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药物详细合成路线

Name Apricitabine;SPD-754;(-)-BCH-10652;(-)-Dotc;BCH-10618
Chemical Name (R,R)-1-[2-(Hydroxymethyl)-1,3-oxathiolan-4-yl]cytosine
      (-)-2-Deoxy-3-oxa-4-thiocytidine
      4-Amino-1-[(2R,4R)-2-(hydroxymethyl)-1,3-dithiolan-4-yl]-2(1H)-pyrimidinone
CAS 160707-69-7
Related CAS
Formula C8H11N3O3S
Structure
Formula Weight 229.25917
Stage II 期临床
Company Shire Pharmaceuticals (Originator)
Activity/Mechanism AIDS Medicines, Anti-HIV Agents, ANTIINFECTIVE THERAPY, Reverse Transcriptase Inhibitors
Syn. Route 2
Route 1
the title compound was prepared starting from the known menthyl 5(s)-acetoxy-1,3-oxathiolan-2(r)-carboxylate (i). transposition of the 5-acetoxy group of (i) to the target 4-acetoxy derivative (vi) was achieved by the following sequence. the acetoxy group of (i) was first removed by reduction with triethylsilaneto give (ii), followed by ester reduction with nabh4, to give the hydroxymethyl oxathiolane (iii). the primary alcohol of (iii) was then protected by silylation with tert-butyldiphenylsilyl chloride. the resultant silylated oxathiolane (iv) was oxidized to a diastereomeric mixture of sulfoxides (v) using m-cpba. pummerer rearrangement of sulfoxides (v) in the presence of ac2o and bu4noac furnished the desired 4-acetoxy thiolane (vi). glycosylation of (vi) with n-acetylcytosine (vii) in the presence of trimethylsilyl triflate provided a mixture of cis- and trans-coupled products, which were separated by preparative tlc. the required cis-isomer (viii) was desilylated with tetrabutylammonium fluoride, followed by acetamide hydrolysis with k2co3 in meoh, to provide the title compound.
List of intermediates No.
Reference 1:
    mansour, t.s.; et al.; structure-activity relationships among a new class of antiviral heterosubstituted 2,3-dideoxynucleoside analogs. nucleosides nucleotides 1995, 14, 3-5, 627.
Reference 2:
    wang, w.; et al.; synthesis of optically active 2,3-dideoxy-3-oxa-4-thio-ribonucleoside analogs by transposition of a leaving group on chiral oxathiolanes via a reductive-oxidative process. tetrahedron lett 1994, 35, 27, 4739.
Reference 3:
    mansour, t.s.; et al.; anti-human immunodeficiency virus and anti-hepatitis-b virus activities and toxicities of the enantiomers of 2-deoxy-3-oxa-4-thiocytidine and their 5-fluoro analogues in vitro. j med chem 1995, 38, 1, 1.
Reference 4:
    mansour, t.s.; jin, h. (shire biochem inc.); substd. 1,3-oxathiolanes with antiviral properties. ep 0756595; ep 1153924; jp 1997512526; wo 9529176 .

Route 2
a new asymmetric synthesis has been reported. oxidative cleavage of mono-benzoyl glycerol (ix) by means of naio4 provided aldehyde (x). condensation of (x) with mercaptoethanol (xi) in the presence of ploystyryl diphenylphosphane-iodine complex gave rise to the oxathiolane (xii). sharpless asymmetric oxidation of (xii) using tert-butyl hydroperoxide and l-diethyl tartrate led to an 82:18 mixture of (e)- and (z)-sulfoxides (xiii) and (xiv). the desired (e)-isomer (xiii) was then isolated by column chromatography, displaying an enantiomeric excess of 60%. coupling of (xiii) with n-acetylcytosine (vii) under pummerer rearrangement conditions led to an equimolecular mixture of (z)- and (e)-adducts (xv) and (xvi). after chromatographic separation of the desired (z)-isomer (xv), the acetyl and benzoyl protecting groups were removed by treatment with sodium methoxide.
List of intermediates No.
6,6-dimethyl-8-(1-oxido-2-pyridiniumyl)-7,8-dihydro-6h-[1,2,5]oxadiazolo[3,4-g][1,4]benzoxazin-3-ium-3-olate (x)
3-(4-fluorophenyl)-2-methylpropionic acid (xxi)
Reference 1:
    caputo, r.; et al.; a new strategy for the asymmetric synthesis of 1,3-oxathiolane-based nucleoside analogues. eur j org chem 1999, 6, 1455.

来源:药化网

作者:药化小编

摘要:本文合成路线介绍的是药物中文名阿立他滨;英文名Apricitabine;SPD-754;(-)-BCH-10652;(-)-Dotc;BCH-10618;CAS[160707-69-7]

 
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