Torcitabine, L-dC, NV-02C, -Drug Synthesis Database

【结构式】

【药物名称】Torcitabine, L-dC, NV-02C

【化学名称】4-Amino-1-[(2S,4R,5S)-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]pyrimidin-2(1H)-one
　　　　　　beta-L-Deoxycytidine
　　　　　　4-Amino-1-(2-deoxy-beta-L-erythro-pentofuranosyl)pyrimidin-2(1H)-one

【CA登记号】40093-94-5

【分子式】C₉H₁₃N₃O₄

【分子量】227.22166

【开发单位】Idenix (Originator)

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

合成路线1 合成路线2

合成路线1

Uracil (I) was silylated with hexamethyldisilazan, and the resulting bis-silylated uracil (II) was condensed with protected xylofuranose (III) in the presence of trimethylsilyl triflate to afford nucleoside (IV). Selective hydrolysis of the acetate ester of (IV) employing hydrazine and AcOH in pyridine yielded (V). Isomerization of xylofuranosyl uracil (V) to the arabinofuranosyl analogue (VI) was achieved by reaction with dicyclohexylcarbodiimide and dichloroacetic acid followed by treatment with NaBH4. Subsequent deoxygenation of the 2'-hydroxyl group of (VI) was effected via condensation with phenyl chlorothionoformate, and then reduction of the resulting thiocarbonate (VII) with tris(trimethylsilyl)silane and azobis(isobutyronitrile) (AIBN). The resultant 2'-deoxyuridine derivative (VIII) was treated with Lawesson's reagent to give the thiocarbonyl analogue (IX). Finally, sulfur displacement with concomitant benzoate ester hydrolysis employing methanolic ammonia at 100 C in a pressure bomb furnished the title compound.

参考文献中间体

【1】 Bryant, M.L.; Gosselin, G.; Imbach, J.-L. (CNRS (Centre National de la Recherche Scientifique); Novirio Pharmaceuticals Ltd.); beta-L-2'-Deoxy-nucleosides for the treatment of hepatitis B. WO 0009531 .

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)	30921	2,4(1H,3H)-pyrimidinedione; Uracil	66-22-8	C₄H₄N₂O₂	详情	详情
(II)	29619	2,4-bis[(trimethylsilyl)oxy]pyrimidine; trimethylsilyl 2-[(trimethylsilyl)oxy]-4-pyrimidinyl ether		C₁₀H₂₀N₂O₂Si₂	详情	详情
(III)	39991	[(2S,3R,4S)-4,5-bis(acetoxy)-3-(benzoyloxy)tetrahydro-2-furanyl]methyl benzoate		C₂₃H₂₂O₉	详情	详情
(IV)	39992	(2S,3R,4S,5S)-4-(acetoxy)-2-[(benzoyloxy)methyl]-5-[2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-3-furanyl benzoate		C₂₅H₂₂N₂O₉	详情	详情
(V)	39993	[(2S,3S,4S,5S)-3-(benzoyloxy)-5-[2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-4-hydroxytetrahydro-2-furanyl]methyl benzoate		C₂₃H₂₀N₂O₈	详情	详情
(VI)	39994	[(2S,3R,4R,5S)-3-(benzoyloxy)-5-[2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-4-hydroxytetrahydro-2-furanyl]methyl benzoate		C₂₃H₂₀N₂O₈	详情	详情
(VII)	39995	[(2S,3S,4R,5S)-3-(benzoyloxy)-5-[2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-4-[(phenoxycarbothioyl)oxy]tetrahydro-2-furanyl]methyl benzoate		C₃₀H₂₄N₂O₉S	详情	详情
(VIII)	39996	[(2S,3R,5S)-3-(benzoyloxy)-5-[2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl]methyl benzoate		C₂₃H₂₀N₂O₇	详情	详情
(IX)	40005	[(2S,3R,5S)-3-(benzoyloxy)-5-[2-oxo-4-thioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl]methyl benzoate		C₂₃H₂₀N₂O₆S	详情	详情

合成路线2

In an alternative procedure, reaction of L-arabinose (X) with cyanamide in the presence of ammonium hydroxide produced the cyclic isourea (XI). Subsequent cycloaddition of methyl propiolate (XII) to (XI) generated the fused pyrimidone system (XIII). After protection of the free hydroxyl groups of (XIII) as the dibenzoate ester (XIV), treatment with HCl in DMF furnished uridine derivative (XV). Dechlorination of (XV) employing Bu3SnH and AIBN afforded intermediate (VIII), which was treated with Lawesson's reagent to give the thiocarbonyl analogue (IX). Finally, sulfur displacement with concomitant benzoate ester hydrolysis employing methanolic ammonia at 100 C in a pressure bomb furnished the title compound.

参考文献中间体

【1】 Bryant, M.L.; Gosselin, G.; Imbach, J.-L. (CNRS (Centre National de la Recherche Scientifique); Novirio Pharmaceuticals Ltd.); beta-L-2'-Deoxy-nucleosides for the treatment of hepatitis B. WO 0009531 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VIII)	39996	[(2S,3R,5S)-3-(benzoyloxy)-5-[2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl]methyl benzoate		C₂₃H₂₀N₂O₇	详情	详情
(IX)	40005	[(2S,3R,5S)-3-(benzoyloxy)-5-[2-oxo-4-thioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl]methyl benzoate		C₂₃H₂₀N₂O₆S	详情	详情
(X)	39997	(3R,4R,5S)-5-(hydroxymethyl)tetrahydro-2,3,4-furantriol		C₅H₁₀O₅	详情	详情
(XI)	39998	(3aS,5S,6S,6aR)-2-amino-5-(hydroxymethyl)-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]oxazol-6-ol		C₆H₁₀N₂O₄	详情	详情
(XII)	19588	methyl propiolate	922-67-8	C₄H₄O₂	详情	详情
(XIII)	39999	(2S,3S,3aR,9aS)-3-hydroxy-2-(hydroxymethyl)-2,3,3a,9a-tetrahydro-6H-furo[2',3':4,5][1,3]oxazolo[3,2-a]pyrimidin-6-one	3736-77-4	C₉H₁₀N₂O₅	详情	详情
(XIV)	40000	[(2S,3S,3aR,9aS)-3-(benzoyloxy)-6-oxo-2,3,3a,9a-tetrahydro-6H-furo[2',3':4,5][1,3]oxazolo[3,2-a]pyrimidin-2-yl]methyl benzoate		C₂₃H₁₈N₂O₇	详情	详情
(XV)	40001	[(2S,3S,4S,5S)-3-(benzoyloxy)-4-chloro-5-[2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl]methyl benzoate		C₂₃H₁₉ClN₂O₇	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)