对甲基苯丙氨酸的合成
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摘要
本论文主要采用了一种新的方法合成了对甲基苯丙氨酸,它是一种重要的非天然氨基酸。此氨基酸的合成,对于其它非天然氨基酸的合成也具有借鉴意义,尤其是其它取代的苯基或杂环取代的α-丙氨酸。
针对目标产物,根据逆合成分析,结合相关的文献,比较了其它的路线,最终选择以对甲基苄氯和丙二酸二乙酯为起始原料,经过烷基化、水解、成环、氨解、酰胺降解、五步反应制得目标产物对甲基苯丙氨酸,总收率24-25%。该路线避免了传统路线中使用的含重金属的试剂或者剧毒化学品,所有原料都廉价易得,所有操作都没有过柱分离,操作简单,具有工业化规模生产的潜力。
The dissertation is focused on the synthesis of an important unnatural amino acid p-methyl-phenylalanine. The synthetic route is very guidable to synthesize other unnatural amino acids, especially for other substituted phenyl or heterocylic substituted alpha alanines.
Based on the chemical structure of p-methyl-phenylalanine, we utilized the disconnection method via retrosynthetic analysis to compare several possible routes as well as reaction conditions with the reported literatures. A novel possible route was proposed and established, starting from 1-(chloromethyl)-4-methyl benzene and diethyl malonate via alkylation, hydrolysis, cyclization, ammonation, Hofman degradation, with an overall yield of 24-25%. The synthetic route has several advantages, such as commercially available and cheap raw materials, no heavy metal reagents or highly poisonous chemicals involved. Moreover, all separation operations are not required to column chromatography, large potential to scale up for industrialization, promising to get independent intellectual property rights.
针对目标产物,根据逆合成分析,结合相关的文献,比较了其它的路线,最终选择以对甲基苄氯和丙二酸二乙酯为起始原料,经过烷基化、水解、成环、氨解、酰胺降解、五步反应制得目标产物对甲基苯丙氨酸,总收率24-25%。该路线避免了传统路线中使用的含重金属的试剂或者剧毒化学品,所有原料都廉价易得,所有操作都没有过柱分离,操作简单,具有工业化规模生产的潜力。
The dissertation is focused on the synthesis of an important unnatural amino acid p-methyl-phenylalanine. The synthetic route is very guidable to synthesize other unnatural amino acids, especially for other substituted phenyl or heterocylic substituted alpha alanines.
Based on the chemical structure of p-methyl-phenylalanine, we utilized the disconnection method via retrosynthetic analysis to compare several possible routes as well as reaction conditions with the reported literatures. A novel possible route was proposed and established, starting from 1-(chloromethyl)-4-methyl benzene and diethyl malonate via alkylation, hydrolysis, cyclization, ammonation, Hofman degradation, with an overall yield of 24-25%. The synthetic route has several advantages, such as commercially available and cheap raw materials, no heavy metal reagents or highly poisonous chemicals involved. Moreover, all separation operations are not required to column chromatography, large potential to scale up for industrialization, promising to get independent intellectual property rights.
引文
[1]百度百科http://baike.baidu.com/view/15155.htm.
[2]J. W. Chin, T. A. Cropp, J. C. Anderson, M. Mukherji, Z. Zhang, P. G Schultz, An Expanded Eukaryotic Genetic Code, Science,2003, August 15.
[3]蔡明道,应用非天然氨基酸研究腺苷酸激酶的作用机理,有机化学,1997,17：20-23.
[4]A. Strecker, The preparation of a new material by the reaction of acetaldehyde-ammonia imine and hydrogen cyanide, Liebigs Ann. Chem.,1854,91: 349-351.
[5]T. Okuda, et al., A Simplified Method for the Preparation of N-Acetylphenylalanines, Bull. Chem. Soc. Japan,1957,30:698.
[6]R. Gaudnry, et al., la systhese des acides a-amines par la degra deation de Hofmann des amides, Can. J. Research,1945,23:234.
[7]R. O. Duthaler, Recent Developments in the Stereoselective Synthesis of a-Amino Acids, Terahedron,1994,50(6):1539.
[8]W. S. Knowles, Asymmetric hydrogenation, Ace. Chem. Res,1983:106.
[9]周惠良, Preparation of 2-methyl-4,6-dichloro-5-aminopyrimidine, Zhongguo Yiyao Gongye Zazhi,2007,38:838-839.
[10]刘克良、赵芬芝,几种非天然氨基酸的合成、拆分和保护,氨基酸杂志,1990,1：1-6.
[11]上海医药工业研究院等,氨基酸合成中关键中间体—基丙二酸二乙酯制备方法改进,医药工业,1979,7：3-5.
[12]马士忠,左美林等,甲基苯丙氨酸的合成与拆分,氨基酸和生物资源,2005,27：52-54.
[13]G. J. Wells, M. Tao, K. A. Josef, R. Bihovsky,1,2-Benzothiazine 1,1-dioxide p2-p3 pedide mimetic aldehyde Calain I Inhibitors, J. Med. Chem.,2001,44,3488-3503.
[14]徐敦寿,刘序章.L-苯丙氨酸生产[J],氨基酸杂志,1991,4：32-34.
[15]梁远君,刘克良,苯环取代苯丙氨酸的合成与拆分[J],氨基酸和生物资源,2001,23：36-40.
[16]M. Krasavin, et al., Discovery and potency optimization of 2-Amino-5-arylmethyl-1,3-thiazole derivatives as potential therapeutic agents for prostate cancer, Arch. Pharm. Chem. Life Sci.,2009,342:420-427.
[17]冯小明,曾德超,蒋耀忠,一种新的手性拆分方法—包结拆分,有机化学,2000,20.2：131-137.
[18]冯洪珍,孟昭力,手性药物拆分的几种方法及研究进展,广东医学院学报,2003, Vol 19,No 1.
[19]X. Y. Li, W. Y. Yin, Synthesis of optically active ring-A substituted tryptophans as IDO inhibitors, Tetrahedron Lett.,2004,45:8569-8573.
[20]D. Kim, L. P. Wang, (2R)-4-Oxo-4-[3-(Trifluoromethyl)-5,6-dihydro[1,2,4] triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine:A Potent, Orally Active Dipeptidyl Peptidase IV Inhibitor for the Treatment of Type 2 Diabetes, J. Med. Chem.,2005,48,141-151.
[21]张树政,酶制剂工业一(下册),科学出版社,1984：697.
[22](a)A. Bairoch, Prosite, adictionary of sites patterns in proreins, Nucleic Acide Res., 1991,19:2241-2245. (b)ZhAO Haiyan, MENG Wuyi,Crystallization and preliminary X-ray studies of porcine kidney aminoacylase I, Chinese Science Bulletin Vol.42 No.20 1750-1752.
[23]J. Buekingham, Dictionary of Organic Compounds (5th Ed), NewYork:1982.
[24]N. Nimural, T. Kinoshita, Reversed-phase liquid chromatographic resolution of amino acid enantiomers by derivatization with 2,3,4,6-tetra-o-acetyl-p-d-glucopyranosyl isothiocyanate, J. Chromnotogr.,1980,202: 375.
[25]K. Miller, Thin-layer and high-performance liquid chromatography in the evalution f the lipophilicity of aryloxoalkanoic and arylhydroxyalkanoic acids, J. Chromatogr., 1984,307:335.
[26]S. B. Martin, Synthesis of N-pentathiorobenzoyl-(S)-(-)prolyl-umidazolide, a new electron-capure sensitive reagent for determination of enatiomeric composition, J. Pharm. Sci.,1973,62:821.
[27]N. Nimura, K. Iwaki, T. Kinoshita, Separation of norepinephrine enantiomers, DOPA enantiomers and dopamine derivatized with o-phthalaldehyde-N-acetyl-L-cysteine by high-performance liquid chromatography, J. Chromatogr.,1987,402:387-391.
[28]C. R. Clark, K. Bouhadir, Diastereoisomeric determination and analysis of N-(Phenyl-sulfnyl)-2-phenyl-glycine aldose reductase inhibitiors, J. Chromatogr. Sci., 1990,28:407-12.
[29]W. Linder, et al., Resolution of the Optical Isomers Dansyl Amino Acids by Reversed Phase Liquid Chromatography with Optically Active Metal Chelate Additives, Anal. Chem.,1979,51:433.
[30]H. Nakazawa, H. Yoneda, Chromatographic study of optical resolution II.separation of optically active cobalt(III) complexs using potassium antiomony d-tartrate as eluant. J. Chromatogr.,1978,160:89-99.
[31]P. E. Hare, A. V. Egil, Separation of D and L amino acids by liquid chromatography: use of chrial eluants, Science,1979,204:1226.
[32]徐秀珠,邹利,胡明华等,离子对色谱法分离氨基醇类对映体,分析化学,2001,29：1295-1298.
[33]C. Pettersson, et al., Chromatographic separation of enantiomers of acids with quinine as chiral counter ion, J. Chromatogr.,1984,316:553.
[34]J. H. Knox, J. Jurand, Mechanism of zwitterion-pair chromatography Ⅱ. ampicilline, lysergic acid, tryptophan and other solutes, J. Chromatogr.,1981,218:355.
[35]D. Sybilska, et al., Resolution of Mephenytoin and Some Chiral Barbiturates into Enantiomers by Reversed Phase High Performance Liquid Chromatography via ββ-Cyclodextrin Inclusion Complexes, J. Liq. Chromatogr.,1986,9:591.
[36]A. Dobashi, et al., Enantioselectivity of hydrogenbond associationin in liquid-solid chromatography, Liq. Chromatogr.,1986,9:243.
[37]T. A. Noctor, L. W. Wainer, The Use of Displacement Chromatography to Alter Retention and Enantioselectivity on a Human Serum Albumin-Based HPLC Chiral Stationary Phase:A Mini-Review, J. Liq. Chromatogr.,1993,16:783.
[38]S. C. Chang, Evaluation of a new polar-organic high performance liquid chromatographic mobile phase for cyclodextrin-bonded chiral stationary phases, Trends Anal. Chem.,1993,12:144.
[39]L. Chen. Q. H. Wan,β-氨基酸对映体在涂敷型手性配体交换色谱固定相上的分离,Chin. J. Anal. Chem.,2006,34:474-477.
[40]V. Cannata, Process for the synthesis of the levodopa, US 4962223.
[41]X. X. Shi., L. X. Dai, Mild Halogenation of Stabilized Ester Enolates by Cupric Halides, J. Org. Chem.,1993,58:4596.
[42]T. Kappe, W. Golser, Synthese und Reaktionen mesoionscher 1,3-Oxazine, Chem. Ber.,1979,112:1585-1594.
[43]M. Chorev, Synthesis of Partially Modified Retro-inverso Substance P Analogues and Their Biological Activity, J. Med. Chem.,1983,26,129-135.
[44]刑其毅,基础有机化学,高等教育出版社,P 693-698.
[45]S. Yamada, C. Hongo, Method for the Racemization of Optically Active Amino Acids, J. Org. Chem.,1983,48:843-846.
[46]盛龙生,何丽一等.《药物分析》北京：化学工业出版社,2003.
[47]C. E. Dalgliesh, The Optical Resolution of Aromatic Amino-acids on Paper Chromatogrums, J. Chem. Soc.,1952,137:3940.
[48]P. Marfey, Determination of D-amino acids Ⅱ. Use of a bifunctional reagent,1,5-difluoro-2,4-dinitrobenzene. Carlsberg Res. Comun.,1984,49:591-596.
[49]H. Bruckner, Keller-hoehl C. HPLC Separation of DL-amino acids derivatized with N2-(5-fluoro-2,4-dinitrophenyl)-L-amino acid amides. Chromatographia,1990,30: 621-629.
[50]H. Bruckner, C. Gah, High-performance liquid chromatographic separation of DL-amino acids derivatized with chiral variants of Sanger's reagent, J Chromatoge, 1991,55:81-95.
[51]陈侃,陈衍强,高效液相色谱法测定非天然氨基酸的光学纯度,Chin. J. Charomatography,2001, Vol 18,No 1.
[2]J. W. Chin, T. A. Cropp, J. C. Anderson, M. Mukherji, Z. Zhang, P. G Schultz, An Expanded Eukaryotic Genetic Code, Science,2003, August 15.
[3]蔡明道,应用非天然氨基酸研究腺苷酸激酶的作用机理,有机化学,1997,17：20-23.
[4]A. Strecker, The preparation of a new material by the reaction of acetaldehyde-ammonia imine and hydrogen cyanide, Liebigs Ann. Chem.,1854,91: 349-351.
[5]T. Okuda, et al., A Simplified Method for the Preparation of N-Acetylphenylalanines, Bull. Chem. Soc. Japan,1957,30:698.
[6]R. Gaudnry, et al., la systhese des acides a-amines par la degra deation de Hofmann des amides, Can. J. Research,1945,23:234.
[7]R. O. Duthaler, Recent Developments in the Stereoselective Synthesis of a-Amino Acids, Terahedron,1994,50(6):1539.
[8]W. S. Knowles, Asymmetric hydrogenation, Ace. Chem. Res,1983:106.
[9]周惠良, Preparation of 2-methyl-4,6-dichloro-5-aminopyrimidine, Zhongguo Yiyao Gongye Zazhi,2007,38:838-839.
[10]刘克良、赵芬芝,几种非天然氨基酸的合成、拆分和保护,氨基酸杂志,1990,1：1-6.
[11]上海医药工业研究院等,氨基酸合成中关键中间体—基丙二酸二乙酯制备方法改进,医药工业,1979,7：3-5.
[12]马士忠,左美林等,甲基苯丙氨酸的合成与拆分,氨基酸和生物资源,2005,27：52-54.
[13]G. J. Wells, M. Tao, K. A. Josef, R. Bihovsky,1,2-Benzothiazine 1,1-dioxide p2-p3 pedide mimetic aldehyde Calain I Inhibitors, J. Med. Chem.,2001,44,3488-3503.
[14]徐敦寿,刘序章.L-苯丙氨酸生产[J],氨基酸杂志,1991,4：32-34.
[15]梁远君,刘克良,苯环取代苯丙氨酸的合成与拆分[J],氨基酸和生物资源,2001,23：36-40.
[16]M. Krasavin, et al., Discovery and potency optimization of 2-Amino-5-arylmethyl-1,3-thiazole derivatives as potential therapeutic agents for prostate cancer, Arch. Pharm. Chem. Life Sci.,2009,342:420-427.
[17]冯小明,曾德超,蒋耀忠,一种新的手性拆分方法—包结拆分,有机化学,2000,20.2：131-137.
[18]冯洪珍,孟昭力,手性药物拆分的几种方法及研究进展,广东医学院学报,2003, Vol 19,No 1.
[19]X. Y. Li, W. Y. Yin, Synthesis of optically active ring-A substituted tryptophans as IDO inhibitors, Tetrahedron Lett.,2004,45:8569-8573.
[20]D. Kim, L. P. Wang, (2R)-4-Oxo-4-[3-(Trifluoromethyl)-5,6-dihydro[1,2,4] triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine:A Potent, Orally Active Dipeptidyl Peptidase IV Inhibitor for the Treatment of Type 2 Diabetes, J. Med. Chem.,2005,48,141-151.
[21]张树政,酶制剂工业一(下册),科学出版社,1984：697.
[22](a)A. Bairoch, Prosite, adictionary of sites patterns in proreins, Nucleic Acide Res., 1991,19:2241-2245. (b)ZhAO Haiyan, MENG Wuyi,Crystallization and preliminary X-ray studies of porcine kidney aminoacylase I, Chinese Science Bulletin Vol.42 No.20 1750-1752.
[23]J. Buekingham, Dictionary of Organic Compounds (5th Ed), NewYork:1982.
[24]N. Nimural, T. Kinoshita, Reversed-phase liquid chromatographic resolution of amino acid enantiomers by derivatization with 2,3,4,6-tetra-o-acetyl-p-d-glucopyranosyl isothiocyanate, J. Chromnotogr.,1980,202: 375.
[25]K. Miller, Thin-layer and high-performance liquid chromatography in the evalution f the lipophilicity of aryloxoalkanoic and arylhydroxyalkanoic acids, J. Chromatogr., 1984,307:335.
[26]S. B. Martin, Synthesis of N-pentathiorobenzoyl-(S)-(-)prolyl-umidazolide, a new electron-capure sensitive reagent for determination of enatiomeric composition, J. Pharm. Sci.,1973,62:821.
[27]N. Nimura, K. Iwaki, T. Kinoshita, Separation of norepinephrine enantiomers, DOPA enantiomers and dopamine derivatized with o-phthalaldehyde-N-acetyl-L-cysteine by high-performance liquid chromatography, J. Chromatogr.,1987,402:387-391.
[28]C. R. Clark, K. Bouhadir, Diastereoisomeric determination and analysis of N-(Phenyl-sulfnyl)-2-phenyl-glycine aldose reductase inhibitiors, J. Chromatogr. Sci., 1990,28:407-12.
[29]W. Linder, et al., Resolution of the Optical Isomers Dansyl Amino Acids by Reversed Phase Liquid Chromatography with Optically Active Metal Chelate Additives, Anal. Chem.,1979,51:433.
[30]H. Nakazawa, H. Yoneda, Chromatographic study of optical resolution II.separation of optically active cobalt(III) complexs using potassium antiomony d-tartrate as eluant. J. Chromatogr.,1978,160:89-99.
[31]P. E. Hare, A. V. Egil, Separation of D and L amino acids by liquid chromatography: use of chrial eluants, Science,1979,204:1226.
[32]徐秀珠,邹利,胡明华等,离子对色谱法分离氨基醇类对映体,分析化学,2001,29：1295-1298.
[33]C. Pettersson, et al., Chromatographic separation of enantiomers of acids with quinine as chiral counter ion, J. Chromatogr.,1984,316:553.
[34]J. H. Knox, J. Jurand, Mechanism of zwitterion-pair chromatography Ⅱ. ampicilline, lysergic acid, tryptophan and other solutes, J. Chromatogr.,1981,218:355.
[35]D. Sybilska, et al., Resolution of Mephenytoin and Some Chiral Barbiturates into Enantiomers by Reversed Phase High Performance Liquid Chromatography via ββ-Cyclodextrin Inclusion Complexes, J. Liq. Chromatogr.,1986,9:591.
[36]A. Dobashi, et al., Enantioselectivity of hydrogenbond associationin in liquid-solid chromatography, Liq. Chromatogr.,1986,9:243.
[37]T. A. Noctor, L. W. Wainer, The Use of Displacement Chromatography to Alter Retention and Enantioselectivity on a Human Serum Albumin-Based HPLC Chiral Stationary Phase:A Mini-Review, J. Liq. Chromatogr.,1993,16:783.
[38]S. C. Chang, Evaluation of a new polar-organic high performance liquid chromatographic mobile phase for cyclodextrin-bonded chiral stationary phases, Trends Anal. Chem.,1993,12:144.
[39]L. Chen. Q. H. Wan,β-氨基酸对映体在涂敷型手性配体交换色谱固定相上的分离,Chin. J. Anal. Chem.,2006,34:474-477.
[40]V. Cannata, Process for the synthesis of the levodopa, US 4962223.
[41]X. X. Shi., L. X. Dai, Mild Halogenation of Stabilized Ester Enolates by Cupric Halides, J. Org. Chem.,1993,58:4596.
[42]T. Kappe, W. Golser, Synthese und Reaktionen mesoionscher 1,3-Oxazine, Chem. Ber.,1979,112:1585-1594.
[43]M. Chorev, Synthesis of Partially Modified Retro-inverso Substance P Analogues and Their Biological Activity, J. Med. Chem.,1983,26,129-135.
[44]刑其毅,基础有机化学,高等教育出版社,P 693-698.
[45]S. Yamada, C. Hongo, Method for the Racemization of Optically Active Amino Acids, J. Org. Chem.,1983,48:843-846.
[46]盛龙生,何丽一等.《药物分析》北京：化学工业出版社,2003.
[47]C. E. Dalgliesh, The Optical Resolution of Aromatic Amino-acids on Paper Chromatogrums, J. Chem. Soc.,1952,137:3940.
[48]P. Marfey, Determination of D-amino acids Ⅱ. Use of a bifunctional reagent,1,5-difluoro-2,4-dinitrobenzene. Carlsberg Res. Comun.,1984,49:591-596.
[49]H. Bruckner, Keller-hoehl C. HPLC Separation of DL-amino acids derivatized with N2-(5-fluoro-2,4-dinitrophenyl)-L-amino acid amides. Chromatographia,1990,30: 621-629.
[50]H. Bruckner, C. Gah, High-performance liquid chromatographic separation of DL-amino acids derivatized with chiral variants of Sanger's reagent, J Chromatoge, 1991,55:81-95.
[51]陈侃,陈衍强,高效液相色谱法测定非天然氨基酸的光学纯度,Chin. J. Charomatography,2001, Vol 18,No 1.
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