Dexelvucitabine, RVT, DPC-817, beta-D-D4FC, D-D4FC, Reverset, -Drug Synthesis Database

【结构式】

【药物名称】Dexelvucitabine, RVT, DPC-817, beta-D-D4FC, D-D4FC, Reverset

【化学名称】beta-D-2',3'-Didehydro-2',3'-dideoxy-5-fluorocytidine

【CA登记号】181785-83-1, 134379-77-4 (undefined isomer)

【分子式】C₉H₁₀FN₃O₃

【分子量】227.19675

【开发单位】Bristol-Myers Squibb (Originator), Incyte (Licensee), Pharmasset (Codevelopment)

【药理作用】AIDS Medicines, Anti-HIV Agents, ANTIINFECTIVE THERAPY, DNA Polymerase Inhibitors, Reverse Transcriptase Inhibitors

合成路线1 合成路线2 合成路线3 合成路线4

合成路线1

The acylation of 2,3-O-isopropylidene-alpha-D-xylofuranose (I) with benzoyl chloride and pyridine gives the dibenzoyl ester (II), which is deprotected by means of H2SO4/HOAc in hot THF to yield 3,5-di-O-benzoyl-alpha-D-xylofuranose (III). The reaction of (III) with PPh3, I2 and imidazole in dichloromethane affords the glycal (IV), which is used in the glycosylation of the N,O-disilylated 5-fluorocytosine (V) by means of NIS in dichloromethane to provide the 2'-alpha-iodonucleoside (VI). The treatment of (VI) with Zn in EtOH/ethyl acetate (HOAc is used as catalyst) gives the unsaturated nucleoside (VII), which is finally debenzoylated by means of butylamine in THF.

参考文献中间体

【1】 Chen, S.-H.; Lin, S.; King, I.; Spinka, T.; Dutschman, G.E.; Gullen, E.A.; Cheng, Y.-C.; Doyle, T.W.; Synthesis and comparative evaluation of two antiviral agents: beta-L-Fd4C and beta-D-Fd4C. Bioorg Med Chem Lett 1998, 8, 22, 3245.

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)	41907	(3aR,5R,6S,6aR)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol	20031-21-4	C₈H₁₄O₅	详情	详情
(II)	56701	[(3aR,5R,6S,6aR)-6-(benzoyloxy)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl]methyl benzoate		C₂₂H₂₂O₇	详情	详情
(III)	56702	[(2R,3R,4R,5S)-3-(benzoyloxy)-4,5-dihydroxytetrahydro-2-furanyl]methyl benzoate		C₁₉H₁₈O₇	详情	详情
(IV)	56703	[(2R,3R)-3-(benzoyloxy)-2,3-dihydro-2-furanyl]methyl benzoate		C₁₉H₁₆O₅	详情	详情
(V)	36959	5-fluoro-N-(trimethylsilyl)-2-[(trimethylsilyl)oxy]-4-pyrimidinamine; N-[5-fluoro-2-[(trimethylsilyl)oxy]-4-pyrimidinyl]-N-(trimethylsilyl)amine		C₁₀H₂₀FN₃OSi₂	详情	详情
(VI)	56704	[(2R,3S,4R,5R)-5-[4-amino-5-fluoro-2-oxo-1(2H)-pyrimidinyl]-3-(benzoyloxy)-4-iodotetrahydro-2-furanyl]methyl benzoate		C₂₃H₁₉FIN₃O₆	详情	详情
(VII)	56705	{(2S,5R)-5-[4-amino-5-fluoro-2-oxo-1(2H)-pyrimidinyl]-2,5-dihydro-2-furanyl}methyl benzoate		C₁₆H₁₄FN₃O₄	详情	详情

合成路线2

The condensation of the known acetate (I) with N,O-disylilated cytosine (II) by means of Tms-OTf or SnCl4 gives the selenium containing nucleoside (III), which is submitted to an oxidative elimination reaction by means of H2O2 and pyridine in dichloromethane to yield the unsaturated nucleoside (IV). Finally, this compound is desilylated by means of TBAF in THF.

参考文献中间体

【1】 Shi, J.; et al.; Synthesis and biological evaluation of 2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine (D4FC) analogues: Discovery of carbocyclic nucleoside triphosphates with potent inhibitory activity against HIV-1 reverse transcriptase. J Med Chem 1999, 42, 5, 859.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	12217	(3R,5S)-5-([[tert-butyl(diphenyl)silyl]oxy]methyl)-3-(phenylselanyl)tetrahydro-2-furanyl acetate	C₂₉H₃₄O₄SeSi	详情	详情
(II)	36959	5-fluoro-N-(trimethylsilyl)-2-[(trimethylsilyl)oxy]-4-pyrimidinamine; N-[5-fluoro-2-[(trimethylsilyl)oxy]-4-pyrimidinyl]-N-(trimethylsilyl)amine	C₁₀H₂₀FN₃OSi₂	详情	详情
(III)	56706	1-[(2R,3R,5S)-5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-3-(phenylselanyl)tetrahydro-2-furanyl]-5-fluoro-4-[(trimethylsilyl)amino]-2(1H)-pyrimidinone	C₃₄H₄₂FN₃O₃SeSi₂	详情	详情
(IV)	56707	1-[(2R,5S)-5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2,5-dihydro-2-furanyl]-5-fluoro-4-[(trimethylsilyl)amino]-2(1H)-pyrimidinone	C₂₈H₃₆FN₃O₃Si₂	详情	详情

合成路线3

The bromoacetylation of 5-fluorocytidine (I) with 2-acetoxyisobutyryl bromide (II) in acetonitrile, ethyl acetate or dichloromethane gives a mixture of two bromoacylated compounds (III) and (IV), with minor amounts of two other compounds (V) and (VI) that are separated by chromatography. The mixture of (III) and (IV), without separation, is treated with Zn/Cu in DMF or methanol/ethyl acetate to yield the unsaturated cytidine derivative (VII), which is finally deacylated by means of Na-OMe in methanol to afford the target fluorocytidine derivative.

参考文献中间体

【1】 Confalone, P.N.; Jin, F. (Pharmasset, Inc.); Method for the synthesis of 2',3'-dideoxy-2',3'-didehydronucleosides. WO 0270533 .

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)	58283	4-amino-1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-fluoro-2(1H)-pyrimidinone		C₉H₁₂FN₃O₅	详情	详情
(II)	12806	2-bromo-1,1-dimethyl-2-oxoethyl acetate; alpha-Acetoxy-isobutyryl bromide	40635-67-4	C₆H₉BrO₃	详情	详情
(III)	58284	{(2R,3R,5R)-3-(acetyloxy)-5-[4-amino-5-fluoro-2-oxo-1(2H)-pyrimidinyl]-4-bromotetrahydro-2-furanyl}methyl 2-(acetyloxy)-2-methylpropanoate		C₁₇H₂₁BrFN₃O₈	详情	详情
(IV)	58285	{(2R,4S,5R)-4-(acetyloxy)-5-[4-amino-5-fluoro-2-oxo-1(2H)-pyrimidinyl]-3-bromotetrahydro-2-furanyl}methyl 2-(acetyloxy)-2-methylpropanoate		C₁₇H₂₁BrFN₃O₈	详情	详情
(V)	58286	{(2R,3R,5R)-3-(acetyloxy)-5-[4-amino-5-fluoro-2-oxo-1(2H)-pyrimidinyl]-4-bromotetrahydro-2-furanyl}methyl acetate		C₁₃H₁₅BrFN₃O₆	详情	详情
(VI)	58287	{(2R,5R)-4-(acetyloxy)-5-[4-amino-5-fluoro-2-oxo-1(2H)-pyrimidinyl]-3-bromotetrahydro-2-furanyl}methyl acetate		C₁₃H₁₅BrFN₃O₆	详情	详情
(VII)	58288	{(2S,5R)-5-[4-amino-5-fluoro-2-oxo-1(2H)-pyrimidinyl]-2,5-dihydro-2-furanyl}methyl 2-(acetyloxy)-2-methylpropanoate		C₁₅H₁₈FN₃O₆	详情	详情

合成路线4

The bromoacetylation of 5-fluorouridine (I) with 2-acetoxyisobutyryl bromide (II) in acetonitrile, ethyl acetate or dichloromethane gives a mixture of four bromoacylated compounds (III), (IV), (V) and (VI). This mixture, without separation, is treated with Zn/Ac-OH in DMF or methanol/ethyl acetate to yield two unsaturated uridine derivatives (VII) and (VIII), which are easily separated. The major isomer (VIII) is condensed with 1,2,4-triazole (IX) by means of POCl3 and TEA in acetonitrile to afford the triazolyl derivative (X), which is treated with ammonia in methanol to provide the cytidine derivative (XI). Finally, this compound is deacylated by means of NaOMe in methanol to afford the target fluorocytidine derivative.

参考文献中间体

【1】 Confalone, P.N.; Jin, F. (Pharmasset, Inc.); Method for the synthesis of 2',3'-dideoxy-2',3'-didehydronucleosides. WO 0270533 .

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)	32205	1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-fluoro-2,4(1H,3H)-pyrimidinedione; 5-Fluorouridine	316-46-1	C₉H₁₁FN₂O₆	详情	详情
(II)	12806	2-bromo-1,1-dimethyl-2-oxoethyl acetate; alpha-Acetoxy-isobutyryl bromide	40635-67-4	C₆H₉BrO₃	详情	详情
(III)	58289	{(2R,3R,5R)-3-(acetyloxy)-4-bromo-5-[5-fluoro-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl}methyl 2-(acetyloxy)-2-methylpropanoate		C₁₇H₂₀BrFN₂O₉	详情	详情
(IV)	58290	{(2R,4S,5R)-4-(acetyloxy)-3-bromo-5-[5-fluoro-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl}methyl 2-(acetyloxy)-2-methylpropanoate		C₁₇H₂₀BrFN₂O₉	详情	详情
(V)	58291	{(2R,3R,5R)-3-(acetyloxy)-4-bromo-5-[5-fluoro-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl}methyl acetate		C₁₃H₁₄BrFN₂O₇	详情	详情
(VI)	58292	{(2R,5R)-4-(acetyloxy)-3-bromo-5-[5-fluoro-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl}methyl acetate		C₁₃H₁₄BrFN₂O₇	详情	详情
(VII)	58293	{(2S,5R)-5-[5-fluoro-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-2,5-dihydro-2-furanyl}methyl acetate		C₁₁H₁₁FN₂O₅	详情	详情
(VIII)	58294	{(2S,5R)-5-[5-fluoro-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-2,5-dihydro-2-furanyl}methyl 2-(acetyloxy)-2-methylpropanoate		C₁₅H₁₇FN₂O₇	详情	详情
(IX)	13135	1H-1,2,4-Triazole; 1,2,4-Triazole	288-88-0	C₂H₃N₃	详情	详情
(X)	58295	2-({(2S,5R)-5-[5-fluoro-2-oxo-4-(1H-1,2,4-triazol-1-yl)-1(2H)-pyrimidinyl]-2,5-dihydro-2-furanyl}methoxy)-1,1-dimethyl-2-propenyl acetate		C₁₈H₂₀FN₅O₅	详情	详情
(XI)	58296	2-({(2S,5R)-5-[4-amino-5-fluoro-2-oxo-1(2H)-pyrimidinyl]-2,5-dihydro-2-furanyl}methoxy)-1,1-dimethyl-2-propenyl acetate		C₁₆H₂₀FN₃O₅	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)