几种具有重要生理活性的氨基酸衍生物的合成研究
摘要
本论文主要包括以下两部分内容：(一) 丝氨酸，苏氨酸以及酪氨酸苄基醚的制备研究 (二) 组胺二盐酸盐的合成研究。
第一部分：丝氨酸，苏氨酸，酪氨酸苄基醚不仅对多肽合成有重要价值，也是重要的药物中间体，可用于不育症、糖尿病、动脉硬化等药物的合成。我们通过酯化、保护羧基，氨基保护、醚化、碱水解、酸水解五步反应成功地合成出了丝氨酸，苏氨酸以及酪氨酸的苄基醚，并优化了各步反应的条件，收率分别达到46％，46％，27％。该路线已在国内成功实现了工业化。
第二部分：组胺是人体内具有很强生物活性的物质之一，是Ⅰ型超敏反应中的主要效应分子，并在炎症、胃酸分泌及神经信号传导等病理生理过程中起重要作用。局部生成的组胺还与创伤修复、胚胎发生、血压调节、免疫应答、造血及细胞恶性增殖有密切关系，可用于制备多种药物。
本论文对组胺二盐酸盐的合成进行了研究。我们通过用苯乙酮为催化剂，以正辛醇为反应溶剂，N_2保护下加热回流将组氨酸进行脱羧反应，然后加浓盐酸成盐，制得了组胺二盐酸盐粗品，粗品经过活性炭脱色，甲醇-乙酸乙酯重结晶，可得高纯度产品，总收率达40％。这一路线避免使用环己醇作溶剂，且避免使用干燥HCl气体，成本低廉、操作方便。该路线已在国内率先实现了工业化。
This dissertation comprises two parts (1) studies on the synthesis of Serine(Bzl), Threonine (Bzl) , and Tyrosine (Bzl) (2) studies on the synthesis of histamine dihydrochloride.
The first part: Serine (Bzl), Threonine (Bzl) , and Tyrosine (Bzl) are valuable protected amino acids in polypeptide synthesis, and useful pharmaceutical intermediates, from which many drugs have been prepared to cure such diseases as infertility, diabetes, arteriosclerosis, cardiovascular diseases and so on.
We prepared the three compounds successfully by esterification, amino group protecting, etherification, base catalyzed hydrolysis, and acid catalyzed hydrolysis with yield of 46%, 46%, 27%, respectively. This procedure has been optimized and industrialized in our country for the first time.
The second part: Histamine is a compound possessing significant biological activity and is one of the important mediators of many diseases, such as hypersensitivity, gastric ulcer, inflammation and so on. Moreover, histamine can be used to synthesize many medicines.
In this dissertation, Histamine dihydrochloride has been conveniently synthesized by exploiting the decarboxylation of histidine using acetophenone as catalyst and octanol as solvent. The crude product was decolorized and recrystallized to give pure histamine, and the overall yield up to 40%. Up to now, this is the first time to replace cyclohexanol by octanol as the reacting solvent, and concentrated hydrochloric acid is used instead of dry HC1 gas, so this method is more economical and easier to operate. The process has been industrialized in our country.
第一部分：丝氨酸，苏氨酸，酪氨酸苄基醚不仅对多肽合成有重要价值，也是重要的药物中间体，可用于不育症、糖尿病、动脉硬化等药物的合成。我们通过酯化、保护羧基，氨基保护、醚化、碱水解、酸水解五步反应成功地合成出了丝氨酸，苏氨酸以及酪氨酸的苄基醚，并优化了各步反应的条件，收率分别达到46％，46％，27％。该路线已在国内成功实现了工业化。
第二部分：组胺是人体内具有很强生物活性的物质之一，是Ⅰ型超敏反应中的主要效应分子，并在炎症、胃酸分泌及神经信号传导等病理生理过程中起重要作用。局部生成的组胺还与创伤修复、胚胎发生、血压调节、免疫应答、造血及细胞恶性增殖有密切关系，可用于制备多种药物。
本论文对组胺二盐酸盐的合成进行了研究。我们通过用苯乙酮为催化剂，以正辛醇为反应溶剂，N_2保护下加热回流将组氨酸进行脱羧反应，然后加浓盐酸成盐，制得了组胺二盐酸盐粗品，粗品经过活性炭脱色，甲醇-乙酸乙酯重结晶，可得高纯度产品，总收率达40％。这一路线避免使用环己醇作溶剂，且避免使用干燥HCl气体，成本低廉、操作方便。该路线已在国内率先实现了工业化。
This dissertation comprises two parts (1) studies on the synthesis of Serine(Bzl), Threonine (Bzl) , and Tyrosine (Bzl) (2) studies on the synthesis of histamine dihydrochloride.
The first part: Serine (Bzl), Threonine (Bzl) , and Tyrosine (Bzl) are valuable protected amino acids in polypeptide synthesis, and useful pharmaceutical intermediates, from which many drugs have been prepared to cure such diseases as infertility, diabetes, arteriosclerosis, cardiovascular diseases and so on.
We prepared the three compounds successfully by esterification, amino group protecting, etherification, base catalyzed hydrolysis, and acid catalyzed hydrolysis with yield of 46%, 46%, 27%, respectively. This procedure has been optimized and industrialized in our country for the first time.
The second part: Histamine is a compound possessing significant biological activity and is one of the important mediators of many diseases, such as hypersensitivity, gastric ulcer, inflammation and so on. Moreover, histamine can be used to synthesize many medicines.
In this dissertation, Histamine dihydrochloride has been conveniently synthesized by exploiting the decarboxylation of histidine using acetophenone as catalyst and octanol as solvent. The crude product was decolorized and recrystallized to give pure histamine, and the overall yield up to 40%. Up to now, this is the first time to replace cyclohexanol by octanol as the reacting solvent, and concentrated hydrochloric acid is used instead of dry HC1 gas, so this method is more economical and easier to operate. The process has been industrialized in our country.
引文
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28. Weygand E, Geiger R., Chem. Bet., 89, 647(1956)
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31. Freedman H. Ho, Dubois R. A., Tetrahedron Lett., 3251(1975)
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36． 沈志刚，范培昌，李翠芹，延安大学学报，17(2)，40(1998)
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46． 董华进，中国药理学通报，8(3)，184(1992)
47. Kimora T，Satoh S.,Br.J.Pharmacol.78,133(1983)
48. 汪昌树，刘冰怀，广东医学，15(3)，154(1994)
49. Kniggell, Warberg J., 《国外医学》内分泌学分册，12(2)，81
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51. Kahlson G., Rosengren E., Annu. Rev. Physiol, 48(1), 155(1968)
52． 曹漫明，王森明，张积仁，中华血液学杂志，22(5)，264(2001)
53． 董镕，谢陪利，王亮，南京铁道医学院学报，15(4)，238(1996)
54． 苏葵，刘蜀凡，沈子华，彭隆详，郭绢霞，临床口腔医学杂志，13(3)，132(1997)
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61. Takano S., Nishimura T, Ogasawara K., Heterocycles, 6, 1167(1997)
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63. GB 1008594
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66. Richard W. So, J. Am. Chem. Soc., 74, 2440(1952)
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68. Enzo S., Ada M., J. Chem. Soc., Perkin Ⅰ, 307(1981)
69. Hideo N., Yasuhiko S., Tomishige M., Commun., 142(1982)
70. Ger 56793
2. Ferenc H. F., Malcolm V. R, Eva R., et al, Bioconjugate Chem., 10(5), 781(1999)
3. Mohammed K. R, Jonathan R. D., Morley D. H., Rajendra K. S., Biochemical Pharmacology, 64, 1461(2002)
4． 王德心，鲁桂琛，刘文登，药学学报，26(1)，25(1990)
5． 黄惟德，陈常之著，《多肽合成》，科学出版社
6． 邢其毅，徐瑞秋，周政，裴伟伟著，《基础有机化学》(第二版下册)，高等教育出版社，
7. WO 0044733
8. WO 9624617
9. WO 9321208
10. WO 0059528
11. Bhagirath S., Ester E, Jana W., Serafin E., Indian J. Chem. Sect. B, 23B(12), 1237(1984)
12. JP 02229200
13. EP 214826
14. WO 0187287
15. WO 0027418
16. JP 0931061
17. Panigrahi G, Zhao Bo P., Krepinsky J. J., Sadowski P. D., J. Am. Chem. Soc., 118(48), 12004(1996)
18. Curtius T., Goebel E, J. Prakt. Chem., 37, 150(1880)
19. Fischer E., Chem. Ber., 39, 453(1906)
20. Fischer E., Fourneau F., Chem. Ber., 34, 2868(1901)
21． 加藤哲夫等，日本化学杂志，83，1051(1962)
22． 赵旸，李细清，陈凤恩等，化学通报，12，799(2001)
23. Roeske R. W., J. Org. Chem., 28, 1251(1963)
24. Aboderin A. Ao, Delierre G. R., Fruton J. S., J. Am. Chem. Soc., 87, 5469(1965)
25. Rachele J. R.; J. Org. Chem., 28(10-12), 2898(1963)
26. Angew. Chem., 76, 271(1964)
27. Callahan E M., Anderson G. W., Paul R., Zimmerman J. E., J. Am. Chem. Soc., 85,201(1963)
28. Weygand E, Geiger R., Chem. Bet., 89, 647(1956)
29. Kotecha N.R., Ley S.V., Montegani, Synlett., 395 (1992)
30. Theodora W. G., Peter G. M. W., Protective Groups in Organic synthesis, 3rd edition, 65
31. Freedman H. Ho, Dubois R. A., Tetrahedron Lett., 3251(1975)
32. Theodora W. G., Peter G. M. W., Protective Groups in Organic synthesis, 3rd edition, 265
33. Schmidhammer H., BrossiA., J. Org. Chem., 48, 1469 (1983)
34. Ger 1493658
35． 蒋昌盛，卢紫苏，尤田耙，北京工业职业技术学院学报，1(1)，18(2002)
36． 沈志刚，范培昌，李翠芹，延安大学学报，17(2)，40(1998)
37. Micheli R. A., Hajos Z. G., Cohen N., Parrish D. R., Portland L. A., Scott W. A., Wehrli P. A.,J. Org. Chem., 40, 675(1975)
38. Beyerman H. Co, Heiszwolf G. L., J. Chem. Soc., 755(1963)
39. Schroder E.,Ann. Chem., 670, 127(1963)
40． 李明凯，罗小星，谢建军，生理科学进展，34(1)，53(2003)
41. Ash A. S. F., Schild H. O., Br. J. Pharmacol, 27, 427(1966)
42. Black J. M., Nature, 236, 385(1972)
43. Arrang J. M., Carbarg Mo, Nature, 327, 117(1987)
44. Liu C. H., Ma X. J., Jiang X. X., Mol. Pharmacol, 59, 420(2001)
45． 艾努尔，实用医技杂志，4(11)，843(1997)
46． 董华进，中国药理学通报，8(3)，184(1992)
47. Kimora T，Satoh S.,Br.J.Pharmacol.78,133(1983)
48. 汪昌树，刘冰怀，广东医学，15(3)，154(1994)
49. Kniggell, Warberg J., 《国外医学》内分泌学分册，12(2)，81
50. 洪新，杨肇亨，中华内科杂志，36(6)，413(1997)
51. Kahlson G., Rosengren E., Annu. Rev. Physiol, 48(1), 155(1968)
52． 曹漫明，王森明，张积仁，中华血液学杂志，22(5)，264(2001)
53． 董镕，谢陪利，王亮，南京铁道医学院学报，15(4)，238(1996)
54． 苏葵，刘蜀凡，沈子华，彭隆详，郭绢霞，临床口腔医学杂志，13(3)，132(1997)
55. WO0037459
56. WO9857960
57. EP199845
58. WO9620216
59. Mellqvist U. H., Wallhult E., Brune M., Jacobssom S., Int. J. Immunother, 15(3/4), 125(1999)
60. WO 8910360
61. Takano S., Nishimura T, Ogasawara K., Heterocycles, 6, 1167(1997)
62. Mitsunori H., Yutaka E., Yasutomo O., Toshiaki I., Seiichi A., Chem. Lett., 893(1986)
63. GB 1008594
64. JP 05255204
65. ① CN 1331681
② US 6528654
③ US 6403806
66. Richard W. So, J. Am. Chem. Soc., 74, 2440(1952)
67. Alan R. B., Marcello N., James So, Robert V., J. Chem. Soc., Perkin Ⅰ, 43(1980)
68. Enzo S., Ada M., J. Chem. Soc., Perkin Ⅰ, 307(1981)
69. Hideo N., Yasuhiko S., Tomishige M., Commun., 142(1982)
70. Ger 56793