合成（-）-β-D-2,6-二氨基嘌呤二氧戊环（安多昔韦，DAPD）和（-）-β-D-2-氨基嘌呤二氧戊环（APD）的可扩展方法。
Scaleable processes for the synthesis of (-)-β-D-2,6-diaminopurine dioxolane (Amdoxovir, DAPD) and (-)-β-D-2-aminopurine dioxolane (APD).
作者信息
Zhou Longhu, Coats Steven J, Zhang Hongwang, Junxing Shi, Bobeck Drew R, Schinazi Raymond F
机构信息
Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, and Veterans Affairs Medical Center, Atlanta GA 30033, USA.
出版信息
Tetrahedron. 2012 Jul 22;68(29):5738-5743. doi: 10.1016/j.tet.2012.05.039. Epub 2012 May 16.
Abstract
An efficient and scalable synthesis of (-)-DAPD and (-)-APD has been developed. We discovered that t-butyl cyanoacetate can be used as a new additive for the sugar nucleoside base coupling step en route to DAPD with improved β-selectivity and an isolated yield four fold greater than the original process scale method. Using this new process, (-)-DAPD has been prepared on greater than 20 g scale. In the synthesis of (-)-APD, a key enzyme-catalyzed hydrolysis reaction afforded the water-soluble deprotected α-anomer while leaving the β-anomer completely untouched.
摘要
已开发出一种高效且可扩展的（-）-DAPD和（-）-APD合成方法。我们发现，氰基乙酸叔丁酯可作为糖核苷碱基偶联步骤中的一种新型添加剂，用于合成DAPD，其β-选择性得到改善，分离产率比原始工艺规模方法高出四倍。采用这种新工艺，已制备出规模超过20 g的（-）-DAPD。在（-）-APD的合成中，关键的酶催化水解反应得到了水溶性的脱保护α-异头物，而β-异头物则完全未受影响。
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本文引用的文献
1
Antiviral activity and tolerability of amdoxovir with zidovudine in a randomized double-blind placebo-controlled study in HIV-1-infected individuals.在一项针对HIV-1感染个体的随机双盲安慰剂对照研究中，氨多昔韦与齐多夫定的抗病毒活性及耐受性
Antivir Ther. 2010;15(2):185-92. doi: 10.3851/IMP1514.
2
Lack of pharmacokinetic interaction between amdoxovir and reduced- and standard-dose zidovudine in HIV-1-infected individuals.在 HIV-1 感染者中，amdoxovir 与齐多夫定低剂量和标准剂量之间不存在药代动力学相互作用。
Antimicrob Agents Chemother. 2010 Mar;54(3):1248-55. doi: 10.1128/AAC.01209-09. Epub 2009 Dec 28.
3
The use of beta-D-2,6-diaminopurine dioxolane with or without mycophenolate mofetil in drug-resistant HIV infection.在耐药性HIV感染中使用β-D-2,6-二氨基嘌呤二氧戊环（无论是否联用霉酚酸酯）。
AIDS. 2007 Oct 1;21(15):2025-32. doi: 10.1097/QAD.0b013e3282364381.
4
Synthesis and anti-HIV activity of (-)-beta-D-(2R,4R)-1,3-dioxolane-2,6-diamino purine (DAPD) (amdoxovir) and (-)-beta-D-(2R,4R)-1,3-dioxolane guanosine (DXG) prodrugs.（-）-β-D-（2R，4R）-1,3-二氧戊环-2,6-二氨基嘌呤（DAPD）（安多昔韦）和（-）-β-D-（2R，4R）-1,3-二氧戊环鸟苷（DXG）前药的合成及抗HIV活性
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5
6
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AIDS. 2005 Oct 14;19(15):1607-15. doi: 10.1097/01.aids.0000186822.68606.05.
7
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Chem Rev. 2005 Jan;105(1):313-54. doi: 10.1021/cr040640a.
8
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Nucleosides Nucleotides Nucleic Acids. 2004;23(12):1875-87. doi: 10.1081/NCN-200040643.
9
Combination of enzymes and metal catalysts. A powerful approach in asymmetric catalysis.酶与金属催化剂的组合。不对称催化中的一种强大方法。
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10
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J Org Chem. 2002 Aug 23;67(17):5938-45. doi: 10.1021/jo020249u.
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