α-氨基磷酸二乙酯的不对称合成研究
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摘要
本论文第一部分工作:主要研究了催化剂及催化剂的量、溶剂及温度对α-氨基磷酸二乙酯的诱导不对称合成立体选择性的影响。用31P-NMR积分峰面积求得α-氨基磷酸二乙酯R构型与S构型的比值,得到α-氨基磷酸二乙酯的构型受某些催化剂(如:三氟化硼乙醚和三氯化铝)的影响较大,主要得到S构型的产物,而其他催化剂(如:三氯化铁、二氯化铁、氯化锌等)催化剂的影响较小,主要得到R构型的产物。这是因为三氟化硼乙醚、三氯化铝可以与亚胺中的苯环发生“络合作用”,改变了反应过渡态的构象,使亚磷酸二乙酯对C=N双键加成时,从空间位阻小的内侧方向进攻,使加成方向改变,得到S构型的产物。并且随着催化剂量的增大,亚磷酸二乙酯对亚胺加成反应的立体选择性呈上升趋势。不同溶剂对此加成反应立体选择性也有较大影响,这是由于一些溶剂能使催化剂与苯环的络合作用增强,从而使产物S构型的比率增大;另外一些溶剂则使这种络合作用减弱,不能使加成方向发生改变,产物仍以R构型为主。另外,研究了苯环取代基的电子效应对产物立体选择性造成的影响,选择了Cl取代基和CH3O取代基的亚胺与无取代基的亚胺作比较,发现反应的立体选择性受苯环取代基的影响很小,这主要是因为芳环和C=N双键处在同一个平面上,取代基的变化对过渡态△△G≠的值影响很小的缘故。
温度对加成反应立体选择性的影响,得到低温时反应受动力学控制,亚磷酸二乙酯从空间位阻小的方向进攻,得到R构型的产物;高温时反应受热力学控制,亚磷酸二乙酯可以克服能垒,从空间位阻稍大的内侧进攻,使加成反应的立体选择性改变,得到较为稳定的S构型的产物。并且随着温度的升高S构型产物的比率逐渐增大。
第二部分工作:主要进行了芬太尼类化合物中间体的合成。合成了N,N-双(β-丙酸甲酯)苄胺、1-苄基-4-哌啶酮、1-苄基-4-氰基-4-苯胺基哌啶等芬太尼中间体,通过对这些中间体试验条件的改进,缩短了时间,提高了工作效率,并且使产率得以提高。例如选择制取N,N-双(β-丙酸甲酯)苄胺的粗产品,直接用于下一步1-苄基-4-哌啶酮的合成,产率可达到79%,避免了减压蒸馏过程中产物的损失。
It is obtained that the ratio of R / S configuration ofα-aminoethylphosphite with the peak area of 31P NMR integral.α-aminoethylphosphite configuration subjects to certain catalysts (for example: boron trifluoride diethyl ether and aluminum chloride) in large.Under these of other catalysts is smaller (such as: Tie chloride, the Tie chloride, zinc chloride, and so on). The result is mainly R configuration. This is because the boron trifluoride diethyl ether and aluminum chloride can make a "complex role," with the benzene ring in imine. This changes the conformation of the transition state.Ethyl phosphate attacks to the C = N bond from space in less resistance, this changes the direction of addition. S configuration is the main product.With the increase of catalyst, it is upward trend of the stereoselectivity of addition reaction of ethyl phosphite to imine.
Different solvents have greater impacts on the stereoselectivity of addition reaction.This is because some solvents can enhance complexation between benzene ring and the catalyst. The ratio of S configuration increases. In addition, some solvents make the complex role weakening, not to change the direction addition, R configuration is still main.
We study the electronic effect of the substitute in Benzene ring on the impact of three-dimensional selectivity.And choose Cl and CH3O as replacement of imine to compare H substituted of imine.Found that the impact of the benzene ring substituted is very small to three-dimensional selectivity.This is mainly because the aromatic and C = N double bond in the same plane,substitute little impacts on△△G≠in the transition state.
Inspected the temperature on the impact of stereoselective of the Addition. At low temperature, the reaction controled by the dynamic. Ethyl phosphite attacks from the small space resistance in the direction, R configuration is the main product.At high temperature, the reaction controled by the thermodynamic.Ethyl phosphite still attacks resistance from the high space resistance in the direction.S configuration is main.With the increase of temperature , the ratio of S configuration of the product is gradually increasing.
The second part of the work: We mainly synthesize the intermediates of fentanyl compound.According to literature,we synthesize N,N-di-(β-methyl propionate) benzylamine,1-Benzyl-4-piperidone,4-(Phenylamino)-1-(phenylmethyl)-4-piperidinecarbonitrile,4-(Phenyl-amino)-1-(phenylmethyl)-4-piperidinecarboxamide.Improving test conditions of the intermediates.Shortening the test time,increasing work efficiency and increasing the yield.
For example,we prepared crude products of N,N-di-(β-methyl propionate) benzylamine for the next step, yield up to 79%,avoiding it lost during vacuum distillation.
温度对加成反应立体选择性的影响,得到低温时反应受动力学控制,亚磷酸二乙酯从空间位阻小的方向进攻,得到R构型的产物;高温时反应受热力学控制,亚磷酸二乙酯可以克服能垒,从空间位阻稍大的内侧进攻,使加成反应的立体选择性改变,得到较为稳定的S构型的产物。并且随着温度的升高S构型产物的比率逐渐增大。
第二部分工作:主要进行了芬太尼类化合物中间体的合成。合成了N,N-双(β-丙酸甲酯)苄胺、1-苄基-4-哌啶酮、1-苄基-4-氰基-4-苯胺基哌啶等芬太尼中间体,通过对这些中间体试验条件的改进,缩短了时间,提高了工作效率,并且使产率得以提高。例如选择制取N,N-双(β-丙酸甲酯)苄胺的粗产品,直接用于下一步1-苄基-4-哌啶酮的合成,产率可达到79%,避免了减压蒸馏过程中产物的损失。
It is obtained that the ratio of R / S configuration ofα-aminoethylphosphite with the peak area of 31P NMR integral.α-aminoethylphosphite configuration subjects to certain catalysts (for example: boron trifluoride diethyl ether and aluminum chloride) in large.Under these of other catalysts is smaller (such as: Tie chloride, the Tie chloride, zinc chloride, and so on). The result is mainly R configuration. This is because the boron trifluoride diethyl ether and aluminum chloride can make a "complex role," with the benzene ring in imine. This changes the conformation of the transition state.Ethyl phosphate attacks to the C = N bond from space in less resistance, this changes the direction of addition. S configuration is the main product.With the increase of catalyst, it is upward trend of the stereoselectivity of addition reaction of ethyl phosphite to imine.
Different solvents have greater impacts on the stereoselectivity of addition reaction.This is because some solvents can enhance complexation between benzene ring and the catalyst. The ratio of S configuration increases. In addition, some solvents make the complex role weakening, not to change the direction addition, R configuration is still main.
We study the electronic effect of the substitute in Benzene ring on the impact of three-dimensional selectivity.And choose Cl and CH3O as replacement of imine to compare H substituted of imine.Found that the impact of the benzene ring substituted is very small to three-dimensional selectivity.This is mainly because the aromatic and C = N double bond in the same plane,substitute little impacts on△△G≠in the transition state.
Inspected the temperature on the impact of stereoselective of the Addition. At low temperature, the reaction controled by the dynamic. Ethyl phosphite attacks from the small space resistance in the direction, R configuration is the main product.At high temperature, the reaction controled by the thermodynamic.Ethyl phosphite still attacks resistance from the high space resistance in the direction.S configuration is main.With the increase of temperature , the ratio of S configuration of the product is gradually increasing.
The second part of the work: We mainly synthesize the intermediates of fentanyl compound.According to literature,we synthesize N,N-di-(β-methyl propionate) benzylamine,1-Benzyl-4-piperidone,4-(Phenylamino)-1-(phenylmethyl)-4-piperidinecarbonitrile,4-(Phenyl-amino)-1-(phenylmethyl)-4-piperidinecarboxamide.Improving test conditions of the intermediates.Shortening the test time,increasing work efficiency and increasing the yield.
For example,we prepared crude products of N,N-di-(β-methyl propionate) benzylamine for the next step, yield up to 79%,avoiding it lost during vacuum distillation.
引文
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[2] Ariens E. J. Stereoselectivity of pesticides: Biological and chemical problems. Medicinal Research Reviews, 1986, 6(4): 451-466.
[3]夏仕文,李树本.酶在光学活性药物合成中的应用.合成化学, 1996, 4(3): 201-207.
[4]继成.我国医药原料和中间体发展动向.中国制药信息, 1998, 14(12): 28-31.
[5] Kenner T., Valenzuele Paz P., Keppler B. K. et al. Cisplatin-linked phosphonates in the treatment of the transplantable osteosarcoma in vitro and in vivo. Cancer Treat Reviews, 1990, 17(2-3): 253-259.
[6]龙韫先,张克胜,邱德文. N-吡唑啉酮基-α-氨基膦酸酯的合成及其生物活性的研究.高等学校化学学报, 1996, 17(8): 12471-1249.
[7]李在国,黄润秋,杨昭,邵瑞链.含苯并噻唑杂环的α-氨基膦酸二苯酯的合成及生物活性,应用化学, 1999, 16(2): 90-92.
[8]崔淑华,理学博士论文,中国科学院上海有机所,上海1991.
[9] Chavane, Vincent. Researches on aminomethanephosphonic acid. Bulletin de la Societe Chimique de France, 1948, 15, 774-777.
[10]周在洪,陈茹玉,α-外式-7-氧双环[2.2.1]庚-5-烯-2,3-二甲酰亚氨基-α-取代苯基膦酸二苯酯的合成,应用化学, 1999, 16(4): 6-9.
[11]袁承业,具生物活性有机磷化合物的设计与合成.有机化学, 2001, 21(11): 862-868.
[12] Gilmore W. F., McBride H. A. Synthesis of an optically active-aminophosphonic acid. Journal of the American Chemical Society, 1972, 94(12): 4361-4363.
[13] Glowiakt, Sawka-Dobrowolka W., Kowalik J., et al. Absolute configuration ofoptically active aminophosphonic acids. Tetrahedron Letters, 1977, (45): 3965-3968.
[14] Hanessian, Bennani Y. L., A versatile asymmetric synthesis ofα-amino-α–alkylPhosphonic acids of high enantiometric purity. Tetrahedron Letters, 1990, 31(45): 6465-6468.
[15] Yuan Chengye, Cui Shuhua. Studies on organophosphorus compounds. XLVIII. Structural effect on the induced asymmetric addition of dialkyl phosphite to chiral aldimine derivatives. Phosphorus, Sulfur and Silicon and the Related Elements, 1991, 55(1-4): 159-164.
[16]胡文祥,崔淑华,袁承业,恽榴红.有机药物化学中不对称合成手性产率及其随温度变化规律的研究,中国药物化学杂志, 1993, 3(2): 79-84.
[17] Zon, Jerzy. Asymmetric addition of tris(trimethylsilyl) phosphite to chiral aldimines. Polish Journal of Chemistry. 1981, 55(3): 643-646.
[18] Smith A. B., Taylor C. M., Yager K. M. Journal of the American Chemical Society, 1994, 116, 9327.
[19] Campbell D. A. US5362899, 1994.
[20] Buck R. T., Clarke P. A., et al. The carbenoid approach to peptide synthesis. Chemistry(Weinheim an der Bergstrasse, Germany), 2000, 6(12): 2160-2167.
[21] Smith Amos B., Yager, Kraig M., Taylor Carol M. Enantioselective Synthesis of Diverse-Amino Phosphonate Diesters. Journal of the American Chemical Society, 1995, 117(44): 10879-10888.
[22] Huber R., Vasella A. The kinetic anomeric effect.Additions of nucleophiles and of dipolarophiles to N-glycosylnitrones and to N-pseudoglycosylnitrones Tetrahedron letters, 1990, 46(1): 33-58.
[23] Denmark S. E., Chatani N., Pansare S. V. Asymmetric electrophilic amination of chiral phosphorus-stabilized anions. Tetrahedron Letters, 1992, 48(11): 2191-2208.
[24] Maury Catherine, Royer Jacques, Husson Henri Philippe. A simple and general method for the asymmetric synthesis ofα-aminophosphonic acids. Tetrahedron Letters, 1992, 33(41): 6127-6130.
[25] Hamilton R., Walker B. J., Walker B., Highly Conventent Route to Optically Pure Alpha-aminophosphonic Acids. Tetrahedron Letters. 1995, 36(25): 4451-4454.
[26] Schoellkopf, Ulrich, Schuetze, Rainer. Asymmetric synthesis ofα-Aminophosph–onic acids. III. Asymmetric synthesis of diethyl (S)-(1-aminoalkyl) phosphonates using (+)-camphor as chiral auxiliary agent. Liebigs Annalen der Chemie. 1987, (1): 45-49.
[27] Christine F., Ute S., Silke Z., Ingrid G. US5886217, 1999.
[28] Sawamura M., Hamashima H., Ito Y. Rhodium-Catalyze Enantioselective Michael Addition of (1-Cyanoethyl)-phosphonate: Synthesis of Optically Active Phosphonic Acid Derivatives with Phosphorus-Substituted Quaternary Asymmetric Carbon Center, Bulletin of the Chemical Society of Japan, 2000, 73, 2559-2562.
[29]廖本仁,洪镰裕.光学活性α-氨基膦酸及其酯的不对称合成,化学通报, 2001, 64(2): 102-108.
[30]江明性.药理学第二版,北京:人民卫生出版社, 1996, 116-119.
[31] Chu Peter. Manay, Setphen, et al.Journal of Biological Chemistry, 1997, 43: 272-273.
[32]彭司郧.药物化学.北京:人民卫生出版社, 1998, 59(30): 723-725.
[33] Janssen P. A. J. A review of the chemical features associated with strong morphine-like activity. British Journal of Aanaesthesia, 1962, 34: 260-268.
[34] Colapret J. A., Diamantidis G., Spencer H. K., et al. Synthesis and Pharmacological evaluation of 4, 4-dissubstituted piperidines. Journal of Medicinal Chemistry, 1989, 32: 968-974.
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