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【结 构 式】 
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【分子编号】12241 【品名】(2R,3S)-2-(Hydroxymethyl)-5-methoxytetrahydro-3-furanol 【CA登记号】 |
【 分 子 式 】C6H12O4 【 分 子 量 】148.15888 【元素组成】C 48.64% H 8.16% O 43.2% |
合成路线1
该中间体在本合成路线中的序号：(II)A new synthesis of stavudine has been reported: The condensation of thymine (I) with methyl 2-deoxyribofuranoside (II) by means of N-bromosuccinimide (NBS) followed by protection with TBDPS-Cl gives the intermediate (III), which is cyclized by means of trimethylsilyl triflate (TMS-OTf), yielding the cyclothymidine derivative (IV). The deprotection of (IV) with tetrabutylammonium fluoride affords the unprotected compound (V), which is finally treated successively with triflate anhydride, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and Zn/acetic acid. The unprotected intermediate compound (V) can also be obtained by cyclization of thymidine (VI) by means of NBS in DMF, catalyzed by trifluoroacetic acid.
| 【1】 Lowe, R.F.; Lipshutz, B.H.; Stevens, K.L.; A novel route to the anti-HIV nucleoside d4T. Tetrahedron Lett 1995, 36, 16, 2711. |
| 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) | 12204 | 5-Methyl-2,4(1H,3H)-pyrimidinedione; Thymine | 65-71-4 | C5H6N2O2 | 详情 | 详情 |
| (II) | 12241 | (2R,3S)-2-(Hydroxymethyl)-5-methoxytetrahydro-3-furanol | C6H12O4 | 详情 | 详情 | |
| (III) | 12242 | 5-Bromo-6-[((2R,3S)-3-[[tert-butyl(diphenyl)silyl]oxy]-5-methoxytetrahydro-2-furanyl)methoxy]-5-methyldihydro-2,4(1H,3H)-pyrimidinedione | C27H35BrN2O6Si | 详情 | 详情 | |
| (IV) | 12243 | (1R,10R,11S)-6-Bromo-11-[[tert-butyl(diphenyl)silyl]oxy]-6-methyl-8,13-dioxa-2,4-diazatricyclo[8.2.1.0(2,7)]tridecane-3,5-dione | C26H31BrN2O5Si | 详情 | 详情 | |
| (V) | 12244 | (1R,10R,11S)-6-Bromo-11-hydroxy-6-methyl-8,13-dioxa-2,4-diazatricyclo[8.2.1.0(2,7)]tridecane-3,5-dione | C10H13BrN2O5 | 详情 | 详情 | |
| (VI) | 12161 | Thymidine; 1-[(2R,4S,5R)-4-Hydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-methyl-2,4(1H,3H)-pyrimidinedione | 50-89-5 | C10H14N2O5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)The reaction of 2-deoxy-D-ribose (I) with MeOH and HCl gives the methylglycoside (II), which is selectively silylated with TBDPSCl and DMAP in pyridine to yield the monosilylated glycoside (III). The reaction of (III) with TsCl in pyridine affords the 3'-tosylate (IV), which is condensed with the bis(trimethylsilyl)thymine (VI) by means of TMS-OTf in MeCN to provide 5'-O-(tert-butydiphenylsilyl)-3'-O-tosylthymidine (VII). Finally this compound is treated with TBAF in refluxing THF.
| 【1】 Kofoed, T.; Larsen, E.; Pedersen, E.B.; Synthesis of 2',3'-anhydro-2'-deoxyuridines and 2',3'-didehydro-2',3'-dideoxyuridines using polymer supported fluoride. Synthesis 1995, 1121. |
| 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) | 41897 | (4S,5R)tetrahydro-2H-pyran-2,4,5-triol | 35536-75-5 | C5H10O4 | 详情 | 详情 |
| (II) | 12241 | (2R,3S)-2-(Hydroxymethyl)-5-methoxytetrahydro-3-furanol | C6H12O4 | 详情 | 详情 | |
| (III) | 41898 | (2R,3S)-2-([[tert-butyl(diphenyl)silyl]oxy]methyl)-5-methoxytetrahydro-3-furanol | C22H30O4Si | 详情 | 详情 | |
| (IV) | 41899 | (2R,3S)-2-([[tert-butyl(diphenyl)silyl]oxy]methyl)-5-methoxytetrahydro-3-furanyl 4-methylbenzenesulfonate | C29H36O6SSi | 详情 | 详情 | |
| (V) | 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 |
| (VI) | 41901 | (2R,3S,5R)-2-([[tert-butyl(diphenyl)silyl]oxy]methyl)-5-[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-3-furanyl 4-methylbenzenesulfonate | C33H38N2O7SSi | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XIII)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4
该中间体在本合成路线中的序号：(LIV)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 |
合成路线5
该中间体在本合成路线中的序号：(VII)
| 【1】 Storer R. Moussa A. Wang JY. et al. 2005. Synthesis of β-L-2-deoxy-nucleosides from furanoses and pyranoses via a chloro-sugar and anhydro-l-furanosyl-nucleobase intennediatcs as potential antiviral and antineoplastic agents. W0 2005003374 |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IX) | 37194 | (2R,3S)-5-Chloro-2-[[(4-methylbenzoyl)oxy]methyl]tetrahydro-3-furanyl 4-methylbenzoate | 4330-21-6 | C21H21ClO5 | 详情 | 详情 |
| （X） | 12204 | 5-Methyl-2,4(1H,3H)-pyrimidinedione; Thymine | 65-71-4 | C5H6N2O2 | 详情 | 详情 |
| (I) | 17520 | (3R,4S,5S)tetrahydro-2H-pyran-2,3,4,5-tetrol; L-(+)-Arabinose | 7296-56-2 | C5H10O5 | 详情 | 详情 |
| (II) | 66774 | 2-methoxytetrahydro-2H-pyran-3,4,5-triol | C6H12O5 | 详情 | 详情 | |
| (III) | 66775 | (7R)-6-methoxy-2,2-dimethyltetrahydro-3aH-[1,3]dioxolo[4,5-c]pyran-7-ol | C9H16O5 | 详情 | 详情 | |
| (IV) | 66776 | (7R)-6,7-dimethoxy-2,2-dimethyltetrahydro-3aH-[1,3]dioxolo[4,5-c]pyran | C10H18O5 | 详情 | 详情 | |
| (V) | 66777 | 6-methoxy-2,2-dimethyltetrahydro-3aH-[1,3]dioxolo[4,5-c]pyran | C9H16O4 | 详情 | 详情 | |
| (VI) | 66778 | tetrahydro-2H-pyran-2,4,5-triol | C5H10O4 | 详情 | 详情 | |
| (VII) | 12241 | (2R,3S)-2-(Hydroxymethyl)-5-methoxytetrahydro-3-furanol | C6H12O4 | 详情 | 详情 | |
| (VIII) | 62915 | {(2S,3R)-5-methoxy-3-[(4-methylbenzoyl)oxy]tetrahydro-2-furanyl}methyl 4-methylbenzoate | C22H24O6 | 详情 | 详情 | |
| (XI) | 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6
该中间体在本合成路线中的序号：(VI)
| 【1】 Storer R. Moussa A. Wang JY. et al. 2005. Synthesis of β-L-2-deoxy-nucleosides from furanoses and pyranoses via a chloro-sugar and anhydro-l-furanosyl-nucleobase intennediatcs as potential antiviral and antineoplastic agents. W0 2005003374 |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| （X） | 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 | |
| (I) | 17520 | (3R,4S,5S)tetrahydro-2H-pyran-2,3,4,5-tetrol; L-(+)-Arabinose | 7296-56-2 | C5H10O5 | 详情 | 详情 |
| (II) | 66779 | tetrahydro-2H-pyran-2,3,4,5-tetrayl tetraacetate | C13H18O9 | 详情 | 详情 | |
| (III) | 20353 | (2S,3R,4S,5S)-3,5-bis(acetoxy)-2-bromotetrahydro-2H-pyran-4-yl acetate | C11H15BrO7 | 详情 | 详情 | |
| (IV) | 54162 | (3S,4R)-3-(acetyloxy)-3,4-dihydro-2H-pyran-4-yl acetate | n/a | C9H12O5 | 详情 | 详情 |
| (V) | 66780 | 3,4-dihydro-2H-pyran-3,4-diol | C5H8O3 | 详情 | 详情 | |
| (VI) | 12241 | (2R,3S)-2-(Hydroxymethyl)-5-methoxytetrahydro-3-furanol | C6H12O4 | 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) | 37194 | (2R,3S)-5-Chloro-2-[[(4-methylbenzoyl)oxy]methyl]tetrahydro-3-furanyl 4-methylbenzoate | 4330-21-6 | C21H21ClO5 | 详情 | 详情 |
| (IX) | 12204 | 5-Methyl-2,4(1H,3H)-pyrimidinedione; Thymine | 65-71-4 | C5H6N2O2 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(VIII)
| 【1】 Storer R. Moussa A. Wang JY. et al. 2005. Synthesis of β-L-2-deoxy-nucleosides from furanoses and pyranoses via a chloro-sugar and anhydro-l-furanosyl-nucleobase intennediatcs as potential antiviral and antineoplastic agents. W0 2005003374 |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| （X） | 12204 | 5-Methyl-2,4(1H,3H)-pyrimidinedione; Thymine | 65-71-4 | C5H6N2O2 | 详情 | 详情 |
| (I) | 11471 | 1,4-Pentadien-3-ol | 922-65-6 | C5H8O | 详情 | 详情 |
| (II) | 66795 | (S)-1-((S)-oxiran-2-yl)prop-2-en-1-ol | C5H8O2 | 详情 | 详情 | |
| (III) | 66796 | (2R,3S)-1-(benzyloxy)pent-4-ene-2,3-diol | C12H16O3 | 详情 | 详情 | |
| (IV) | 66797 | C15H20O3 | 详情 | 详情 | ||
| (V) | 66798 | 2-((4R,5R)-5-((benzyloxy)methyl)-2,2-dimethyl-1,3-dioxolan-4-yl)acetaldehyde | C15H20O4 | 详情 | 详情 | |
| (VI) | 66799 | (5R)-5-((benzyloxy)methyl)tetrahydrofuran-2,4-diol | C12H16O4 | 详情 | 详情 | |
| (VII) | 66800 | (2R)-2-((benzyloxy)methyl)-5-methoxytetrahydrofuran-3-ol | C13H18O4 | 详情 | 详情 | |
| (VIII) | 12241 | (2R,3S)-2-(Hydroxymethyl)-5-methoxytetrahydro-3-furanol | C6H12O4 | 详情 | 详情 | |
| (IX) | 37194 | (2R,3S)-5-Chloro-2-[[(4-methylbenzoyl)oxy]methyl]tetrahydro-3-furanyl 4-methylbenzoate | 4330-21-6 | C21H21ClO5 | 详情 | 详情 |
| (XIV) | 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 |