下载文档原格式
1,1环己基二乙酸单酰胺合成摘要：1.1 环己基二乙酸单酰胺的合成方法2.1 环己基二乙酸单酰胺的用途3.1 环己基二乙酸单酰胺的合成过程注意事项正文：1.1 环己基二乙酸单酰胺的合成方法1 环己基二乙酸单酰胺（1-Cyclodexyldiacylhydrazine）是一种有机化合物，具有广泛的应用。
其合成方法通常采用酰胺化反应。
具体步骤如下：首先，将环己醇与过量的乙酸在酸性催化下反应，生成1 环己基二乙酸酯。
然后，在碱性条件下，将1 环己基二乙酸酯与亚硝酸钠反应，生成1 环己基二乙酸亚硝酸酯。
最后，在酸性条件下，将1 环己基二乙酸亚硝酸酯与过量的氢氰酸反应，生成1 环己基二乙酸单酰胺。
2.1 环己基二乙酸单酰胺的用途1 环己基二乙酸单酰胺具有广泛的应用，主要用于有机合成、医药、农药等领域。
在有机合成中，1 环己基二乙酸单酰胺可作为合成其他有机化合物的中间体，例如，可用于合成环己酮、环己胺等。
在医药领域，1 环己基二乙酸单酰胺可用于合成抗肿瘤药物、抗病毒药物等。
在农药领域，1 环己基二乙酸单酰胺可用于合成杀虫剂、杀菌剂等。
3.1 环己基二乙酸单酰胺的合成过程注意事项在1 环己基二乙酸单酰胺的合成过程中，应注意以下几点：（1）在酰胺化反应中，应控制反应温度和压力，避免高温高压导致的副反应。
（2）在碱性条件下，应注意搅拌速度，避免过快搅拌导致的剧烈反应。
（3）在酸性条件下，应注意氢氰酸的添加速度，避免过快添加导致的剧烈反应。
（4）在合成过程中，应使用无水、无氧的溶剂和试剂，避免水分和氧气的影响。
总之，1 环己基二乙酸单酰胺的合成方法采用酰胺化反应，具有广泛的应用。
专利名称：一种制备N‑Ts‑3‑取代吲哚啉衍生物的方法专利类型：发明专利
发明人：杨健国,邱方利,金秀秀,陈帝,莫寒劼
申请号：CN201710938694.7
申请日：20170930
公开号：CN107474005A
公开日：
20171215
专利内容由知识产权出版社提供
摘要：本发明公开一种制备N‑Ts‑3‑取代吲哚啉衍生物的方法，该方法以N‑Ts‑邻碘苯胺和苯基苄基醚类化合物为原料，N,N‑二甲基甲酰胺为溶剂，金属钯催化下，在氮气保护体系中，合成目标化合物，具体步骤如下：将N‑Ts‑邻碘苯胺(1mmol)、n‑BuNCl(1mmol)、NaHCO(2mmol)、
Pd(dppe)Cl(0.05mmol)依次加入反应管中，将苯基苄基醚(1mmol)溶于4mL N,N‑二甲基甲酰胺中，在氮气保护下，将溶于N,N‑二甲基甲酰胺后的苯基苄基醚注入至反应管中，然后放置在130摄氏度油浴中反应，反应12小时，反应完成后，将反应液转移至250mL分液漏斗中，先加入乙酸乙酯和饱和食盐水各25mL，分液后水相再用乙酸乙酯萃取2次，合并有机相，有机相再用饱和食盐水洗涤1次，然后用无水NaSO干燥有机相，过滤，旋蒸浓缩，最后用流动相为石油醚：乙酸乙酯＝10:1柱色谱进行分离，得到白色固体。
申请人：台州学院
地址：318000 浙江省台州市椒江区市府大道1139号
国籍：CN
代理机构：台州蓝天知识产权代理有限公司
代理人：王卫兵
更多信息请下载全文后查看。
β2D 呋喃果糖苷酶合成低聚果糖的工艺研究马 莺1 孙建华21(东北农业大学食品学院,哈尔滨,150030) 2(黑龙江省应用微生物研究所,哈尔滨,150010)摘 要 以蔗糖为底物,采用来源于米曲霉中的β-D -呋喃果糖苷酶(EC31211126)合成低聚果糖,酶反应最佳条件为:反应温度35℃,酶反应体系的p H 为810～812,酶浓度217IU/g(蔗糖),酶反应时间为8h 。
低聚果糖的最大转化率为54%,82%的蔗糖被转化。
关键词 β2D 2呋喃果糖苷酶,酶反应,低聚果糖第一作者:博士,教授。
收稿时间:2002-05-27,改回时间:2002-12-26 低聚果糖(fructo 2oligosaccharides ),又称寡果糖或蔗果三糖族低聚糖,是指在蔗糖分子的果糖残基上通过β(1→2)糖苷键连接1～3个果糖基而成的蔗果三糖(GF2)、蔗果四糖(GF3)、蔗果五糖(GF4)及其混合物。
以蔗糖为底物合成低聚果糖的酶是β2果糖转移酶(β2D 2fructosyltransferase ,Ftase ,EC3121119)或β2呋喃果糖苷酶(β2D 2fructofura 2nosidase ,Ftase ,EC 31211126)。
本研究以米曲霉(Aspergill us oryz ae )提取的β2D 2呋喃果糖苷酶(EC 31211126)作为合成低聚果糖的酶系,对影响酶反应合成低聚果糖产量的主要因素:反应体系的p H 、温度、反应时间、底物的浓度和酶的使用量进行了详细的讨论。
米曲霉培养条件简单、培养基的成本低,提取的β2D 2呋喃果糖苷酶(EC 31211126)是胞外酶,酶的提取、纯化较容易,低聚果糖的转化率与黑曲霉中提取的β2D 2呋喃果糖苷酶(EC 31211126)的转化率基本一致。
1 实验材料与方法111 实验材料β2D 2呋喃果糖苷酶,自制;蔗糖,分析纯;所用其他化学试剂亦为分析纯。
关于哒嗪酮类中间体药物及其合成进展哒嗪酮（Dazopirone）是一种潜在的多效性抗抑郁和抗焦虑药物，属于哒嗪衍生物，具有较好的生物活性和良好的安全性。
它在中枢神经系统中的作用机制包括5-羟色胺受体和5-羟色胺转运蛋白的调节，以及对γ-氨基丁酸（GABA）和谷氨酸（GLU）系统的影响。
由于其独特的药理特性，哒嗪酮成为目前嗜睡药中的一种新的发展方向。
哒嗪酮的合成方法主要通过N-pivaloyloxyphthalimide（PvPI）法、Vilsmeier-Haack 反应法、过氧化铴法和环化反应法等来制备。
PvPI法是一个基于羧酸酐与样品的反应而形成N-酰极化物的方法，这种方法通过溶液中的光敏引发剂诱导的自由基引发氮杂底物的氧化来实现。
Vilsmeier-Haack反应是由亮氨酸和二碳酰胺（DMFDMA）与二级胺之间的反应转化而来，该方法具有高产率和可靠性的特点。
过氧化铴法则是集成了氧化过程和铵化过程的一种方法，采用过氧化铴为氧化剂，在氧气环境中将结合物氧化成相应的羰基化合物。
环化反应法是指通过环化反应合成哒嗪衍生物，在反应中引入合适的底物和反应条件，可得到哒嗪酮及其结构类似物。
哒嗪酮的合成研究主要集中在其中间体药物的合成以及合成路线的改进等方面。
通过改进合成方法，减少副反应的产生，提高产率和纯度，以提高哒嗪酮的合成效果。
研究人员还通过改变结构，引入新的官能团，以增强其活性和选择性。
近年来，许多研究中心和制药公司都在开展哒嗪酮类中间体药物及其合成的研究。
目前，哒嗪酮已被用于治疗抑郁症和焦虑症等疾病的临床试验，并取得了一定的治疗效果。
虽然还有一些挑战存在，如药物代谢和毒理学研究等，但哒嗪酮在精神药理学领域的合成研究仍然具有重要的意义。
哒嗪酮类中间体药物的合成研究已经取得了一定的进展，但仍需要进一步的研究以实现其在临床上的应用。
随着对该类药物机制的深入研究以及合成方法的不断改进，相信哒嗪酮类中间体药物会在抗抑郁和抗焦虑疗法中发挥重要作用，并为神经科学和药物学领域的发展做出贡献。
一种西达本胺的合成方法西达本胺（Sertraline）是一种常用的抗抑郁药物，它属于选择性血清素再摄取抑制剂（SSRI）。
西达本胺的合成方法有多种，以下为其中一种常用的方法。
西达本胺的合成方法是通过N-芳磺酰基化反应来合成。
具体步骤如下：步骤一：合成芳磺酸盐的前体首先需要合成芳磺酸盐的前体。
将安息香酮（acetophenone）与甲基硫酸钠（methylsulphonic acid sodium）反应，在碱的催化下进行芳烃甲基化反应，生成对甲基芳酮（p-methylacetophenone）。
反应方程如下：CH3C6H5+NaSO3CH3+NaOH→p-CH3C6H4C(O)CH3+NaOH+CH3SO3H步骤二：N-芳磺酰基化反应将步骤一中合成的对甲基芳酮与氯硫酰胺（thionyl chloride）反应，再用邻苯二酚（hydroquinone）进行缩合反应，生成对苯二酮衍生物。
该反应需要在惰性气氛下进行，且引入过量的氯化钠（NaCl）用于部分中和HCl产生的副产物。
反应方程如下：p-CH3C6H4C(O)CH3+SOCl2→p-CH3C6H4C(O)SO2Cl+HClp-CH3C6H4C(O)SO2Cl+C6H5(OH)→p-CH3C6H4C(O)OC6H4OH+HCl步骤三：西达本胺的合成西达本胺的合成通过步骤二中合成得到的对苯二酮衍生物与氨气（NH3）反应得到。
反应时需要催化剂和溶剂的存在，通常采用铜催化剂，并在液氨中进行。
p-CH3C6H4C(O)OC6H4OH+4NH3→p-CH3C6H4CH2NC6H4ONH2+H2O步骤四：西达本胺的后续处理西达本胺合成后，还需要进行一些后续处理。
通常，首先对反应混合物进行酸化处理，以去除多余的氨气。
然后，通过适当的提取和结晶纯化方法，得到纯净的西达本胺。
最后，通过干燥和加工处理，制成成品。
需要注意的是，西达本胺的合成方法是一个简化的表述，并且实际操作时会有更多的细节和考虑因素。
华中科技大学硕士学位论文丙酰左卡尼汀盐酸盐的合成及制剂研究姓名：熊微申请学位级别：硕士专业：无机化学指导教师：杨祥良20060511华中科技大学硕士学位论文摘要丙酰左卡尼汀盐酸盐（Propionyl Levocarnitine hydrochloride，PLC）是左卡尼汀（Levocarnitine，LC）的酯化物，其生理活性与LC相似，主要药理作用表现在改善受损心肌的物质与能量代谢。
目前仅有意大利Sigma-tau公司首先上市了PLC盐酸盐的片剂和冻干针，临床上用于治疗下肢动脉病变和慢性心功能不全；在国内尚无企业获得生产许可。
为此，本文研制了PLC原料药及其两个制剂，并按照规范进行了结构确证、质量研究等工作内容。
1. PLC合成工艺研究。
采用LC与丙酰氯一步反应合成PLC，反应温度60 ℃，时间6 h，产物精制后总收率约为51 %，其结构经IR、MS、NMR及元素分析确证。
该合成工艺反应条件温和，易于操作，成本较低，较适合于工业化生产。
2. 建立了PLC原料药有机残留溶剂、有关物质和含量测定的检测方法。
有关物质检查和含量测定采用HPLC法，色谱柱为NH2柱（Kromasil KR100-5，250 mm×4.6 mm，粒径5µm），流动相为乙腈-0.05 mol/L KH2PO4溶液（70:30，v/v），检测波长205 nm。
GC法检测丙酮有机残留溶剂含量，色谱柱为聚乙二醇毛细管柱（30 m×0.32 mm，1 µm），载气为氮气，以程序升温方式使丙酮得到完全分离，检测器为氢火焰离子化检测器；HPLC法检测丙酸残留含量，色谱柱为C18柱（Hanban，250 mm×4.6 mm，粒径5µm），流动相为0.05 mol/L KH2PO4溶液，检测波长210 nm。
所建立方法均简便快速、灵敏度高，适合PLC质量研究工作。
3. 研制了PLC片剂和冻干针，并对其进行了质量控制。
2,3-位稠杂环喹唑啉酮类化合物的合成研究进展刘举;王洋;周云鹏;李春艳;陈烨;姜明俊;徐利锋【摘要】2,3-位稠环喹唑啉酮类化合物由于具有多种优良的生物和生理活性而广泛应用于药物领域,其合成方法是目前药物研究的热点领域之一.本文主要介绍了包括以2-氨基苯甲酸类化合物、2-氨基苯甲酸甲酯类化合物、靛红酸酐类化合物、喹唑啉酮类化合物等为原料合成2,3-位稠环喹唑啉酮类化合物的方法,并对这些方法进行了简单的评述.%2,3-fused heterocyclic quinolinones have shown many excellent biological activities in the areas of medicine. Their synthetic methods are important topics of pharmaceutical researches at present. Several major synthetic methods of the 2,3-fused heterocyclic quinolinones are reviewed, including the reactions in which anthracitic acids, methyl anthranilates, isatoic anhydrides, quinolinones was used as the main materials and briefly evaluate their advantages and disadvantages.【期刊名称】《化学研究》【年(卷),期】2011(022)006【总页数】11页(P85-95)【关键词】喹唑啉酮;稠杂环化合物;生物活性;合成;进展【作者】刘举;王洋;周云鹏;李春艳;陈烨;姜明俊;徐利锋【作者单位】辽宁大学药学院药物研究所,辽宁沈阳110036;辽宁大学药学院药物研究所,辽宁沈阳110036;辽宁大学药学院药物研究所,辽宁沈阳110036;辽宁盛生医药集团有限公司,辽宁沈阳110179;辽宁大学药学院药物研究所,辽宁沈阳110036;辽宁大学药学院药物研究所,辽宁沈阳110036;辽宁大学药学院药物研究所,辽宁沈阳110036【正文语种】中文【中图分类】O626.4稠杂环化合物尤其含氮稠杂环化合物是目前有机化学和药物化学的研究热点.2，3－位稠杂环喹唑啉酮类化合物作为喹唑啉酮稠杂环化合物中的一个重要分支，表现出很广泛的生物活性.大量的含有该结构的化合物被应用于医药领域，表现出很好的生物活性；作为磷酸二酯酶1（PDE1）的抑制剂，具有良好的抗帕金森作用[1].该类化合物具有抗肿瘤[2－4]、降血压[5－6]、抗菌[7－8]、抗炎[9－11]和抗疟[12]等活性.该类化合物具有较多的靶标点，而引起化学工作者极大的兴趣.基于该类化合物的重要作用以及近年对此类化合物的广泛的研究，本文综述了2，3－位稠杂环类喹唑啉酮化合物的主要合成方法.Mikhalev等[9]研究发现，邻氨基苯甲酸1和2－氯代－3－取代吡啶类化合物2在冰乙酸中回流能够顺利反应生成吡啶并[2，1－b]喹唑啉酮3（Scheme 1），产率在60%～80%.原因是在浓冰乙酸中，化合物2中吡啶环上的氮原子被质子化了，卤素更容易被芳香胺所置换而形成中间体，中间体再进一步环合生成吡啶并喹唑啉酮类化合物.该方法原料廉价易得，操作方法简单，产率高.Francois等[13]以邻氨基苯甲酸衍生物4与氯代苯并嘧啶类化合物5为原料，冰乙酸为溶剂，在100W微波辅助下105℃反应20min合成了喹唑啉并[4，3－b]喹唑啉酮类化合物6（Scheme 2）.产率在41%～85%.微波反应大大缩短了反应时间，产率也有了进一步的提高.是合成2，3－嘧啶并喹唑啉酮类化合物较好的方法.早在1971年，John等[14]就报道了用邻氨基苯甲酸1和亚胺类甲基硫醚化合物7在二甲基乙酰胺中，150～160℃下反应生成2，3－位稠环喹唑啉酮类化合物8（Scheme 3），产率为20%.Francois等[13]利用石墨负载的邻氨基苯甲酸衍生物4与亚胺类甲基硫醚9在60W微波辅助下150℃反应30min合成了喹唑啉并[4，3－b]喹唑啉酮类化合物6（Scheme 4），产率29%～79%.和传统的加热方法比较，该方法具有产率高，反应时间短，产物易分离的优点.2001年，Lisianne等[15]也将微波辐射引入此类反应，以邻氨基苯甲酸类化合物10和亚胺硫醚类化合物11在微波条件下，以石墨为反应加热介质合成了2，3－位稠环喹唑啉酮类化合物12（Scheme 5），产率有了进一步的提高.1996年，Juan等[16]以邻氨基苯甲酸类化合物13为原料运用两种方法合成2，3－稠环喹唑啉酮类化合物16（Scheme 6），第一种方法是邻氨基苯甲酸类化合物与环亚胺醚类14在无溶剂条件下反应，产率65%～95%.第二种方法是取代邻氨基苯甲酸经过与氯化亚砜反应制备酰氯后与内酰胺15反应，产率为30%～65%.实验证明，第一种方法的产率远远高于第二种方法的产率.2009年，Tan等[17]将上述工艺进行了改进.用2－氨基－4－硝基苯甲酸或2－氨基－5－硝基苯甲酸17在三氯氧磷存在下与2－吡咯烷酮18在甲苯中回流一步反应得到喹唑啉酮19（Scheme 7）.产率中等.2009年，Chen等[5]利用此方法，以邻氨基苯甲酸类化合物20和二氯亚砜反应生成的活性中间体与2－哌啶酮21反应闭环生成喹唑啉酮母体，经过与取代苯基重氮盐反应制备了腙23，23再闭环生成了天然产物吴茱萸次碱的类似物24（Scheme 8）.该合成方法为合成天然产物提供了一个新的思路.2007年，Sachin等人[18]报道了通过取代的邻氨基苯甲酸类化合物25和吡啶并[2，3－d]嘧啶类化合物26在微波辐射下合成新型1，3，10，12－四取代－8H－吡啶并[2′，3′∶4，5]嘧啶并[6，1－b]喹唑啉－8－酮类化合物27（Scheme 9）.通过微波辅助合成、常规加热、熔融三种方法的对比，得出最佳合成条件是在多聚磷酸存在下微波辐射10min.和经典的加热方法相比，具有反应温度低、时间短、产率高等优点.产率高达75%～95%.2005年，Liu等人[19]利用廉价易得的邻氨基苯甲酸28和Boc－保护的氨基酸29为起始原料，以亚磷酸三苯酯为催化剂，吡啶为溶剂，在230℃下微波辅助反应20min，运用一锅法合成了生物碱sclerotigenin（30a），（±）－circumdatin F（30b）和（±）－asperlicin C（30c），产率分别为55%、32%和20%.该反应是一种典型的多米诺反应.在该文章中，又通过微波辅助合成的方法，利用三组分一锅连续反应法制备了生物碱circumdatin E的类似物33a和33b，产率分别为34%和29%.这两种合成方法虽然产率不高，但是具有步骤简单，反应时间短的特点.不失为合成2，3－位稠环喹唑啉类化合物的较好方法.2006年，Liu等人[4]又利用邻氨基苯甲酸类化合物34与等当量的Boc－5－氨基戊酸35以吡啶为溶剂在三苯氧基膦存在下，220℃微波辐射反应10min后，再加入苯甲醛类化合物36，然后升温230℃下微波辐射反应12min制得目标化合物，实现了微波辅助三组分一锅法合成了67种目标化合物37（Scheme 11）.该方法是快速合成化合物库的很好的方法.1998年，Mahavir[20]报道了邻氨基苯甲酸甲酯38在冰乙酸回流条件下和三氧化硫脲39反应制备喹唑啉稠杂环化合物40（Scheme 12）.2004年，Maria报道了[21]通过4，5－二氯－1，2，3－二噻唑氯化物合成新型3，4－二氢－2H－吡嗪并[2，1－b]喹唑啉酮（Scheme 13），通过实验条件摸索加入乙二胺的量（1或3当量）显示，过量的乙二胺有利于二氢咪唑并[2，1－b]喹唑啉酮44a～c的生成，而吡嗪并[2，1－b]喹唑啉酮43a～c的生成量减少.有意思的是，4，5－二甲氧基邻氨基苯甲酸甲酯和3倍量的乙二胺反应却仅仅得到了产物43d，更换方法，例如：使用1倍量或者3倍量乙二胺在加热或者不加热情况下，都没有生成化合物44d（Table 1）.早在1971年，John等[14]报道，靛红酸酐45和甲基硫脲胺类化合物46在1，4－二氧六环中，100℃反应4 h，以37%的产率得到了产物喹唑啉酮47（Scheme 14）.1972年，Timothy等[22]利用靛红酸酐类化合物48和2－（乙基硫代）－2－咪唑啉49在DMF中加热得到四氢咪唑并[2，1－b]喹唑啉酮类化合物50（Scheme 15）.Fadda等[23]在2001年报道了以靛红酸酐45和邻苯二胺51为原料，在冰乙酸中回流，以85%的产率得到了2，3－稠杂环喹唑啉酮化合物52（Scheme 16），该方法步骤简单，产率较高，是一种较好的合成苯并咪唑并喹唑啉的方法.2002年，Vedula等[2]以靛红酸酐类化合物53和靛红类化合物54为原料，在三乙胺存在下，甲苯中回流2～4h，一步合成了具有喹唑啉酮结构的色胺酮类化合物55，该反应产率较高（70%～85%），操作简单.而靛红酸酐45和靛红类化合物56在三乙胺存在下，甲苯中回流反应制备该类化合物的产率却较低，仅为25%～30%（Scheme 17）.2007年Sang等用类似的方法[24]采用5－甲氧基靛红和靛红酸酐为原料，在氢化钠存在下，DMF中50℃反应，得到了8－甲氧基色胺酮，产率为77%.2001年，Sharief等[25]报道了以2－磺酰胺－3－氨基喹唑啉酮类化合物58和苯甲醛类化合物为原料，在冰乙酸回流后得到中间体化合物59，化合物59在以DMF为溶剂、三乙胺为碱性催化剂条件下回流反应得到了2，3－稠杂环喹唑啉酮化合物60（Scheme 18）.各个步骤产率中等以上（60%～70%）.2002年，Vijay等[26]用3－氨基－2－甲基－6－硝基－4（3H）喹唑啉酮61和苊醌62为原料，在乙酸酐中回流5～6h，以70%的产率得到产物11－氨基－13H－苊并[1，2－e]哒嗪[3，2－b]喹唑啉－13－酮63（Scheme 19）.2008年，Sharief等[27]用3－氨基－2－（苯氨基）喹唑啉－4（3H）－酮64为原料，在乙酸酐中回流反应4h，生成了2－甲基－3－苯基－[1，2，4]三唑并[5，1－b]喹唑啉酮65（Scheme 20）.2006年，Abhijeet等[28]利用喹唑啉66在经二氯化锡还原后和糖反应一锅法合成了含糖的喹唑啉稠杂环类化合物68、69（Scheme 21）.合成的各种化合物产率也均在70%以上.该合成方法是一种合成含糖取代基的喹唑啉类化合物的好方法. 1993年，Giancarlo等人[29]利用l－溴－4－[3，4－二氢－4－氧代喹唑啉－2－基]－2－丁醇类化合物70在乙腈中回流反应3～10h，得到四氢吡啶并[2，1－b]喹唑啉酮类化合物71（Scheme 22），产率为17%～64%.1998年，Wang等[30]以化合物72为原料，二氯甲烷为溶剂，在20%的哌啶存在的条件下，室温环合，经二氧化硅处理后合成了吡嗪并[2，1－b]喹唑啉酮类天然产物Fumiquinazoline G73，该文献又采用类似的方法合成了fiscalin B74（Scheme 23）.2004年，Chavan等[11]利用化合物75为原料，在60%的乙醇硫酸溶液中回流环合，生成了骆驼宁碱A（Luotonins A），产率73%.化合物77在60%的盐酸中回流反应，以70%的产率生成骆驼宁碱B（Luotonins B），化合物77在浓盐酸和甲醇（1∶1）的溶液中回流反应，以50%的产率生成骆驼宁碱E（Luotonins E）（Scheme 24），该反应条件简单易行，产率较高.2008年，Tseng[31]将固相肽合成法（SPPS）引入2，3－稠环喹唑啉酮类化合物合成方法中，利用树脂连接的氨基酸衍生物80先与邻氨基苯甲酸反应，产物81再和9－芴甲氧羰基保护的氨基酸酰氯反应得到相应的三肽类化合物82.该三肽类化合物82在路易斯酸三氟甲烷磺酸锌催化下，一锅法合成了吡嗪并[2，1－b]喹唑啉－3，6－二酮类化合物83（Scheme 25），该反应具有产率高，反应快速等优点.早在1965年，Bird报道了[32]1－氰基吲唑化合物84在加热到270℃时，发生重排反应，得到2，3－稠环喹唑啉酮类化合物85（Scheme 26），产率40%.有研究发现[33]，2－氨基苯并咪唑86和邻溴苯甲酸或邻氯苯甲酰氯87在金属铜催化下，通过反应温度为170℃的Ullman反应，也能顺利地以中等产率得到2，3－稠杂环喹唑啉类化合物85（Scheme 27）.1987年，Tilley等人[34]利用对异丙基苯胺和6－氯烟酸在加热条件下生成二芳基胺，该二芳基胺经过溴代、羧酸还原、关环等步骤，生成[2，1－b]喹唑啉酮衍生物.结语：2，3－位稠环喹唑啉酮类化合物具有广泛的生物活性和药理活性，近年来受到药物化学家和有机化学家的极大关注.随着有机合成化学的不断发展，将会出现更有效、更环保的新方法、新技术应用于2，3－位稠环喹唑啉酮类化合物的合成，推动着2，3－位稠环喹唑啉酮类化合物的开发和应用.可以预见，随着有机化学、药物化学和化学生物学等学科的飞速发展，将会有越来越多的2，3－位稠环喹唑啉酮类化合物被发现并应用到更广的领域.【相关文献】[1]SACHIN S L，SATYENDRA P B.A new therapeutic approach in Parkinson’s disease：some novel quinazoline derivatives as dual selective phosphodiesterase 1inhibitors and anti－inflammatory agents[J].Bioorg Med Chem，2009，17（19）：6796－6802.[2]VEDULA M.Novel indolo[2，1－b]quinazoline analogues as cytostatic agents：synthesis，biological evaluation and structure activity relationship[J].Bioorg Med Chem Lett，2002，12（17）：2303－2307.[3]ZHONG Ze Ma，HANO Y，NOMURA T，et al.Two new quinazolinequinoline alkaloids from peganum nigellastrum[J].Heterocycles，1997，46：541－546.[4]LIU Ji Feng，CHRISTOPHER J W，YE P，et al.Privileged structure－based quinazolinone natural product－templated libraries：Identification of novel tubulin polymerizationinhibitors[J].Bioorg Med Chem Lett，2006，16（3）：686－690.[5]CHEN Zhuo，GAO Yun Hua，DAI Li，et al.Synthesis and vasodilator effects of rutaecarpine analogues which might be involved transient receptor potential vanilloid subfamily，member 1（TRPV1）[J].Bioorg Med Chem，2009，17（6）：2351－2359. [6]YANG Li Ming，CHEN C F，LEE K H.Synthesis of rutaecarpine and cytotoxic analogues[J].Bioorg Med Chem Lett，1995，5（5）：465 468.[7]POOJA P B，KEIR A R，VIRALI J P，et al.Antimicrobial activity of tryptanthrins in Escherichia coli[J].J Med Chem，2010，53（9）：3558－3565.[8]SUBHASH P C.A facile total synthesis of rutaecarpine[J].Tetrahedron Lett，2004，45（5）：997－999.[9]MIKHALEV A I，KONSHIN M E，OVODENKO L A.Synthesis，anti－inflammatory and analgesic activity of pyrido[2，1－b]quinazoline derivatives[J].Pharm Chem J，1995，29（2）：124－126.[10]OTTO M C，BRAMHA N，BRIAN T，et al.A versatile new synthesis of quinolines and related fused pyridines.Part 9.Synthetic application of the 2－chloroquinoline－3－carbaldehydes[J].J Chem Soc，Perkin Trans 1，1981：2509－2517.[11]CHAVAN S P，SIVAPPA R.A short and efficient general synthesis of luotonin A，B and E[J].Tetrahedron，2004，60（44）：9931－9935.[12]APURBA K B，MARK G H，DANIEL A N，et al.Structure－activity relationship study of antimalarial indolo[2，1－b]quinazoline－6，12－diones（tryptanthrins）.Three dimensional pharmacophore modeling and identification of new antimalarial candidates[J].Eur J Med Chem，2004，39（1）：59－67.[13]FRANCOIS R A，AMAYA B，ROGER W，et al.Novel series of 8H－quinazolino[4，3－b]quinazolin－8－ones viatwo Niementowski condensations[J].Tetrahedron，2003，59（9）：1413－1419.[14]JOHN H G，LOUIS C I，WILLIAM B H.Tetracyclic quinazolinone derivatives[J].J Med Chem，1971，14（9）：878－882.[15]LISIANNE D，CATHERINE L C，AXELLE G，et al.Efficient modified von niementowski synthesis of novel derivatives of 5a，14b，15－triazabenzo[a]indeno[1，2－c]anthracen－5－one from indolo[1，2－c]quinazoline[J].Tetrahedron Lett，2001，42（38）：6671－6674.[16]JUAN C J，VLAD E G，CHET L，et al.Acetylcholinesterase inhibition by fused dihydroquinazoline compounds[J].Bioorg Med Chem Lett，1996，6（6）：737－742. [17]TAN Jia Heng，OU Tian Miao，HOU Jin Qiang，et al.Isaindigotone derivatives：A new class of highly selective ligands for telomeric g－quadruplex DNA [J].J Med Chem，2009，52（9）：2825－2835.[18]SACHIN S L，SATAYENDRA P B.Efficient niementowski synthesis of novel 1，3，10，12－tetrasubstituted－8H－pyrido[2＇，3＇：4，5]pyrimido[6，1－b]quinazolin－8－ones[J].Arkivoc，2007，（xvi）：1－11.[19]LIU Ji Feng，MIRA K，YUKO I，et al.Microwave－assisted concise total syntheses of quinazolino benzodiazepine alkaloids[J].J Org Chem，2005，70（25）：10488－10493.[20]MAHAVIR P，CHEN LI JIAN，OLJAN R，et al.A new reaction of aminoiminomethanesulfonic acid with methyl anthranilates[J].Synth Commun，1998，28（11）：2125－2129.[21]MARIA F P，FRANCOIS R A，VALERIE T.A rapid and convenient synthesis of novel 1－imino－2，3－dihydro－1H－pyrazino[2，1－b]quinazolin－5－ones[J].Tetrahedron Lett，2004，45（15）：3097－3099.[22]TIMOTHY J，BARBARA D，HELENE B，et al.A new class of antihypertensive agents.1，2，3，5－tetrahydroimidazo[2，1－b]quinazolines[J].J Med Chem，1972，15（7）：727－731.[23]FADDA A A，REFAT H M，ZAKI M E.Synthesis of some new quinazolone fused heterocycles，2－substituted anilinoheterocyclic derivatives and other related compounds[J].Synth Commun，2001，31（22）：3537－3545.[24]SANG K L，GHEE H K，DONG H K，et al.Identification of a tryptanthrin metabolite in rat liver microsomes by liquid chromatography/electrospray ionization－tandem mass spectrometry[J].Biol Pharm Bull，2007，30（10）：1991－1995.[25]SHARIEF A M，AMMAR Y A.，ZAHRAN M A，et al.Aminoacids in the synthesis of heterocyclic systems：the synthesis of triazinoquinazolinones，triazepinoquinazolinones and triazocinoquinazolinones of potential biological interest[J].Molecules，2001，6：267－278.[26]VIJAY H P，MANISH P P，RANJAN G P.Fused heterocycle 11－amino－13H－acenaphtho[1，2－e]pyridazino[3，2－b]quinazoline－13－one based monoazo disperse dyes[J].Dyes and Pigments，2002，52：191－198.[27]SHARIEF E L，MICKY A A，SHARAF H F.Synthesis and antimicrobial activity of newly fused quinazolinone derivatives[J].J Taibah Univ Sci，2008，1：51－60.[28]ABHIJEET D R，ARUNACHALAM S，BALARAM M，et al.A one－pot synthesis of novel sugar derived 5，6－dihydroquinazolino[4，3－b]quinazolin－8－ones：an entry towards highly functionalized sugar－heterocyclic hybrids[J].Tetrahedron Lett，2006，47（38）：6857－6860.[29]GIANCARLO F，MARCO F，ALESSANDRO M，et al.Tetrahydropyrido[2，1－b]quinazolin－11－ones and tetrahydropyrido[l，2－a]quinazolin－6－ones viathermal cyclization of 2－substituted 4（3H）－quinazolinones[J].J Org Chem，1993，58（3）：741－743.[30]WANG Hai Shan，GANESAN A.Total synthesis of the quinazoline alkaloids（－）－fumiquinazoline G and （－）－fiscalin B[J].J Org Chem，1998，63（8）：2432－2433.[31]TSENG M C，CHU Yen Ho.Zinc triflate－catalyzed synthesis of pyrazino[2，1－b]quinazoline－3，6－diones [J].Tetrahedron，2008，64（40）：9515－9520.[32]BIRD C W.The rearrangement of 2－cyano－1－phenylpyrazolederivatives[J].Tetrahedron，1965，21（8）：2179－2182.[33]DALLA V L，GIA O，MARCIANI M S，et al.Synthesis，invitro antiproliferative activity and DNA－interaction of benzimidazoquinazoline derivatives as potential anti－tumor agents[J].II Farmaco，2001，56（3）：159－167.[34]TILLEY J W，COFFEN D L，SCHAER B H，et al.A palladium－catalyzed carbonyl insertion route to pyrido[2，1－b]quinazoline derivatives[J].J Org Chem，1987，52（12）：2469－2474.。
半胱氨酸脲基甲基化英文英文回答：Cysteine carbamylation is a post-translational modification (PTM) in which a carbamyl group is added to the side chain of cysteine residues. This modification can alter the structure and function of proteins, and has been implicated in a variety of diseases, including cancer and neurodegenerative disorders.Cysteine carbamylation is catalyzed by the enzyme carbamyltransferase. This enzyme transfers a carbamyl group from carbamoyl phosphate to the side chain of cysteine residues. Carbamoyl phosphate is a high-energy moleculethat is synthesized from glutamine and bicarbonate.The reaction mechanism of cysteine carbamylation is as follows:1. Carbamoyltransferase binds to carbamoyl phosphateand a cysteine-containing protein.2. Carbamoyltransferase transfers the carbamyl group from carbamoyl phosphate to the side chain of a cysteine residue.3. Carbamoyltransferase releases the carbamylated protein.Cysteine carbamylation can have a variety of effects on the structure and function of proteins. For example, carbamylation can alter the charge of a protein, which can affect its interactions with other proteins. Carbamylation can also alter the stability of a protein, which can affect its function.Cysteine carbamylation has been implicated in a variety of diseases, including cancer and neurodegenerative disorders. For example, cysteine carbamylation has been shown to promote the growth of cancer cells and to contribute to the development of Alzheimer's disease.Cysteine carbamylation is a reversible modification. The enzyme carbamidase can remove the carbamyl group from cysteine residues. Carbamidase is a zinc-dependent enzyme that is expressed in a variety of tissues.Cysteine carbamylation is a complex and dynamic process that plays an important role in a variety of cellular processes. Further research is needed to understand therole of cysteine carbamylation in health and disease.中文回答：半胱氨酸脲基甲基化。
ORIGINAL ARTICLESynthesis of Didodecylmethylcarboxyl Betaine and Its Application in Surfactant–Polymer FloodingZheng-gang Cui •Xiang-rui Du •Xiao-mei Pei •Jian-zhong Jiang •Feng WangReceived:15August 2011/Accepted:6August 2012/Published online:24August 2012ÓAOCS 2012Abstract Enhanced crude oil recovery by chemical flooding has been a main measure for postponing the overall decline of crude oil output in China,and surfactant-polymer (SP)flooding may replace alkali-surfactant-poly-mer flooding in the future for avoiding the undesired effects of using alkali.In this paper the synthesis of a surfactant with a large hydrophobe,didodecylmethylcarb-oxyl betaine (diC 12B),and its adaptability in SP flooding were investigated.The results show that diC 12B can be synthesized by reaction of didodecylmethyl amine,a product commercially available,with chloroacetic acid in the presence of NaOH,with a resulting yield as high as 80wt%under appropriate conditions.With double dodecyl chain diC 12B is highly surface active as displayed by its low CMC,3.7910-6mol L -1,low c CMC ,27mNm -1,as well as high adsorption and small cross section area (B 0.25nm 2)at both air/water and oil/water interfaces at 25°C.By mixing with conventional hydrophilic surfac-tants diC 12B can be well dissolved in Daqing connate water and reduce the Daqing crude oil/connate water interfacial tension to about 10-3mN m -1at 45°C in a wide total surfactant concentration range,from 0.01to 0.5wt%.And a tertiary oil recovery,18±1.5%OOIP,can been achieved by SP flooding using natural cores without adding any alkaline agent or neutral electrolyte.DiC 12B seems thus to be a good surfactant for enhanced oil recovery by SP flooding.Keywords Didodecylmethylcarboxyl betaine ÁSynthesis ÁSP flooding ÁInterfacial tensionIntroductionIt is well known that the domestic oil production in China is far from being sufficient to meet the rapid increase in oil consumption.In fact most of the giant oilfields in China have passed their peak production levels [1]and an overall decline in oil output is unavoidable in the near future.On the other hand there is still 60–70%remaining of crude oil trapped in the reservoir [2,3]after primary and second recoveries.It is thus attractive to try to recover some of this residual oil by tertiary or enhanced oil recovery (EOR)techniques [4,5].Among various EOR techniques [4]chemical flooding such as polymer flooding and alkali-surfactant-polymer (ASP)flooding [5]have been recognized to be suitable for most of the oilfields in China [6–19],and various surfac-tants,mostly anionic types,such as petroleum sulfonates [5],lignosulfonate [17],heavy alkylbenzene sulfonates [20],natural fatty acid carbonates and synthesized petro-leum carbonates [21],have been developed and tested since the 1980s.However recent field tests in China have revealed that the ASP flooding may bring some undesired effects [19,21–23]such as blocking of small pores in porous rocks and stain deposits on the apparatus and pipelines in injection systems,due to the formation of insoluble precipitates by the reaction of alkali with ions in connate water and sandstones.To avoid these side effects,improved ASP flooding using gentle alkaline agents such as Na 2CO 3or Na 2SiO 4[18,21]and surfactant-polymer (SP)flooding free of any alkaline agent [24–37]have been suggested in China.Z.Cui (&)ÁX.Du ÁX.Pei ÁJ.Jiang ÁF.WangThe Key Laboratory of Food Colloids and Biotechnology,Ministry of Education,School of Chemical and Material Engineering,Jiangnan University,1800Lihu Road,Wuxi 214122,Jiangsu,People’s Republic of China e-mail:cuizhenggang@J Surfact Deterg (2012)15:685–694DOI 10.1007/s11743-012-1396-2Both ASPflooding and SPflooding rely on reaching ultralow(\0.01mNm-1)interfacial tension(IFT),which can be attained with a surfactant or surfactant mixture with a large lipophilic tail and a large hydrophilic head at a Winsor ratio(R)of1,i.e.at a balanced interaction on both sides of a surfactantfilm[38].For specified crude oil this optimum physicochemical condition(R=1)can be obtained by varying the salinity of the brine,the molar ratio of a hydrophobic surfactant and a hydrophilic sur-factant in surfactant mixtures,the temperature(usually for nonionic surfactants),or by adding co-surfactants etc. [38–40].It has been recognized that in ASPflooding the ultralow IFT is usually achieved by means of the synergy between the surfactants added and those produced in situ via the reaction of alkali with acidic components in crude oil[6,8–10].Accordingly in the absence of alkali it is usually difficult to achieve an ultralow IFT using solely the surfactants for ASPflooding[6,8–10,12–15,17,18, 21]and new surfactants and surfactant formulations need to be designed.Individual surfactants alone are in general not perfect for SPflooding because their hydrophile-lipophile balances (HLB)do not match the optimum formulation condition with oil/connate water systems.This problem,however, can be solved by using surfactant mixtures[27,30]where a relatively hydrophilic surfactant is mixed with a relatively lipophilic surfactant and the overall HLB of the mixture can be adjusted by adjusting the composition of the com-ponents mixed.In the last decade many surfactants have been investigated for their adaptability in SPflooding, including various sulfonates[24–30],alkyl polyglycoside [31,32],alkylethanolamides[32,33],some zwitterionic surfactants[34–36],and cationic gemini surfactants[37]. These surfactants,however,are in general relatively hydrophilic.To develop surfactants with large hydrophobe character,at least two difficulties should be overcome.One is that the hydrophobic raw materials industrially available have usually a hydrocarbon chain no more than C18,which might not be sufficiently lipophilic for SPflooding with low salinity.The other is how to design a molecule to result in both enough lipophilicity and high adsorption at the oil/ water interface,as well as preventing precipitation from aqueous solution.These requirements,however,are not always consistent.For example,heavy alkylbenzene sul-fonates,mostly with two alkyls connected to a benzene ring,are relatively lipophilic but display large cross sectional areas at the oil/water interface.Similarly dode-cyllauroylbenzene sulfonate,a surfactant with a large lipophilic tail formed by connecting a lauroyl to dodecyl-benzene sulfonate,suffers from the same problem[41]. Other examples include dialkyl sodium sulfosuccinates which are sufficiently lipophilic but exhibit a low adsorp-tion per unit area.It has been reported that surfactants with branched or double hydrocarbon chains usually display strong interac-tion with oils and thus increase their adsorption at thefluid interface[27,42].However,the branched raw materials commercially available,such as branched alcohols,are mainly limited to those for preparing conventional surfac-tants(relatively hydrophilic).Thus we have paid special attention to the surfactants with double long hydrocarbon chains and single headgroup.Synthetically it is easier to connect double hydrocarbon chains to a nitrogen atom than to a carbon atom,the tertiary amines with double hydro-carbon chains are therefore ideal starting materials.In this paper we pleased to be able to report that didodecylmeth-ylcarboxyl betaine,synthesized by the reaction of didode-cylmethyl amine,a commercially available product,with chloroacetic acid in the presence of NaOH,is a surfactant with a large lipophilic tail good for SPflooding. Materials and MethodsMaterialsDidodecylmethyl amine(diC12A)of95%purity and chloroacetic acid of98%purity were supplied by Rhodia Feixiang Chemicals Co.Ltd.,China.Sodium hydroxide (NaOH)of97%purity was purchased from the Sinopharm Chemical Reagent Co.Sodium dodecyl sulfate(SDS)of 99%purity and Hyamine1,622of99%purity were purchased from Sigma.Dodecanol polyoxethylene(7) ether(AEO7)of98%was purchased from Haian Petro-leum Chemicals Co.,China.These chemicals were all used as received.Chloroform,ethanol,isopropanol,n-hexane, n-nonane,hydrochloric acid,and other reagents used are all of AR grade and were purchased from Sinopharm Chem-ical Reagent Co.Ultrapure water with a resistance of 18.2M X cm at25°C was purchased from a local micro-electronics factory,Huawei Co.Ltd.,Wuxi,China.Natural cores,crude oil,connate water and polymer(HPAM)were supplied by the Daqing Oilfield,China.SynthesisFirst,20g(0.052mol)diC12A was put into a250-cm3 3-neckflask,followed by adding40cm3pure water in which a certain amount of chloroacetic acid was dissolved to keep the chloroacetic acid/diC12A molar ratio at1.1/1. The mixture was stirred vigorously and heated to higher than80°C.Then a certain amount of NaOH aqueous solution(20wt%)was added dropwise from a funnel in 30min with the NaOH/chloroacetic acid molar ratio kept at1.1/1.The mixture was stirred and allowed to react at reflux temperature for8h.The product was thenneutralized using NaOH to pH7and was transferred to a funnel of250cm3and allowed to separate into three layers. The middle layer(raw product)was collected,analyzed, and further purified if necessary.The synthesis reaction and possible side reactions are shown in Scheme1.CharacterizationThe yield of the didodecylmethylcarboxyl betaine(diC12B) was examined by determining the content of diC12A remaining after reaction.This was accomplished by titrat-ing a solution of1g sample in20cm3isopropanol using 0.1M standard HCl-in-isopropanol solution with bromo-phenol blue as the indicator until the color of the solution changed from blue to yellow.The raw product was then further purified to remove salts (by-products)and unreacted amines.About15g dried(in a vacuum)raw product was dissolved in200cm3of ethyl acetate by heating and the suspension wasfiltered to remove insoluble salts.Thefiltrate was collected and cooled in a refrigerator to below0°C to allow the diC12B to crystallize from the ethyl acetate.The product was re-crystallized once more at a cooler temperature and further re-crystallized three times at room temperature from ethyl acetate.The purified product as a dry powder was then obtained byfil-tration followed by drying in a vacuum at60°C.The purified product was characterized by chemical analysis,IR(FTLA200-104,Boman,Canada)and ESI–MS (ZMD-4000LC/MS,Waters,USA)spectra respectively. The chemical analysis includes the measurement of un-reacted tertiary amine as described above,determina-tion of the contents of Na?and Cl-ions byflame atomic absorption spectrometry(TAS-990MFG,Beijing Puxi, China)and ionic chromatography(Metrohm-883),respec-tively,and determination of the content of active matter (diC12B)by the two phase titration method[43]using dimidium bromide-disulfine blue mixed indicator(from Sigma)where both diC12B and tertiary amine behave as cationic surfactants under acidic conditions[44].Since the tertiary amine was already determined independently,the content of active matter can then be calculated.Isoelectric Point MeasurementA series of aqueous solutions containing a1:1(molar ratio) mixture of purified diC12B and dodecanol polyoxyethylene (7)ether(AEO7)at a total concentration of2mM were prepared with the pH adjusted by adding HCl or NaOH. Then n-nonane-in-water emulsions were prepared by mixing7cm3of the aqueous solution and7cm3of n-nonane in a25cm3of glass bottle followed by homog-enizing at5000rpm for2min.After settling for24h,the emulsions were diluted with the corresponding aqueous solutions and the pH values and the zeta potentials of the droplets were measured respectively using a pH meter (FE20,Mettler Toledo)and a Zeta Potential&Particle Size Analyzer(Nano-ZS90,Malvern)at25°C.Surface and Interfacial Tension MeasurementThe surface tension of diC12B solutions in pure water was measured using the Du Nou¨y ring method at25±0.1°C. The dynamic interfacial tension(IFT)between surfactant–polymer solutions in connate water and crude oil from Daqing oilfield,China,as function of time was measured using a Texas500model tensiometer at45±0.1°C and the values at120min were taken as equilibrium IFTs.Oil Displacement Test with Natural CoreThe oil displacement tests using natural cores by SP flooding was done in the Laboratory of Oil Recovery, Institute of Petroleum Exploring and Development of Daqing,China.The related details are described in Ref.[33].Results and DiscussionSynthesis and Characterization of the ProductThe yield of diC12B as a function of reaction time was examined and this indicated that an8-h reaction issufficient for reaching a maximum yield under specified conditions.It was found that a yield as low as ca.50wt%is obtained under conditions for synthesizing conventional betaine surfactants such as dodecyldimethylcarboxyl beta-ine(C12B),probably due to the steric obstacle of the double long alkyls on the carboxymethylation reaction.To increase the yield,a higher temperature is necessary and a yield as high as80%can be approached at reflux tem-perature(ca.100°C).It is difficult to increase the yield further because at such a high temperature the hydrolysis of chloroacetic acid is significant and any measure against the hydrolysis will also inhibit the carboxymethylation reac-tion.Although increasing the chloroacetic acid/diC12A molar ratio can provide extra chloroacetic acid in the reaction system,the high molar ratio will result in the formation of the hydrochloric acid salt of the tertiary amine (diC12AÁHCl),which gives an acidic aqueous solution when dissolved in neutral water and decomposes in alka-line media.As a double chain surfactant,diC12B is less soluble in the electrolyte solution.The product thus separates after neutralization into three layers with the NaCl and otherwater soluble by-products dissolved in the water(lower) layer and the unreacted amine in the upper layer.The raw (middle)product contains typically60–65wt%diC12B, 5–10wt%un-reacted amine,and ca.25–35wt%moisture. To measure the surface activity parameters of the diC12B, the raw product was further purified and analyzed with the composition listed in Table1,which shows that apart from volatile components(moisture and solvents)the active matter is as high as98.3wt%.The IR spectrum of the diC12B together with that of the raw material,diC12A,is illustrated in Fig.1.It can be seen that after the reaction,the absorption of alkyl groups at 2,956,2,854,1,466,1,387,and721cm-1is present,and the C–N stretching vibration and bending vibration absorption appears at1,066and885cm-1respectively,where the latter is a little shifted due to the quaternization of N.A strong absorption appeared at1,635cm-1represents the C=O group,indicating formation of betaine.The strong and wide absorption at3,397cm-2,which usually refers to the absorption of associated hydroxyl groups,indicates the presence of moisture in the purified product.The ESI–MS spectrum(positive)of the purified product is shown in Fig.2.The peaks at m/z=426.3corresponds to[M?H]?where M=425.3is the molar mass of the diC12B,and a sub-peak at m/z=258.3corresponds to the betaine with one C12H25group replaced by H.Isoelectric Point of the diC12BIt is well known that alkylbetaines are zwitterionic at pH values equal to and higher than their isoelectric points(pI) and cationic below their pI[45].We tried to determine the pI of diC12B by measuring the zeta potentials of oil-in-water emulsion droplets stabilized by diC12B.However,no stable oil-in-water emulsion can be formed using diC12B solely due to its large lipophilic tail.By using an equal molar mixture of diC12B and AEO7,a hydrophilic nonionic surfactant,stable n-nonane-in-water emulsions with dif-ferent pH in aqueous phase were obtained.The zeta potentials of the oil droplets24h after formation were measured at25°C and compared with that of the droplets stabilized by AEO7solely,as illustrated in Fig.3.It is seen that the zeta potentials of the droplets stabilized by AEO7 solely are close to zero,indicating that the zeta potentials of the droplets stabilized by diC12B/AEO7mixture depends on the charge of the diC12B molecules adsorbed.It is seenTable1Compositions of diC12B purified by chemical analysisdiC12B/wt%diC12AÁHCl a/wt%Tertiary amine/wt%NaCl b/wt%Moisture and solvent/wt%Total/wt%diC12B in solid/wt%92.7±0.33Not detected 1.60±0.130.03±0.001 5.93100.398.3a Based on the content of Cl-measured by ionic chromatographb Based on the total Na?measured byflame atomic absorbance spectrometry and ignored HOCH2COONathat at low pH the zeta potentials are strongly positive,which then decreases with increasing pH,and approaches to zero at pH [5.4.The isoelectric point,pI =5.4,at acidic region indicates that the dissociation of the negative charge is stronger than that of the positive charge in diC 12B molecules.Surface Activity Parameters of diC 12BThe raw product is quite soluble in pure water at room temperature and at relatively high concentration,for example at 50mM,the solution has a pH value close to 6,and is an appropriate fluid rather than a gelatinous solution as with octadecyldimethylcarboxy betaine (C 18B).How-ever the re-crystallized diC 12B is less soluble in pure water and turbid solutions are obtained at concentrations beyond 0.1mM.Nevertheless transparent aqueous solutions can be prepared with concentrations no more than 0.1mM.The surface tensions of the solutions as a function of concen-tration at different conditions are examined and illustratedin Fig.4.It can be seen that the surface tension in the presence of 1:1(molar ratio)NaCl shows no difference from that in the absence of NaCl.This is expected since the concentration of NaCl is very low (\0.1mM).In the presence of 0.1M NaCl,however,the c -LogC curve of diC 12B moves leftwards,probably due to the salting out effects.Since the pH of the aqueous solution is close to 6,a little higher than its pI,diC 12B molecules in solutions are zwitterionic without net charge.The adsorption of diC 12B at air/water interface can then be obtained using Gibbs adsorption equation for nonionic surfactants:C ¼À1RT d c d ln C T ¼À12:303RT d cd log C T ð1Þwith and without the presence of excess NaCl.Table 2lists the saturated adsorption,C ?,of the diC 12B at air/water interface in three cases,together with other surface activity parameters such as CMC,c CMC (surface tension at CMC),and a ?,the cross section area of the molecule at saturated adsorption.It can be seen that diC 12B is highly surface active as displayed by its low CMC,3.7910-6mol L -1,low c CMC ,27.0mNm -1,and high saturated adsorption,8.0910-10mol cm -2,whichgivesFig.2ESI-MS spectrum of diC 12Ba cross sectional area,0.21nm2,at the air/water interface, much lower than that of SDS(0.5nm2).Compared with the CMC value of C18B(ca.4.2910-6mol L-1)the CMC of diC12B(totally C24)is relatively high,indicating that the presence of double long alkyl chains in a molecule inhibits formation of micelle and is beneficial to attain a lower c CMC.In the presence of0.1M NaCl,the saturated adsorption is also high(6.6910-10molcm-2)and a similar cross section area(0.25nm2)is obtained.The IFT of n-nonane/diC12B aqueous solution as function of diC12B concentration at25°C was also measured,as illustrated in Fig.5.The CMC obtained is 3.0910-6mol L-1,in good agreement with that from surface tension measurement.The saturated adsorption at oil/water interface is even higher than that at air/water interface,with the cross section area decreasing to 0.125nm2.The diC12B is thus expected to be a good surfactant for reducing crude oil/water IFT and favorable for SPflooding.Ultralow Crude Oil/Connate Water Interfacial Tension and Tertiary Oil Recovery by SP FloodingUltralow IFT can usually be achieved at both low(\0.5%) and high(3–5%)surfactant concentration ranges[46].The former is achieved by adsorption of the surfactant at the oil/ water interface whereas the latter is correlated to phase behavior,in particular to the existence of Winsor III mi-croemulsions[38].In both cases the IFT is strongly affected by the alkane carbon number(ACN)of the oil or the equivalent alkane carbon number(EACN)of a crude oil,salinity of the aqueous phase,temperature and co-surfactants added[43–49],and ultralow IFT is onlyachieved when interactions of the surfactantfilm with both water and oil sides are balanced.It is thus essentially impossible to use a single surfactant to achieve ultralow IFT and mixed surfactants are usually needed.For obtaining optimum formulations researchers have pre-sented a series of criterions and methods,such as the par-tition coefficient method[39,47],the Winsor R ratio method[38],the packing parameter method[27,38],the solubilization parameter method[38],as well as HLB and PIT[48,49]and HLD and SAD methods[40,49].Here we focus on achieving an ultralow IFT in dilute surfactant system with respect to specific(Daqing)crude oil (EACN=9)and connate water at afixed temperature (45°C),without adding any alkaline agent,neutral elec-trolyte and co-surfactant.The variable affecting formula-tion properties is simply the hydrophilic-lipophilic interactions of the surfactantfilm at the oil/water interface.For the Daqing crude oil/connate water system it is found that the diC12B is relatively lipophilic for obtaining ultralow IFT and hydrophilic surfactants need to be added to balance the hydrophilic-lipophilic interactions.Figure6 illustrates the dynamic IFT between Daqing crude oil andTable2Surface activity parameters of diC12B at25°Interface NaCl CMC/mol L-1c CMC/mNm-1C?/mol cm-2a?/nm2molec-1Air/water No 3.7910-627.08.0910-100.211:1 3.7910-627.08.0910-100.210.1M 2.0910-627.0 6.6910-100.25Nonane/water No 3.0910-60.6413.3910-100.125connate water containing 1,000mg L -1polymer (HPAM with a molecular weight of 25millions)and mixed surfac-tants (formulation 1)at a total concentration between 0.025and 0.3wt%at 45°C in the absence of any alkaline agent and neutral electrolyte added.The mixed surfactants are composed of diC 12B (raw product),dodecyl polyoxyethyl-ene (3)ether sulfate (AES),and a mixed alkyldimethyl-carboxyl betaine C n B (n between 12and 18)at molar proportions 45/20/35.The connate water has a total ion concentration of 5,334mg L -1with NaCl,Na 2CO 3and NaHCO 3being the dominant native electrolytes,as shown in Table 3,and behaves as a buffer solution giving a pH =8.68at 45°C.The mixed surfactants dissolved well in the connate water and the pH of the solutions remains con-stant over wide surfactant concentrations (0.01–0.5wt%).DiC 12B thus behaves as zwitterionic in the connate water.It is seen that the IFT drops to 10-3mNm -1in \10min and remains stable for 120min except at high concentration,0.3wt%,where an increase is observed after 80min,though the equilibrium IFT is still below 0.01mN m -1.The dynamic IFT behavior of another formulation (formulation 2)is illustrated in Fig.7where the mixed surfactants are composed of diC 12B,C n B,and lauroyldi-glycol amide (LDGA)at molar proportions 25/20/55/.Similar characteristics are observed,and the total effective concentration is even wider,from 0.01to 0.5wt%.Figures 8,9and 10illustrate how the balance between the lipophilic and hydrophilic interactions of the surfactant film affects the achieving of ultralow IFT with formulation2.In Figs.8and 9the molar fraction of LDGA is kept constant (0.55)and the hydrophilic interaction of the sur-factant film increases with increasing molar fraction of C n B and decreases with increasing molar fraction of diC 12B.It is seen that at a total concentration of 0.2wt%,ultralow IFTs are attainable when the molar ratio of diC 12B/C n B is between 0.225/0.225and 0.175/0.275,and the optimum formulation is diC 12B/C n B/LDGA with proportions 0.20/0.25/0.55.Figure 9indicates that at a lower total concen-tration (0.05wt%)the effective diC 12B/C n B molar ratioTable 3Ion composition of connate water from Daqing oilfield,China IonsCO 32-HCO 3-Cl -SO 42-Ca 2?Mg 2?Na ?Total Amount/mg L -1244.92,427.4890.868.734.16.41,662.05,334.3range is even wider(between0.25/0.2and0.175/0.275).In Fig.10the diC12B/C n B molar ratio is kept at1/1.25and the molar fraction of LDGA displays also an optimum range (between0.5and0.6).The equilibrium IFTs of the two formulations are sum-marized in Fig.11and they indicate that over a wide range of total concentrations,the crude oil/connate water IFT can be reduced to the order of10-3mNm-1,which has been regarded as a necessary condition for obtaining good ter-tiary recovery[32,35].The oil recovery of SPflooding using mixed surfac-tants(formulation1)at a total surfactant concentration of 0.3wt%was conducted using natural cores at45°C with crude oil and connate water from factory No2, Daqing Oilfield,China.The results are listed in Table4, and they show that an average tertiary recovery of18% OOIP can be achieved by SPflooding after water flooding.The diC12B synthesized is thus a proper sur-factant with large hydrophobe character for SPflooding and we believe that it may be used for more crude oils/ connate water systems once the formulation is adjusted to being optimum by mixing with suitable conventional hydrophilic surfactants.ConclusionsDidodecylmethylcarboxyl betaine(diC12B)may be syn-thesized by reacting didodecylmethyl amine,a tertiary amine commercially available,with chloroacetic acid in the presence of NaOH,with a yield as high as80wt%in appropriate conditions.The structure of purified diC12B was confirmed by IR and ESI–MS spectra,and the surface activity was investigated by measuring the surface and interfacial tensions.With double dodecyl chains(totally C24)diC12B is highly surface active as displayed by its low CMC,3.7910-6mol L-1,low c CMC,27mNm-1,and high adsorption and a small cross sectional area (\0.25nm2)at both air/water and oil/water interfaces. Although diC12B solely is not much soluble in connate water,it can be readily dissolved by mixing with suitable conventional hydrophilic surfactants.The mixed surfac-tants can reduce Daqing crude oil/connate water interfacial tension down to10-3mNm-1at45°C in over a wide total surfactant concentration range,i.e.from0.01to0.5wt%, and achieve a tertiary oil recovery of about18%OOIP by SPflooding using natural cores,without adding any alka-line agent or neutral electrolyte.DiC12B displays an iso-electric point,pI=5.4,at25°C suggesting that diC12B molecules are zwitterionic in both pure water and theTable4Oil recovery by SPflooding(formulation1)using natural cores at45°CNo.Core permeability(10-3l m2)Crude oilsaturation(%)Recovery of waterflooding(%)Recovery of SPflooding(%)Totalrecovery(%)Tertiary recovery(av)by SPflooding(%)171163.9537.3617.5854.9418.04±1.50 280172.7032.5016.2548.75380871.6040.3020.3060.50A0.1-PV polymer solution was initially injected,followed by injecting a0.3-PV SP solution and a0.2-PV polymer solution.The total surfactant concentration in SP solution was0.3wt%and the concentrations of polymer were1,000mg L-1Daqing connate water which behaves as a weak alkaline buffer solution(pH=8.68at45°C)due to containing Na2CO3and NaHCO3as the dominant native electrolytes. Acknowledgments The authors thank the Laboratory of Oil Recovery,Institute of Petroleum Exploring and Development of Daqing,China,forfinancial support and the measurement of oil recovery using natural cores.The authors also thank Miss Shan Cheng,Miss Wen-yan Zhang,and Mr.Chuan-wen Liao,who did parts of the experimental work as M.Sc.students.References1.Ho¨o¨k M,Tang X,Pang XQ,Aleklett K(2010)Developmentjourney and outlook of Chinese giant oilfields.Petrol Explor Dev 37:237–2492.Egbogah EO(1994)EOR target oil and techniques of its esti-mation.J Petroleum Sci Eng10:337–3493.Babadagli T(2007)Development of mature oilfields—a review.J Petroleum Sci Eng57:221–2464.Adasani AA,Bai B(2011)Analysis of EOR projects and updatedscreening criteria.J Petroleum Sci Eng79:10–245.Hirasaki GJ,Miller CA,Puerto M(2008)Recent advances insurfactant EOR.Paper SPE115386.Presentation in International Petroleum Technology Conference,Kuala Lumpur,Malaysia, 3–5December20086.Nedjhioui M,Moulai-Mostefa N,Morsli A,Bensmaili A(2005)Combined effects of polymer/surfactant/oil/alkali on physical chemical properties.Desalination185:543–5507.Carrero E,Queipo NV,Pintos S,Zerpa LE(2007)Global sen-sitivity analysis of alkali-surfactant-polymer enhanced oil recovery process.J Petroleum Sci Eng58:30–428.Taylor KC,Nasr-El-Din HA(1996)The effect of synthetic sur-factants on the interfacial behaviour of crude oil/alkali/polymer systems.Colloid and Surf A108:49–729.Chatterjee J,Wasan DT(1998)A kinetic model for dynamicinterfacial tension variation in an acidic oil/alkali/surfactant system.Chem Eng Sci53:2711–272510.Chatterjee J,Wasan DT(1998)An interfacial model for mixedadsorbed for a ternary system application to an acidic oil/alkali/ surfactant system.Colloid Surf A132:107–12511.Dong MZ,Ma SZ,Liu Q(2009)Enhanced heavy oil recoverythrough interfacial instability:a study of chemicalflooding for Brintnell heavy oil.Fuel88:1049–105612.Cao Y,Li H(2002)Interfacial activity of a novel family ofpolymeric surfactants.Euro Polym J38:1457–146313.Liu Q,Dong M,Zhou W,Ayub M,Zhang YP,Huang S(2004)Improved oil recovery by adsorption–desorption in chemical flooding.J Petroleum Sci Eng43:75–8614.Yang J,Qiao W,Li Z,Cheng L(2005)Effects of branching inhexadecylbenzene sulfonate isomers on interfacial tension behavior in oil/alkali systems.Fuel84:1607–161115.Zhang S,Yan J,Qi H,Luan J,Qiao W,Li Z(2005)Interfacialtensions of phenyltetradecane sulfonates for enhanced oil recovery upon the addition of fatty acids.J Petroleum Sci Eng 47:117–12216.Zhang H,Dong M,Zhao S(2010)Which one is more importantin chemicalflooding for enhanced court heavy oil recovery, lowering interfacial tension or reducing water mobility?Energy Fuels24:1829–183617.Jian YH,Xu ZG,Qiao WH,Li ZS,Cheng LB(2004)Research onsynthesis and performance of novel modified lignosulfonate surfactants.J Dalian Univ Technol44(1):44–47(Ch)18.Guo WK,Yang ZY,Wu XL,Zhang GY,Wang HF(2006)Newtype weak alkali surfactant applied to tertiary oil recovery.Acta Petrol Ei Sinica27:75–78(Ch)19.Hou JR,Liu ZC,Yue XA(2006)Effect of multisystem ultralowinterfacial tension and alkali in oil displacement process.PGODD 25:82–86(Ch)20.Cui ZG,Zou WH,Zhang TL,Zhang DG(1999)Synthesis ofheavy alkylbenzene sulfonates and their applications in enhanced oil recovery.J East China Univ Sci Technol(Natural Science Edition)25:339–346(Ch)21.Yue XY,Lou ZH,Han D,Yuan SY(2004)Synthesis andproperties of petroleum sulfonates surfactant for weak-base sys-tem for EOR.Adv Fine Petrochem5:7–10(Ch)22.Han M,Kang XD,Zhang J,Xiang WT(2006)Progress in EORby means of surfactants.China Offshore Oil Gas18:408–412 (Ch)23.Zhao FL(2007)Research advances of chemicals for oil pro-duction.J China University Petroleum31:163–172(Ch)24.Chiu YC,Kuo PR(1999)An empirical correlation between lowinterfacial tension and micellar size and solubilization for petroleum sulfonates in enhanced oil recovery.Colloids Surf A 152:235–24425.Berger PD,Lee CH(2002)Ultra low concentration surfactantsfor sandstone and limestonefloods.SPE75186.Presented at the 2002SPE/DOE improved oil recovery symposium,Tulsa Okla-homa,13–17April200226.Zhang S,Xu Y,Qiao W,Li Z(2004)Interfacial tensions upon theaddition of alcohols to phenylalkane sulfonate monoisomer sys-tems.Fuel83:2059–206327.Rosen MJ,Wang H,Shen P,Zhu Y(2005)Ultralow interfacialtension for enhanced oil recovery at very low surfactant ngmuir21:3749–375628.Xu Z,Li P,Qiao W,Li Z,Cheng L(2006)Effect of aromatic ringin the alkyl chain on surface properties of arylalkyl surfactant solutions.J Surf Deterg9:245–24829.Zhao Z,Liu F,Qiao W,Li Z,Cheng L(2006)Novel alkylmethylnaphthalene sulfonate surfactants:a good candidate for enhanced oil recovery.Fuel85:1815–182030.Aoudia M,Al-Shibli MN,Al-Kasimi LH,Al-Maamari R,Al-Bemani A(2006)Novel surfactants for ultralow interfacial ten-sion in a wide range of surfactant concentration and temperature.J Surf Deterg9:287–29331.Iglauer S,Wu Y,Shuler P,Tang Y,Goddard WA III(2009)Alkyl polyglycoside surfactant-alcohol cosolvent formulations for improved oil recovery.Colloids Surf A339:48–5932.Iglauer S,Wu Y,Shuler P,Tang Y,Goddard WA III(2010)Newsurfactant classes for enhanced oil recovery and their tertiary oil recovery potential.J Petroleum Sci Eng71:23–2933.Cui ZG,Song HX,Yu JJ,Jiang JZ,Wang F(2011)Synthesis ofN-(3-oxapropanoxyl)dodecanamide and its application in sur-factant–polymerflooding.J Surf Deterg14:317–32434.Wu WX,Yan W,Liu CD(2007)The results of corefloodingexperiment by sulfobetaine/polymer combinational system.Oil-field Chem24(57–59):60–62(Ch)35.Xia HF,Wang G,Ma WG,Liu CD,Wang YW(2008)Influenceof viscoelasticity and interfacial tension of non-alkali binary compound solution on recovery efficiency of residual oil after waterflooding.Acta Petrol Ei Sinica29:106–115(Ch)36.Ma T,Shao HY,Wang HB,Jiang P,Wei TJ,Tang DZ(2008)Alaboratory study of the composite two-component oil-displace-ment system without alkali.China Offshore Oil Gas2:41–47(Ch) 37.Chen H,Han L,Luo P,Ye Z(2004)The interfacial tensionbetween oil and Gemini surfactant solution.Surf Sci552:L53–L5738.Bourrel M,Schechter RS(1988)Microemulsion and relatedsystems:formulation,solvency,and physical properties.。
