尼洛替尼的合成
摘要
尼洛替尼是一种具有高度选择性的酪氨酸激酶抑制剂,临床用于治疗对伊马替尼耐药或不能耐受的成人慢性期和加速期的慢性粒细胞白血病。在本论文中,以三氟甲苯为原料,经硝化-溴化“一锅煮”、还原、与4-甲基-1-咪唑亲核取代反应得到重要中间体5-(4-甲基-1H-1-咪唑基)-3-三氟甲基苯胺。对甲基苯甲酸经溴化、酯化制得中间体3-溴-4-甲基苯甲酸乙酯,3-乙酰基吡啶与N,N-二甲基甲酰胺二甲缩醛缩合、与硝酸胍环合得到中间体4-(3-吡啶基)-2-氨基嘧啶,然后,3-溴-4-甲基苯甲酸乙酯与4-(3-吡啶基)-2-氨基嘧啶发生亲核取代、水解得到重要中间体4-甲基-3-[[4-(3-吡啶基)-2-嘧啶基]氨基]苯甲酸。最后,5-(4-甲基-1H-1-咪唑基)-3-三氟甲基苯胺与4-甲基-3-[[4-(3-吡啶基)-2-嘧啶基]氨基]苯甲酸发生酰胺化反应得到目标产物尼洛替尼,总收率46.4%。其中,采用三氟甲苯为原料,经硝化-溴化“一锅煮”制备1-溴-3-硝基-5-三氟甲苯,操作简便,后处理简单。采用3-溴-4-甲基苯甲酸乙酯与4-(3-吡啶基)-2-氨基嘧啶发生亲核取代制备4-甲基-3-[[4-(3-吡啶基)-2-嘧啶基]氨基]苯甲酸乙酯,步骤简便,条件温和,收率较高。
中间体及目标产物的化学结构经MS、1H NMR确证,并讨论了影响各步反应的主要因素,从中得到合成尼洛替尼较佳的反应条件。
Nilotinib is a highly selective tyrosine kinases inhibitor for the clinical treatment of chronic myelogenous leukemia patients possessing imatinib resistance. In this dissertation of the part for the synthesis of nilotinib, trifluoromethylbenzene was nitrated and brominated with "one-pot" process, followed a reduction, and a nucleophilic substitution with 4-methyl-1H-imidazole to achieve a key intermediate 5-(4-methyl-lH-imidazol-l-yl)-3-trifluoromethylaniline. Another key intermediate,4-methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl) amino)benzoic acid was prepared from 3-bromo-4-methylbenzoic acid via a serial of reactions of esterification, nucleophilic substitution with 4-(pyridin-3-yl)-2-aminopyrimidine, which was synthesized by condensation reaction between 3-acetyl-pyridine and N,N-dimethylformamide dimethyl acetal and cyclization reaction with guanidine nitate and hydrolysis. In the last step,4-methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)benzoic acid was amidated with 5-(4-methyl-1H-imidazol-1-yl)-3-trifluoromethylaniline to give the target niltinib with an overall yield of 46.4%. In the preparation of 1-bromo-3-nitro-5-(trifluoromethyl)benzene, the "one-pot" process was carried out since its convenient operation and easy workup. A unique nucleophilic substitution between ethyl 3-bromo-4-methylbenzoate and 4-(pyridin-3-yl)-2-aminopyrimidine was employed to decrease the reaction steps and make the reaction more modrerate and efficient. The structures of the intermediates and products were confirmed by 1H-NMR and MS. Better technical parameters of synthesizing nilotinib were obtained from the discussion of factors of affecting the reactions above.
中间体及目标产物的化学结构经MS、1H NMR确证,并讨论了影响各步反应的主要因素,从中得到合成尼洛替尼较佳的反应条件。
Nilotinib is a highly selective tyrosine kinases inhibitor for the clinical treatment of chronic myelogenous leukemia patients possessing imatinib resistance. In this dissertation of the part for the synthesis of nilotinib, trifluoromethylbenzene was nitrated and brominated with "one-pot" process, followed a reduction, and a nucleophilic substitution with 4-methyl-1H-imidazole to achieve a key intermediate 5-(4-methyl-lH-imidazol-l-yl)-3-trifluoromethylaniline. Another key intermediate,4-methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl) amino)benzoic acid was prepared from 3-bromo-4-methylbenzoic acid via a serial of reactions of esterification, nucleophilic substitution with 4-(pyridin-3-yl)-2-aminopyrimidine, which was synthesized by condensation reaction between 3-acetyl-pyridine and N,N-dimethylformamide dimethyl acetal and cyclization reaction with guanidine nitate and hydrolysis. In the last step,4-methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)benzoic acid was amidated with 5-(4-methyl-1H-imidazol-1-yl)-3-trifluoromethylaniline to give the target niltinib with an overall yield of 46.4%. In the preparation of 1-bromo-3-nitro-5-(trifluoromethyl)benzene, the "one-pot" process was carried out since its convenient operation and easy workup. A unique nucleophilic substitution between ethyl 3-bromo-4-methylbenzoate and 4-(pyridin-3-yl)-2-aminopyrimidine was employed to decrease the reaction steps and make the reaction more modrerate and efficient. The structures of the intermediates and products were confirmed by 1H-NMR and MS. Better technical parameters of synthesizing nilotinib were obtained from the discussion of factors of affecting the reactions above.
引文
[1]朝长万左男.白血病[J].日本医学介绍,2004,25(10)：445-446.
[2]癌症数据评论,2000-2003.
[3]黄葆华,陈丽明,于伟娟等.慢性粒细胞白血病23例染色体核型分析[J].河北医学,2002,8(9)：857-858.
[4]小泽敬也.白血病[J].日本医学介绍,2007,28(8)：345-347.
[5]抗癌药nilotinib[J]药学进展,2007,31(5)：236-237.
[6]Elias J, Samih E A, Jorge C, et al. Nilotinib:a novel Bcr-Abl tyrosine kinase inhibitor for the treatment of leukemias[J]. Expert Opin. Investig. Drugs,2008,17(7):1127-1136.
[7]Hagop K, Francis G, Lydia W, et al. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL[J]. N Engl J Med.,2006,254(24):2542-2551.
[8]Deininger, Michael W. nilotinib[J]. Clin Cancer Res.,2008,14(13):4027-4031.
[9]Breitenstein W, Furet P, Jacob S, et al. Inhibitors of tyrosine kinases. WO,2004005281 [P]. 2004-01-15.
[10]Mckenna J, Shieh W C. Process for the synthesis of organic compounds. WO, 2006135641 [P].2006-12-21.
[11]陈永江,王丽华,周红,等.尼罗替尼的合成[J].中国医药工业杂志,2009,40(6)：401-403.
[12]Wang Y L, Li J, Kansal V K, et al. Processes for preparation of nilotinib and intermediates. WO,2010009402[P].2010-1-21.
[13]Yeori A, Wang Y L, Li J, et al. Processes for preparation of nilotinib and intermediates. WO,2010060074[P].2010-5-27.
[14]Huang WS, Shakespeare WC. An efficient synthesis of nilotinib (AMN107)[J]. Synthesis, 2007, (14):2121-2124.
[15]Abel S, Acemoglu M, Erb B, et al. Process for the synthesis of organic compounds. WO, 2006135640[P].2006-12-21.
[16]Kim D Y, Cho D J, Lee G Y, et al. N-Phenyl-2-pyrimidine-amine derivatives and process for the preparation thereof. WO,2007018325 [P].2007-2-15
[17]Seeliger M A, Ranjitkar P, Kasap C, et al. Equally potent inhibition of c-Src and Abl by compounds that recognize inactive kinase conformations[J]. Cancer Research,2009, 69(6),2384-2392.
[18]Yuan G, Ren J W. Technique for preparing 3-bromo-5-trifluoromethylaniline. CN, 101168510[P].2008-3-30
[19]Yan S Q, Appleby T, Gunic E, et al. Isothiazoles as active-site inhibitors of HCV NS5B polymerase[J]. Bioorganic and Medicinal Chemistry Letters,2007,17(1):28-33.
[20]许丹倩,徐振元,李淑玲.间三氟甲基苯胺的合成[J].中国现代应用药学杂志,1998,15(2)：33-35.
[21]蔡春,吕春绪.间羟基三氟甲苯的合成[J].农药,2002，43(9):12-13.
[22]邓维,刘磊,郭庆祥.铜催化交叉偶联反应研究的新进展田.有机化学，2004,24(2):150-165.
[23]Zhang R, Lei L, Xu Y G, et al. Benzimidazol-2-yl or benzimidazol-2-ylthiomethyl benzoylguanidines as novel Na+/H+ exchanger inhibitors, synthesis and protection against ischemic-reperfusion injury[J]. Bioorganic & Medicinal Chemistry Letters,2007, 17(9):2430-2433.
[24]David W M, Jason S. 1,2-Bis-(substituted-phenyl)-2-propen-1-ones and pharmaceutical compositions thereof. WO,2006004903[P].2006-1-12
[25]Curran D P, Yang F L, Cheong J H. Relative Rates and Approximate Rate Constants for Inter- and Intramolecular Hydrogen Transfer Reactions of Polymer-Bound Radicals[J]. Journal of the American Chemical Society,2002,124(50):14993-15000.
[26]Sengupta S, Drew M G, Mukhopadhyay R, et al. Stereoseleetive syntheses of (±)-komaroviquinone and (±)-faveline methyl ether through intramolecular Heck reaction[J]. Journal of Organic Chemistry,2005,70(19):7694-7700.
[27]Alvarez S, Khanwalkar H, Alvarez H, et al. C3 Halogen and C8" Substituents on Stilbene Arotinoids Modulate Retinoic Acid Receptor Subtype Function[J]. ChemMedChem,2009,4(10):1630-1640.
[28]Rozen S, Brand M, Lidor R. Aromatic bromination using bromine fluoride with no Friedel-Crafts catalyst[J]. Journal of Organic Chemistry,1988,53(23):5545-5547.
[29]Pechlivanidis Z, Hopf H, Emst L. Paracyclophanes:Extending the Bridges. Synthesis[J]. European Journal of Organic Chemistry,2009,2009(2):223-237.
[30]Zhurnal Organicheskoi Khimii,22(1),30-9; 1986
[31]Vestsi Natsyyanal'nai Akademii Navuk Belarusi. [J].Seryya Khimichnykh Navuk, (2), 84-90; 2010
[32]Karlheinz B, Alexander F, Erwin G, et al. Modulators for amyloid beta. WO, 2009103652[P],2009-8-27.
[33]Kalesh K A, Sim D S, Wang J G, et al. Small molecule probes that target Ab1 kinase[J]. Chemical Communications,2010,46(7):1118-1120.
[34]Szakacs Z, Beni S, Varga Z, et al. Acid-Base Profiling of Imatinib (Gleevec) and Its Fragments[J]. Journal of Medicinal Chemistry,2005,48(1):249-255.
[35]Li S X, Liu Y X, Zhao Y J, et al. Benzamide derivatives with anti-proliferative activity, pharmaceutical preparations thereof. WO,2008113255[P],2008-9-25
[36]白亚军,刘毅锋,张娟,等.3-N,N-二甲基氨基-1-芳杂环基-2-丙烯-1-酮合成[J].西 北大学学报(自然科学版),2007,37(2)：231-234.
[37]Liu Y F, Wang C L, Bai Y J, et al. A facile total synthesis of imatinib base and its analogues[J]. Organic Process Research & Development,2008,12(3):490-495.
[38]Mustafa I, Lee S H. Design and synthesis of new anticancer pyrimidines with multiple-kinase inhibitory effect[J]. Bioorganic & Medicinal Chemistry,2010,18(11): 3860-3874.
[39]Yan X N, Zhang H D.4-substituent-2-amido pyrimidine compound and preparation method thereof. CN,101602757[P],2009-12-16.
[40]Kalesh K A, Liu K, Yao S Q. Rapid synthesis of Abelson tyrosine kinase inhibitors using click chemistry[J]. Org Biomol Chem,2009,7(24):5129-5136.
[41]Chianelli D, Li X L, Lu X D, et al. Compounds and compositions as protein kinase inhibitors. WO,2008058037[P],2008-5-15.
[42]Li X L, Lu X D, Molteni V. Pyrimidine derivatives and compositions as C-KIT and PDGFR kinase inhibitors. WO,2008137605[P],2008-11-13.
[43]Sengupta P, Puri C S, Chokshi H, et al. Novel hydrazide containing tyrosine kinase inhibitors. WO,2009109991 [P],2009-9-11.
[44]蔡春,姚红,吕春绪.间羟基三氟甲苯的合成[J].江苏化工,2002,30(5)：46-47.
[45]闻韧.药物合成反应[M].第2版,北京：化学工业出版社,2002.8.
[46]Lindley J. Copper assisted nucleophilic substitution of aryl halogen[J]. Tetrahedron, 1984,40(9); 1433-1456.
[47]Cohen T, Wood J, Dietz A G. Organocopper intermediates in the exchange reaction of aryl halides with salts of copper(I)[J]. Tetrahedron Lett,1974,40; 3555-3558.
[48]Aalten H L, Koten G V, Grove D M, et al. The copper catalysed reaction of sodium methoxide with aryl bromides. A mechanistic study leading to a facile synthesis of anisole derivatives[J]. Tetrahedron,1989,45(17):5565-5578.
[49]Paine A J. Mechanism and models for copper mediated nucleophilic aromatic substitution[J]. J Am Chem Soc,1987,109:1496-1502.
[50]Klapars A, Huang X H, Buchwald S L. A general and efficient copper catalyst for the amidation of aryl halides[J]. J Am Chem Soc,2002,124:7421-7428.
[51]Kwong F Y, Klapars A, Buchwald S L. Copper-cataylzed coupling of alkylamines and aryl iodides:An efficient system even in an air atmosphere[J]. Org Lett,2002,4(4): 581-584.
[52]Kiyomori A, Marcoux J F, Buchwald S L. An efficient copper-catalyzed coupling of aryl halides with imidazoles[J]. Tetrahedron Lett,1999,40:2657-2660.
[2]癌症数据评论,2000-2003.
[3]黄葆华,陈丽明,于伟娟等.慢性粒细胞白血病23例染色体核型分析[J].河北医学,2002,8(9)：857-858.
[4]小泽敬也.白血病[J].日本医学介绍,2007,28(8)：345-347.
[5]抗癌药nilotinib[J]药学进展,2007,31(5)：236-237.
[6]Elias J, Samih E A, Jorge C, et al. Nilotinib:a novel Bcr-Abl tyrosine kinase inhibitor for the treatment of leukemias[J]. Expert Opin. Investig. Drugs,2008,17(7):1127-1136.
[7]Hagop K, Francis G, Lydia W, et al. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL[J]. N Engl J Med.,2006,254(24):2542-2551.
[8]Deininger, Michael W. nilotinib[J]. Clin Cancer Res.,2008,14(13):4027-4031.
[9]Breitenstein W, Furet P, Jacob S, et al. Inhibitors of tyrosine kinases. WO,2004005281 [P]. 2004-01-15.
[10]Mckenna J, Shieh W C. Process for the synthesis of organic compounds. WO, 2006135641 [P].2006-12-21.
[11]陈永江,王丽华,周红,等.尼罗替尼的合成[J].中国医药工业杂志,2009,40(6)：401-403.
[12]Wang Y L, Li J, Kansal V K, et al. Processes for preparation of nilotinib and intermediates. WO,2010009402[P].2010-1-21.
[13]Yeori A, Wang Y L, Li J, et al. Processes for preparation of nilotinib and intermediates. WO,2010060074[P].2010-5-27.
[14]Huang WS, Shakespeare WC. An efficient synthesis of nilotinib (AMN107)[J]. Synthesis, 2007, (14):2121-2124.
[15]Abel S, Acemoglu M, Erb B, et al. Process for the synthesis of organic compounds. WO, 2006135640[P].2006-12-21.
[16]Kim D Y, Cho D J, Lee G Y, et al. N-Phenyl-2-pyrimidine-amine derivatives and process for the preparation thereof. WO,2007018325 [P].2007-2-15
[17]Seeliger M A, Ranjitkar P, Kasap C, et al. Equally potent inhibition of c-Src and Abl by compounds that recognize inactive kinase conformations[J]. Cancer Research,2009, 69(6),2384-2392.
[18]Yuan G, Ren J W. Technique for preparing 3-bromo-5-trifluoromethylaniline. CN, 101168510[P].2008-3-30
[19]Yan S Q, Appleby T, Gunic E, et al. Isothiazoles as active-site inhibitors of HCV NS5B polymerase[J]. Bioorganic and Medicinal Chemistry Letters,2007,17(1):28-33.
[20]许丹倩,徐振元,李淑玲.间三氟甲基苯胺的合成[J].中国现代应用药学杂志,1998,15(2)：33-35.
[21]蔡春,吕春绪.间羟基三氟甲苯的合成[J].农药,2002，43(9):12-13.
[22]邓维,刘磊,郭庆祥.铜催化交叉偶联反应研究的新进展田.有机化学，2004,24(2):150-165.
[23]Zhang R, Lei L, Xu Y G, et al. Benzimidazol-2-yl or benzimidazol-2-ylthiomethyl benzoylguanidines as novel Na+/H+ exchanger inhibitors, synthesis and protection against ischemic-reperfusion injury[J]. Bioorganic & Medicinal Chemistry Letters,2007, 17(9):2430-2433.
[24]David W M, Jason S. 1,2-Bis-(substituted-phenyl)-2-propen-1-ones and pharmaceutical compositions thereof. WO,2006004903[P].2006-1-12
[25]Curran D P, Yang F L, Cheong J H. Relative Rates and Approximate Rate Constants for Inter- and Intramolecular Hydrogen Transfer Reactions of Polymer-Bound Radicals[J]. Journal of the American Chemical Society,2002,124(50):14993-15000.
[26]Sengupta S, Drew M G, Mukhopadhyay R, et al. Stereoseleetive syntheses of (±)-komaroviquinone and (±)-faveline methyl ether through intramolecular Heck reaction[J]. Journal of Organic Chemistry,2005,70(19):7694-7700.
[27]Alvarez S, Khanwalkar H, Alvarez H, et al. C3 Halogen and C8" Substituents on Stilbene Arotinoids Modulate Retinoic Acid Receptor Subtype Function[J]. ChemMedChem,2009,4(10):1630-1640.
[28]Rozen S, Brand M, Lidor R. Aromatic bromination using bromine fluoride with no Friedel-Crafts catalyst[J]. Journal of Organic Chemistry,1988,53(23):5545-5547.
[29]Pechlivanidis Z, Hopf H, Emst L. Paracyclophanes:Extending the Bridges. Synthesis[J]. European Journal of Organic Chemistry,2009,2009(2):223-237.
[30]Zhurnal Organicheskoi Khimii,22(1),30-9; 1986
[31]Vestsi Natsyyanal'nai Akademii Navuk Belarusi. [J].Seryya Khimichnykh Navuk, (2), 84-90; 2010
[32]Karlheinz B, Alexander F, Erwin G, et al. Modulators for amyloid beta. WO, 2009103652[P],2009-8-27.
[33]Kalesh K A, Sim D S, Wang J G, et al. Small molecule probes that target Ab1 kinase[J]. Chemical Communications,2010,46(7):1118-1120.
[34]Szakacs Z, Beni S, Varga Z, et al. Acid-Base Profiling of Imatinib (Gleevec) and Its Fragments[J]. Journal of Medicinal Chemistry,2005,48(1):249-255.
[35]Li S X, Liu Y X, Zhao Y J, et al. Benzamide derivatives with anti-proliferative activity, pharmaceutical preparations thereof. WO,2008113255[P],2008-9-25
[36]白亚军,刘毅锋,张娟,等.3-N,N-二甲基氨基-1-芳杂环基-2-丙烯-1-酮合成[J].西 北大学学报(自然科学版),2007,37(2)：231-234.
[37]Liu Y F, Wang C L, Bai Y J, et al. A facile total synthesis of imatinib base and its analogues[J]. Organic Process Research & Development,2008,12(3):490-495.
[38]Mustafa I, Lee S H. Design and synthesis of new anticancer pyrimidines with multiple-kinase inhibitory effect[J]. Bioorganic & Medicinal Chemistry,2010,18(11): 3860-3874.
[39]Yan X N, Zhang H D.4-substituent-2-amido pyrimidine compound and preparation method thereof. CN,101602757[P],2009-12-16.
[40]Kalesh K A, Liu K, Yao S Q. Rapid synthesis of Abelson tyrosine kinase inhibitors using click chemistry[J]. Org Biomol Chem,2009,7(24):5129-5136.
[41]Chianelli D, Li X L, Lu X D, et al. Compounds and compositions as protein kinase inhibitors. WO,2008058037[P],2008-5-15.
[42]Li X L, Lu X D, Molteni V. Pyrimidine derivatives and compositions as C-KIT and PDGFR kinase inhibitors. WO,2008137605[P],2008-11-13.
[43]Sengupta P, Puri C S, Chokshi H, et al. Novel hydrazide containing tyrosine kinase inhibitors. WO,2009109991 [P],2009-9-11.
[44]蔡春,姚红,吕春绪.间羟基三氟甲苯的合成[J].江苏化工,2002,30(5)：46-47.
[45]闻韧.药物合成反应[M].第2版,北京：化学工业出版社,2002.8.
[46]Lindley J. Copper assisted nucleophilic substitution of aryl halogen[J]. Tetrahedron, 1984,40(9); 1433-1456.
[47]Cohen T, Wood J, Dietz A G. Organocopper intermediates in the exchange reaction of aryl halides with salts of copper(I)[J]. Tetrahedron Lett,1974,40; 3555-3558.
[48]Aalten H L, Koten G V, Grove D M, et al. The copper catalysed reaction of sodium methoxide with aryl bromides. A mechanistic study leading to a facile synthesis of anisole derivatives[J]. Tetrahedron,1989,45(17):5565-5578.
[49]Paine A J. Mechanism and models for copper mediated nucleophilic aromatic substitution[J]. J Am Chem Soc,1987,109:1496-1502.
[50]Klapars A, Huang X H, Buchwald S L. A general and efficient copper catalyst for the amidation of aryl halides[J]. J Am Chem Soc,2002,124:7421-7428.
[51]Kwong F Y, Klapars A, Buchwald S L. Copper-cataylzed coupling of alkylamines and aryl iodides:An efficient system even in an air atmosphere[J]. Org Lett,2002,4(4): 581-584.
[52]Kiyomori A, Marcoux J F, Buchwald S L. An efficient copper-catalyzed coupling of aryl halides with imidazoles[J]. Tetrahedron Lett,1999,40:2657-2660.