新型钙拮抗剂尼伐地平的合成研究
|
摘要
本文介绍了抗高血压药物的应用现状及分类。钙拮抗剂因具有降压效果确切、对末梢血管选择性高、对各种代谢无副作用、禁忌症少和血管扩张作用等优点，而成为临床应用较广的心血管药物。尼伐地平属于第二代二氢吡啶类钙拮抗剂，其与Ca~(2+)通道特异部位的结合力比硝苯地平强10倍，作用持续时间较之长2-3倍，血药浓度较为平稳，良好的降压作用能维持24小时以上。因此，尼伐地平是安全、高效的首选高血压治疗药物，其应用前景十分广阔，市场潜力十分巨大。
本文重点研究设计了尼伐地平的合成工艺路线，通过实验合成了尼伐地平及其五个中间体，并对其进行了分析表征。通过考察各步反应的影响因素，得到了最佳工艺条件，具体如下：
(1)以50％乙醛酸水溶液和原甲酸三甲酯为主要原料，经浓硫酸催化，合成二甲氧基乙酸甲酯。在考察了合成工艺条件的基础上，通过正交实验设计对反应条件进行了优化，得到了最佳反应条件。二甲氧基乙酸甲酯的收率可达92.16％。
太原理工大学硕士学位论文
(2)以二甲氧基乙酸甲酷和乙酸甲酷为主要原料，经甲
醇钠催化制备二甲氧基乙酞乙酸甲醋。在考察了原料摩尔比、
催化剂用量、加料温度、反应温度和反应时间等影响因素对反
应收率影响的基础上，通过均匀实验设计优化了反应条件。在
最佳合成条件下，二甲氧基乙酞乙酸甲酷的收率可达43.56%。
(3)以二甲氧基乙酞乙酸甲醋和间硝基苯甲醛为原料，
呱咤和冰醋酸为催化剂，合成2一(3一硝基亚节基)一4，4一二甲基
乙酞乙酸甲酷。通过考察原料配比、催化剂用量及加料方式、
反应时间等因素对产率的影响，得到了最佳合成条件。粗产品
产率可达112.30%。(粗产品不经提纯，直接用于下一步反应)。
(4)以2一(3一硝基亚节基)一4，4一二甲基乙酞乙酸甲醋和
3一氨基巴豆酸异丙醋为主要原料，缩合脱水生成3一甲氧梭基
一2，2一二甲氧基甲基一4一(3一硝基苯基)一6一甲基一1，4一二氢毗陡一5-
梭基异丙酷。通过考察原料配比、反应温度和反应时间等因素
对收率的影响，得到了最佳合成条件。3一甲氧梭基一2，2一二甲氧
基甲基一4一(3一硝基苯基)一6一甲基一1，4一二氢毗陡一5一梭基异丙酷
的收率可达83.52%。
(5)以3一甲氧梭基一2，2一二甲氧基甲基一4一(3一硝基苯基)
一6一甲基一1，4一二氢毗吮一5一梭基异丙醋和6mol几盐酸为原料，丙
太原理工大学硕士学位论文
酮作溶剂，缩合得到3一甲氧梭基一2一甲酞基一4一(3一硝基苯基)
一6一甲基一1，4一二氢毗淀一5一梭酸异丙醋。通过考察配料比、反应
温度及反应时间等因素的影响，得到了最佳合成条件。3一甲氧
梭基一2一甲酞基一4一(3一硝基苯基)一6一甲基一1，4一二氢毗陡一5一梭酸
异丙酉旨可达85.44%。
(6)以3一甲氧梭基一2一甲酞基一4一(3一硝基苯基)一6一甲基一1，4-
二氢毗陡一5一竣酸异丙酷和盐酸经胺为原料，无水乙酸钠和乙酸
配为脱水剂，合成尼伐地平。通过考察原料摩尔比、脱水剂用
量、反应时间和反应温度等因素的影响，得到了最佳合成条件。
尼伐地平的收率可达33.76%。
在上述最佳反应条件下，尼伐地平的总收率可达10.86%。
在国内未见与本研究内容相同的报道。
In this paper, the present situation of application and classfication of pharmaceutical for treatment of hypertesion were introduced. Calcium antagonists has been accepted for the treatment of cardiovascular diseases in clinical. It has many predominace such as the better for decreasing of blood pressure, high selectivity for distal blood vessel, and no side affection for all kinds of metabolism, small taboo symptom and affection for vascular expand etc.. Nilvadipine is the second generation of dihydropyridine calcium antagonists. Its cohesion with the special location of calcium ion is 10 times stronger than previous Nifeddipine and affect lasting 2 to 3 times longer than that. The blood pressure decreasing can be maintained well for 24 hours because of its steady pharmceutical concentrationin blood. So Nilvadipine is a safe, efficacious and first-selective pharmceutical in treatment of hypertension. Therefor it has a wild potential in the market.
The synthesis process of Nilvadipine and its five intermediates were designed. The optimum reaction conditions were obtained as followry:
(1) A new process has been developed to synthesize dimethoxyacetic acid methyl ester with the 50% solution of glyoxylic acid and methyl
orthoformate in the presence of concentrated sulfuric acid. The reaction conditions have been optimized by orthogonal experimental design. The yield of dimethoxyacetic acid methyl ester was to 92.16%.
(2) A new process has been developed to synthesize dimethoxy methyl aceto acetate with dimethoxyacetic acid methyl ester and methyl acetate in the presence of sodium methanol. On the basis of investigating effects of the mole ratio of raw material, amount of catalyst, reaction temperature and time, the optimum reaction conditions were obtained by using uniform design, and the yield of dimethoxy methyl aceto acetate was to 43.56%.
(3) A new process has been developed to synthesize mehtyl 2-(3-nitrobenzyliene)-4,4-dimethoxyacetoacetate with dimethoxy methyl aceto acetate and 3-nitrobenzal dehyde in the presence of piperidine and acetic acid ylacial. The effects of the mole ratio of raw material, the amount and feeding method of catalyst, reaction time on the yield were investigated. The optimum reaction conditions were obtained. The rate of production of methyl 2-(3-nitrobenzyliene)-4,4-dimethoxyacetoacetate was to 112.30%, which was used in the following reaction without purification.
(4) A new process has been developed to synthesize 2,2-dimethoxyme-thyl-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid 3-methyl 5-(l-methylethyl) diester with methyl 2-(3-nitrobenzyliene) -4,4-dimethoxyacetoacetate and 3-aminocaotonic acid isproxycarbonyl ester. The optimum reaction conditions were obtained by investigating effects of the mole ratio of raw material, reaction temperature and time on the yield. The yield of 2,2-dimemoxymethyl-ls4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid 3-methyl 5-(l-methylethyl) diester was to
83.52%.
(5) A new process has been developed to synthesize 2-formyl-l,4- dihy-dro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid 3-mehtylethyl diester with 2,2-dimethoxymethyl-l,4-dihydro-6-methyl-4-(3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3-methyl 5-(l-methylethyl) diester and 6mol/L hydrochloric acid in the presence of acetone as solvent. The optimum reaction conditions were obtained by investigating the effects of mole ratio of raw material, reaction temperature and time on the yield. The yield of 2-formyl-l,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid 3-methylethyl diester was to 85.44%.
(6) A new process has been developed to synthesize Nilvadipine with 2-formyl-l,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid 3-methylethyl diester and hydroxylamine hydrochloride in the presence of sodium acetate anhydrous as dehydrate. The optimum reaction conditions were obtained by investigating effects of the mole ratio of raw material, amount of dehydrate, re
本文重点研究设计了尼伐地平的合成工艺路线，通过实验合成了尼伐地平及其五个中间体，并对其进行了分析表征。通过考察各步反应的影响因素，得到了最佳工艺条件，具体如下：
(1)以50％乙醛酸水溶液和原甲酸三甲酯为主要原料，经浓硫酸催化，合成二甲氧基乙酸甲酯。在考察了合成工艺条件的基础上，通过正交实验设计对反应条件进行了优化，得到了最佳反应条件。二甲氧基乙酸甲酯的收率可达92.16％。
太原理工大学硕士学位论文
(2)以二甲氧基乙酸甲酷和乙酸甲酷为主要原料，经甲
醇钠催化制备二甲氧基乙酞乙酸甲醋。在考察了原料摩尔比、
催化剂用量、加料温度、反应温度和反应时间等影响因素对反
应收率影响的基础上，通过均匀实验设计优化了反应条件。在
最佳合成条件下，二甲氧基乙酞乙酸甲酷的收率可达43.56%。
(3)以二甲氧基乙酞乙酸甲醋和间硝基苯甲醛为原料，
呱咤和冰醋酸为催化剂，合成2一(3一硝基亚节基)一4，4一二甲基
乙酞乙酸甲酷。通过考察原料配比、催化剂用量及加料方式、
反应时间等因素对产率的影响，得到了最佳合成条件。粗产品
产率可达112.30%。(粗产品不经提纯，直接用于下一步反应)。
(4)以2一(3一硝基亚节基)一4，4一二甲基乙酞乙酸甲醋和
3一氨基巴豆酸异丙醋为主要原料，缩合脱水生成3一甲氧梭基
一2，2一二甲氧基甲基一4一(3一硝基苯基)一6一甲基一1，4一二氢毗陡一5-
梭基异丙酷。通过考察原料配比、反应温度和反应时间等因素
对收率的影响，得到了最佳合成条件。3一甲氧梭基一2，2一二甲氧
基甲基一4一(3一硝基苯基)一6一甲基一1，4一二氢毗陡一5一梭基异丙酷
的收率可达83.52%。
(5)以3一甲氧梭基一2，2一二甲氧基甲基一4一(3一硝基苯基)
一6一甲基一1，4一二氢毗吮一5一梭基异丙醋和6mol几盐酸为原料，丙
太原理工大学硕士学位论文
酮作溶剂，缩合得到3一甲氧梭基一2一甲酞基一4一(3一硝基苯基)
一6一甲基一1，4一二氢毗淀一5一梭酸异丙醋。通过考察配料比、反应
温度及反应时间等因素的影响，得到了最佳合成条件。3一甲氧
梭基一2一甲酞基一4一(3一硝基苯基)一6一甲基一1，4一二氢毗陡一5一梭酸
异丙酉旨可达85.44%。
(6)以3一甲氧梭基一2一甲酞基一4一(3一硝基苯基)一6一甲基一1，4-
二氢毗陡一5一竣酸异丙酷和盐酸经胺为原料，无水乙酸钠和乙酸
配为脱水剂，合成尼伐地平。通过考察原料摩尔比、脱水剂用
量、反应时间和反应温度等因素的影响，得到了最佳合成条件。
尼伐地平的收率可达33.76%。
在上述最佳反应条件下，尼伐地平的总收率可达10.86%。
在国内未见与本研究内容相同的报道。
In this paper, the present situation of application and classfication of pharmaceutical for treatment of hypertesion were introduced. Calcium antagonists has been accepted for the treatment of cardiovascular diseases in clinical. It has many predominace such as the better for decreasing of blood pressure, high selectivity for distal blood vessel, and no side affection for all kinds of metabolism, small taboo symptom and affection for vascular expand etc.. Nilvadipine is the second generation of dihydropyridine calcium antagonists. Its cohesion with the special location of calcium ion is 10 times stronger than previous Nifeddipine and affect lasting 2 to 3 times longer than that. The blood pressure decreasing can be maintained well for 24 hours because of its steady pharmceutical concentrationin blood. So Nilvadipine is a safe, efficacious and first-selective pharmceutical in treatment of hypertension. Therefor it has a wild potential in the market.
The synthesis process of Nilvadipine and its five intermediates were designed. The optimum reaction conditions were obtained as followry:
(1) A new process has been developed to synthesize dimethoxyacetic acid methyl ester with the 50% solution of glyoxylic acid and methyl
orthoformate in the presence of concentrated sulfuric acid. The reaction conditions have been optimized by orthogonal experimental design. The yield of dimethoxyacetic acid methyl ester was to 92.16%.
(2) A new process has been developed to synthesize dimethoxy methyl aceto acetate with dimethoxyacetic acid methyl ester and methyl acetate in the presence of sodium methanol. On the basis of investigating effects of the mole ratio of raw material, amount of catalyst, reaction temperature and time, the optimum reaction conditions were obtained by using uniform design, and the yield of dimethoxy methyl aceto acetate was to 43.56%.
(3) A new process has been developed to synthesize mehtyl 2-(3-nitrobenzyliene)-4,4-dimethoxyacetoacetate with dimethoxy methyl aceto acetate and 3-nitrobenzal dehyde in the presence of piperidine and acetic acid ylacial. The effects of the mole ratio of raw material, the amount and feeding method of catalyst, reaction time on the yield were investigated. The optimum reaction conditions were obtained. The rate of production of methyl 2-(3-nitrobenzyliene)-4,4-dimethoxyacetoacetate was to 112.30%, which was used in the following reaction without purification.
(4) A new process has been developed to synthesize 2,2-dimethoxyme-thyl-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid 3-methyl 5-(l-methylethyl) diester with methyl 2-(3-nitrobenzyliene) -4,4-dimethoxyacetoacetate and 3-aminocaotonic acid isproxycarbonyl ester. The optimum reaction conditions were obtained by investigating effects of the mole ratio of raw material, reaction temperature and time on the yield. The yield of 2,2-dimemoxymethyl-ls4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid 3-methyl 5-(l-methylethyl) diester was to
83.52%.
(5) A new process has been developed to synthesize 2-formyl-l,4- dihy-dro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid 3-mehtylethyl diester with 2,2-dimethoxymethyl-l,4-dihydro-6-methyl-4-(3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3-methyl 5-(l-methylethyl) diester and 6mol/L hydrochloric acid in the presence of acetone as solvent. The optimum reaction conditions were obtained by investigating the effects of mole ratio of raw material, reaction temperature and time on the yield. The yield of 2-formyl-l,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid 3-methylethyl diester was to 85.44%.
(6) A new process has been developed to synthesize Nilvadipine with 2-formyl-l,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid 3-methylethyl diester and hydroxylamine hydrochloride in the presence of sodium acetate anhydrous as dehydrate. The optimum reaction conditions were obtained by investigating effects of the mole ratio of raw material, amount of dehydrate, re
引文
1．黄哲生．高血压病的研究进展[J]．中南民族学院学报(自然科学版)，1994，13(1)117-119
2．匡长春，汤韧，王平．抗高血压药物的应用现状与进展[J]．药学实践，2000，18(3)：139-142
3．高振同．抗高血压药物的评价[J]．中国药房，1995，6(3)：28-29
4．刘卫，刘建国，苏立冯。评价高血压药的新观点和新方法—对靶器官功能的影响[J]．中国药学杂志，1999，34(3)：147
5．上海市高血压研究所《高血压》编写组．高血压病[M]．上海科学技术出版社，1975
6．毛晓明．抗高血压药物的分类及其作用机理与临床应用[J]．辽宁实用糖尿病杂志，2000，8(1)：54-57
7．黄震华．抗高血压治疗中钙通道阻滞剂的应用[J]．国外医学内科学分册，2000，27(10)：423-426
8．张廷杰．钙拮抗剂的应用与进展[J]．心血管病学进展，1995，16(1)：43-51
9．白树华，陈玉彬．二氢吡啶类钙拮抗剂研究的新进展[J]．药学进展，1999，23(1)：13-19
10．徐济民．抗高血压药物应用进展[J]．上海预防医学杂志，1994，6(9)：21-22
11．李彦博，陈井，刘军．钙拮抗剂的分类及在治疗中高血压中的应用[J]．辽宁医学杂志，2001，15(2)：101-102
12．陈惠民，叶惠珍．二氢吡啶类钙拮抗剂在治疗高血压中的研究进展[J]．国外医药—合成药、生化药、制剂分册，1994，15(2)：72-76
13．孙安阳．钙拮抗剂—朋友还是敌人[J]．国外医学药学分册，1997，24(1)：29
14．胡大一，王宏宇．钙拮抗剂的展望[J]．中国医刊，2001，36(10)：20-23
15．松冈博昭．钙拮抗剂的正确评价问题[J]．日本医学介绍，1997，18(5)：216-218
16．方欢，石刚刚．钙拮抗剂研究进展[J]．汕头大学医学院学报，2001，14(2)：140-142
17．Pahor M et al．对钙拮抗剂有效性和安全性的反思[J]．国外医学药学分册，1997，24(5)291-203
18. Kazuyuki Miya Shita, Masahiso Nishimoto,Tetsuya Ishino, et al. Studies on novel and chial 1,4-dihydropyridines[J]. Terahedron, 1997,53(12):4279
19．赵克健主编．《中国化学药品大全》[M](第二版)．北京，新时代出版社，1999：241
20．陈芬儿主编．《有机药物合成法》(第一卷)[M]．北京，中国医药科技出版社，1999：443-446
21. Y.Satoh, M. Ichihashi, K.Okumura.Studies on nilvadipine. Ⅰ. Synthesis and structure-activity relationships of 1,4-dihydropyridine containing novel substituents at the 2-position[J]. Chemical & Pharmaceutical Bulletin, 1991, 39(12):3189-3201
22. Y. Satoh, M. Ichihashi, K.Okumura. Studies on nilvadipine. Ⅱ. Synthesis and Structure-Activity Relationships of 2-Hydroxymethyl-and 2-Cyano-1,4-dihydropyridines Containing Heteroatom-Substituted Ester at the 5-Position[J]. Chemical & Pharmaceutical Bulletin, 1992,40(4):912-917
23. Y. Satoh, K.Okumura, Y. Shiokawa.Studies on nilvadipine. Ⅲ. Synthesis of metbolites of nilvadipine and their related compounds[J]. Chemical & Pharmaceutical Bulletin, 1992,40(7): 1799-1807
24．岳步星．新型钙通道拮抗剂尼伐地平[J]．国外医药一合成药、生化药、制剂分册，1996，17(1)：27-29
25．吴苏敏，宋明，华峰等．尼莫地平的合成工艺改进[J]．中国药科大学学报，1998，
29(3)：232-233
26．宋泽远，杨爱华，毛阿莉．两步法合成尼群地平的工艺改进[J]．常德师范学院学报，2000，12(2)：50-51
27．鲍春和，陈子明，杜玉民．尼莫地平合成工艺的改进[J]．中国医药工业杂志，1996，27(7)：295-296
28. Sato,Yoshinari. Pharmaceutic 1,4-dihydropyridine compounds. DE, patent specification, 2756226,29 Jun 1978
29. Sato,Yoshinari. 1,4-dihydropyridine derivatives and process for preparation thereof, GB, patent specification, 1591089, 14 Dec 1981
30. Hisatoyo Yazawa,Norio Hashimoto, Koji Kakara, Preparation of dialkoxyacetate esters as intermediates for pharmaceuticais, JP,公开特许公报，6248648,03 Mar 1987
31．方开泰，马长兴．正交与均匀实验设计[M]．北京，科学出版社，2001：31-113
32．吴贵生，于治福，于淑政等．试验设计与数据处理[M]．北京，冶金工业出版社，1997：46-75
33．栾军．现代试验设计优化方法[M]．上海，上海交通大学出版社，1995：14-175
34．朱明华．仪器分析[M](第二版)．北京，高等教育出版社，1992：355-386
35．余仲建，李松兰，张殿坤编著．现代有机分析[M]．天津科学技术出版社，1994
36．宁永成编著．有机化合物结构鉴定与有机波谱学[M](第二版)．科学出版社，2000
37．谢晶曦，常俊标，王结明编著．红外光谱在有机化学和药物化学中的应用[M](修订版)．科学出版社，2001：23-339
38. Gory M, Coppola, Robert E. Domn. 3-(2-Pyrrolidinyl)-2,4-furandione Analoys[J], Journal of Heterocyclic Chemistry, 1990, 27 (1): 815-817
39. John A. Secrist Ⅲ, Charles J.Hickey, and Robert E.Norris. A Convent Total
Synthesis of (±)-(7E,9E)-Trisporic Acid B Methyl Ester[J]. The Journal of Organic Chemistry, 1977,42(1):525-527
40．徐寿昌．有机化学[M]．北京，高等教育出版社，1998
41．王积涛，胡青眉，张宝审等编著．有机化学[M]．南开大学出版社，1993
42．闻韧．药物合成反应[M]．北京，化学工业出版社，1988：222-238
43．jie Jack Li著，荣国斌译．Name Reaction A Coollection of Detailed Reaction Mechanisms[M]．华东理工大学出版社，2003：172-220
44．黄宪，王彦光，陈振初编著．新编有机合成化学[M]．化学工业出版社，2002：512-514
2．匡长春，汤韧，王平．抗高血压药物的应用现状与进展[J]．药学实践，2000，18(3)：139-142
3．高振同．抗高血压药物的评价[J]．中国药房，1995，6(3)：28-29
4．刘卫，刘建国，苏立冯。评价高血压药的新观点和新方法—对靶器官功能的影响[J]．中国药学杂志，1999，34(3)：147
5．上海市高血压研究所《高血压》编写组．高血压病[M]．上海科学技术出版社，1975
6．毛晓明．抗高血压药物的分类及其作用机理与临床应用[J]．辽宁实用糖尿病杂志，2000，8(1)：54-57
7．黄震华．抗高血压治疗中钙通道阻滞剂的应用[J]．国外医学内科学分册，2000，27(10)：423-426
8．张廷杰．钙拮抗剂的应用与进展[J]．心血管病学进展，1995，16(1)：43-51
9．白树华，陈玉彬．二氢吡啶类钙拮抗剂研究的新进展[J]．药学进展，1999，23(1)：13-19
10．徐济民．抗高血压药物应用进展[J]．上海预防医学杂志，1994，6(9)：21-22
11．李彦博，陈井，刘军．钙拮抗剂的分类及在治疗中高血压中的应用[J]．辽宁医学杂志，2001，15(2)：101-102
12．陈惠民，叶惠珍．二氢吡啶类钙拮抗剂在治疗高血压中的研究进展[J]．国外医药—合成药、生化药、制剂分册，1994，15(2)：72-76
13．孙安阳．钙拮抗剂—朋友还是敌人[J]．国外医学药学分册，1997，24(1)：29
14．胡大一，王宏宇．钙拮抗剂的展望[J]．中国医刊，2001，36(10)：20-23
15．松冈博昭．钙拮抗剂的正确评价问题[J]．日本医学介绍，1997，18(5)：216-218
16．方欢，石刚刚．钙拮抗剂研究进展[J]．汕头大学医学院学报，2001，14(2)：140-142
17．Pahor M et al．对钙拮抗剂有效性和安全性的反思[J]．国外医学药学分册，1997，24(5)291-203
18. Kazuyuki Miya Shita, Masahiso Nishimoto,Tetsuya Ishino, et al. Studies on novel and chial 1,4-dihydropyridines[J]. Terahedron, 1997,53(12):4279
19．赵克健主编．《中国化学药品大全》[M](第二版)．北京，新时代出版社，1999：241
20．陈芬儿主编．《有机药物合成法》(第一卷)[M]．北京，中国医药科技出版社，1999：443-446
21. Y.Satoh, M. Ichihashi, K.Okumura.Studies on nilvadipine. Ⅰ. Synthesis and structure-activity relationships of 1,4-dihydropyridine containing novel substituents at the 2-position[J]. Chemical & Pharmaceutical Bulletin, 1991, 39(12):3189-3201
22. Y. Satoh, M. Ichihashi, K.Okumura. Studies on nilvadipine. Ⅱ. Synthesis and Structure-Activity Relationships of 2-Hydroxymethyl-and 2-Cyano-1,4-dihydropyridines Containing Heteroatom-Substituted Ester at the 5-Position[J]. Chemical & Pharmaceutical Bulletin, 1992,40(4):912-917
23. Y. Satoh, K.Okumura, Y. Shiokawa.Studies on nilvadipine. Ⅲ. Synthesis of metbolites of nilvadipine and their related compounds[J]. Chemical & Pharmaceutical Bulletin, 1992,40(7): 1799-1807
24．岳步星．新型钙通道拮抗剂尼伐地平[J]．国外医药一合成药、生化药、制剂分册，1996，17(1)：27-29
25．吴苏敏，宋明，华峰等．尼莫地平的合成工艺改进[J]．中国药科大学学报，1998，
29(3)：232-233
26．宋泽远，杨爱华，毛阿莉．两步法合成尼群地平的工艺改进[J]．常德师范学院学报，2000，12(2)：50-51
27．鲍春和，陈子明，杜玉民．尼莫地平合成工艺的改进[J]．中国医药工业杂志，1996，27(7)：295-296
28. Sato,Yoshinari. Pharmaceutic 1,4-dihydropyridine compounds. DE, patent specification, 2756226,29 Jun 1978
29. Sato,Yoshinari. 1,4-dihydropyridine derivatives and process for preparation thereof, GB, patent specification, 1591089, 14 Dec 1981
30. Hisatoyo Yazawa,Norio Hashimoto, Koji Kakara, Preparation of dialkoxyacetate esters as intermediates for pharmaceuticais, JP,公开特许公报，6248648,03 Mar 1987
31．方开泰，马长兴．正交与均匀实验设计[M]．北京，科学出版社，2001：31-113
32．吴贵生，于治福，于淑政等．试验设计与数据处理[M]．北京，冶金工业出版社，1997：46-75
33．栾军．现代试验设计优化方法[M]．上海，上海交通大学出版社，1995：14-175
34．朱明华．仪器分析[M](第二版)．北京，高等教育出版社，1992：355-386
35．余仲建，李松兰，张殿坤编著．现代有机分析[M]．天津科学技术出版社，1994
36．宁永成编著．有机化合物结构鉴定与有机波谱学[M](第二版)．科学出版社，2000
37．谢晶曦，常俊标，王结明编著．红外光谱在有机化学和药物化学中的应用[M](修订版)．科学出版社，2001：23-339
38. Gory M, Coppola, Robert E. Domn. 3-(2-Pyrrolidinyl)-2,4-furandione Analoys[J], Journal of Heterocyclic Chemistry, 1990, 27 (1): 815-817
39. John A. Secrist Ⅲ, Charles J.Hickey, and Robert E.Norris. A Convent Total
Synthesis of (±)-(7E,9E)-Trisporic Acid B Methyl Ester[J]. The Journal of Organic Chemistry, 1977,42(1):525-527
40．徐寿昌．有机化学[M]．北京，高等教育出版社，1998
41．王积涛，胡青眉，张宝审等编著．有机化学[M]．南开大学出版社，1993
42．闻韧．药物合成反应[M]．北京，化学工业出版社，1988：222-238
43．jie Jack Li著，荣国斌译．Name Reaction A Coollection of Detailed Reaction Mechanisms[M]．华东理工大学出版社，2003：172-220
44．黄宪，王彦光，陈振初编著．新编有机合成化学[M]．化学工业出版社，2002：512-514