【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 |