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【结 构 式】 
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【分子编号】62914 【品名】(4R,5S)-5-(hydroxymethyl)tetrahydro-2,4-furandiol 【CA登记号】 |
【 分 子 式 】C5H10O4 【 分 子 量 】134.132 【元素组成】C 44.77% H 7.51% O 47.71% |
合成路线1
该中间体在本合成路线中的序号：(VI)The reaction of L-arabinose (I) with acetic anhydride and HBr gives tri-O-acetyl-b-L-arabinopyranosyl bromide (II), which is treated with Zn and Cu-Zn couple in aqueous AcOH to yield 3,4-di-O-acetyl-L-arabinal (III) (1). Reaction of compound (III) with HCl followed by treatment with refluxing methanol affords methyl 3,4-di-O-acetyl-2-deoxy-L-riboside (IV), which is deacetylated by means of NaOMe in methanol to provide methyl 2-deoxy-L-riboside (V). Reaction of riboside (V) with benzoic acid gives 2-deoxy-L-ribofuranose (VI), which, alternatively, can be obtained directly from diacetate (III) by treatment with aqueous HClO4 in AcOH/Ac2O. Reaction of ribofuranose (VI) with p-toluoyl chloride and methanol gives methyl 3,4-di-O-toluoyl-2-deoxy-L-riboside (VII), which is demethylated with HCl to yield 3,4-di-O-toluoyl-2-deoxy-L-ribose (VIII). Acylation of the ribose (VIII) with Ac2O and pyridine affords 1-O-acetyl-3,4-di-O-toluoyl-2-deoxy-L-ribose (IX), which is treated with HCl to provide the chloro-ribose (X). Condensation of compound (X) with thymine (XI) by means of HgCl2 and CdCO3 gives the acylated thymidine (XII), which is finally deacylated by treatment with NaOMe in methanol.
| 【1】 Smejkal, J.; Sorm, F.; Nucleic acids components and their analogues. LIII. Preparation of 1-2'-deoxy-beta-L-ribofuranosylthymine, "L-thymidine". Coll Czech Chem Commun 1964, 29, 11, 2809. |
| 【2】 Sorbera, L.A.; Castañer, J.; Castañer, R.M.; Bayes, M.; Telbivudine. Drugs Fut 2003, 28, 9, 870. |
| 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) | 20353 | (2S,3R,4S,5S)-3,5-bis(acetoxy)-2-bromotetrahydro-2H-pyran-4-yl acetate | C11H15BrO7 | 详情 | 详情 | |
| (III) | 54162 | (3S,4R)-3-(acetyloxy)-3,4-dihydro-2H-pyran-4-yl acetate | n/a | C9H12O5 | 详情 | 详情 |
| (IV) | 62912 | (3S,4R)-4-(acetyloxy)-6-methoxytetrahydro-2H-pyran-3-yl acetate | C10H16O6 | 详情 | 详情 | |
| (V) | 62913 | (3S,4R)-6-methoxytetrahydro-2H-pyran-3,4-diol | C6H12O4 | 详情 | 详情 | |
| (VI) | 62914 | (4R,5S)-5-(hydroxymethyl)tetrahydro-2,4-furandiol | C5H10O4 | 详情 | 详情 | |
| (VII) | 62915 | {(2S,3R)-5-methoxy-3-[(4-methylbenzoyl)oxy]tetrahydro-2-furanyl}methyl 4-methylbenzoate | C22H24O6 | 详情 | 详情 | |
| (VIII) | 62916 | {(2S,3R)-5-hydroxy-3-[(4-methylbenzoyl)oxy]tetrahydro-2-furanyl}methyl 4-methylbenzoate | C21H22O6 | 详情 | 详情 | |
| (IX) | 62917 | {(2S,3R)-5-(acetyloxy)-3-[(4-methylbenzoyl)oxy]tetrahydro-2-furanyl}methyl 4-methylbenzoate | C23H24O7 | 详情 | 详情 | |
| (X) | 37194 | (2R,3S)-5-Chloro-2-[[(4-methylbenzoyl)oxy]methyl]tetrahydro-3-furanyl 4-methylbenzoate | 4330-21-6 | C21H21ClO5 | 详情 | 详情 |
| (XI) | 12204 | 5-Methyl-2,4(1H,3H)-pyrimidinedione; Thymine | 65-71-4 | C5H6N2O2 | 详情 | 详情 |
| (XII) | 62918 | {(2S,3R,5S)-3-[(4-methylbenzoyl)oxy]-5-[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl}methyl 4-methylbenzoate | C26H26N2O7 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)2-Deoxy-L-ribose (VI) is converted into 1-chloro-1,2-dideoxy-3,5-di-O-p-toluoyl-L-ribose (X) by using Hoffer's method for the D-enantiomer. Treatment of 2-deoxy-L-ribose with MeOH in HCl/MeOH provides methyl 2-deoxy-L-riboside (XIII), which is condensed with p-toluoyl chloride by means of KHCO3 in pyridine to give methyl 2-deoxy-3,5-di-O-p-toluoyl-L-riboside (VII). Chlori-nation of riboside (VII) with glacial AcOH and HCl affords 1-chloro-1,2-dideoxy-3,5-di-O-p-toluoyl-L-ribose (X), which is condensed with 5-methyl-2,4-bis(trimethylsilyl-oxy)pyrimidine (XIV) by means of p-nitrophenol in chloroform to yield the protected thymidine (XII). Finally, this compound is deprotected by means of NH3 in methanol.
| 【1】 Fujimori, S.; Iwanami, N.; Hashimoto, Y.; Shudo, K.; A convenient and stereoselective synthesis of 2'-deoxy-beta-L-ribonucleosides. Nucleosides Nucleotides 1992, 11, 2-4, 341. |
| 【2】 Sorbera, L.A.; Castañer, J.; Castañer, R.M.; Bayes, M.; Telbivudine. Drugs Fut 2003, 28, 9, 870. |
| 【3】 Hoffer, M.; alpha-Thymidine. Chem Ber 1960, 93, 2777. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 62914 | (4R,5S)-5-(hydroxymethyl)tetrahydro-2,4-furandiol | C5H10O4 | 详情 | 详情 | |
| (VII) | 62915 | {(2S,3R)-5-methoxy-3-[(4-methylbenzoyl)oxy]tetrahydro-2-furanyl}methyl 4-methylbenzoate | C22H24O6 | 详情 | 详情 | |
| (X) | 37194 | (2R,3S)-5-Chloro-2-[[(4-methylbenzoyl)oxy]methyl]tetrahydro-3-furanyl 4-methylbenzoate | 4330-21-6 | C21H21ClO5 | 详情 | 详情 |
| (XII) | 62918 | {(2S,3R,5S)-3-[(4-methylbenzoyl)oxy]-5-[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl}methyl 4-methylbenzoate | C26H26N2O7 | 详情 | 详情 | |
| (XIII) | 12241 | (2R,3S)-2-(Hydroxymethyl)-5-methoxytetrahydro-3-furanol | C6H12O4 | 详情 | 详情 | |
| (XIV) | 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 |
合成路线3
该中间体在本合成路线中的序号：(VI)Cyclization of L-arabinose (VI) with cyanamide and NH3 in methanol gives the bicyclic oxazoline (XV), which is submitted to a cycloaddition with methyl propynoate (XVI) in refluxing ethanol/water to yield the tricyclic pyrimidinone system (XVII). Benzoylation of the two OH groups of compound (XVII) with either benzoyl cyanide and triethylamine in DMF or benzoyl chloride in anhydrous pyridine affords the dibenzoate (XVIII), which is treated with HCl in hot DMF to provide the chlorouridine derivative (XIX). Dechlorination of compound (XIX) by means of Bu3SnH and AIBN in refluxing benzene gives 3,5-di-O-benzoyl-2'deoxy-b-L-uridine (XX), which is debenzoylated by means of NaOMe in methanol to yield 2'-deoxy-b-L- uridine (XXI). Finally, this compound is methylated by reaction with formaldehyde and KOH in hot water followed by hydrogenation with H2 over Pd/C in EtOH/HCl. Optionally, telbivudine can be purified by benzoylation with benzoyl cyanide and TEA, crystallization in EtOH/ether and final hydrolysis with refluxing MeOH/ NaOMe.
| 【1】 Sorbera, L.A.; Castañer, J.; Castañer, R.M.; Bayes, M.; Telbivudine. Drugs Fut 2003, 28, 9, 870. |
| 【2】 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. |
| 【3】 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 . |
| 【4】 Weis, A.L.; Goodhue, C.T.; Shanmuganathan, K. (Genencor International, Inc.); L-Ribofuranosyl nucleosides. WO 9613512 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 62914 | (4R,5S)-5-(hydroxymethyl)tetrahydro-2,4-furandiol | C5H10O4 | 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) | 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 | |
| (XIX) | 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 | |
| (XX) | 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 | |
| (XXI) | 11875 | 1-[(2R,4S,5R)-4-Hydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-2,4(1H,3H)-pyrimidinedione; 2'-Deoxyuridine | 951-78-0 | C9H12N2O5 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VI)The oxidative cleavage of 1,2,5,6-di-O-isopropylidene-D-galactofuranose (XLVII) with NaIO4 and H5IO6 gives aldehyde (XLVIII), which is reduced with NaBH4 in methanol to yield the 1,2-di-O-isopropylidene-L-arabinose (XLIX). Protection of the OH groups of compound (XLIX) with benzyl chloride and KOH in refluxing dioxane affords the dibenzyl ether (L), which is submitted to cleavage of the acetonide group by means of HCl in methanol to provide the methyl dibenzyl-L-arabinoside (LI). Reaction of the free OH group of (LI) with triflic anhydride and pyridine in dichloromethane gives the triflate (LII), which is reduced with Bu4NBH4 in refluxing benzene to yield methyl 3,5-di-O-benzyl-2-deoxy-L-riboside (LIII). Deben-zylation of (LIII) wit H2 over Pd/C affords methyl 2-deoxy-L-riboside (LIV), which is finally treated with Dowex [H+] in hot water to provide the telbivudine intermediate 2-deoxy-L-ribose (VI).
| 【1】 Shi, Z.-D.; Yang, B.-H.; Wu, Y.-L.; A stereospecific synthesis of L-deoxyriboside, L-ribose and L-ribosides. Tetrahedron 2002, 58, 16, 3287. |
| 【2】 Sorbera, L.A.; Castañer, J.; Castañer, R.M.; Bayes, M.; Telbivudine. Drugs Fut 2003, 28, 9, 870. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 62914 | (4R,5S)-5-(hydroxymethyl)tetrahydro-2,4-furandiol | C5H10O4 | 详情 | 详情 | |
| (XLVII) | 59011 | (5R,6S,6aR)-5-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol | C12H20O6 | 详情 | 详情 | |
| (XLVIII) | 62929 | (5R,6S,6aR)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole-5-carbaldehyde | C8H12O5 | 详情 | 详情 | |
| (XLIX) | 62930 | (5S,6S,6aR)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol | C8H14O5 | 详情 | 详情 | |
| (L) | 62931 | (5S,6S,6aR)-6-(benzyloxy)-5-[(benzyloxy)methyl]-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole; [(5S,6S,6aR)-6-(benzyloxy)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl]methyl benzyl ether | C22H26O5 | 详情 | 详情 | |
| (LI) | 62932 | (3R,4R,5S)-4-(benzyloxy)-5-[(benzyloxy)methyl]-2-methoxytetrahydro-3-furanol | C20H24O5 | 详情 | 详情 | |
| (LII) | 62933 | (3R,4S,5S)-4-(benzyloxy)-5-[(benzyloxy)methyl]-2-methoxytetrahydro-3-furanyl trifluoromethanesulfonate | C21H23F3O7S | 详情 | 详情 | |
| (LIII) | 62934 | (2S,3R)-3-(benzyloxy)-2-[(benzyloxy)methyl]-5-methoxytetrahydrofuran; benzyl [(2S,3R)-3-(benzyloxy)-5-methoxytetrahydro-2-furanyl]methyl ether | C20H24O4 | 详情 | 详情 | |
| (LIV) | 12241 | (2R,3S)-2-(Hydroxymethyl)-5-methoxytetrahydro-3-furanol | C6H12O4 | 详情 | 详情 |