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【结 构 式】 
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【分子编号】12007 【品名】ethyl (2S)-5-oxotetrahydro-2-furancarboxylate; (S)-(+)-gamma-Ethoxycarbonyl-gamma-butyrolactone 【CA登记号】55094-96-7 |
【 分 子 式 】C7H10O4 【 分 子 量 】158.154 【元素组成】C 53.16% H 6.37% O 40.47% |
合成路线1
该中间体在本合成路线中的序号：(III)A new synthesis of 2',3'-dideoxyadenosine has been described: The stereospecific deamination - lactonization of L-glutamic acid (I) with NaNO2 - HCl in water gives (S)-(+)-gamma-carboxy-gamma-butyrolactone (II), which is esterified with ethanol - p-toluenesulfonic acid to the ester (III). The selective reduction of (III) with NaBH4 in ethanol yields (S)-(+)-gamma-(hydroxymethyl)-gamma-butyrolactone (IV), which is benzoylated with benzoyl chloride as usual, affording the benzoate (V). The selective reduction of (V) with disiamyl borane in THF gives the alcohol (VI), which is acetylated with acetic anhydride in pyridine to the acetate (VII). The reaction of (VII) with trimethylsilyl bromide in dichloromethane yields the tetrahydrofuryl bromide (VIII), which is condensed with the silylated adenine (IX) to afford 5'-O-benzoyl-2',3'-dideoxyadenosine (X). Finally, this compound is deprotected with NH3 in methanol.
| 【1】 Farina, V.; Benigni, D.A.; 2',3'-dideoxynucleosides for AIDS chemotherapy. Tetrahedron Lett 1988, 29, 11, 1239-42. |
| 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) | 12005 | L-2-Amino propane dicarboxylic acid; (-)-2-Aminoglutaric acid; L-2-Aminopentanoic acid; L-Glutamic acid | 56-86-0 | 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) | 12008 | (5S)-5-(Hydroxymethyl)dihydro-2(3H)-furanone; (S)-(+)-Dihydro-5-(hydroxymethyl)-2(3h)-furanone | 32780-06-6 | C5H8O3 | 详情 | 详情 |
| (V) | 12009 | [(2S)-5-oxotetrahydro-2-furanyl]methyl benzoate | C12H12O4 | 详情 | 详情 | |
| (VI) | 12010 | [(2S)-5-hydroxytetrahydro-2-furanyl]methyl benzoate | C12H14O4 | 详情 | 详情 | |
| (VII) | 12011 | [(2S)-5-(acetoxy)tetrahydro-2-furanyl]methyl benzoate | C14H16O5 | 详情 | 详情 | |
| (VIII) | 12012 | [(2S)-5-bromotetrahydro-2-furanyl]methyl benzoate | C12H13BrO3 | 详情 | 详情 | |
| (IX) | 12013 | N,9-Bis(trimethylsilyl)-9H-purin-6-amine; N-(Trimethylsilyl)-N-[9-(trimethylsilyl)-9H-purin-6-yl]amine | 17995-04-9 | C11H21N5Si2 | 详情 | 详情 |
| (X) | 12014 | [(2S,5R)-5-(6-amino-9H-purin-9-yl)tetrahydro-2-furanyl]methyl benzoate | C17H17N5O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(III)1) The stereospecific deamination - lactonization of L-glutamic acid (I) with NaNO2 - HCl in water gives (S)-(+)-gamma-carboxy-gamma-butyrolactone (II), which is esterified with ethanol and p-toluenesulfonic acid in the usual way, yielding the ethyl ester (III). The selective reduction of (III) with NaBH4 in ethanol affords (S)-(+)-gamma-(hydroxymethyl)-gamma-butyrolactone (IV), which is benzoylated with benzoyl chloride to the benzoate (V). The selective reduction of (V) with disiamyl borane in THF yields the alcohol (VI), which is acetylated with acetic anhydride in pyridine to the acetate (VII). The reaction of (VII) with trimethylsilyl bromide in dichloromethane affords the tetrahydrofuryl bromide (VIII), which is then condensed with the adenine (IX), giving 5'-O-benzoyl-2',3'-dideoxyadenosine (X). The deprotection of (X) with NH3 in methanol yields 2',3'-dideoxyadenosine, which is finally deaminated enzymatically with the enzyme adenosine deaminase.
| 【1】 Farina, V.; Benigni, D.A.; 2',3'-dideoxynucleosides for AIDS chemotherapy. Tetrahedron Lett 1988, 29, 11, 1239-42. |
| 【2】 Prous, J.; Castaner, J.; DIDEOXYINOSINE. Drugs Fut 1990, 15, 6, 569. |
| 【3】 Taniguchi, M.; Koga, K.; Yamada, S.; Stereoselective synthesis of D-ribose from L-glutamic acid. Tetrahedron 1974, 30, 3547-52. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 60593 | p-xylene | C8H10 | 详情 | 详情 | ||
| (I) | 12005 | L-2-Amino propane dicarboxylic acid; (-)-2-Aminoglutaric acid; L-2-Aminopentanoic acid; L-Glutamic acid | 56-86-0 | 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) | 12008 | (5S)-5-(Hydroxymethyl)dihydro-2(3H)-furanone; (S)-(+)-Dihydro-5-(hydroxymethyl)-2(3h)-furanone | 32780-06-6 | C5H8O3 | 详情 | 详情 |
| (V) | 12009 | [(2S)-5-oxotetrahydro-2-furanyl]methyl benzoate | C12H12O4 | 详情 | 详情 | |
| (VI) | 12010 | [(2S)-5-hydroxytetrahydro-2-furanyl]methyl benzoate | C12H14O4 | 详情 | 详情 | |
| (VII) | 12011 | [(2S)-5-(acetoxy)tetrahydro-2-furanyl]methyl benzoate | C14H16O5 | 详情 | 详情 | |
| (VIII) | 12012 | [(2S)-5-bromotetrahydro-2-furanyl]methyl benzoate | C12H13BrO3 | 详情 | 详情 | |
| (IX) | 12013 | N,9-Bis(trimethylsilyl)-9H-purin-6-amine; N-(Trimethylsilyl)-N-[9-(trimethylsilyl)-9H-purin-6-yl]amine | 17995-04-9 | C11H21N5Si2 | 详情 | 详情 |
| (X) | 12014 | [(2S,5R)-5-(6-amino-9H-purin-9-yl)tetrahydro-2-furanyl]methyl benzoate | C17H17N5O3 | 详情 | 详情 | |
| (XI) | 12787 | [(2S,5R)-5-(6-Amino-9H-purin-9-yl)tetrahydro-2-furanyl]methanol; Dideoxyadenosine | 4097-22-7 | C10H13N5O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(III)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 |