叔丁基苯氧甲基喹啉酸的一锅法合成及其闭环反应的研究

2-溴甲基-3-喹啉酸乙酯与叔丁基酚发生Williamson反应,反应的中间产物与碱液发牛水解反应,两步一锅法高收率地合成了标题化合物.所得的叔丁基苯氧甲基喹啉酸在Eaton's reagent(P2O5-CH3SO3H)的作用下进行分子内的Friedel-Crafts酰基化反应得到叔丁基取代的苯并杂卓并喹啉酮化合物.化合物叔丁基苯氧甲基喹啉酸、叔丁基取代的苯并杂卓并喹啉酮化合物是未见文献报道的新化合物.它们的结构经红外光谱、核磁共振氢谱和元素分析得以证实.     

N-甲基-3,3-二甲基螺[2H-吲哚-2,3-[3H]萘并[2,1-b][1,4]噁嗪]的微波合成与表征

以三乙胺为催化剂,1-亚硝基-2-萘酚和1,3,3,-三甲基-2-亚甲基吲哚啉为原料合成了N-甲基-3,3-二甲基螺[2H-吲哚-2,3,-[3H]萘并[2,1-b][1,4]噁嗪]。本反应在无溶剂下的微波反应,相比传统有机反应大大缩短了反应时间。并且探讨了反应温度、反应时间、催化剂用量对反应的影响。对产物进行了IR、~1HNMR、~(13)CNMR等表征,结果表明:反应温度150℃,反应10 min,可以获得较高产率的纯产物。     

7-溴-9-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚的合成

以6-溴吲哚-3-甲醛为原料,通过N-甲基化、Henry反应、烯烃还原、硝基还原、Pictet-Spengler等反应5步合成得到7-溴-9-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚的合成,5步反应总收率25.1%。产物结构经1H NMR和ESI-MS确证。并对色胺衍生物(5)与乙醛酸的Pictet-Spengler反应的条件进行考察,确定最佳反应条件为:浓盐酸为质子酸催化剂;反应温度50℃;反应时间8h。     

噻唑并[3,2-b][1,2,4]三唑酮衍生物的合成及抗癌活性研究

以3,4,5-三甲氧基苯甲酸为原料,经过Claisen缩合等反应设计合成一系列新的噻唑并[3,2-b][1,2,4]三唑-6-酮稠杂环衍生物并测定其体外抗肿瘤活性。目标化合物经~1HNMR、~(13)CNMR和高分辨质谱等表征后,在He La、HCT116、BEL-7402及L-02细胞中用MTT法测定其抑制细胞增殖的程度,并初步判断化合物的体外抗癌活性。结果表明,与临床常用药顺铂(DDP)相比,多数化合物具有抑制肿瘤细胞增殖活性。其中,5-(4-苄氧基苯亚甲基)-2-(3,4,5-三甲氧基苯基)噻唑并[3,2-b][1,2,4]三唑-6(5H)-酮、5-(4-乙酰氧基苯亚甲基)-2-(3,4,5-三甲氧基苯基)噻唑并[3,2-b][1,2,4]三唑-6(5H)-酮、5-(α-呋喃亚甲基)-2-(3,4,5-三甲氧基苯基)噻唑并[3,2-b][1,2,4]三唑-6(5H)-酮和5-(α-噻吩亚甲基)-2-(3,4,5-三甲氧基苯基)噻唑并[3,2-b][1,2,4]三唑-6(5H)-酮对HCT116等3种癌细胞的抑制率高于正常细胞L-02,且对癌细胞有选择性抑制作用,而对正常细胞无毒性,具有良好的后续研究价值。5-(4-氟苯亚甲基)-2-(3,4,5-三羟苯基)噻唑并[3,2-b][1,2,4]三唑-6(5H)-酮对BEL-7402等细胞的抑制率有大幅度提高,但对L-02正常细胞的毒性更大。     

3,4-二甲基-2,5-二甲酸乙酯噻吩[2,3-b]并噻吩选择性酰肼化

以乙酰丙酮和二硫化碳为原料合成出3,4-二甲基-2,5-二甲酸乙酯噻吩,它在不同溶剂中与过量水合肼反应,得到不同的产物:在乙醇中回流24 h,以66%的产率得到单酰肼化产物3,4-二甲基-噻吩[2,3-b]并噻吩-2-甲酸乙酯-5-甲酰肼;以DMF为溶剂80℃反应得到的主要产物是3,4-二甲基-2,5-噻吩[2,3-b...     

2-甲基-5-(4-甲氧基苯磺酰胺)萘并[1,2-b]呋喃-3-羧酸乙酯的合成

乙酰乙酸乙酯与对甲苯胺、磷酸二氢钾反应得到3-(对甲苯氨基)-2-丁烯酸乙酯(化合物3);4-氨基-1-萘酚盐酸盐与甲氧基苯磺酰氯反应得到4-甲氧基-N-(4-羟基萘)苯磺酰胺(化合物6),之后经高碘酸钠氧化得到4-甲氧基-N-(4-氧代萘)苯磺酰胺(化合物7);中间体3和7发生环化得到目标物2-甲基-5-(4-甲氧基苯磺酰胺)萘并[1,2-b]呋喃-3-羧酸乙酯(化合物8),其结构经1H NMR、13C NMR和HRMS确证.对中间体3、中间体7以及目标物8的合成条件进行优化,滴加原料对甲苯胺、使用KH2PO4作为催化剂时,可在较低温度下顺利得到中间体3;控制氧化剂用量、使用乙醇含量高的水溶液作为溶剂有利于中间体7的生成和后处理;在反应体系中加入少量水,可减少化合物8的副产物生成.该方法为N-(萘并[1,2-b]呋喃-5-基)苯磺酰胺类化合物的合成提供了参考.     

5,6,7,8-四氢吡啶并[3,4-b]吡嗪的合成

3,4-二氨基吡啶与乙二醛环化得到吡啶并[3,4-b]吡嗪,进一步与氯甲酸乙酯在硼氢化锂的作用下发生还原反应得到乙基5,6-二氢吡啶并[3,4-b]吡嗪-6(5H)-羧酸酯,然后经钯碳氢化得到乙基-5,6,7,8-四氢-二氢吡啶并[3,4-b]吡嗪-6(5H)-羧酸酯,最后在碱性条件下去保护基团合成了5,6,7,8-四氢吡啶并[3,4-b]吡嗪。对还原反应进行了工艺研究,确定优化反应条件:硼氢化锂为还原剂,反应时间为1 h,反应温度为-15℃。总收率为48.4%。产品结构经1H NMR确证。     

6-(1-苯基-乙基)-8H-吡咯并[3,4-b]吡啶的合成

以2,3-吡啶二羧酸作为起始原料,通过环合、氢化及内酰胺还原反应合成标题化合物,作为合成莫西沙星侧链(S,S)-2,8-二氮杂双环[4.3.0]壬烷的新型中间体。对各个中间体制备过程中原料的用量比进行了探究:在2,3-吡啶二酸酐的制备中,2,3-吡啶二羧酸与SOCl2的物质的量比为1∶1.35;在6-(1-苯基-乙基)-吡咯并[3,4-b]吡啶-5,7-二酮的制备中,2,3-吡啶二酸酐与SOCl2的物质的量比为n(2,3-吡啶二酸酐)∶n(SOCl2)=1∶1.10;在目标产物的制备中,n(6-(1-苯基-乙基)-6H-吡咯并[3,4-b]吡啶-5,7-二酮)∶n(Na BH4)∶n(BF3·Et2O)=1∶3.2∶3.2×0.95。另外,在氢化还原反应中,选用冰醋酸作为反应溶剂,目标化合物总收率73.7%,并通过1HNMR对中间体及产物结构进行了确证。该研究为(S,S)-2,8-二氮杂双环[4.3.0]壬烷的合成提供了新思路。     

7-苄氨基-9,10-二氢-1,2,4-三氮唑并[4,3-a]喹啉衍生物的合成及环合反应的探讨

以6-氨基-3,4-二氢-2(1H)-喹啉酮为起始原料,经缩合、还原、硫代、环合等反应合成了5个7-苄氨基-9,10-二氢-1,2,4-三氮唑并[4,3-a]喹啉衍生物。产物的结构经核磁共振谱和质谱确证。     

6-甲基-4-羟基-噻嗯并[2,3-b]噻喃-2-磺酰胺的合成

以2-巯基噻吩和巴豆酸为起始原料,经加成缩合制得3-(2-噻吩巯基)丁酸;在P2O5催化下环合制得6-甲基-4-氧-噻嗯并[2,3-b]噻喃;再用氯磺酸进行氯磺化、氨水氨解制得6-甲基-4-氧-噻嗯并[2,3-b]噻喃-2-磺酰胺;最后用硼氢化钠还原得到盐酸杜塞酰胺的中间体6-甲基-4-羟基-噻嗯并[2,3-b]噻喃-2-磺酰胺,合成总收率为16.0%。其化学结构经IR,1H NMR,MS得以确证。     

3-Amino-thieno[2,3-b]furane und 3-Amino-thieno[3,2-b]furane

3-Amino-thieno[2,3-b]furans and 3-Amino-thieno[3,2-b]furans The O-alkylation of 2-hydroxy-thiophene-3-carbonitriles ( 1 ) with α-bromocarbonyl compounds yields the 2-alkoxy-thiophene-3-carbonitriles ( 2a–f ) among them 2-benzoylmethoxy-thiophene-3-carbonitriles ( 2a–c ) which undergo Thorpe-Ziegler-cyclization to form the 3-amino-2-benzoyl-thieno[2,3–b]furans ( 3 ) in low yields. The 2-acyl-3-amino-thieno[3,2–b]furans and ethyl 3-amino-thieno[3,2–b]furan-2-carboxylates ( 6 ) are synthesized in similar manner from 3-hydroxy-thiophene-2-carbonitriles ( 4 ) and α-halogencarbonyl compounds via 3-acylmethoxy- and 3-ethoxycarbonylmethoxy-thiophene-2-carbonitriles ( 5 ) with high yields.     

咪唑并[1，2-b]哒嗪

介绍了咪唑并[1,2-b]哒嗪的合成方法、用途、生产及需求.以3,6-二录哒嗪为原料,经氨化、环合、脱氯得咪唑并[1,2-b]哒嗪。咪唑并[1,2-b]哒嗪是合成头孢类抗生素的侧链中间体,因合成难度较大,成为国内开发头孢唑兰的瓶颈.     

SYNTHESIS OF DIHYDRODIOLS OF PHENANTHRO[3,4-b]THIOPHENE AND PHENANTHRO[4,3-b]THIOPHENE

A number of sulfur analogs of polynuclear aromatic hydrocarbons (thia-PAHs) have been identified in cigarette smoke condensate. Phenanthro[3,4-b]thiophene (P[3,4-b]T) and phenanthro[4,3-b]thiophene (P[4,3-b]T) are sulfur analogs of benzo[c]phenanthrene, which is known to be metabolized to one of the most tumorigenic fjord region diol epoxides tested thus far. Although fjord region diol epoxides of P[3,4-b]T and P[4,3-b]T are expected to be potent mutagens and tumorigens, these two thia-PAHs differ greatly in their mutagenic potencies. In contrast to P[3,4-b]T which is as mutagenic as benzo[a]pyrene, its isoster P[4,3-b]T is a nonmutagenic compound. In order to understand the basis underlying the difference in the mutagenic potency of P[3,4-b]T and P[4,3-b]T, we require these thia-PAHs and their dihydrodiol derivatives for investigating their metabolism and mutagenic/carcinogenic activity. In these studies, we have investigated the Suzuki cross-coupling reaction for an abbreviated synthesis of P[3,4-b]T, P[4,3-b]T, and their dihydrodiol derivatives from easily available reagents.     

3-Amino-isothiazolo[5,4-b]pyridine

3-Amino-isothiazolo[5,4-b]pyridines The reaction of 3-cyanopyridine-2-thiones 1 with hydroxyl-amine-O-sulfonic acid leads to 3-cyanopyridine-2-sulfenamides 2 which in the presence of bases immediately cyclize to form 3-amino-isothiazolo[5,4-b]pyridines 3 . Side reaction is the oxidation which occurs predominantly in the reaction of 1 with chloramine to form the disulfides 4 . With chloramine, the isothiazolopyridine is obtained only in the case of 4,6-dimethyl-3-cyano-pyridine-2-thione.     

3-Amino-furo[2.3-b]pyridine

3-Amino-furo[2,3-b]pyridines The reaction of the 3-cyano-2-pyridones 1 with α-halogen carbonyl compounds yields 2-alkoxy-pyridines 2 which can be cyclized in the presence of sodium ethoxide to form 3-amino-furo[2,3-b]pyridines 3 . From 4,6-dimethyl-3-cyano-2-pyridone, mixtures of N- and O-alkylated compounds are obtained which by cyclization in addition to 3-amino-furopyridines 6 yield indolizinones 7 . From 3 , pyridofuro-pyrimidines 9 can be synthesized.     

Two-component,one-pot synthesis of pyrimido[1,2-b] [1,2,4,5]tetrazines

Derivatives containing the cyclohepta4′,5′thieno[2′,3′:4,5]pyrimido[1,2-b][1,2,4,5]-tetrazin-6-one system were prepared from the reaction of 3-amino-2-thioxo-1,2,3,5,6,7,8,9-octahydro-4H-cyclohepta[4,5]thieno[2,3-d]pyrimidin-4-one (5) or its 2-methylthio derivative 6 with hydrazonoyl chlorides 9. The mechanism of the studied reactions has been discussed and the biological activity of the isolated products has been evaluated.