奈韦拉平及其吡啶并二氮杂卓类似物的合成研究
摘要
艾滋病(Acquired Immune Deficiency Syndrome，AIDS)已经成为严重危害人类身体健康的疾病。中国目前有艾滋病病毒感染者约84万，艾滋病感染人数正高速增长，预计到2010年中国的艾滋病感染者将达到1000万。因此，研发价格低廉的抗HIV药物，已经成为摆在中国政府和科研工作者面前一个十分迫切和重要的课题。
本论文以氰基乙酰胺和乙酰乙酸乙酯为起始原料，经环合、氯化、氰基水解、霍夫曼重排、催化加氢脱氯、选择性氯化、酰化、芳香氯的胺解和胺的N-芳基化反应，合成了5，11-二氢-6H-二吡啶[3，2-b∶2’，3’-e][1，4]二氮杂卓-6-酮类的5个化合物和非核苷类逆转录酶抑制剂奈韦拉平(nevirapine)，其中合成奈韦拉平的九步反应总收率为30.9％。目标化合物结构运用IR、MS、~1H-NMR进行了表征。重点对中间体2-氯-3-胺基-4-甲基吡啶的合成工艺进行了优化，中间体总收率比文献值提高了9个百分点；在加氢脱氯反应中，加入助催化剂W后，Pd／C催化剂用量、溶剂用量分别降低为文献用量的30％和50％，反应收率90.5％，与文献值相同。首次采用醋酸成盐法对奈韦拉平进行精制研究，优化提纯工艺可使产品纯度达到99％以上。另外选用极性溶剂S水溶液重结晶法对奈韦拉平进行精制研究，极性溶剂S浓度为40％时，精制产品的纯度高于99.0％，回收率高于70％，母液可回收套用，样品质量达到德国伯明翰公司产品指标。对奈韦拉平中主要杂质的分离进行了研究，发现主要杂质是2-(2-环丙胺基-3-吡啶)-7-甲基-恶唑[5，4-b]吡啶，其结构运用IR、MS、~1H-NMR进行了表征。探讨了Cu催化二吡啶[3，2-b∶2’，3’-e][1，4]二氮杂卓-6-酮类化合物的合成，未见文献报道。
Acquired Immune Deficiency Syndrome (AIDS) has become one of the most serious diseases in the world. There are about 840, 000 people infected with HIV in China reported by the government on Dec. 1st, 2003. The number of people infected with HIV is increasing rapidly nowadays and will be 10,000,000 by the end of 2010 if no effective measures would be taken right now. Drugs used to treat AIDS in China mostly depend on importation. Most patients cannot afford for their high price. Therefore, researching anti~HIV drugs with low price has become a vital task to be accomplished by the government and researchers as soon as possible.
From cyanoacetamide and ethyl acetoacetate, non-nucleoside reverse transcriptase inhibitor nevirapine and five other compounds, as 5, ll-dihydro-6H-dipyrido[2, 3-b:2 ,3 -e][1, 4]diazepin-6-one analogues, are prepared via ring closure reactions chlorinations hydrolyzation Hoffmann rearrangement catalytic hydrogenation regioselective chlorination acylation aryl amination. The total yield of nevirapine synthesis is 30. 9%. The structures are confirmed by IR, MS 1H-NMR. Much stress is laid on the synthesis of the intermediate 2-chloro-3-amino-4-methylpyridine (CAPIC), and 9 percent is increased in the total yield of CAPIC. Nevirapine is purified through two different methods, and the quality of the sample meets the demand of the company Boehriger-Ingelheim. The primary impurity in nevirapine is separated and it is 2-(2-cyclopropylamino-3-pyridyl)-7-methyl-oxazolo[5,4-b]pyridine, whose structure is confirmed by IR MS 1H-NMR. It is the first time applying CuI as catalyst to form C-N bond in the synthesis of 5, 11-
dihydro-6H-dipyrido[2, 3-b: 2 , 3'-e][1, 4]diazepin-6-ones.
本论文以氰基乙酰胺和乙酰乙酸乙酯为起始原料，经环合、氯化、氰基水解、霍夫曼重排、催化加氢脱氯、选择性氯化、酰化、芳香氯的胺解和胺的N-芳基化反应，合成了5，11-二氢-6H-二吡啶[3，2-b∶2’，3’-e][1，4]二氮杂卓-6-酮类的5个化合物和非核苷类逆转录酶抑制剂奈韦拉平(nevirapine)，其中合成奈韦拉平的九步反应总收率为30.9％。目标化合物结构运用IR、MS、~1H-NMR进行了表征。重点对中间体2-氯-3-胺基-4-甲基吡啶的合成工艺进行了优化，中间体总收率比文献值提高了9个百分点；在加氢脱氯反应中，加入助催化剂W后，Pd／C催化剂用量、溶剂用量分别降低为文献用量的30％和50％，反应收率90.5％，与文献值相同。首次采用醋酸成盐法对奈韦拉平进行精制研究，优化提纯工艺可使产品纯度达到99％以上。另外选用极性溶剂S水溶液重结晶法对奈韦拉平进行精制研究，极性溶剂S浓度为40％时，精制产品的纯度高于99.0％，回收率高于70％，母液可回收套用，样品质量达到德国伯明翰公司产品指标。对奈韦拉平中主要杂质的分离进行了研究，发现主要杂质是2-(2-环丙胺基-3-吡啶)-7-甲基-恶唑[5，4-b]吡啶，其结构运用IR、MS、~1H-NMR进行了表征。探讨了Cu催化二吡啶[3，2-b∶2’，3’-e][1，4]二氮杂卓-6-酮类化合物的合成，未见文献报道。
Acquired Immune Deficiency Syndrome (AIDS) has become one of the most serious diseases in the world. There are about 840, 000 people infected with HIV in China reported by the government on Dec. 1st, 2003. The number of people infected with HIV is increasing rapidly nowadays and will be 10,000,000 by the end of 2010 if no effective measures would be taken right now. Drugs used to treat AIDS in China mostly depend on importation. Most patients cannot afford for their high price. Therefore, researching anti~HIV drugs with low price has become a vital task to be accomplished by the government and researchers as soon as possible.
From cyanoacetamide and ethyl acetoacetate, non-nucleoside reverse transcriptase inhibitor nevirapine and five other compounds, as 5, ll-dihydro-6H-dipyrido[2, 3-b:2 ,3 -e][1, 4]diazepin-6-one analogues, are prepared via ring closure reactions chlorinations hydrolyzation Hoffmann rearrangement catalytic hydrogenation regioselective chlorination acylation aryl amination. The total yield of nevirapine synthesis is 30. 9%. The structures are confirmed by IR, MS 1H-NMR. Much stress is laid on the synthesis of the intermediate 2-chloro-3-amino-4-methylpyridine (CAPIC), and 9 percent is increased in the total yield of CAPIC. Nevirapine is purified through two different methods, and the quality of the sample meets the demand of the company Boehriger-Ingelheim. The primary impurity in nevirapine is separated and it is 2-(2-cyclopropylamino-3-pyridyl)-7-methyl-oxazolo[5,4-b]pyridine, whose structure is confirmed by IR MS 1H-NMR. It is the first time applying CuI as catalyst to form C-N bond in the synthesis of 5, 11-
dihydro-6H-dipyrido[2, 3-b: 2 , 3'-e][1, 4]diazepin-6-ones.
引文
[1] 刘云凯，罗茂凰，吕智军．2002年全球艾滋病流行状况．口岸卫生控制，2003，8(3)：41-43
[2] Shao Xingwu. Reverse transcriptase assays for analysis of resistance to anti-HIV drugs and their mechanism of action. Sweden: Kopieringshuset AB, 2003. 1-6
[3] 喻菡．艾滋病毒概述．湖北预防医学杂志，2003，14(2)：43-44
[4] Isaka Y., Miki S., Kawauchi S., et al. Isolation and Characterization of simian immunodefiecy virus variants that are resistant to nonnucleoside reverse transcriptase inhibitors. Arch Virol, 2000, 145:2481-2492
[5] Erik De Clercq. New developments in anti-HIV chemotherapy. Biochimica et Biophysica Acta, 2002,1578:258-275
[6] Erik De Clercq. Antiviral drugs: current state of the art. Journal of Clinical Virology, 2001, 22:73-89
[7] Isaka Y., Miki S., Kawauchi S., et al. A single amino acid change at Leu-188 in the reverse transcriptase of HIV-2 and SIV renders them sensitive to non-nucleoside reverse transcriptase inhibitors. Arch Virol, 2001, 146:743-755
[8] Erik De Clercq. The role of non-nucleoside reverse transcriptase inhibitors(NNRTIs) in the therapy of HIV-1 infection. Antiviral Research, 1998, 38:153-179
[9] Erik De Clercq. Perspectives of non-nucleoside reverse transcriptase inhibitors (NNRTIs) in the therapy of HIV-1 infection. IL Farmaco, 1999, 54:26-45
[10] 陶佩珍．抗艾滋病病毒药物研究进展．中国新药杂质，2002，11(11)：842-846
[11] 涂国刚，李少华．非核苷类逆转录酶抑制剂奈韦拉平．中国临床药理学于治疗学，2003，8(6)：604-607
[12] 瞿虹．艾滋病治疗药物及研究进展．天津药学，2003，15(4)：57-59
[13] Hargrave K.D., Proudfoot J.R.,Grozinger K.G.,et al. Novel Non nucleoside inhibitors of HIV-1 reverse transcriptase. 1. Tricyclic pyridobenzo-and dipyridodiazepinones. J. Med. Chem.,1991,34:2231-2241
[114] Klunder J.M., Hargrave K. D.,West M., et al. Novel Non nucleoside inhibitors of HIV-1 reverse transcriptase. 2. Tricyclic pyridobenzoxazepinones and Dibenzoxa-zepinones. J. Med. Chem.,1992,35:1887-1897
[15] Proudfoot J.R., Patel U.R., Kapadia S.R., et al. Novel Non nucleoside inhibitors of HIV-1 reverse transcriptase. 3. Dipyrido[2,3-b:2',3'-e] diazepinone. J. Med. Chem.,1995,38:1406-1410
[16] Kelly T.A., Proudfoot J.R.,Daniel W., et al. Novel Non nucleoside inhibitors of HIV-1 reverse transcriptase. 5. 4-substituted and 2,4-disubstituted analogs of nevirapine. J. Med. Chem.,1995,38:4839-4847
[17] Proudfoot J.R. The synthesis of a dipyrido[3,2-b:3,4-e][1,4]diazepinone: convenient access to a c-ring isomer of the HIV-1 reverse transcriptase inhibitor nevirapine. Bioorganic & Medicinal Chemistry Letters, 1995, 5(2):163-166
[18] Mario Di Braccio, Giancarlo Grossi, Giorgio Roma, et al. 1,5-benzodiazepines. Synthesis
and biological evaluation of tricyclic and tetracyclic 1,5-benzodiazepine derivatives as nevirapine analogues. Eur. J. Med. Chem., 2001,36:935-949
[19] Ma Dawei, Xia Chengfeng. CuI-Catalyzed Coupling Reaction of β-Amino Acids or Esters with Aryl Halides at Temperature Lower Than That Emplyed in the Normal Ullmann Reaction. Facile synthesis of SB-214857. Organic Letters, 2001, 3(16):2583-2586
[20] 邓维，刘磊，郭庆祥．铜催化交叉偶联反应研究的新进展．有机化学，2004，24(2)：150-165
[21] Grozinger K. G., Fuchs V., Hargrave K. D., et al. Synthesis of Nevirapine and its Major Metabolite. J. Heterocyclic Chem., 1995, 32:259-263
[22] Laurence John Nummy. Method for the preparation of 3-amino-2-chloro-4-alkyl pyridines. [P].US:5654429, 1997-8-5
[23] Bakke J. M., Riha J. Preparation of 4-sustituted 3-Amino-2-Chloropyridines. J. Heterocyclic Chem., 2001, 38:99-103
[24] Grozinger Karl. Synthesis of 3-amino-2-chloro-4-methylpyridine from malono-nitrile and acetone. [P].US:6111112, 2000-8-29
[25] Grozinger Karl. Synthesis of 3-amino-2-chloro-4-methylpyridine from acetone and ethylcyanoacetate.[P].US:6136982, 2000-10-24
[26] Zhang Tony Y., Stout James R., Keay G., et al. Regioselective Synthesis of 2-Chloro-3-Pyridinecarboxylates. Tetrahedron, 1995, 51(48):13177-13184
[27] Bernard Franklin Gupton. Process for making 3-amino-2-chloro-4-methyl pyridine.[P].US:6399781, 2002-6-4
[28] Grozinger Karl. Method of preparing 3-amino-2-chloro-4-alkylpyridines. [P]. US:5200522, 1993-4-6
[29] Heinrich Schneider. Method of preparing 3-amino-2-chloro-4-alkylpyridine or-4-arylpyridine. [P]. US:5686618, 1997-11-11
[30] Heinrich Schneider. Process for preparing nevirapine. [P]. US:5569760, 1996-10-29
[2] Shao Xingwu. Reverse transcriptase assays for analysis of resistance to anti-HIV drugs and their mechanism of action. Sweden: Kopieringshuset AB, 2003. 1-6
[3] 喻菡．艾滋病毒概述．湖北预防医学杂志，2003，14(2)：43-44
[4] Isaka Y., Miki S., Kawauchi S., et al. Isolation and Characterization of simian immunodefiecy virus variants that are resistant to nonnucleoside reverse transcriptase inhibitors. Arch Virol, 2000, 145:2481-2492
[5] Erik De Clercq. New developments in anti-HIV chemotherapy. Biochimica et Biophysica Acta, 2002,1578:258-275
[6] Erik De Clercq. Antiviral drugs: current state of the art. Journal of Clinical Virology, 2001, 22:73-89
[7] Isaka Y., Miki S., Kawauchi S., et al. A single amino acid change at Leu-188 in the reverse transcriptase of HIV-2 and SIV renders them sensitive to non-nucleoside reverse transcriptase inhibitors. Arch Virol, 2001, 146:743-755
[8] Erik De Clercq. The role of non-nucleoside reverse transcriptase inhibitors(NNRTIs) in the therapy of HIV-1 infection. Antiviral Research, 1998, 38:153-179
[9] Erik De Clercq. Perspectives of non-nucleoside reverse transcriptase inhibitors (NNRTIs) in the therapy of HIV-1 infection. IL Farmaco, 1999, 54:26-45
[10] 陶佩珍．抗艾滋病病毒药物研究进展．中国新药杂质，2002，11(11)：842-846
[11] 涂国刚，李少华．非核苷类逆转录酶抑制剂奈韦拉平．中国临床药理学于治疗学，2003，8(6)：604-607
[12] 瞿虹．艾滋病治疗药物及研究进展．天津药学，2003，15(4)：57-59
[13] Hargrave K.D., Proudfoot J.R.,Grozinger K.G.,et al. Novel Non nucleoside inhibitors of HIV-1 reverse transcriptase. 1. Tricyclic pyridobenzo-and dipyridodiazepinones. J. Med. Chem.,1991,34:2231-2241
[114] Klunder J.M., Hargrave K. D.,West M., et al. Novel Non nucleoside inhibitors of HIV-1 reverse transcriptase. 2. Tricyclic pyridobenzoxazepinones and Dibenzoxa-zepinones. J. Med. Chem.,1992,35:1887-1897
[15] Proudfoot J.R., Patel U.R., Kapadia S.R., et al. Novel Non nucleoside inhibitors of HIV-1 reverse transcriptase. 3. Dipyrido[2,3-b:2',3'-e] diazepinone. J. Med. Chem.,1995,38:1406-1410
[16] Kelly T.A., Proudfoot J.R.,Daniel W., et al. Novel Non nucleoside inhibitors of HIV-1 reverse transcriptase. 5. 4-substituted and 2,4-disubstituted analogs of nevirapine. J. Med. Chem.,1995,38:4839-4847
[17] Proudfoot J.R. The synthesis of a dipyrido[3,2-b:3,4-e][1,4]diazepinone: convenient access to a c-ring isomer of the HIV-1 reverse transcriptase inhibitor nevirapine. Bioorganic & Medicinal Chemistry Letters, 1995, 5(2):163-166
[18] Mario Di Braccio, Giancarlo Grossi, Giorgio Roma, et al. 1,5-benzodiazepines. Synthesis
and biological evaluation of tricyclic and tetracyclic 1,5-benzodiazepine derivatives as nevirapine analogues. Eur. J. Med. Chem., 2001,36:935-949
[19] Ma Dawei, Xia Chengfeng. CuI-Catalyzed Coupling Reaction of β-Amino Acids or Esters with Aryl Halides at Temperature Lower Than That Emplyed in the Normal Ullmann Reaction. Facile synthesis of SB-214857. Organic Letters, 2001, 3(16):2583-2586
[20] 邓维，刘磊，郭庆祥．铜催化交叉偶联反应研究的新进展．有机化学，2004，24(2)：150-165
[21] Grozinger K. G., Fuchs V., Hargrave K. D., et al. Synthesis of Nevirapine and its Major Metabolite. J. Heterocyclic Chem., 1995, 32:259-263
[22] Laurence John Nummy. Method for the preparation of 3-amino-2-chloro-4-alkyl pyridines. [P].US:5654429, 1997-8-5
[23] Bakke J. M., Riha J. Preparation of 4-sustituted 3-Amino-2-Chloropyridines. J. Heterocyclic Chem., 2001, 38:99-103
[24] Grozinger Karl. Synthesis of 3-amino-2-chloro-4-methylpyridine from malono-nitrile and acetone. [P].US:6111112, 2000-8-29
[25] Grozinger Karl. Synthesis of 3-amino-2-chloro-4-methylpyridine from acetone and ethylcyanoacetate.[P].US:6136982, 2000-10-24
[26] Zhang Tony Y., Stout James R., Keay G., et al. Regioselective Synthesis of 2-Chloro-3-Pyridinecarboxylates. Tetrahedron, 1995, 51(48):13177-13184
[27] Bernard Franklin Gupton. Process for making 3-amino-2-chloro-4-methyl pyridine.[P].US:6399781, 2002-6-4
[28] Grozinger Karl. Method of preparing 3-amino-2-chloro-4-alkylpyridines. [P]. US:5200522, 1993-4-6
[29] Heinrich Schneider. Method of preparing 3-amino-2-chloro-4-alkylpyridine or-4-arylpyridine. [P]. US:5686618, 1997-11-11
[30] Heinrich Schneider. Process for preparing nevirapine. [P]. US:5569760, 1996-10-29
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