Scaleable processes for the synthesis of (-)-β-D-2,6-diaminopurine dioxolane (Amdoxovir, DAPD) and (-)-β-D-2-aminopurine dioxolane (APD)

被引：5

作者：

Zhou, Longhu ^{[1
,2
]}

Coats, Steven J. ^{[3
]}

Zhang, Hongwang ^{[1
,2
]}

Shi, Junxing ^{[3
]}

Bobeck, Drew R. ^{[3
]}

Schinazi, Raymond F. ^{[1
,2
]}

机构：

[1] Emory Univ, Ctr AIDS Res, Biochem Pharmacol Lab, Dept Pediat,Sch Med, Atlanta, GA 30033 USA

[2] Vet Affairs Med Ctr, Atlanta, GA 30033 USA

[3] RFS Pharma LLC, Tucker, GA 30084 USA

来源：

TETRAHEDRON | 2012年 / 68卷 / 29期

关键词：

Amdoxovir; DAPD; Diaminopurine; Dioxolane; Nucleoside; Glycosylation; ANTI-HIV ACTIVITY; METABOLITE (-)-BETA-D-DIOXOLANE GUANINE; ORGANIC-SYNTHESIS; ASYMMETRIC-SYNTHESIS; NUCLEOSIDE ANALOGS; (-)-BETA-D-2-AMINO-6-CHLOROPURINE DIOXOLANE; HIV-1-INFECTED INDIVIDUALS; CARBOCYCLIC NUCLEOSIDES; REVERSE-TRANSCRIPTASE; ANTIVIRAL ACTIVITY;

D O I：

10.1016/j.tet.2012.05.039

中图分类号：

O62 [有机化学];

学科分类号：

070303 ; 081704 ;

摘要：

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 beta-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 alpha-anomer while leaving the beta-anomer completely untouched. Published by Elsevier Ltd.

引用

页码：5738 / 5743

页数：6

共 49 条

[1]

[Anonymous], 2010, GLOB SUMM AIDS EP DA

[2] In vitro selection of mutations in the human immunodeficiency virus type 1 reverse transcriptase that decrease susceptibility to (-)-β-D-dioxolane-guanosine and suppress resistance to 3′-azido-3′-deoxythymidine [J].

Bazmi, HZ ;

Hammond, JL ;

Cavalcanti, SCH ;

Chu, CK ;

Schinazi, RF ;

Mellors, JW .

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2000, 44 (07) :1783-1788

[3]

Belleau B., 1989, [No title captured], Patent No. [EP 0337713, 0337713, 337713]

[4]

Butt S., 1987, CHEM BR, P127

[5] High-performance liquid chromatographic determination of (-)-beta-D-2-aminopurine dioxolane and (-)-beta-D-2-amino-6-chloropurine dioxolane, and their metabolite (-)-beta-D-dioxolane guanine in monkey serum, urine and cerebrospinal fluid [J].

Chen, H ;

Manouilov, KK ;

Chu, CK ;

Schinazi, RF ;

McClure, HM ;

Boudinot, FD .

JOURNAL OF CHROMATOGRAPHY B, 1997, 691 (02) :425-432

[6] Pharmacokinetics of (-)-beta-D-2-aminopurine dioxolane and (-)-beta-D-2-amino-6-chloropurine dioxolane and their antiviral metabolite (-)-beta-D-dioxolane guanine in rhesus monkeys [J].

Chen, HC ;

Boudinot, FD ;

Chu, CK ;

McClure, HM ;

Schinazi, RF .

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 1996, 40 (10) :2332-2336

[7] INSITU COMPLEXATION DIRECTS THE STEREOCHEMISTRY OF N-GLYCOSYLATION IN THE SYNTHESIS OF OXATHIOLANYL AND DIOXOLANYL NUCLEOSIDE ANALOGS [J].

CHOI, WB ;

WILSON, LJ ;

YEOLA, S ;

LIOTTA, DC ;

SCHINAZI, RF .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1991, 113 (24) :9377-9379

[8]

Chu C.K., 1990, U.S. Patent, Patent No. 5179104

[9] ASYMMETRIC-SYNTHESIS OF ENANTIOMERICALLY PURE (-)-(1'R,4'R)-DIOXOLANE-THYMINE AND ITS ANTI-HIV ACTIVITY [J].

CHU, CK ;

AHN, SK ;

KIM, HO ;

BEACH, JW ;

ALVES, AJ ;

JEONG, LS ;

ISLAM, Q ;

VANROEY, P ;

SCHINAZI, RF .

TETRAHEDRON LETTERS, 1991, 32 (31) :3791-3794

[10]

DAMKJAER DL, 1994, NUCLEOS NUCLEOT, V13, P1801

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