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Name Clevudine;Levovir;L-FMAU
Chemical Name 1-(2-Deoxy-2-fluoro-beta-L-arabinofuranosyl)-5-methyluracil
      1-(2-Deoxy-2-fluoro-beta-L-arabinofuranosyl)thymine
CAS 163252-36-6
Related CAS
Formula C10H13FN2O5
Structure
Formula Weight 260.22391
Stage 中止开发
Company University of Georgia (Originator), Yale University (Originator), Gilead (Licensee)
Activity/Mechanism Anti-Hepatitis B Virus Drugs, Anti-Hepatitis Virus Drugs, ANTIINFECTIVE THERAPY, Antiviral Drugs
Syn. Route 2
Route 1
previously, it was reported that d-ribose was synthesized from d-xylose, the epimer of d-ribose, via a stereoselective oxidation-reduction procedure, albeit in low yield. this strategy was adapted to prepare the l-ribose derivative (v) for the practical synthesis of l-fmau as well as related nucleosides. after pyridinium dichromate (pdc) oxidation, ketone (iii) was reduced to an alcohol using nabh4. it should be mentioned that due to the stereoelectronic effects of the 1,2-o-isopropylidene group, the hydride preferentially attacks from the beta-face. after a series of reactions, compound (v) was obtained and treated with saturated hydrogen chloride in ch2cl2 at 0 c followed by the migration of the benzoyl group and treatment with so2cl2 and imidazole in dmf/ch2cl2 to give a imidazolyl intermediate. the imidazole derivative was fluorinated with a mixture of khf2 and 48% hf/h2o to give 1,3,5-tri-o-benzoyl-2-fluoro-alpha-l-arabinofuranose, which was converted to bromosugar (vi) using 45% hbr/acoh. without further purification, the bromosugar was condensed with silylated thymine in anhydrous chcl3 in refluxing conditions to give protected l-fmau with high stereoselectivity, which was further treated with nh3/ch3oh for debenzoylation to give l-fmau. due to the availability and high cost of l-xylose, however, we have developed another procedure from l-arabinose. l-arabinose is a natural sugar with reasonable cost. the anomeric position was protected with a benzyl group in acidic conditions to the pyranose form and the vicinal cis-hydroxy groups were protected with an isopropylidene group. in similar conditions as for l-xylose, pdc was used for the oxidation reaction to obtain ketone (iv), which was reduced with nabh4 in methanol with high stereoselectivity as described for l-xylose. after deprotection of compound (iv) using 4% cf3co2h, the resulting l-ribose was sequentially treated with 1% hcl/meoh, bzcl/pyridine and h2so4/aco/acoh to obtain compound (v). the remaining steps to l-fmau were the same as described for the l-xylose route.
List of intermediates No.
methyl (1s,5r,6s)-5-(methoxymethoxy)-7-oxabicyclo[4.1.0]hept-3-ene-3-carboxylate (i)
methyl (3r,4s,5r)-5-azido-4-hydroxy-3-(methoxymethoxy)-1-cyclohexene-1-carboxylate (ii)
methyl (3r,4s,5r)-5-azido-3-(methoxymethoxy)-4-[(methylsulfonyl)oxy]-1-cyclohexene-1-carboxylate (iii)
methyl (1r,5r,6r)-5-(methoxymethoxy)-7-azabicyclo[4.1.0]hept-3-ene-3-carboxylate (iv)
methyl (3r,4r,5s)-4-amino-5-azido-3-(methoxymethoxy)-1-cyclohexene-1-carboxylate (v)
methyl (3r,4r,5s)-5-azido-3-hydroxy-4-(tritylamino)-1-cyclohexene-1-carboxylate (vi)
Reference 1:
    oka, k.; wada, h.; synthesis of d-ribose from d-xylose. yakugaku zasshi 1963, 83, 890-1.
Reference 2:
    brundidge; tann, c.h.; brodfuehrer, p.r.; et al.; fluorocarbohydrates in synthesis. an efficient synthesis of 1-(2-deoxy-2-fluoro-?-d-arabinofuranosyl)-thymine (?-d-fmau). j org chem 1985, 50, 3644-6.

Route 2
a new synthesis of clevudine has been described:peracetylation of l-arabinose (i) with acetic anhydride and pyridine provides acetylated arabinose (ii), which is then brominated by means of hbr in acoh/ac2o to furnish the bromo-sugar (iii). treatment of the sugar (iii) with zn dust, cuso4 and naoac in acoh/h2o, followed by chromatographic separation, gives l-arabinal (iv), which is then converted to the fluoro derivative (v) by reaction with selectfluor?(f-teda-bf4) in refluxing nitromethane/h2o. deacetylation of compound (v) with naome in meoh yields compound (vi), which is then converted into the methyl furanoside (vii) by treatment with h2so4 in meoh. benzoylation of the furanoside (vii) with benzoyl chloride in pyridine affords a mixture of isomers, from which (viii) is separated by chromatography and then brominated with hbr/acoh in ch2cl2 to provide the bromo-sugar (ix). condensation of the sugar (ix) with the silylated pyrimidine derivative (x) in refluxing chloroform affords 3,5-di-o-benzoylclevudine (xi), which is finally deprotected by treatment with n-butylamine in refluxing methanol. compound (x) is obtained by treatment of thymine (xii) with hmds (1,1,1,3,3,3-hexamethyldisilazane) and ammonium sulfate in refluxing chloroform.
List of intermediates No.
1-bromo-2-[(e)-3-bromo-1-propenyl]benzene (xii)
methyl (3r,4s,5r)-5-azido-4-hydroxy-3-(methoxymethoxy)-1-cyclohexene-1-carboxylate (i)
methyl (3r,4r,5s)-5-azido-3-hydroxy-4-(tritylamino)-1-cyclohexene-1-carboxylate (ix)
tert-butyl(dimethyl)silyl (1s,3e)-7-iodo-1-[(e)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4-[(trityloxy)methyl]-3-heptenyl ether; 4-{(1e,3s,5e)-3-{[tert-butyl(dimethyl)silyl]oxy}-9-iodo-2-methyl-6-[(trityloxy)methyl]-1,5-nonadienyl}-2-methyl-1,3-thiazole (x)
(2s,3s,4r,6r)-6-{[(2r,3s,4s,5r,6r)-5-(acetyloxy)-6-{[(4r,5r,6s,8r,9r,10s,14r)-4-(acetyloxy)-10-amino-8-(2,2-dimethoxyethyl)-5-methoxy-9,14-dimethyl-2-oxooxa-11-cyclotetradecen-6-yl]oxy}-4-(dimethylamino)-2-methyltetrahydro-2h-pyran-3-yl]oxy}-4-hydroxy-2,4-dimethyltetrahydro-2h-pyran-3-yl 3-methylbutanoate (ii)
Reference 1:
    almond, m.r.; pesyan, a.; sznaidman, m.l.; new synthesis of l-fmau from l-arabinose. nucleosides nucleotides nucleic acids 2002, 21, 2, 155.

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克拉夫定;英文名Clevudine;Levovir;L-FMAU;CAS[163252-36-6]

 
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