对溴苯甲醛合成过程中影响因素研究

本文以二苄醚、Br₂为主要原料,经加Br₂、HNO₃氧化两步反应得到对溴苯甲醛,通过单因素变量实验验证了反应温度、反应时间、原料配比以及催化剂用量对对溴苯甲醛收率的影响,提出了最佳反应控制条件：反应器内温度为50℃,反应时间为8h,原料中Br₂与二苄醚物质的量之比为2.2∶1,催化剂Fe最佳用量为0.5g·L^-1,在该组合条件下对溴苯甲醛收率为77.2%。研究结论可为进一步揭示对溴苯甲醛生成机制提供理论参考。     

6α-溴青霉烷酸-1-氧化物对硝基苄酯的制备

6α氨基青霉烷酸经重氮化、溴化转变为6α溴代青霉烷酸,在双氧水与苯酚存在的情况下被氧化为6α溴青霉烷酸1氧化物,再使用对硝基溴化苄保护6α溴青霉烷酸1氧化物中的3位羧基,生成6α溴青霉烷酸1氧化物对硝基苄酯。该方法操作简便,条件温和,总收率达58.6%。探讨了氧化及保护的反应条件。其中第3步反应收率比文献提高了2%,并且首次使用超声波促进反应,使反应时间缩短了16h。     

丁醚脲的合成

以2,6-二异丙基苯胺为原料,在双氧水存在的条件下与氢溴酸发生溴代反应,然后与苯酚在8-羟基喹啉铜、铜、DMAP的复合催化下反应得2,6-二异丙基-4-苯氧基苯胺,再与CS2反应,再与对甲苯磺酰氯作用生成异硫氰酸酯,最后与叔丁胺反应生成丁醚脲。与原有合成路线相比,该工艺路线将Ullmann反应所需的时间缩短至3 h,提高了收率,同时将合成异硫氰酸酯所需的温度降至40℃左右,降低了能耗成本,丁醚脲的总收率提高到了37.5%。产物结构用核磁共振氢谱、碳谱进行了表征。     

抗氧剂330合成工艺研究

研究了以中间体3,5-二叔丁基-4-羟基苄基甲基醚（简称苄醚）与均三甲苯为原料，在硫酸催化剂的作用下合成1,3,5-三甲基-2,4,6-三（3,5-二叔丁基-4-羟基苄基）苯（简称抗氧剂330）的工艺条件，确定了主要杂质的种类和结构，提出了副反应的反应机理，确定了副反应抑制剂的类型和用量。结果表明，合适的反应条件：硫酸含量为94.0%(w)，催化剂与苄醚摩尔比1.2∶1.0，促进剂乙酸用量为苄醚质量的20%，反应温度宜控制在-10℃，苄醚与均三甲苯摩尔比（3.2∶1.0）～(3.3∶1.0)；确定了影响抗氧剂330透光率和收率的2种主要杂质及其结构，分别为4,4′-双-（2,6-二叔丁基苯酚）甲烷和1,3,5-三甲基-2,4-二（3,5-二叔丁基-4-羟基苄基）苯；在反应体系中添加甲缩醛，可以抑制副反应的发生，合适的用量为苄醚质量的2.5%～5.0%；在优化的工艺条件下合成抗氧剂330，平均收率为87.7%,425,500 nm透光率均超过95%，达到了优级品的要求。     

间苯氧基苯甲醛制备方法的改进

一、前言间苯氧基苯甲醛(简称醚醛)是氰戊菊酯、氯氰菊酯、溴氰菊酯、氟氰菊酯等的重要中间体。由间苯氧基甲苯低温侧链氯化得到的氯化物(亦称混合氯苄),主要为二氯苄。其组成为二氯苄45～55%;一氯苄25～35%;三氯苄<4%。在50～60%混酸介质中水解制醚醛。其结果:反应5小时的醚醛平均收率达90%;     

5-(2-氧代哌嗪)烟酸的合成

以2-哌嗪酮、烟酸为原料,分别经氯甲酸苄酯、苄醇保护后,再与碘化铜、磷酸钾和配体二甲基乙烯基二胺反应生成中间体,最后脱掉保护基得到5-(2-氧代哌嗪)烟酸。研究了几种常见保护基对反应的影响,并对第三步反应条件进行了优化。该方法原料易得、反应温和、成本低,总收率达到75%。     

3-甲氧基-4-苄氧基苯乙胺盐酸盐的合成

以香草醛为原料,先与溴苄合成苄醚,再与硝基甲烷缩合,经NaBH4/BF3.Et2O还原得相应的芳基乙胺,最后与氯化氢的乙酸乙酯溶液成盐,合成了目标产物3-甲氧基-4-苄氧基苯乙胺盐酸盐。考察了缩合反应的投料比、反应温度和反应时间,还原反应的还原剂用量和反应时间对反应收率的影响。优化后4步反应的总收率为79.4%,产品经ESI-MS和1HNMR确证了结构。     

2,4-二硝基苯苄醚合成改进及表征

以2,4-二硝基酚、苄基氯等为原料,合成了2,4-二硝基苯苄醚。从反应机理角度并用正交实验研究了Williamson醚合成中反应溶剂、反应温度、反应时间等因素对产品收率的影响,最终优化了反应条件,反应收率由75％提高到91．2％。     

乙酸苄酯合成工艺的研究

以固体超强酸SO4^2-/TiO2为催化剂,二苄醚和乙酸酐为原料合成乙酸苄酯,并考察了影响反应的主要因素．结果表明最适宜的反应条件是：乙酸酐和二苄醚的摩尔比为1．5：1,催化剂用量0．5％(二苄醚的质量分数),反应时间1h,反应温度150—160℃,催化剂的焙烧温度550℃,焙烧时间3h,收率达83．7％。该法具有反应速度快,产品收率高,产品香气好,后处理简单,催化剂可重复使用等优点。     

N-苄氧羰基-L-丝氨酸苄酯的合成

以苄氧羰基氯、L-丝氨酸为原料,合成了N-苄氧羰基-L-丝氨酸。通过正交实验考察了反应温度、pH、原料的摩尔比、相转移催化剂对N-苄氧羰基-L-丝氨酸收率的影响。优化反应条件后N-苄氧羰基-L-丝氨酸收率为93.2%。N-苄氧羰基-L-丝氨酸和苄溴反应生成了目标产物-N-苄氧羰基-L-丝氨酸苄酯,重点探讨了酯化过程中缚酸剂、原料的投料顺序及产品后处理对目标产物收率的影响。选择具有催化作用的三乙胺为缚酸剂,用质量分数10%的亚硫酸氢钠对产品进行后处理使N-苄氧羰基-L-丝氨酸苄酯的色谱纯度达98.5%。通过红外、核磁、熔点、旋光度等对目标产品进行了结构表征,用高效液相色谱对产品的纯度进行了测定。     

O-苄基-L-酪氨酸合成工艺改进

D-苄基-L-酪氨酸是合成新型抗糖尿病药物PPARr／α激动剂手性中间体s(-)3-(4-羟基苯基)-2-乙氧基丙酸乙酯的重要原料。本文在氢氧化钠作用下,L-酪氨酸、硫酸铜、溴化苄反应得到D-苄基酪氨酸铜配合物,然后采用EDTA-2Na-锅法的后处理新工艺,得到D-苄基-L-酪氨酸。该后处理方法,省去了用稀盐酸-氨水或稀盐酸-乙醇钠反复处理的麻烦,且产物无需重结晶,收率提高了22．6％。     

N^α-9-芴甲氧羰基-N^ε-叔丁氧基羰基-L-赖氨酸的合成研究

Using H2O-acetone as solvent, sodium bicarbonate as acid binder and catalyst, N^ε-tert-butoxycarbony- L-lysine copper （Ⅱ） complex was synthesized successfully by Nε-tert-butoxycarbonylation of L-lysine copper （Ⅱ） complex which was furnished by protection of the α-amino and carbonyl of L-lysine with copper （Ⅱ） sulfate pentahydrate. The free α-amino was released from Nε-tert -butoxycarbonylation of L-lysine copper （Ⅱ）complex promoted by copper catching regent, and followed by Nα-9-fluorenylmethyloxycarbonylation catalysted by sodium carbonate with H2O-acetone as solvent to form Nα-9-fluorenylmethyloxycarbonyl-Nε-tert-butyloxycarbonyl-l-lysine （Fmoc-L-Lys （Boc） -OH）. The effects of four kinds of copper catching regents on the Nα -9- fluorenylmethyloxycarbonylation were studied, and the results showed the excellent copper catching regent were sodium sulfide and 8-hydroxyquinoline. The reaction conditions of Nα-9-fluorenylmethyloxycarbonylation such as ratio of Nε-tert-butoxycarbony-L-lysine copper （Ⅱ） complex to Fmoc-Osu, reaction time, reaction temperature were investigated in detail. The optimum reaction conditions were obtained as follow： the mole ratio of Nε-tert- butoxycarbony-L-lysine copper （Ⅱ） complex to Fmoc-Osu is 1.00 ： 0.98, the reaction temperatureare is room temperatureare and the reaction time is 3 h. Under those conditions, Fmoc-L-Lys （Boc）-OH was reached in 91.7% yield with 99.1% purity.     

3-苄氧基-4-丁基苯胺盐酸盐的合成工艺

引言 甲苄氧喹啉(nequinate)即4-羟基-6-丁基-7-苄氧基喹啉-3-羧酸甲酯,与丁喹酯(buquinolate)、癸氧喹酯(decoquinate)等同属抗鸡球虫病的喹啉类疫苗.鸡球虫病是由艾美耳属(Eimeria)的多种单细胞寄生虫引起的严重危害鸡生长发育的一种疾病[1-5].     

The First Total Syntheses of Enantiomerically Pure Naturally Occuring Ellagitannins Gemin D and its Regioisomer Hippomanin A

The total syntheses of naturally occuring ellagitannins gemin D ( 1 ) and its regioisomer hippomanin A ( 2 ) are reported. In addition, the phase-transfer catalyzed benzylation reaction of the 2,3-glucopyranoside diols 3–7 is described. Our studies have illustrated the influence of the structure of 2,3-glucopyranoside diols on the regioselectivity of the phase-transfer catalyzed benzylation at their free 2,3-OH groups. We could show, that both phase-transfer catalyzed benzylations of 2,3-glucopyranoside diols using tetrabutyl-ammonium hydrogensulfate (Bu4NHSO4) or using tetrabutylammonium iodide (Bu4NI) disfavour the formation of the corresponding 3-O-monobenzylated products and preferrentially give the 2- O-monobenzylated products. However, the ratio of the generated 2- versus 3-O-mono- and 2,3-dibenzylated products from these reactions also strongly depends upon the nature of the starting materials. The glucopyranosides 3 and 4 are the first examples, which allow the completely regioselective monobenzylation at the 2-OH positions by a phase-transfer catalyzed reaction.     

拉氧头孢钠的合成

拉氧头孢母核经四氮唑巯基取代、甲氧化、侧链裂解得到7β-氨基-7α-甲氧基-3-(1-甲基-5-四唑基)硫甲基-1-氧杂去硫杂-3-头孢烯-4-羧酸二苯甲酯,再经酰化、脱羧酸保护基、成盐反应制得目标化合物,总收率约30%,纯度为97.2%。     

苄基红景天的工艺改进

以无水葡萄糖和对羟基苯乙醇为起始原料,经过乙酰化、苄基保护、苷化三步反应合成了苄基红景天,总收率21.8%;考察了反应物料配比、干燥条件、反应时间对收率的影响。目标化合物的结构经IR和1H NMR确证。改进后的工艺降低了合成成本,简单可行,适合工业化生产。     

高收率美罗培南侧链中间体的合成

针对现有美罗培南侧链中间体（硫醇内酯）制备工艺成本较高、反应路线复杂、副反应多、收率及粗品纯度较低等缺点，研究了一种简便制备硫醇内酯的方法，通过将M1[(2S，4R)-2-羧基-1-(4-硝基苄氧羰基)吡咯烷)]羧基活化、羟基活化和硫化成环合为一锅法以及添加相转移催化剂法制备硫醇内酯，再进行开环反应得到美罗培南侧链。研究了氯甲酸异丙酯、甲基磺酰氯（MsCl）、三乙胺（TEA）、Na₂S·9H₂O和三类相转移催化剂[聚乙二醇类（PEG）、季铵盐类和冠醚类]的投料摩尔比对制备硫醇内酯收率和纯度的影响。制备硫醇内酯时加入相转移催化剂既可以加快反应的速率，又可以提高产品纯度及收率。n_M1∶n_{氯甲酸异丙酯}∶n_MsCl∶n_{\mathrm{N}{\mathrm{a}}_{\mathrm{2}}\mathrm{S}·\mathrm{9}{\mathrm{H}}_{\mathrm{2}}\mathrm{O}}∶n_{CTEA（羧基活化时所加TEA）}∶n_{HTEA（羟基活化时所加TEA）}∶n_催化剂为1∶1∶1.3∶1.3∶1.3∶1.2∶(0.07～0.16)，羧基活化和羟基活化反应温度均为-30～-17℃，羧基活化和羟基活化反应时间分别为15min、30min；硫化成环从-30～-17℃升温到0℃，升温反应时间为30min；回流温度为40℃，回流时间165min。硫醇内酯收率为98.4%，纯度为98.3%。     

Palladium‐Catalyzed Benzylic C?H Benzylation via Bis‐Benzylpalladium(II) Complexes in Water: An Effective Pathway for the Direct Construction of N‐(1,2‐Diphenylethyl)anilines

A strategy for the N‐benzylation/benzylic C H benzylation cascade of anilines by the π‐benzylpalladium system using a water‐soluble palladium(0)/sodium diphenylphosphinobenzene‐3‐sulfonate (TPPMS) catalyst and benzyl alcohol in water has been developed. This tandem process is devised as a novel and efficient synthetic route for N‐(1,2‐diphenylethyl)anilines. Benzylic C H activation of a mono‐N‐benzylated intermediate with a π‐benzylpalladium(II) complex affords a bis‐π‐benzylated palladium(II) intermediate. The nucleophilic η¹‐σ‐benzyl anion ligand attacks the electrophilic η³‐π‐benzyl ligand to give a dibenzylated product. The intermolecular competition between mono‐N‐benzylaniline and its monodeuterated form (monodeuterated at the benzylic group) with benzyl alcohol gave a KIE=4.6, suggesting that C H bond cleavage was involved in the rate‐determining step. Hammett studies on the rate constants of benzylation by various substituted anthranilic acids and mono‐N‐benzylanilines show a good correlation between the log(k_X/k_H) and the σ values of the respective substituents. From the slope, negative ρ values are obtained, suggesting that there is a build‐up of positive charge in the transition state. The reaction of anilines with electron‐donating and electron‐withdrawing groups affords the corresponding N‐(1,2‐diphenylethyl)anilines in moderate to good yields (54–86%). Interestingly, the reaction of anthranilic acids proceeded smoothly to give only the corresponding dibenzylated products in good to excellent yields (70–87%). The carboxyl group of the anthranilic acids acts as a directing group in the benzylic C H activation process.

     

In vitro sortagging of an antibody fab fragment: overcoming unproductive reactions of sortase with water and lysine side chains

Sortase A from Staphylococcus aureus attracts growing interest for its use in biotechnological protein modification. This enzyme binds to a short signal sequence at the C terminus of a target protein, cleaves it by formation of an acyl-enzyme intermediate, and subsequently attaches an oligoglycine with a peptide bond. In this work, we explored its usability for the modification of the L19 Fab fragment (specific for fibronectin ED-B), a promising candidate for antibody-based cancer therapy. The Fab fragment was expressed with a sortase signal sequence attached to its light chain, and was successfully modified with a fluorescent oligoglycine probe in good yield. Our interest focused on performance under conditions of limited oligoglycine concentrations. Two unproductive side reactions of sortase were observed. The first was hydrolysis of the acyl-enzyme intermediate; in the second, sortase accepted the ε-amino group of lysine as substrate, thereby resulting in polypeptide crosslinking. In case of the L19 Fab fragment, it led to the covalent connection of the heavy and light chains. Both side reactions were effectively suppressed by sufficient concentrations of the oligoglycine probe.