固体酸催化合成氨基酸酯的工艺研究
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摘要
氨基酸酯的合成是近年来迅速发展起来的一个新研究领域,它在医药、化工、食品、农业等方面有着越来越广泛的应用,可用作药物中间体、食品添加剂、化妆品添加剂和杀菌灭虫合剂等,应用前景十分广阔。研究开发工艺可靠、成本合理的氨基酸酯制备技术具有重要的理论和实际意义。
由于氨基酸属两性化合物,且难溶于有机溶剂,因此对其酯化反应条件的选择、选择性的提高以及产物的分离提纯等都有着严格的要求。如能在制备方法上进行改进,尤其是使用价格相对低廉的催化剂,将会进一步降低氨基酸酯的生产成本。
本论文对氨基酸酯的合成工艺进行了研究,工作主要包括以下几方面:
1.对氨基酸及其酯的薄层色谱监测方法进行了改进,简化了操作、节省了仪器和药品。
2.使用常规加热方法合成了七种氨基酸酯的对甲苯磺酸盐。考察各种因素对酯化反应的影响,优化了氨基酸酯对甲苯磺酸盐的分离提纯条件。同时通过运用红外光谱、核磁共振氢谱和核磁共振碳谱等检测方法确定了最终产品的化学结构。
3.分别使用家用微波炉和Discover微波反应器替代传统加热方式,制备了氨基酸苄酯的对甲苯磺酸盐,与常规加热方法进行了比较,归纳总结了它们的优缺点。
4.用732型阳离子交换树脂作催化剂合成八种游离的氨基酸甲酯和乙酯。对各影响因素进行了分析,确定了最佳反应条件;同时对阳离子交换树脂催化合成氨基酸酯的机理进行了初步的探讨。
Amino acids esters, of which the synthesis has rapidly become a new research field in recent years,have been extensively used as medical semi-product,food additives, cosmetic additives, mineral flotation assitives,germicides,etc. So resesrch on the synthesis of amino acids esters is of great significance both in theoretical and in practical side.
Amino acids have two properties, and are difficult to dissolve in the organic solvents, which made them difficult to choose the right conditions for esterification and to improve the selectivity and to separate and purify the products. It can reduce the cost of preparation amino acid esters if the methods of preparation can be improved especially using the comparatively inexpensive catalyzers.
Preparation technologies of a series of amino acids esters were studied systematically, and it contains several aspects:
1. The method of TLC, which is used to inspect amino acids and their esters, was improved. It made the method reduce operations and save the instruments and reagents.
2. Esterification of amino acids using p-toluenesulfonic acid by common heating methods affords seven p-toluenesulfonic acid salt of amino acids esters. The influentical factors were studied and optimized. Final products were characterized by melting point determination, IR, 1H-NMR, 13C-NMR.
3. Microwave irridation was introduces in the p-toluenesulfonic acid salt of amino acids esters. Theses two technologies were analyzed summarized.
4. Preparing free amino acid esters were studied esterified by strong acid resin, it offords eight free amino acid methyl and ethyl esters. The influentical factors were studied and optimized. Final products were characterized by IR, 1H-NMR.And the mechanism of esterifition of amino acid using strong acid resin as catalyst was primarily dicussed.
由于氨基酸属两性化合物,且难溶于有机溶剂,因此对其酯化反应条件的选择、选择性的提高以及产物的分离提纯等都有着严格的要求。如能在制备方法上进行改进,尤其是使用价格相对低廉的催化剂,将会进一步降低氨基酸酯的生产成本。
本论文对氨基酸酯的合成工艺进行了研究,工作主要包括以下几方面:
1.对氨基酸及其酯的薄层色谱监测方法进行了改进,简化了操作、节省了仪器和药品。
2.使用常规加热方法合成了七种氨基酸酯的对甲苯磺酸盐。考察各种因素对酯化反应的影响,优化了氨基酸酯对甲苯磺酸盐的分离提纯条件。同时通过运用红外光谱、核磁共振氢谱和核磁共振碳谱等检测方法确定了最终产品的化学结构。
3.分别使用家用微波炉和Discover微波反应器替代传统加热方式,制备了氨基酸苄酯的对甲苯磺酸盐,与常规加热方法进行了比较,归纳总结了它们的优缺点。
4.用732型阳离子交换树脂作催化剂合成八种游离的氨基酸甲酯和乙酯。对各影响因素进行了分析,确定了最佳反应条件;同时对阳离子交换树脂催化合成氨基酸酯的机理进行了初步的探讨。
Amino acids esters, of which the synthesis has rapidly become a new research field in recent years,have been extensively used as medical semi-product,food additives, cosmetic additives, mineral flotation assitives,germicides,etc. So resesrch on the synthesis of amino acids esters is of great significance both in theoretical and in practical side.
Amino acids have two properties, and are difficult to dissolve in the organic solvents, which made them difficult to choose the right conditions for esterification and to improve the selectivity and to separate and purify the products. It can reduce the cost of preparation amino acid esters if the methods of preparation can be improved especially using the comparatively inexpensive catalyzers.
Preparation technologies of a series of amino acids esters were studied systematically, and it contains several aspects:
1. The method of TLC, which is used to inspect amino acids and their esters, was improved. It made the method reduce operations and save the instruments and reagents.
2. Esterification of amino acids using p-toluenesulfonic acid by common heating methods affords seven p-toluenesulfonic acid salt of amino acids esters. The influentical factors were studied and optimized. Final products were characterized by melting point determination, IR, 1H-NMR, 13C-NMR.
3. Microwave irridation was introduces in the p-toluenesulfonic acid salt of amino acids esters. Theses two technologies were analyzed summarized.
4. Preparing free amino acid esters were studied esterified by strong acid resin, it offords eight free amino acid methyl and ethyl esters. The influentical factors were studied and optimized. Final products were characterized by IR, 1H-NMR.And the mechanism of esterifition of amino acid using strong acid resin as catalyst was primarily dicussed.
引文
1 J. Jones. The Chemical Synthesis of Peptides.Clarendon Press, 1991, 33~41
2 E. Schrider, K. Lubke. The Peptides. Academic Press, 1965: 52~75
3 A. Bruggink, et al. Penicillin Acylase in the Industrial Production of β-Lactam Antibiotics. J.Org. Process Res. Dev. (Review), 1998, 2(2): 128~133
4 Jer Yiing. Houng, May Ling. Wu, Shui Tein. Chen. Kinetic Resolution of Amino Acids Esters Catalyzed by Lipases. J.Chirality, 1996, 8: 418~422
5 Daniel Amato, FL. Wellington. Amino Acid Esters as Nutrient Supplements and Methods of Use. US 0148669, 2005
6 S. Deshayes, M. Liagre, A. Loupy, et al. Microwave Activation in Phase Transfer Catalysis. J. Tetrahedron, 1999, 55: 10851~10870
7 P. Lidstrom, J. Tierney, B. Wathey, et al. Microwave Assisted Organic Synthesis-A Review. J. Tetrahedron, 2001, 57: 9225~9283
8 Howard Sachs, Erwin Brand. Benzyl Esters of Glutamic Acid. J. Amer. Chem. Soc, 1953, 75(18): 4610~4611
9 Ajioka, Masanobu, Higuchi, Chojiro, et al. Preparation and Isolation of Mineral Acid Salt of an Amino Acid Methyl Ester. EP 0376230, 1989
10 B. Stanley Mirviss, K. Samun Dahod, W. Mark Empie. Synthesis of L-Phenylalanine Methyl Ester. Eng. Chem. Res, 1990, 29: 651~659
11 陈帆.新型手性氨基酸衍生物及其合成方法与应用.CN 1616411, 2005
12 冯光炷,朱春山,王晓君,谢文磊.复合氨基酸月桂醇酯的合成及性能.郑州工程学院学报,2003,24(4):42~45
13 王钝,梁益衡,宫平,赵燕芳.抗糖尿病药物那格列奈的合成.中国药物化学杂志.2003,12(2):94~96
14 Yamamoto, Yasuhito, et al. Process for Production of Optically Active (R or S)-amino Acid or Optically Active (R or S)-amino Acid Ester. WO 2007023948, 2007
15 P. Ravindra Patel, Steven Price. Synthesis of Benzyl Esters of a-Amino Acids. J. Org. Chem, 1965, 30(10): 3575~3576
16 思洋,刘乐乐,张廓等.氨基酸甲乙酯的合成及纯化.内蒙古医学院学报,2005,27(1):33~34
17 龙姝,陈敏,莫文妍等.N-[甲氧(乙氧)羰基亚甲基]-5-取代苯基-2E, 4E-戊二烯酰胺的合成与生物活性研究.华中师范大学学报(自然科学版),2002,36(2):185~187
18 Boedten, Wihelmus, Hubertus, et al. Prosess for Esterification of Amino Acids and Peptides. WO 9849133, 1998
19 Hua Zhao, V. Sanjay Malhotra. Esterification of Amino Acids by Using Ionic Liquid as a Green Catalyst. Chemical Industries, 2003, 89: 667~672
20 F. Bernard Erlanger, M. Ronals Hall. Improved Synthesis of Amino Acid Benzyl Esters. J. Amer. Chem. Soc, 1954, 76: 5781~5782
21 Isamu Arai, Ichiro Muramatsu. A Simple and Convenient Method for Esterification of Tryptophan and Other Amino Acids. J. Org. Chem, 1983, 48: 121~123
22 J. A. Maclaren, W. E. Savige, J. M. Swan. Amino Acids and Peptides. IV. Intermediates for the Synthesis of Certain Cystine-containing Peptide Sequences in Insulin. Australian Journal of Chemistry, 1958, 11: 345~59
23 Roger Roeske. Preparation of t-Butyl Esters of Free Amino Acids. J. Org. Chem, 1963, 28(5): 1251~1253
24 A. Akintola Aboderin, R. Georges Delpierre, S. Joseph Fruton. Benzhydryl Esters of Amino Acids in Peptide Synthesis. J. Amer. Chem. Soc, 1965, 87(23): 5469~5472
25 Sato, Haruyo, Takae, Iwata, Shiho. Optically Active Amino acid Benzyl Esters and Processes for the Preparation of the Same. JP 74920000210, 2000
26 安广杰,王璋,许时婴.蛋氨酸烷基酯的合成.食品添加剂,2004,25(12):107~108
27 Herberkt. Miller, Heinrichw Aelsch. Benzyl Esters of Amino Acids. J. Am. Chem. Soc, 1952, 74: 1092~1093
28 E. James Shields, H. William Mcgregor, H. Frederick Carpenter. Preparation of Benzyl and p-Nitrobenzyl Esters of Amino Acids. J. Org. Chem, 1961, 26: 1491~1494
29 L. Christopher Penney, Pravinkant Shah, Silvio Landi. A Simple Method for the Synthesis of Long-chain Alkyl Esters of Amino Acids. J. Org. Chem, 1985, 50: 1457~1459
30 A. Rivero, S. Heredia, A. Ochoa. Esterification of Amino Acids and Mono AcidsUsing Triphosgene. Synthetic Communications, 2001, 31(14): 2169~2175
31 M. Aleksander Kozodzifjczyk, Marek Slebjoda. A Rapid Procedure for the Esterification of Amino Acids. Systhesis Communications, 1984, 865~866
32 C. Ramesh Anand, Vimal. A Mild and Convenient Procedure for the Esterification of Amino Acid. Synthetic Communications, 1998, 28(11): 1963~1965
33 N. Zander, R. Frank. Polystyrylsulfonyl Chloride Resin: An Efficient Solid-supported Condensation Reagent for the Solution Phase Synthesis of Esters. Tetrahedron. Lett, 2001, 42(44): 7783~7785
34 P. Sieber. An Improved Method for Anchoring of 9-fluorenylmethoxy- carbonyl-amino Acids to 4-alkoxybenzyl Alcohol Resins. Tetrahedron. Lett, 1987, 28(49): 6147~6150
35 B. Blankemeyer-Menge, M. Nimtz, R. Frank. An Efficient Method for Anchoring Fmoc-anino Acids to Hydroxyl-functionalised Solid Supports. Tetrahedron. Lett, 1990, 31(12): 1701~1704
36 Norbert Zander, Jürgen Gerhardt, Ronald Frank. Polystyrylsulfonyl-3-nitro -1H-1,2,4-triazolide-resin: A New Solid-supported Reagent for the Esterification of Amino Acids. Tetrahedron. Lett, 2003, 44: 6557~ 6560
37 M. A. Wegman, J. M. Elzinga, E. Neelemanand, et al. Salt-free Esterification of α-amino Acids Catalysed By Zeolite H-USY. Green Chemistry, 2001, 3: 61~64
38 H. Kise, H. Shirato. Synthesis of Aromatic Amino Acid Ethyl Esters by α-chymotrypsin in Solutions of High Ethanol Concentrations. Tetrahedron. Lett, 1985, 26(49): 6081~6084
39 Shui-Tein Chen, Kung Tsung Wang. Papain Catalysed Esterification of N-Protected Amino Acids. Chem.Commun, 1988: 327~329
40 Yesim Yes?loglul, Ismail Kilic. Polyvinyl Alcohol-Trypsin as a Catalyst for Amino Acid Ester Synthesis in Organic Media. Preparative Biochemistry & Biotechnology, 2004, 34(4): 365~375
41 Ganga-Ramu Vasanthakumar, S. Basanagoud Patil, Vommina Venkata Suresh Babu. Microwave Assisted Facile Synthesis of Amino Acid Benzyl Ester p-toluenesulfonate and Hydrochloride Salts. Letters in Peptide Science, 2002, 9: 207~209.
42 Matthias Pascaly Munster, Dietrich Maass Altenberge, et al. Processs forPreparing Amino Acid Esters and Their Acid Addition Salts. US 0192460, 2005
43 Ueda, Kazuo. A Convenient Method of Preparing p-toluenesulfonates of Ethyl Esters of Amino Acids Using Ethyl p-toluenesulfonate. Bulletin of the Chemical Society of Japan, 1979, 52(6): 1879~1880
44 邓斌,黄海英,李强国等.SnCl4?5H2O/C催化合成谷氨酸月桂酯.合成化学.2005,13(2):208~210
45 Sathe Manisha, M. P. Kaushik. An Efficient Method for the Esterification of Amino Acids Using Silica Chloride. Catalysis Communications, 2006, 7(9): 644~646
46 孙建军,崔丽鸿.固体超强酸催化合成谷氨酸月桂醇酯表面活性剂.日用化学工业,2001,3:64~65
47 Daniel Amato, F. L. Wellington. Amino Acid Esters as Nutrient Supplements and Methods. US 0148669, 2005
48 K. Y. Tao, G. h. He, etal. Method for Producing Ionic Liquid of Amino Acid Ester Cation. CN 1621152, 2005
49 G. A. Fletcher, J. H. Jomes. List of Amino Acid Derivatives Which are Useful in Peptide Synthesis. International Journal of Peptide & Protein Research. 1972, 4(5): 347~371
50 Kamashita Tomoko, Yamashita Hiroyuki, et al. Method of Extracting Amino Acid Esters from Aqueous Solutions of Their Mineral Acid Salts. EP 474096, 1992
2 E. Schrider, K. Lubke. The Peptides. Academic Press, 1965: 52~75
3 A. Bruggink, et al. Penicillin Acylase in the Industrial Production of β-Lactam Antibiotics. J.Org. Process Res. Dev. (Review), 1998, 2(2): 128~133
4 Jer Yiing. Houng, May Ling. Wu, Shui Tein. Chen. Kinetic Resolution of Amino Acids Esters Catalyzed by Lipases. J.Chirality, 1996, 8: 418~422
5 Daniel Amato, FL. Wellington. Amino Acid Esters as Nutrient Supplements and Methods of Use. US 0148669, 2005
6 S. Deshayes, M. Liagre, A. Loupy, et al. Microwave Activation in Phase Transfer Catalysis. J. Tetrahedron, 1999, 55: 10851~10870
7 P. Lidstrom, J. Tierney, B. Wathey, et al. Microwave Assisted Organic Synthesis-A Review. J. Tetrahedron, 2001, 57: 9225~9283
8 Howard Sachs, Erwin Brand. Benzyl Esters of Glutamic Acid. J. Amer. Chem. Soc, 1953, 75(18): 4610~4611
9 Ajioka, Masanobu, Higuchi, Chojiro, et al. Preparation and Isolation of Mineral Acid Salt of an Amino Acid Methyl Ester. EP 0376230, 1989
10 B. Stanley Mirviss, K. Samun Dahod, W. Mark Empie. Synthesis of L-Phenylalanine Methyl Ester. Eng. Chem. Res, 1990, 29: 651~659
11 陈帆.新型手性氨基酸衍生物及其合成方法与应用.CN 1616411, 2005
12 冯光炷,朱春山,王晓君,谢文磊.复合氨基酸月桂醇酯的合成及性能.郑州工程学院学报,2003,24(4):42~45
13 王钝,梁益衡,宫平,赵燕芳.抗糖尿病药物那格列奈的合成.中国药物化学杂志.2003,12(2):94~96
14 Yamamoto, Yasuhito, et al. Process for Production of Optically Active (R or S)-amino Acid or Optically Active (R or S)-amino Acid Ester. WO 2007023948, 2007
15 P. Ravindra Patel, Steven Price. Synthesis of Benzyl Esters of a-Amino Acids. J. Org. Chem, 1965, 30(10): 3575~3576
16 思洋,刘乐乐,张廓等.氨基酸甲乙酯的合成及纯化.内蒙古医学院学报,2005,27(1):33~34
17 龙姝,陈敏,莫文妍等.N-[甲氧(乙氧)羰基亚甲基]-5-取代苯基-2E, 4E-戊二烯酰胺的合成与生物活性研究.华中师范大学学报(自然科学版),2002,36(2):185~187
18 Boedten, Wihelmus, Hubertus, et al. Prosess for Esterification of Amino Acids and Peptides. WO 9849133, 1998
19 Hua Zhao, V. Sanjay Malhotra. Esterification of Amino Acids by Using Ionic Liquid as a Green Catalyst. Chemical Industries, 2003, 89: 667~672
20 F. Bernard Erlanger, M. Ronals Hall. Improved Synthesis of Amino Acid Benzyl Esters. J. Amer. Chem. Soc, 1954, 76: 5781~5782
21 Isamu Arai, Ichiro Muramatsu. A Simple and Convenient Method for Esterification of Tryptophan and Other Amino Acids. J. Org. Chem, 1983, 48: 121~123
22 J. A. Maclaren, W. E. Savige, J. M. Swan. Amino Acids and Peptides. IV. Intermediates for the Synthesis of Certain Cystine-containing Peptide Sequences in Insulin. Australian Journal of Chemistry, 1958, 11: 345~59
23 Roger Roeske. Preparation of t-Butyl Esters of Free Amino Acids. J. Org. Chem, 1963, 28(5): 1251~1253
24 A. Akintola Aboderin, R. Georges Delpierre, S. Joseph Fruton. Benzhydryl Esters of Amino Acids in Peptide Synthesis. J. Amer. Chem. Soc, 1965, 87(23): 5469~5472
25 Sato, Haruyo, Takae, Iwata, Shiho. Optically Active Amino acid Benzyl Esters and Processes for the Preparation of the Same. JP 74920000210, 2000
26 安广杰,王璋,许时婴.蛋氨酸烷基酯的合成.食品添加剂,2004,25(12):107~108
27 Herberkt. Miller, Heinrichw Aelsch. Benzyl Esters of Amino Acids. J. Am. Chem. Soc, 1952, 74: 1092~1093
28 E. James Shields, H. William Mcgregor, H. Frederick Carpenter. Preparation of Benzyl and p-Nitrobenzyl Esters of Amino Acids. J. Org. Chem, 1961, 26: 1491~1494
29 L. Christopher Penney, Pravinkant Shah, Silvio Landi. A Simple Method for the Synthesis of Long-chain Alkyl Esters of Amino Acids. J. Org. Chem, 1985, 50: 1457~1459
30 A. Rivero, S. Heredia, A. Ochoa. Esterification of Amino Acids and Mono AcidsUsing Triphosgene. Synthetic Communications, 2001, 31(14): 2169~2175
31 M. Aleksander Kozodzifjczyk, Marek Slebjoda. A Rapid Procedure for the Esterification of Amino Acids. Systhesis Communications, 1984, 865~866
32 C. Ramesh Anand, Vimal. A Mild and Convenient Procedure for the Esterification of Amino Acid. Synthetic Communications, 1998, 28(11): 1963~1965
33 N. Zander, R. Frank. Polystyrylsulfonyl Chloride Resin: An Efficient Solid-supported Condensation Reagent for the Solution Phase Synthesis of Esters. Tetrahedron. Lett, 2001, 42(44): 7783~7785
34 P. Sieber. An Improved Method for Anchoring of 9-fluorenylmethoxy- carbonyl-amino Acids to 4-alkoxybenzyl Alcohol Resins. Tetrahedron. Lett, 1987, 28(49): 6147~6150
35 B. Blankemeyer-Menge, M. Nimtz, R. Frank. An Efficient Method for Anchoring Fmoc-anino Acids to Hydroxyl-functionalised Solid Supports. Tetrahedron. Lett, 1990, 31(12): 1701~1704
36 Norbert Zander, Jürgen Gerhardt, Ronald Frank. Polystyrylsulfonyl-3-nitro -1H-1,2,4-triazolide-resin: A New Solid-supported Reagent for the Esterification of Amino Acids. Tetrahedron. Lett, 2003, 44: 6557~ 6560
37 M. A. Wegman, J. M. Elzinga, E. Neelemanand, et al. Salt-free Esterification of α-amino Acids Catalysed By Zeolite H-USY. Green Chemistry, 2001, 3: 61~64
38 H. Kise, H. Shirato. Synthesis of Aromatic Amino Acid Ethyl Esters by α-chymotrypsin in Solutions of High Ethanol Concentrations. Tetrahedron. Lett, 1985, 26(49): 6081~6084
39 Shui-Tein Chen, Kung Tsung Wang. Papain Catalysed Esterification of N-Protected Amino Acids. Chem.Commun, 1988: 327~329
40 Yesim Yes?loglul, Ismail Kilic. Polyvinyl Alcohol-Trypsin as a Catalyst for Amino Acid Ester Synthesis in Organic Media. Preparative Biochemistry & Biotechnology, 2004, 34(4): 365~375
41 Ganga-Ramu Vasanthakumar, S. Basanagoud Patil, Vommina Venkata Suresh Babu. Microwave Assisted Facile Synthesis of Amino Acid Benzyl Ester p-toluenesulfonate and Hydrochloride Salts. Letters in Peptide Science, 2002, 9: 207~209.
42 Matthias Pascaly Munster, Dietrich Maass Altenberge, et al. Processs forPreparing Amino Acid Esters and Their Acid Addition Salts. US 0192460, 2005
43 Ueda, Kazuo. A Convenient Method of Preparing p-toluenesulfonates of Ethyl Esters of Amino Acids Using Ethyl p-toluenesulfonate. Bulletin of the Chemical Society of Japan, 1979, 52(6): 1879~1880
44 邓斌,黄海英,李强国等.SnCl4?5H2O/C催化合成谷氨酸月桂酯.合成化学.2005,13(2):208~210
45 Sathe Manisha, M. P. Kaushik. An Efficient Method for the Esterification of Amino Acids Using Silica Chloride. Catalysis Communications, 2006, 7(9): 644~646
46 孙建军,崔丽鸿.固体超强酸催化合成谷氨酸月桂醇酯表面活性剂.日用化学工业,2001,3:64~65
47 Daniel Amato, F. L. Wellington. Amino Acid Esters as Nutrient Supplements and Methods. US 0148669, 2005
48 K. Y. Tao, G. h. He, etal. Method for Producing Ionic Liquid of Amino Acid Ester Cation. CN 1621152, 2005
49 G. A. Fletcher, J. H. Jomes. List of Amino Acid Derivatives Which are Useful in Peptide Synthesis. International Journal of Peptide & Protein Research. 1972, 4(5): 347~371
50 Kamashita Tomoko, Yamashita Hiroyuki, et al. Method of Extracting Amino Acid Esters from Aqueous Solutions of Their Mineral Acid Salts. EP 474096, 1992