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药物详细合成路线

Name Troxacitabine;SPD-758;beta-L-OddC;BCH-4556;Troxatyl
Chemical Name (2S,4S)-1-[2-(Hydroxymethyl)-1,3-dioxolan-4-yl]cytosine
      (2,4S)-4-Amino-[2-(hydroxymethyl)-1,3-dioxolan-4-yl]pyrimidin-2-one
      (-)-beta-L-Dioxolanecytidine
CAS 145918-75-8
Related CAS
Formula C8H11N3O4
Structure
Formula Weight 213.19457
Stage III 期临床
Company Shire Pharmaceuticals (Originator)
Activity/Mechanism Breast Cancer Therapy, Colorectal Cancer Therapy, Leukemia Therapy, Lung Cancer Therapy, Melanoma Therapy, Myeloid Leukemia Therapy, Non-Small Cell Lung Cancer Therapy, Oncolytic Drugs, Ovarian Cancer Therapy, Pancreatic Cancer Therapy, Prostate Cancer Therapy, Renal Cancer Therapy, Antimitotic Drugs, DNA Polymerase Inhibitors
Syn. Route 2
Route 1
displacement of the chlorine atom of (i) with potassium benzoate in boiling dmf afforded benzoate ester (ii). the hydroxymethyl group of (ii) was subsequently oxidized to carboxylic acid (iii) employing pyridinium dichromate. conversion of acid (iii) to the corresponding mixed anhydride with ethyl chloroformate, followed by baeyer-villiger oxidation with m-chloroperbenzoic acid, gave rise to the m-chlorobenzoyloxy dioxolane (iv). this was then coupled to cytosine (v) following a previously reported procedure to produce adduct (vi) as a cis/trans mixture. after acetylation with ac2o, the desired cis-isomer (vii) was isolated by flash chromatography. the title compound was finally obtained by basic hydrolysis (vii).
List of intermediates No.
isonicotinic acid (v)
n-(4-hydroxy-3-isopropylphenyl)acetamide (iii)
Reference 1:
    belleau, b.; dixit, d.; nguyen-ba, n. (shire biochem inc.); 2-substd.-4-substd.-1,3-dioxolanes, synthesis and use thereof. ep 0337713 .

Route 2
in a related procedure, 1,6-anhydro-l-gulose (ix) was obtained from l-gulose (viii) by treatment with 0.5 n hcl. oxidative cleavage of (ix) by naio4, followed by reduction of the aldehyde groups with nabh4, led to the dioxolane triol (x), which was further protected as the isopropylidene ketal (xi). benzoylation of the free hydroxyl of (xi), followed by acidic hydrolysis of the acetonide group, furnished the benzoate diol (xii). then, oxidation of the vicinal diol moiety of (xii), by means of ruo2 in the presence of naio4, afforded carboxylic acid (iii). oxidative decarboxylation of acid (iii) with lead tetraacetate produced the key acetoxy dioxolane (xiii). this was coupled with the silylated n-acetylcytosine (xiv) in the presence of trimethylsilyl triflate to yield a mixture of anomers, which were separated by column chromatography. final hydrolysis of the desired isomer (vii) was then performed by treatment with methanolic ammonia.
List of intermediates No.
2-propylphenol (ix)
n-(4-hydroxy-3-isopropylphenyl)acetamide (iii)
n-[3-[(tert-butylamino)methyl]-4-hydroxy-5-isopropylphenyl]acetamide (xiii)
ethyl (3r,4r,5s)-4-(acetamido)-5-(allylamino)-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate (viii)
Reference 1:
    kim, h.o.; et al.; potent anti-hiv and anti-hbv activities of (-)-l-beta-dioxolane-c and (+)-l-beta-dioxolane-t and their asymmetric syntheses. tetrahedron lett 1992, 33, 46, 6899.

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曲沙他滨;英文名Troxacitabine;SPD-758;beta-L-OddC;BCH-4556;Troxatyl;CAS[145918-75-8]

 
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