抗艾滋病新药Fosamprenavir及抗乙肝新药AD酯的合成研究
摘要
本论文第一部分是抗AIDS新药Fosamprenavir的合成研究。Fosamprenavir为蛋白酶抑制剂amprenavir的前体药物，是一种具有高度水溶性的低活性磷酸酯，用药方便，有很好的发展前景。该品由英国GSK和美国Vertex公司共同开发，已于2003年10月在美国上市。我们以L—苯丙氨酸为原料，通过氧化、亲核加成、脱水关环、缩合等十八步反应(包括两个侧链的合成)完成了目标分子的全合成。我们对其中重要的反应环节和操作进行了改进：使用NaBH_4/I_2代替NaBH_4/H_2SO_4还原L—苯丙氨酸，使之操作简便更适合工业化；使用Swern氧化替代SO_3．Pyridine/DMSO氧化，使得苯丙氨醛的收率由70％上升至90％以上；用一步法改进了对硝基苯磺酰氯的制备，使反应步骤简短，产率由19％提高到31％；通过寻找合适溶剂重结晶分离出了非对映异构体并通过分析反应机理认为非对映异构体的生成是导致本反应产率较低的原因；尝试直接将BOC保护的苯丙胺醛与硫叶立德反应并利用空间位阻效应诱导生成所需的环氧化物，同时也对空间位阻对手性诱导的影响进行了研究；尝试研究了将HKR反应应用到上述制备所得中间体中，以期发现手性诱导作用对于HKR反应的影响。
本论文第二部分是抗乙肝新药AD酯的合成研究。阿德福韦酯(adefovir dipivoxil)是腺嘌呤磷酸酯化合物阿德福韦(adefovir)的前药，口服后可迅速水解为阿德福韦而发挥抗病毒作用。本品由Gilead Sciences公司研制开发，并已于2002年在美国上市。我们从腺嘌呤出发，经缩合、亲核取代、水解脱脂、酯化等六步反应完成了阿德福韦酯的全合成。我们对部分反应环节进行了分析和改进：腺嘌呤的取代反应主要发生在9-位上，有时也会有少量3-位取代产物的生成；对9-[2-(二乙氧基膦酰基甲氧基)乙基]腺嘌呤的合成进行了改进，采用t-BuONa代替NaH，使得产率和反应安全性均有了很大的提高，产率由29％提高到39％；在制备阿德福韦酯的实验中，控制反应温度提高了反应产率，在减少了反应副产物的同时也使得产品提纯变得简便。对于两个中间体，均提出了适合工业化生产的合成方法。
The first part of this paper relates to a research into a route of synthesizing a new anti-AIDS agent-Fosamprenavir. Fosamprenavir is an inactive phosphate ester that is a highly water soluble prodrug of amprenavir. It allows more convenient dosing as compared to amprenavir and it has been selected for further development. The Vertex Pharmaceutical prepared Fosamprenavir and licensed it to GlaxoSmithKline for development. It was marked in America in 2003.
Herein we describe the synthesis of Fosamprenavir: we start from the L-phenylalanine and eventually finish the total synthesis work (including the synthesis of two side chains) in a eighteen-step sequence of reactions including oxidation, nucleophilic substitution, dehydration and cyclization, condensation, etc. In the synthesis of L-phenylalaninol, we make progress in the important conductions and replace the NaBEH4/H2SO4 for NaBH4/I2, making the reaction become safer and more convenient to conduct. In the preparation of Benzyl-phenylalaninal, we use the Swern oxidation instead of the SO3.Pyridine/DMSO and improve the yield from 70% to over 90%. We also improve the operation of the oxidation in the manufacture of para-nitrobenzene sulfonyl chloride, simplify the steps and make the yield arise from 19% to 31%. Furthermore, we disclose the mechanism of the synthesis of chlorohydrin and find that the isomerical product causes the yield become very low. Next we get the suitable solvent to separate the isomerica
l product. In the experiment of preparing the compound 6, we make the reaction between Boc-phenylalaninal and sulfur ylide directly to produce the oxide under the space effect of the substituent. At the same time, we also do some research in the space effect function on the chiral induction. And we apply the above product to HKR reaction in order to find the effect of the chiral induction function on the HKR reaction.
The second part of this paper is on the synthesis of a new antiviral agent AD ester. Adefovir dipivoxil is the prodrug of Adefovir, after being taken into the human body, it can be rapidly hydrolyzed to Adefovir and exhibit its antiviral functions. This
product is researched by Gilead Sciences Co., and it was marked in America in 2002. Herein we start from adenine doing by a series of six reactions for example: condensation, nuleophilic substitution, hydrolysis, esterification, etc. The substitution reaction of the adenine was performed at the 9-substituted mainly, but sometimes it also produce some 3-substitued ones. We make progress in the synthesis of diethyl-PMEA, and replace t-BuONa for NaH, which makes the reaction's yield and safety arise greatly and improve the yield from 29% to 39%. In the preparation of AD ester, we improve the yield by adjusting the reaction's temperature, make the byproduct fewer and also simplify the product's purification. As for the manufacture of two intermediates, we put forward the practical synthetic route, which is suitable to large-scale preparation.
本论文第二部分是抗乙肝新药AD酯的合成研究。阿德福韦酯(adefovir dipivoxil)是腺嘌呤磷酸酯化合物阿德福韦(adefovir)的前药，口服后可迅速水解为阿德福韦而发挥抗病毒作用。本品由Gilead Sciences公司研制开发，并已于2002年在美国上市。我们从腺嘌呤出发，经缩合、亲核取代、水解脱脂、酯化等六步反应完成了阿德福韦酯的全合成。我们对部分反应环节进行了分析和改进：腺嘌呤的取代反应主要发生在9-位上，有时也会有少量3-位取代产物的生成；对9-[2-(二乙氧基膦酰基甲氧基)乙基]腺嘌呤的合成进行了改进，采用t-BuONa代替NaH，使得产率和反应安全性均有了很大的提高，产率由29％提高到39％；在制备阿德福韦酯的实验中，控制反应温度提高了反应产率，在减少了反应副产物的同时也使得产品提纯变得简便。对于两个中间体，均提出了适合工业化生产的合成方法。
The first part of this paper relates to a research into a route of synthesizing a new anti-AIDS agent-Fosamprenavir. Fosamprenavir is an inactive phosphate ester that is a highly water soluble prodrug of amprenavir. It allows more convenient dosing as compared to amprenavir and it has been selected for further development. The Vertex Pharmaceutical prepared Fosamprenavir and licensed it to GlaxoSmithKline for development. It was marked in America in 2003.
Herein we describe the synthesis of Fosamprenavir: we start from the L-phenylalanine and eventually finish the total synthesis work (including the synthesis of two side chains) in a eighteen-step sequence of reactions including oxidation, nucleophilic substitution, dehydration and cyclization, condensation, etc. In the synthesis of L-phenylalaninol, we make progress in the important conductions and replace the NaBEH4/H2SO4 for NaBH4/I2, making the reaction become safer and more convenient to conduct. In the preparation of Benzyl-phenylalaninal, we use the Swern oxidation instead of the SO3.Pyridine/DMSO and improve the yield from 70% to over 90%. We also improve the operation of the oxidation in the manufacture of para-nitrobenzene sulfonyl chloride, simplify the steps and make the yield arise from 19% to 31%. Furthermore, we disclose the mechanism of the synthesis of chlorohydrin and find that the isomerical product causes the yield become very low. Next we get the suitable solvent to separate the isomerica
l product. In the experiment of preparing the compound 6, we make the reaction between Boc-phenylalaninal and sulfur ylide directly to produce the oxide under the space effect of the substituent. At the same time, we also do some research in the space effect function on the chiral induction. And we apply the above product to HKR reaction in order to find the effect of the chiral induction function on the HKR reaction.
The second part of this paper is on the synthesis of a new antiviral agent AD ester. Adefovir dipivoxil is the prodrug of Adefovir, after being taken into the human body, it can be rapidly hydrolyzed to Adefovir and exhibit its antiviral functions. This
product is researched by Gilead Sciences Co., and it was marked in America in 2002. Herein we start from adenine doing by a series of six reactions for example: condensation, nuleophilic substitution, hydrolysis, esterification, etc. The substitution reaction of the adenine was performed at the 9-substituted mainly, but sometimes it also produce some 3-substitued ones. We make progress in the synthesis of diethyl-PMEA, and replace t-BuONa for NaH, which makes the reaction's yield and safety arise greatly and improve the yield from 29% to 39%. In the preparation of AD ester, we improve the yield by adjusting the reaction's temperature, make the byproduct fewer and also simplify the product's purification. As for the manufacture of two intermediates, we put forward the practical synthetic route, which is suitable to large-scale preparation.
引文
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24. a)Brandes, B.D.; Jacobsen, E.N. Tetrahedron: Asymmetry. 1997, 8, 3927 b)Hinterding, K.; Jacobsen, E.N. J.Org.Chem. 1999, 64, 2164 c)Furrow, M.E.; Schaus, S.E.; Jacobsen, E.N. J.Org.Chem. 1998, 63, 6776
25. Schaus, S. E.; Bridget, D.; Brandes, Jay.F.J.Am.Chem.Soc. 2002, 124(7), 1307
2. Haubrich, R.; Lalezari, J.; Follansbee, S.E. Antivir Ther. 1998, 3, 33
3. Cameron, D.W.; Heath-Chiozzi, M.; Danner, S. Lancet. 1998, 351,543～549
4．郑马庆 药学进展 2003，27(2)，123
5. a)Pierre, L. Beaulieu. J.Org.Chem. 1996, 61, 3635～3645 b)Norio, Shibata. Tetrahedron Letters. 1997, 38(4), 619-620
6. Robertson, Mark. Stuart. WO 9948885
7. Murcko, Mark.A. WO 9405639
8. Tung, Roger. D. WO 9633184
9. David, P. Rotella. Tetrahedron Letters. 1995, 36(31), 5453-5456
10. Ping Chen, Peter. T. Tetrahedron Letters. 1997, 38(18), 3175-3178
11. Jay, R. Luly. J.Org.Chem. 1987, 52, 1487-1492
12. Shaw, K.J. J.Org.Chem. 1985, 50, 4515
13. Pierre L. Beaulieu. Tetrahedron Letters. 1995, 36(19), 3317-3320
14. Abiko, A.; Masamune, S. Tetrahedron Letters. 1992, 33, 5517-5518
15. Fang X, Bandarage. J. Org. Chem. 2001, 66(11), 4019-4021
16. Pierre L. Beaulieu. US5550291
17. Hayashi, H.; Nakanishi, K.; Brandon, C. J.Am.Chem.Soc. 1973, 95, 8749
18. Wynberg, H., Bantjes, A Org. Synth. 1958, 38, 37
19. Bell Journal of the Chemical Society. 1928, 2776
20. Michael, Witte. US 2465951
21. Baker, Christopher. T. WO 9933815
22. Baker, Christopher. T. WO 9933792
23. Tokunaga, M.; Larrow, J. E; Jacobsen, E.N. Science. 1997, 277, 936～938
24. a)Brandes, B.D.; Jacobsen, E.N. Tetrahedron: Asymmetry. 1997, 8, 3927 b)Hinterding, K.; Jacobsen, E.N. J.Org.Chem. 1999, 64, 2164 c)Furrow, M.E.; Schaus, S.E.; Jacobsen, E.N. J.Org.Chem. 1998, 63, 6776
25. Schaus, S. E.; Bridget, D.; Brandes, Jay.F.J.Am.Chem.Soc. 2002, 124(7), 1307