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烷氧基联苯类化合物的合成及抗病毒活性研究
Studies on the Synthesis and Activity of Anti-Virus of Alkyloxy-biphenyl Compounds
【作者】 程森祥;
【导师】 陈荣峰;
【作者基本信息】 郑州大学 , 有机化学, 2004, 博士
【摘要】 以4,4′-二甲氧基-5,6,5′,6′-二亚甲二氧基联苯为先导化合物,构建了两类由取代苄基哌嗪修饰的新型烷氧基联苯化合物,测定了部分化合物的抗病毒活性;为构建联苯分子骨架,对烷氧基溴苯的偶合方法进行了研究;通过直接不对称Ullmann偶合或Ullmann-type偶合反应及构象转化方法制备了轴手性烷氧基联苯化合物。 1.第一类化合物建立在先导化合物4,4′-二甲氧基-5,6,5′,6′-二亚甲二氧基联苯′2,2′-二甲酸二甲酯的基础上。首先,由2-溴-3,4-亚甲二氧基-5-甲氧基-苯甲酸甲酯在活性铜或镍的作用下偶合得到4,4′二甲氧基-5,6,5′,6′-二亚甲二氧基联苯-2,2′-二甲酸二甲酯,再转化为三种4,4′-二甲氧基-5,6,5′,6′-二亚甲二氧基联苯-2,2′-二甲酸单酯。然后与另外制备的取代苄基哌嗪进行反应,在DMAP,DCC的作用下生成新化合物4,4′-二甲氧基-5,6,5′,6′-二亚甲二氧基-2-烷氧甲酰基-2′-(4-取代苯甲基-哌嗪-1-羰基)-联苯。采取NMR,ESI-MS,IR等手段进行了结构确证。 选取部分化合物进行抗SIV活性测定,结果表明,合成的新化合物具有不同程度的抑制SIV活性,并且细胞毒性较小。浓度7.8μg/mL时,化合物2-24,2-30,2-42,分别表现出47.4,38.0,32.3%的病毒抗原细胞抑制率,尤其是化合物2-20表现出较高的活性,浓度2.0μg/mL(2.9μM)时,病毒抗原细胞抑制率达44.7%。 2.为制备第二类烷氧基联苯化合物,关键中间体4,4′-二甲氧基-5,6,5′,6′-二亚甲二氧基-2-羟甲基-2′-烷氧甲酰基联苯由两种途径制得。硼氢化钠-碘直接选择性还原4,4,一二甲氧基一5,6,5‘,6,一二亚甲二氧基联苯一2,2‘一二甲酸单酷的游离梭基;或在曝吩一2一甲酸亚铜的作用下,2一嗅一5一甲氧基一3,4一亚甲二氧基苯甲酸一2‘一澳一5‘一甲氧基一3’,4‘一亚甲二氧基节酷进行分子内偶合及醇解。4,4’一二甲氧基一5,6,5’,6’一二亚甲二氧基一2一轻甲基一2’一烷氧甲酞基联苯经氯乙酸酷化后,与取代节基呱嗦作用生成第二类化合物。利用ID,ZD NMR,ES工一MS对化合物的结构进行了确证。o//‘\oCOOMeOCOOMeOO勺份0o/产、J、、o Rl=H;4一F;4一CI;4一Br;4一MeO;3,4一di MeO 3.利用铜作用下的Ullinann偶合及镍作用下的类Ullmann偶合方法制备了手性4,4‘一二甲氧基一5,6,5,,6‘一二亚甲二氧基一2,2,一二唔哇琳联苯。2一澳一3,4-亚甲二氧基一5一甲氧基一苯甲酸甲醋经水解、酞氯化、与L一2一氨基丙醇进行酞胺化反应、醇经基氯代、碱性条件下成环得手性中间体(S卜2一(2一溟一5一甲氧基一3,4一亚甲二氧基苯基关4一甲基嗯哇琳一(简称(S关嗯哇琳澳苯),(S)一嗯哇琳溟苯在活性铜作用下进行立体选择性Ullm撇偶合反应,生成了以S构型为主的4,4,一二甲氧基一5,6,5‘,6’一二亚甲二氧基一2,2’一二嗓哇琳联苯。 4.首次将Ni(即h3)2CI/Zn/NaH偶合剂用于两个邻位取代基分别为亚甲氧基和手性嗒哩琳基团的澳代苯的偶合。(S)一2一(4一甲基嗯哇琳基关4一甲氧基一5,6一亚甲二氧基嗅苯在偶合剂Ni(PPh3)3C12/Z川NaH作用下,于甲苯中进行不对称偶合,生成轴手性S或R构型过量的非对映异构体二嗦哇琳联苯。随Ni(P Ph小Cl:加入量的不同,二嚷哇琳联苯的总转化率、主要产物的构型均发生变化。以嗯哇琳- e M O O Ce七夕M资声O||人、f澳苯的用量计算,使用等摩尔的Ni(P Ph扔C12,则偶合产物以联苯S构型为优势;使用0.5 equlv.的Ni(PPh3)3C12,则偶合产物以联苯R构型为优势,但偶合转化率较低。 5.由光学纯(S)一4,4‘一二甲氧基一5,6,5‘,6‘一二亚甲二氧基一2,2,一二((S)一4-甲基嚷哇琳)制备了轴手性(S)一4,4‘一二甲氧基一5,6,5‘,6‘一二亚甲二氧基联苯一2,2‘一二甲酸二甲酉旨。 6.本文还考察了手性嗯哇琳基团对消旋4,4’一二甲氧基一5,6,5‘,6‘一二亚甲二氧基联苯手性轴的影响。消旋4,4‘一二甲氧基一5,6,5,,6‘一二亚甲二氧基联苯一2,2‘一二甲酸甲酷,经水解、酞氯化、与(S)一2一氨基丙醇反应成酞胺、轻基氯代、环化得4,4‘一二甲氧基一5,6,5‘,6‘一二亚甲二氧基一2,2‘一二((S)一4一甲基嚷哇琳)联苯。HPLC分析表明,其两个非对映异构体的比率为1:1。甲苯中,在碘化亚铜作用下,非对映异构体混合物转化为轴手性为S构型的单一异构体。 e M O O Ue卜夕M谈厂01人z\丫亘︶八/吸\<。沈夕 n~产r产~、女卜向COOMe oMe oMe 6Me 7.对铜作用下及镍作用下的立体选择性Ullmann偶合及Unm~一tyPe偶合的机理、对一Cul作用下(R/S)4,4‘一二甲氧基一5,6,5‘,6’一二亚甲二氧基一2,2‘一二((S)一4一甲基德哇琳)联苯构象转化机理进行了探讨。 本沦文工作共计合成化合物91个,其中新?
【Abstract】 Based on the similar structure of alkyloxy-biphenyl compounds with biological activity, two kinds of new biphenyl compounds containing alkyloxy-biphenyl modified by substituted benzylpiperazine were designed and synthesized by parallel synthesis. Anti-virus activity of some biphenyls was examined. The Ullmann-type coupling reaction to synthesize alkyloxy-biphenyl was carried out in the presence of Ni(PPh3)2Cl/Zn/NaH. Moreover, Chiral 4,4’-dimethoxy-5,6,5’,6’-dimethenedioxy-biphenyl were afforded through asymmetric coupling reaction of arylbromide or configuration transform of corresponding compound.The first kind of compounds were synthesized, Based on the lead compound, dimethyl-4,4’-dimethoxy-5,6,5’, 6’-dimethenedioxy-biphenyl-2, 2’-dicarbonylate. At first, dimethyl-4, 4’-dimethoxy-5, 6, 5’, 6’-dimethenedioxy-biphenyl-2,2’- dicarbony-late were synthesized through coupling reaction of methyl 2-bromo-3,4-methenedi-oxy-5-methoxy-benzene carbonylate in the presence of active copper or coupling agent Ni(PPh3)2Cl/Zn/NaH in good yield, and then it was converted to 4,4’ -dimethoxy-5,6,5’ ,6’ -dimethenedioxy-biphenyl-2-alkyloxycarbonyl-2’ -carboxylic acid. The compounds have been further modified by substituted N-benzyl piperazines to afford corresponding novel biphenyls. The structure of these new compounds was confirmed by 1H NMR, IR and ESI-MS.Activity, against simian immunodeficiency virus, of some novel biphenyl compounds, was tested in vitro. All of those showed activity of anti-virus. At the compounds concentration of 7.8 ug/mL, compounds, 2-24, 2-30, 2-42, showed 47.4,38.0, 32.3% reduction in antigen, respectively. Among the three compounds, compound 2-24 possesses the more potent anti-HIV activity. It is noticeable that compound 2-20 exhibit 44.7% reduction in antigen at concentration of 2.0 u.g/mL(2.9uM).The second type of novel compounds, 4,4’-dimethoxy-5,6,5’,6’-dimethenedioxy-2-(2-(4-substituted-benzyl~piperazine-l-yl-)-acetoxymethyl)-2’-methoxycarbonyl-biphenyl, were synthesized. The key intermediate, 4,4’-dimethoxy-5,6,5’,6’-dimethenedioxyl-2-hydroxymethyl-2’-methoxycarbonyl-biphenyl, was prepared by two methods. One method was selective reduction of methyl-4,4’-dimethoxy-5,6,5’, 6’-dimethenedioxy-biphenyl-2,2’-dicarbonylate by NaBH4-I2. The second was intramolecular coupling of 2-bromo-5-methoxy-3,4- methenedioxybenzyl 2-bromo-5-methoxy-3,4-methenedioxybenzoate in the presence of activated copper or CuTC. The structure of the aimed compounds was confirmed by means of 1H NMR, 13C NMR, HSQC, HMBC, NOESY and ESI-MS.(S)-4,4’-dimethoxy-5,6,5’,6’-dimethenedioxy-2,2’-di-(4(S)-methyl-oxazoline-l)-biphenyl was synthesized through asymmetric Ullmann coupling reaction or asymmetric Ullmann-type coupling reaction in the presence of Ni(PPh3)2Cl/Zn/NaH.In the thesis, it was found for the first time that the arylbromide with ortho metheneoxy and chiral oxazoline group can couple to give corresponding biphenyl in the presence of Ni(PPh3)2Cl/Zn/NaH. In the asymmetric Ullmann-type, It was noticeable that which was excessive among the biphenyl with S or R configuration was dependent on ratio of Ni(PPh3)2Cl2 to aryl bromide. 0.5 equiv Ni(PPh3)2Cl2 gaveexcessive R and 1 equiv or more Ni(PPh3)2Cl2 afforded excessive S. The different stereoselectivity should reflect two kinds of coupling mechanism, intermolecular and intramolecular coupling of Ni-complex intermediate.we have also found another efficacious method to prepare (S)-4,4’-dimethoxy-5,6,5’,6’-dimethenedioxy-2,2’-di-[4(S)-methyl-oxazoline-l]-biph enyl through configuration transform of (R/S)-4,4’-dimethoxy-5,6,5’,6’-dimethenedioxy-2,2’-di-(4(S)-methyl-oxazoline-l)-bi-biphenyl in excellent yield promoted by interaction between chiral oxazolines moiety of biphenyl and Cu(I). (S)-dimethyl-4,4’-dimethoxy-5,6,5’,6’-dimethenedioxy-biphen-yl-2,2’-dicarboxylate was prepared from (S)-2,2’-dioxazoline biphenyl isomer conveniently.At last, the mechanism of asymmetric Ullmann coupling, asymmetric Ullmann-t