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【结 构 式】

【药物名称】Elvucitabine, ACH-126443, L-D4FC, beta-L-Fd4C

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

【CA登记号】181785-84-2

【 分 子 式 】C9H10FN3O3

【 分 子 量 】227.19675

【开发单位】Yale University (Originator), Achillion (Licensee), Vion (Licensee)

【药理作用】AIDS Medicines, Anti-Hepatitis B Virus Drugs, Anti-Hepatitis Virus Drugs, Anti-HIV Agents, ANTIINFECTIVE THERAPY, Antiviral Drugs, DNA Polymerase Inhibitors, Reverse Transcriptase Inhibitors

合成路线1

The reaction of D-glutamic acid (I) with NaNO2 and HCl gives the lactone carboxylic acid (II), which is esterified with EtOH and Ts-OH to yield the ester (III), reduced with NaBH4 in ethanol and silylated with Tbdps-Cl and imidazole to afford the protected chiral lactone (IV). The selenation of lactone (IV) with N-(phenylseleno)phthalimide (V) by means of LiHMDS and Tms-Cl in THF gives a mixture of diastereomers with a higher ratio (3:1) of the desired isomer (VI). (The unwanted isomer (VII) can be isomerized by reaction with DBU in THF.) The reduction of the lactone (VI) with DIBAL in toluene affords the lactol (VIII), which is treated with Ac2O and TEA to provide the acetoxy compound (IX). The condensation of (IX) with 5-fluoro-N,O-bis(trimethylsilyl)cytosine (X) by means of Tms-OTf in dichloromethane gives the selenated cytosine derivative (XI), which is treated with H2O2 in THF/pyridine to yield the unsaturated silylated precursor (XII). Finally, this compound is desilylated with HF and TEA in THF to afford the target cytosine derivative.

1 Bayes, M.; Sorbera, L.A.; Castaner, J.; ACH-126443. Drugs Fut 2002, 27, 12, 1131.
2 Chen, S.-H.; et al.; Stereoselective syntheses of beta-L-FD4C and beta-L-FddC. J Org Chem 1997, 62, 11, 3449.
3 Chen, S.-H.; Xiuyan, L. (Vion Pharmaceuticals, Inc.); Processes for high-yield diastereoselective synthesis of dideoxynucleosides. WO 9747635 .
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) 54708 (R)-(-)-Glutamic acid; (R)-2-Aminoglutaric acid; D-(+)-Glutamic acid; D-2-Aminoglutaric acid; D-glutamic acid 6893-26-1 C5H9NO4 详情 详情
(II) 12006 (R)-(-)-5-Oxo-2-tetrahydrofurancarboxylic acid; (2S)-5-oxotetrahydro-2-furancarboxylic acid 53558-93-3 C5H6O4 详情 详情
(III) 12007 ethyl (2S)-5-oxotetrahydro-2-furancarboxylate; (S)-(+)-gamma-Ethoxycarbonyl-gamma-butyrolactone 55094-96-7 C7H10O4 详情 详情
(IV) 56922 (5R)-5-({[tert-butyl(diphenyl)silyl]oxy}methyl)dihydro-2(3H)-furanone C21H26O3Si 详情 详情
(V) 54701 N-(Phenylseleno)phthalimide 71098-88-9 C14H9NO2Se 详情 详情
(VI) 54702 (4R,5S)-5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-4-(phenylselanyl)dihydro-2(3H)-furanone C27H30O3SeSi 详情 详情
(VII) 54703 (4S,5S)-5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-4-(phenylselanyl)dihydro-2(3H)-furanone C27H30O3SeSi 详情 详情
(VIII) 54704 (4R,5S)-5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-4-(phenylselanyl)tetrahydro-2-furanol C27H32O3SeSi 详情 详情
(IX) 54705 (4R,5S)-5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-4-(phenylselanyl)tetrahydro-2-furanyl acetate C29H34O4SeSi 详情 详情
(X) 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
(XI) 54706 4-amino-1-[(2S,4R,5S)-5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-4-(phenylselanyl)tetrahydro-2-furanyl]-5-fluoro-2(1H)-pyrimidinone C31H34FN3O3SeSi 详情 详情
(XII) 54707 4-amino-1-[(2S,5R)-5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2,5-dihydro-2-furanyl]-5-fluoro-2(1H)-pyrimidinone C25H28FN3O3Si 详情 详情

合成路线2

The reaction of the 2'-deoxy uracil derivative (XIII) with Ms-Cl and pyridine gives the dimesylate (XIV), which is treated with NaOH in ethanol to yield the unstable intermediate (XV), which rearranges to the epoxide (XVI). The reaction of (XVI) with 1,2,4-triazole (XVII) by means of chlorophenyl dichlorophosphate (CPCP) and pyridine affords the triazolyl derivative (XVIII), which is hydrolyzed with NaOH in dioxane to provide the cytosine intermediate (XIX). Finally, the epoxide ring of (XIX) is cleaved by means of tBu-OK in DMSO to furnish the target cytosine derivative.

1 Lin, T.-S.; Cheng, Y.-C. (Yale University); L-2',3'-Dideoxy nucleoside analogs as anti-hepatitis B (HBV) and anti-HIV agents. EP 0707481; JP 1996510747; US 5627160; WO 9427616 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XIII) 54714 5-fluoro-1-[(2S,4R,5S)-4-hydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-2,4(1H,3H)-pyrimidinedione C9H11FN2O5 详情 详情
(XIV) 54709 {(2S,3R,5S)-5-[5-fluoro-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-3-[(methylsulfonyl)oxy]tetrahydro-2-furanyl}methyl methanesulfonate C11H15FN2O9S2 详情 详情
(XV) 54710 [(1S,9S,10S)-4-fluoro-5-oxo-8,11-dioxa-2,6-diazatricyclo[7.2.1.0~2,7~]dodeca-3,6-dien-10-yl]methyl methanesulfonate C10H11FN2O6S 详情 详情
(XVI) 54711 1-[(1S,3S,5S)-2,6-dioxabicyclo[3.2.0]hept-3-yl]-5-fluoro-2,4(1H,3H)-pyrimidinedione C9H9FN2O4 详情 详情
(XVII) 13135 1H-1,2,4-Triazole; 1,2,4-Triazole 288-88-0 C2H3N3 详情 详情
(XVIII) 54712 1-[(1S,3S,5S)-2,6-dioxabicyclo[3.2.0]hept-3-yl]-5-fluoro-4-(1H-1,2,4-triazol-1-yl)-2(1H)-pyrimidinone C11H10FN5O3 详情 详情
(XIX) 54713 4-amino-1-[(1S,3S,5S)-2,6-dioxabicyclo[3.2.0]hept-3-yl]-5-fluoro-2(1H)-pyrimidinone C9H10FN3O3 详情 详情

合成路线3

Reaction of L-arabinose (XIII) with cyanamide (XIV) in aqueous methanolic ammonia gives the oxazolidine derivative (XV), which is cyclized with methyl propynoate (XVI) in refluxing ethanol to yield the anhydro uridine (XVII). Acylation of both OH groups of (XVII) by means of benzoyl cyanide (XVIII) in DMF affords the dibenzoate (XIX), which is treated with anhydrous HCl in DMF to provide the chloro uridine derivative (XX) or with HI in DMF or LiI and BH3/Et2O in DMF to provide the iodo uridine (XXI). Dehalogenation of (XX) or (XXI) by means of tri-butyltin hydride in refluxing benzene furnishes 3',5'-di-O-benzoyl-2'-deoxy-b-L-uridine (XXII). The trans-glycosylation of (XXII) with bis(trimethylsilyl)-5-fluorouracil (XXIII) by means of TMS-OTf in acetonitrile gives the corresponding 5-fluoro-L-uridine derivative (XXIV) as a mixture of the a- and b-anomers that is separated by chromatography. Debenzoylation of (XXIV) with ammonia in methanol yields 2'-deoxy-b-L-uridine (XXV), which is treated with MsCl and pyridine to afford the dimesylate (XXVI). Reaction of compound (XXVI) with NaOH in methanol/water provides the unstable intermediate (XXVII) that rearranges to the cyclic ether (XXVIII). Treatment of (XXVIII) with 1,2,4-triazole (XXIX) and p-chlorophenyl dichlorophosphate in pyridine provides the adduct (XXX), which by cleavage of the triazole ring by means of NH4OH in dioxane gives the corresponding cytidine derivative (XXXI). Finally, this compound is treated with potassium tert-butoxide in DMSO.

3 Gullen, E.; Zhu, Y.-L.; Liu, M.-C.; Dutschman, G.E.; Cheng, Y.-C.; Luo, M.-Z.; Lin, T.-S.; Design and synthesis of 2',3'-dideoxy-2',3'-didehydro-beta-L-cytidine (beta-L-d4C) and 2',3'-dideoxy-2',3'-didehydro-beta-L-5-fluorocytidine (beta-L-Fd4C), two exceptionally potent inhibitors of human hepatitis B virus (HBV) and potent inhibitors of human. J Med Chem 1996, 39, 9, 1757.
1 Holy, A.; Nucleic acid components and their analogues. CLIII. Preparation of 2'-deoxy-L-ribonucleosides of the pyrimidine series. Coll Czech Chem Commun 1972, 37, 12, 4072.
2 Bayes, M.; Sorbera, L.A.; Castaner, J.; ACH-126443. Drugs Fut 2002, 27, 12, 1131.
4 Lin, T.-S.; Cheng, Y.-C. (Yale University); L-2',3'-Dideoxy nucleoside analogs as anti-hepatitis B (HBV) and anti-HIV agents. EP 0707481; JP 1996510747; US 5627160; WO 9427616 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XIII) 56917 alpha-L-arabinofuranose C5H10O5 详情 详情
(XIV) 19648 Cyanamide 420-04-2 CH2N2 详情 详情
(XV) 56918 (3aS,5S,6S,6aR)-5-(hydroxymethyl)-2-iminohexahydrofuro[2,3-d][1,3]oxazol-6-ol C6H10N2O4 详情 详情
(XVI) 19588 methyl propiolate 922-67-8 C4H4O2 详情 详情
(XVII) 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
(XVIII) 56919 2-oxo-2-phenylacetonitrile C8H5NO 详情 详情
(XIX) 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
(XX) 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
(XXI) 56920 {(2S,3S,4S,5S)-3-(benzoyloxy)-5-[2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-4-iodotetrahydro-2-furanyl}methyl benzoate C23H19IN2O7 详情 详情
(XXII) 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
(XXIII) 47859 5-fluoro-2-[(trimethylsilyl)oxy]-4-pyrimidinyl trimethylsilyl ether; 5-fluoro-2,4-bis[(trimethylsilyl)oxy]pyrimidine 17242-85-2 C10H19FN2O2Si2 详情 详情
(XXIV) 56921 {(2S,3R,5S)-3-(benzoyloxy)-5-[5-fluoro-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl}methyl benzoate C23H19FN2O7 详情 详情
(XXV) 54714 5-fluoro-1-[(2S,4R,5S)-4-hydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-2,4(1H,3H)-pyrimidinedione C9H11FN2O5 详情 详情
(XXVI) 54709 {(2S,3R,5S)-5-[5-fluoro-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-3-[(methylsulfonyl)oxy]tetrahydro-2-furanyl}methyl methanesulfonate C11H15FN2O9S2 详情 详情
(XXVII) 54710 [(1S,9S,10S)-4-fluoro-5-oxo-8,11-dioxa-2,6-diazatricyclo[7.2.1.0~2,7~]dodeca-3,6-dien-10-yl]methyl methanesulfonate C10H11FN2O6S 详情 详情
(XXVIII) 54711 1-[(1S,3S,5S)-2,6-dioxabicyclo[3.2.0]hept-3-yl]-5-fluoro-2,4(1H,3H)-pyrimidinedione C9H9FN2O4 详情 详情
(XXIX) 13135 1H-1,2,4-Triazole; 1,2,4-Triazole 288-88-0 C2H3N3 详情 详情
(XXX) 54712 1-[(1S,3S,5S)-2,6-dioxabicyclo[3.2.0]hept-3-yl]-5-fluoro-4-(1H-1,2,4-triazol-1-yl)-2(1H)-pyrimidinone C11H10FN5O3 详情 详情
(XXXI) 54713 4-amino-1-[(1S,3S,5S)-2,6-dioxabicyclo[3.2.0]hept-3-yl]-5-fluoro-2(1H)-pyrimidinone C9H10FN3O3 详情 详情

合成路线4

Condensation of the chiral lactone (IV) with 2,4,6-tris-isopropylphenylsulfanyl chloride (XXXII) by means of LiHMDS and TMS-OTf in THF gives the adduct (XXXIII), which is reduced with DIBAL in toluene to yield the lactol (XXXIV). Reaction of compound (XXXIV) with Ac2O and pyridine in THF affords the acetoxy derivative (XXXV), which is condensed with the silylated 5-fluorouracil (XXIII) by means of SnCl4 in dichloromethane to provide the nucleoside (XXXVI). Oxidation of the sulfanyl group of (XXXVI) with magnesium monoperoxyphthalate (MMPP) in THF, followed by desulfurization by heating with DBU in refluxing toluene, gives 5'-O-TBDPS-2',3'-dideoxy-2',3'-didehydro-5-fluoro-b-L-uridine (XXXVII), which by treatment with Bu4NF in THF yields 2',3'-dideoxy-2',3'-didehydro-b-L-uridine (XXXIX). Finally, this compound is converted into 2',3'-dideoxy-2',3'-didehydro-b-L-cytidine by conventional methods.

1 Bayes, M.; Sorbera, L.A.; Castaner, J.; ACH-126443. Drugs Fut 2002, 27, 12, 1131.
2 Schinazi, R.F.; Liotta, D.C. (Emory University); [5-Carboxamido or 5-fluoro]-[2',3'-unsaturated or 3'-modified]-pyrimidine nucleosides. EP 0805683; JP 1998512887; US 5703058; WO 9622778 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IV) 56922 (5R)-5-({[tert-butyl(diphenyl)silyl]oxy}methyl)dihydro-2(3H)-furanone C21H26O3Si 详情 详情
(XXIII) 47859 5-fluoro-2-[(trimethylsilyl)oxy]-4-pyrimidinyl trimethylsilyl ether; 5-fluoro-2,4-bis[(trimethylsilyl)oxy]pyrimidine 17242-85-2 C10H19FN2O2Si2 详情 详情
(XXXII) 56923 2,4,6-triisopropylbenzenesulfenyl chloride C15H23ClS 详情 详情
(XXXIII) 56924 (3R,5R)-5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-3-[(2,4,6-triisopropylphenyl)sulfanyl]dihydro-2(3H)-furanone C36H48O3SSi 详情 详情
(XXXIV) 56925 (3R,5R)-5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-3-[(2,4,6-triisopropylphenyl)sulfanyl]tetrahydro-2-furanol C36H50O3SSi 详情 详情
(XXXV) 56926 (3R,5R)-5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-3-[(2,4,6-triisopropylphenyl)sulfanyl]tetrahydro-2-furanyl acetate C38H52O4SSi 详情 详情
(XXXVI) 56927 1-{(2S,3R,5R)-5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-3-[(2,4,6-triisopropylphenyl)sulfanyl]tetrahydro-2-furanyl}-5-fluoro-2,4(1H,3H)-pyrimidinedione C40H51FN2O4SSi 详情 详情
(XXXVII) 56928 1-[(2S,5R)-5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2,5-dihydro-2-furanyl]-5-fluoro-2,4(1H,3H)-pyrimidinedione C25H27FN2O4Si 详情 详情
(XXXIX) 56929 5-fluoro-1-[(2S,5R)-5-(hydroxymethyl)-2,5-dihydro-2-furanyl]-2,4(1H,3H)-pyrimidinedione C9H9FN2O4 详情 详情
Extended Information