嘌呤类核苷化合物的研究
摘要
腺苷是一种重要的生物大分子，研究表明它有多种心脏保护作用，可以作为心脏病的治疗药物，还可以用于冠心病的诊断和愈后评价。以腺苷为原料合成的8—溴腺苷是重要的医药中间体，可以用于合成多种具有抗病毒活性和抗肿瘤作用的核苷类似物。
本文以四乙酰核糖和腺嘌呤为原料，采用三种方法合成β-腺苷。(1)熔融法，在减压高温的条件及碘的催化作用下用四乙酰核糖和碱基反应，再经脱酰基，合成腺苷。该法比较简单方便，但糖基化的立体选择性差，得到的产物是α-和β-构型的混合物，需要经过硅胶柱分离；(2)重金属法，用N~6-苯甲酰基腺嘌呤的氯化汞盐与三乙酰氯代核糖反应得到产物，氯化汞在反应过程中起到催化剂作用。该法具有很好的立体选择性，得到的产物主要是β-腺苷，不需要经硅胶柱分离；(3)硅烷化法，将N~6—苯甲酰基腺嘌呤经预先硅烷化后，不经分离即直接在SnCl_4的催化作用下与四乙酰核糖进行糖基化反应，操作简便，反应条件比较温和，但产品同样是混合物，需要经硅胶柱分离。
实验在合成腺苷的基础上探讨了8—溴腺苷的合成工艺：在乙酸钠的缓冲溶液中腺苷与溴发生选择性溴化反应，得到高产率的8—溴腺苷。
As an important biological molecue, adenosine is widely used in iatrology as a clinical medicine to protect heart or treat coronary heart disease. 8-Bromoadenosine is a useful intermediate on the synthesis of some analogs of adenosine, which can restrain the virus' vitality or tumour.
Three methods are described to synthesize β-adenosine by using tetraacetyl -ribofuranose and adenine as two reactants. l)Fusion Method, tetraacetylriblfuranose and heterocycle base react in the precense of iodine by heating.Because of its shortage in stereoelective,the mixture of a- and P-adenosine is obtained after deacetylation and then needs to be separated through silicagel column. 2)Heavy metal method, P-adenosineis obtained by using chloromeruri N6-benzoyladenie and triacetylribo -furanosyl chloride as reagents in which chloromercuiri is used as catalyst. Because of its better stereoelective, silicagel column is not needed.3)Silylation method, Silylated N6-benzoyladenine without separation reacts with tetraacetylribofuranose, catalysted by SnCl4. It is not stereospecific and the product also needs to be separated through silicagel column regardless of the simple process and the moderate condition.
Furthermore, the synthesis of 8-bromoadenosine of which the productivity is pretty high is also discussed by using adenosine and bromine reacting in the buffer solution ofNaOAc.
本文以四乙酰核糖和腺嘌呤为原料，采用三种方法合成β-腺苷。(1)熔融法，在减压高温的条件及碘的催化作用下用四乙酰核糖和碱基反应，再经脱酰基，合成腺苷。该法比较简单方便，但糖基化的立体选择性差，得到的产物是α-和β-构型的混合物，需要经过硅胶柱分离；(2)重金属法，用N~6-苯甲酰基腺嘌呤的氯化汞盐与三乙酰氯代核糖反应得到产物，氯化汞在反应过程中起到催化剂作用。该法具有很好的立体选择性，得到的产物主要是β-腺苷，不需要经硅胶柱分离；(3)硅烷化法，将N~6—苯甲酰基腺嘌呤经预先硅烷化后，不经分离即直接在SnCl_4的催化作用下与四乙酰核糖进行糖基化反应，操作简便，反应条件比较温和，但产品同样是混合物，需要经硅胶柱分离。
实验在合成腺苷的基础上探讨了8—溴腺苷的合成工艺：在乙酸钠的缓冲溶液中腺苷与溴发生选择性溴化反应，得到高产率的8—溴腺苷。
As an important biological molecue, adenosine is widely used in iatrology as a clinical medicine to protect heart or treat coronary heart disease. 8-Bromoadenosine is a useful intermediate on the synthesis of some analogs of adenosine, which can restrain the virus' vitality or tumour.
Three methods are described to synthesize β-adenosine by using tetraacetyl -ribofuranose and adenine as two reactants. l)Fusion Method, tetraacetylriblfuranose and heterocycle base react in the precense of iodine by heating.Because of its shortage in stereoelective,the mixture of a- and P-adenosine is obtained after deacetylation and then needs to be separated through silicagel column. 2)Heavy metal method, P-adenosineis obtained by using chloromeruri N6-benzoyladenie and triacetylribo -furanosyl chloride as reagents in which chloromercuiri is used as catalyst. Because of its better stereoelective, silicagel column is not needed.3)Silylation method, Silylated N6-benzoyladenine without separation reacts with tetraacetylribofuranose, catalysted by SnCl4. It is not stereospecific and the product also needs to be separated through silicagel column regardless of the simple process and the moderate condition.
Furthermore, the synthesis of 8-bromoadenosine of which the productivity is pretty high is also discussed by using adenosine and bromine reacting in the buffer solution ofNaOAc.
引文
1 郑集，陈均辉．普通生物化学(第三版)．高等教育出版社，1998，139～139
2 花文廷．杂环化学．北京大学出版社，1991，505～515
3 赵雁来，何森泉等．高等教育出版社，1992，400～408
4 张亮仁，于宏武和张礼和．核酸药物化学．北京医科大学、中国协和医科大学联合出版社，1997
5 Farrell G C. Clinical Potential of Emerging New Agents in Hepatitis B. Drags. 2000, 60, 701～710
6 刘丽萍，吴素体．核苷类抗病毒药物的开发与临床应用概述．传染病信息，1999，12(1)：34～36
7 Sluis-Cremer N, D Arion, et al. Molecular Mechanism of HIV-1 Resistance to Nucleoside Reverse Transcriptase Inhibitors. Cellular and Molecular Life Science, 2000, 576, 1408～1422
8 Lopez-Navarro AT, Gil A, and Sanchez-Pozo A. Deprivation of Dietarynucleotides Results in A Transient Decrease in Acid-soluble Nucleotides and RNA Concentration in Rat Liver. Nutr.,1995, 125, 2090～2095
9 Labranche C C, Galasso G, et. al. HIV Fusion and Its Inhibition. Antiviral Res., 2001, 50, 95～115
10 瞿瑶．核苷类药物抗肝炎病毒的态势．中西医结合肝病杂志，2002，12(4)：193～195．
11 王心赵．腺苷．日本医学介绍，2003，24(10)：480
12 黄振华．腺苷与心血管疾病．国外医学内科学分册，1999，26(3)：100～103
13 吴杰．腺苷的临床应用价值．国外医学：心血管疾病分册，2002，29(3)：165～166
14 Chidangli, Phool C Mishra. Relationship for Some 2',3'-Dideoxy Nucleoside Anti-HIV Drugs Using Molecular Eletrostatic Potential Mupping. J. Molecular Modeling, 1997, 3, 172～181
15 林桂椿，刘莉等．8-氯腺苷衍生物的合成及生物活性研究．合成化学，2002，10，405～408
16 沈同，王镜岩．生物化学(上)，第二版，高等教育出版社，2000年
17 Perigaud C, Gosselin G, and Imbach J L. Nucleoside Analogues as Clemotherapeutie Agents. Nucleosides and Nucleotides., 1992, 11(4): 903～945
18 Lin Tai Shun, Cheng Jia Chong. Purine and 8-Substituted Purine Arabinofuranosyl and Ribofuranosyl Nucleosides Derivatives as Potential Inducers of the Differentiation of the Friend Erythroleukemia. J. Med. Chem., 1985, 28(10): 1481～1485
19 Masakatsu Kaneko, Misako Kineko, and Bunji Shimizu. Synthesis and Properties of
8,2'-Cyclothioguanosine and Related Compounds. Chem. Pharm. Bull., 1972, 20(3): 635～637
20 Richard E Holmes and Roland K Robins. Purines Nucleosides. ⅤⅡ. Direct Bromination of Adenosine Deoxyadenosine, Guanosine, and Related Purine Ucloosides. J. Am. Chem. Soc., 1964, 86, 1242～1245
21 Morio Ikehara, Yuji Nakahara, and Shoji Yamada. Studies of Nucleosides and Nucleotides. (14)Synthesis and Properties of Cyclonucleosides Derived from 9-D-Xylofuranosyladenine. Chem. Pharm. Bull., 1971, 19(3): 538～544
22 Morio Ikehara, Masakatsu Kaneko and Yuko Ogiso. Cleavage of 8,2'-Anhydro-8-Oxy-9-β-D-Arabinofuranosyladenine with hydrogen sulfide and its interconversion with 8,5'-Cyclonu-cleoside. Tetrahedron Letters, 1970, (53), 4673～4676
23 李子成，蒋宁等．核苷类抗病毒蓟物的研究进展化学研究与应用，2002，14(1)：15～20．
24 M I Lim and R S Klein. Synthesis of '9-Deazaadenosine': A New Cytotoxic C-nucleoside Isostere of adenosine. Tetra. Lett., 1981, 22(1): 25～28
25 Y Mizuno, T Itoh, and A Nomura. Synthesis of Naturall Occurring Uridine-α-amino Acid Der-ivatives by the Apllication of Ugi Reaction. Nuceic Acids Symp. Ser., 1981, 10, 13～16
26 Y Mizuno, C W Taylor, and A R Todd. An investigation of the Hall Effect in Impurity Hopping Conduction. J. Chem. Soc., 1949, 1620～1624
27 M Bobek and J Farkas. Nucleic Acid Components and Their Analogs. CX ⅤⅢ. Synthesis of 8-β-D- Ribofuranosyladenine Starting from 2,5-Anhydro-D-allonic Acid. Coll. Czech. chem. Cummun., 1969, 34, 247～251
28 辉瑞产品公司．合成核苷类似物的方法．CN，1275575A，2000
29 E Fisher and B Helferich. Synthetic Glucosides of the Purines. Chem. Ber., 1914, 47, 210～212
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33 Giinter Wulffand Gerhard Rohle. Results and Problems of O-Glycoside Synthesis. Angew. Chem. internat. Edit., 1974, 13(3): 157～170
34 李中军．蔡孟深．糖苷和寡糖的立体选择性合成研究进展．高等学校化学学报，1997，18(7)：1113～1119
35 Niedbulla U, Vorbrueggen H Synthesis of Nucleosides. 9. General synthesis of N-Glycosides.
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2 花文廷．杂环化学．北京大学出版社，1991，505～515
3 赵雁来，何森泉等．高等教育出版社，1992，400～408
4 张亮仁，于宏武和张礼和．核酸药物化学．北京医科大学、中国协和医科大学联合出版社，1997
5 Farrell G C. Clinical Potential of Emerging New Agents in Hepatitis B. Drags. 2000, 60, 701～710
6 刘丽萍，吴素体．核苷类抗病毒药物的开发与临床应用概述．传染病信息，1999，12(1)：34～36
7 Sluis-Cremer N, D Arion, et al. Molecular Mechanism of HIV-1 Resistance to Nucleoside Reverse Transcriptase Inhibitors. Cellular and Molecular Life Science, 2000, 576, 1408～1422
8 Lopez-Navarro AT, Gil A, and Sanchez-Pozo A. Deprivation of Dietarynucleotides Results in A Transient Decrease in Acid-soluble Nucleotides and RNA Concentration in Rat Liver. Nutr.,1995, 125, 2090～2095
9 Labranche C C, Galasso G, et. al. HIV Fusion and Its Inhibition. Antiviral Res., 2001, 50, 95～115
10 瞿瑶．核苷类药物抗肝炎病毒的态势．中西医结合肝病杂志，2002，12(4)：193～195．
11 王心赵．腺苷．日本医学介绍，2003，24(10)：480
12 黄振华．腺苷与心血管疾病．国外医学内科学分册，1999，26(3)：100～103
13 吴杰．腺苷的临床应用价值．国外医学：心血管疾病分册，2002，29(3)：165～166
14 Chidangli, Phool C Mishra. Relationship for Some 2',3'-Dideoxy Nucleoside Anti-HIV Drugs Using Molecular Eletrostatic Potential Mupping. J. Molecular Modeling, 1997, 3, 172～181
15 林桂椿，刘莉等．8-氯腺苷衍生物的合成及生物活性研究．合成化学，2002，10，405～408
16 沈同，王镜岩．生物化学(上)，第二版，高等教育出版社，2000年
17 Perigaud C, Gosselin G, and Imbach J L. Nucleoside Analogues as Clemotherapeutie Agents. Nucleosides and Nucleotides., 1992, 11(4): 903～945
18 Lin Tai Shun, Cheng Jia Chong. Purine and 8-Substituted Purine Arabinofuranosyl and Ribofuranosyl Nucleosides Derivatives as Potential Inducers of the Differentiation of the Friend Erythroleukemia. J. Med. Chem., 1985, 28(10): 1481～1485
19 Masakatsu Kaneko, Misako Kineko, and Bunji Shimizu. Synthesis and Properties of
8,2'-Cyclothioguanosine and Related Compounds. Chem. Pharm. Bull., 1972, 20(3): 635～637
20 Richard E Holmes and Roland K Robins. Purines Nucleosides. ⅤⅡ. Direct Bromination of Adenosine Deoxyadenosine, Guanosine, and Related Purine Ucloosides. J. Am. Chem. Soc., 1964, 86, 1242～1245
21 Morio Ikehara, Yuji Nakahara, and Shoji Yamada. Studies of Nucleosides and Nucleotides. (14)Synthesis and Properties of Cyclonucleosides Derived from 9-D-Xylofuranosyladenine. Chem. Pharm. Bull., 1971, 19(3): 538～544
22 Morio Ikehara, Masakatsu Kaneko and Yuko Ogiso. Cleavage of 8,2'-Anhydro-8-Oxy-9-β-D-Arabinofuranosyladenine with hydrogen sulfide and its interconversion with 8,5'-Cyclonu-cleoside. Tetrahedron Letters, 1970, (53), 4673～4676
23 李子成，蒋宁等．核苷类抗病毒蓟物的研究进展化学研究与应用，2002，14(1)：15～20．
24 M I Lim and R S Klein. Synthesis of '9-Deazaadenosine': A New Cytotoxic C-nucleoside Isostere of adenosine. Tetra. Lett., 1981, 22(1): 25～28
25 Y Mizuno, T Itoh, and A Nomura. Synthesis of Naturall Occurring Uridine-α-amino Acid Der-ivatives by the Apllication of Ugi Reaction. Nuceic Acids Symp. Ser., 1981, 10, 13～16
26 Y Mizuno, C W Taylor, and A R Todd. An investigation of the Hall Effect in Impurity Hopping Conduction. J. Chem. Soc., 1949, 1620～1624
27 M Bobek and J Farkas. Nucleic Acid Components and Their Analogs. CX ⅤⅢ. Synthesis of 8-β-D- Ribofuranosyladenine Starting from 2,5-Anhydro-D-allonic Acid. Coll. Czech. chem. Cummun., 1969, 34, 247～251
28 辉瑞产品公司．合成核苷类似物的方法．CN，1275575A，2000
29 E Fisher and B Helferich. Synthetic Glucosides of the Purines. Chem. Ber., 1914, 47, 210～212
30 E Fisher and B Heiferich. Synthesis method of nucleosides. Chem. Ber., 1914, 47, 1377～1378
31 J Davoll, B Lythgoe, and A R Todd. J. Chem. Soc., 1948,967
32 J Davoll and B A Lowy. Some Synthetic Analogs of Natural Purine Nucleosides. J. Am.Chem. Soc., 1952, 74, 1563～1566
33 Giinter Wulffand Gerhard Rohle. Results and Problems of O-Glycoside Synthesis. Angew. Chem. internat. Edit., 1974, 13(3): 157～170
34 李中军．蔡孟深．糖苷和寡糖的立体选择性合成研究进展．高等学校化学学报，1997，18(7)：1113～1119
35 Niedbulla U, Vorbrueggen H Synthesis of Nucleosides. 9. General synthesis of N-Glycosides.
Ⅰ. Synthesis of Pyrimidine Nucleosides. J. Org. Chem., 1974, 39(25): 3654～3659
36 Piskala Alois and Sorm Frantisek. Ger. Offen. 2423824, 1975
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