Clevudine, Levovir, L-FMAU, -Drug Synthesis Database

【结构式】

【药物名称】Clevudine, Levovir, L-FMAU

【化学名称】1-(2'-Deoxy-2'-fluoro-beta-L-arabinofuranosyl)-5-methyluracil
　　　　　　1-(2'-Deoxy-2'-fluoro-beta-L-arabinofuranosyl)thymine

【CA登记号】163252-36-6

【分子式】C₁₀H₁₃FN₂O₅

【分子量】260.22391

【开发单位】University of Georgia (Originator), Yale University (Originator), Gilead (Licensee)

【药理作用】Anti-Hepatitis B Virus Drugs, Anti-Hepatitis Virus Drugs, ANTIINFECTIVE THERAPY, Antiviral Drugs

合成路线1 合成路线2

合成路线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.

参考文献中间体

【1】 Oka, K.; Wada, H.; Synthesis of D-ribose from D-xylose. Yakugaku Zasshi 1963, 83, 890-1.
【2】 Brundidge; Tann, C.H.; Brodfuehrer, P.R.; et al.; Fluorocarbohydrates in synthesis. An efficient synthesis of 1-(2-deoxy-2-fluoro-ß-D-arabinofuranosyl)-thymine (ß-D-FMAU). J Org Chem 1985, 50, 3644-6.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	17519	(3R,4S,5R)tetrahydro-2H-pyran-2,3,4,5-tetrol; L-(-)-Xylose	609-06-3	C₅H₁₀O₅	详情	详情
(II)	17520	(3R,4S,5S)tetrahydro-2H-pyran-2,3,4,5-tetrol; L-(+)-Arabinose	7296-56-2	C₅H₁₀O₅	详情	详情
(III)	17521	[(3aS,5S,6aR)-2,2-dimethyl-6-oxotetrahydrofuro[2,3-d][1,3]dioxol-5-yl]methyl benzoate		C₁₅H₁₆O₆	详情	详情
(IV)	17522	(3aS,6S,7aR)-6-(benzyloxy)-2,2-dimethyldihydro-4H-[1,3]dioxolo[4,5-c]pyran-7(6H)-one		C₁₅H₁₈O₅	详情	详情
(V)	17523	[(2S,3S,4S,5R)-5-(acetoxy)-3,4-bis(benzoyloxy)tetrahydro-2-furanyl]methyl benzoate	6974-32-9	C₂₈H₂₄O₉	详情	详情
(VI)	17524	[(2S,3S,4R,5S)-3-(benzoyloxy)-5-bromo-4-fluorotetrahydro-2-furanyl]methyl benzoate		C₁₉H₁₆BrFO₅	详情	详情

合成路线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.

参考文献中间体

【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.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	17520	(3R,4S,5S)tetrahydro-2H-pyran-2,3,4,5-tetrol; L-(+)-Arabinose	7296-56-2	C₅H₁₀O₅	详情	详情
(II)	48936	D-Arabinose tetraacetate		C₁₃H₁₈O₉	详情	详情
(III)	54161	(2R,3R,4S,5S)-3,5-bis(acetyloxy)-2-bromotetrahydro-2H-pyran-4-yl acetate	n/a	C₁₁H₁₅BrO₇	详情	详情
(IV)	54162	(3S,4R)-3-(acetyloxy)-3,4-dihydro-2H-pyran-4-yl acetate	n/a	C₉H₁₂O₅	详情	详情
(V)	54163	(3R,4S,5S)-5-(acetyloxy)-3-fluoro-2-hydroxytetrahydro-2H-pyran-4-yl acetate	n/a	C₉H₁₃FO₆	详情	详情
(VI)	54164	(3R,4S,5S)-3-fluorotetrahydro-2H-pyran-2,4,5-triol	n/a	C₅H₉FO₄	详情	详情
(VII)	54167	(2S,3S,4R)-4-fluoro-2-(hydroxymethyl)-5-methoxytetrahydro-3-furanol	n/a	C₆H₁₁FO₄	详情	详情
(VIII)	54165	[(2S,3S,4R,5R)-3-(benzoyloxy)-4-fluoro-5-methoxytetrahydro-2-furanyl]methyl benzoate	n/a	C₂₀H₁₉FO₆	详情	详情
(IX)	17524	[(2S,3S,4R,5S)-3-(benzoyloxy)-5-bromo-4-fluorotetrahydro-2-furanyl]methyl benzoate		C₁₉H₁₆BrFO₅	详情	详情
(X)	41900	5-methyl-2,4-bis[(trimethylsilyl)oxy]pyrimidine; 5-methyl-2-[(trimethylsilyl)oxy]-4-pyrimidinyl trimethylsilyl ether	7288-28-0	C₁₁H₂₂N₂O₂Si₂	详情	详情
(XI)	54166	{(2S,3S,4R,5S)-3-(benzoyloxy)-4-fluoro-5-[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl}methyl benzoate	n/a	C₂₄H₂₁FN₂O₇	详情	详情
(XII)	12204	5-Methyl-2,4(1H,3H)-pyrimidinedione; Thymine	65-71-4	C₅H₆N₂O₂	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)