～I₁₂)。以2-巯基苯并咪唑(1)为原料，经缩合和还原得到2-(4-氨基苯硫基)苯并咪唑(3)，再与异硫氰酸苯甲酰酯反应得双取代硫脲(4)，4经水解和S-烷基化得到关键中间体S-乙基-n-［4-(苯并咪唑-2-硫基)苯基］异硫脲氢碘酸盐(6)，6与伯胺或仲胺反应得目标化合物I₁～I₁₂。这些化合物的结构经IR，¹H NMR，MS和元素分析得到确证。初步的iNOS抑制活性测定结果显示，3个化合物(I₁，I₈和I₁₀)的活性强于阳性对照药氨基胍，其中化合物I₁的活性是氨基胍的5.5倍。     

酚类化合物芳环酰化反应机制的研究

三氯化铝催化下的酚类化合物芳环酰化反应,是一个傅-克反应和傅瑞斯重排反应的竟争反应。在反应初期,傅-克反应占据主导地位;在反应后期,傅瑞斯重排反应占据主导地位。另外,通过理化性质,光谱数据和化学相关法,四个新化合物的结构也分别被确定为:2-羟基-3-甲基-4-甲氧基-6-丁酰氧基苯甲酸甲酯(Ⅵ),2-丁酰氧基-3-甲基-4-甲氧基-6-羟基苯甲酸甲酯(Ⅶ),2,4-二甲氧基-3-甲基-6-丁酰氧基苯甲酸甲酯(Ⅷ),4,6-二甲氧基-2-丁酰氧基-3-甲基苯甲酸甲酯(Ⅸ)。     

Synthesis and biological investigations of new thiazolidinone and oxadiazoline coumarin derivatives

Ethyl (coumarin-4-oxy)acetate 1 was prepared through the reaction of 4-hydroxycoumarin with ethyl bromoacetate. Compound 1 was allowed to react with hydrazine hydrate to produce coumarin-4-oxyacetic hydrazide 2. The synthesis of N-(arylidene and alkylidene)-coumarin-4-oxyacetic hydrazones 3-20 was performed. The preparation of 2-substituted-3-[(coumarin-4-oxy) acetamido]thiazolidinones 21-26 and 2-[(coumarin-4-oxy)methyl]-4-acetyl-5-substituted-delta2-1,3,4-oxadiazolines 27-33 was performed by the reaction of the hydrazones 3, 4, 7, 9, 12, 14 with mercaptoacetic acid and the hydrazones 3, 4, 5, 7, 12, 15, 16 with acetic anhydride, respectively. The antiviral activities, cytotoxicities and structure-activity relationship (SAR) towards different microorganisms of the prepared compounds were studied.     

Convenient synthesis and antimicrobial activity of new 3-substituted 5-(benzofuran-2-yl)-pyrazole derivatives

The reaction of ethyl 4-(benzofuran-2-yl)-2,4-dioxobutanoate 2 with two moles of hydrazine hydrate afforded 5-(benzofuran-2-yl)-1H-pyrazole-3-carbohydrazide 4a, while its reaction with equimolar amount of phenylhydrazine gave ester 3b which then converted to 5-(benzofuran-2-yl)-1-phenyl-1H-pyrazole-3-carbohydrazide 4b. Various new compounds such as imides 5 and 6, acyl hydrazones 7 and 8, bi-pyrazoles 9-12, and 1,3-thiazole derivatives 14 and 15 were prepared from carbohydrazide derivatives 4a, b. The new compounds are tested for their antimicrobial activity. Compounds 2, 5, 7, and 8 showed antifungal activities against C. albicans. Also, compounds 2, 6, 8, and 15 showed antibacterial activities.     

Chemistry and pharmacology of pyran derivatives. XVII. Synthesis of 2-(dialkylamino)-5-hydroxychromones and their transformation to derivatives of 2H-pyran[4,3,2-de]-1-benzopyran

Through the reaction of resorcin with N,N-dialkylethoxy-carbonylacetamides in suitable conditions 2-(dialkylamino)-5-hydroxychromones (II) were available. Transformation of these compounds into [5-acetoxy-2-(dialkylamino)-4H-chromen-4-ylidene] malononitriles (VII) by reaction with malononitrile in acetic anhydride and treatment of (VII) with hydrochloric acid gave rise to the formation of 5-(dialkylamino)-2-imino-2H-pyrano [4,3,2-de]-1-benzo-pyrans (VIII). Furthermore 5-hydroxychromones (II) when treated with methyl iodide gave the corresponding 5-methoxychromones (III) which in turn yielded 4H-chromen-4-ylidene derivatives (X) by reaction with malononitrile in acetic anhydride. The hydrolysis of the latter compounds with hydrochloric acid resulted in the formation of 2-(dialkylamino)-4-methyl-5-methoxychromenilium salts (XI). Among the compounds which were submitted to pharmacological screening for their antiallergic properties 5-methoxychromone (III a) and 2H-pyrano [4,3,2-de]-1-benzopyran (VIII b) showed a notable activity but also high toxicity.     

洛索洛芬钠合成工艺研究Ⅱ.高区域选择性烷基化合成法

在叔丁醇钠和二甲基亚砜的存在下,2-(对溴甲基苯基)丙酸对2-乙氧羰基环戊酮进行C-烷基化,再经水解脱羧,成盐即得洛索洛芬钠,以2-(对溴甲基苯基)丙酸计算,总收率为72%。探索了不同溶剂和反应温度对烷基化收率的影响。