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【结 构 式】 
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【分子编号】54708 【品名】(R)-(-)-Glutamic acid; (R)-2-Aminoglutaric acid; D-(+)-Glutamic acid; D-2-Aminoglutaric acid; D-glutamic acid 【CA登记号】6893-26-1 |
【 分 子 式 】C5H9NO4 【 分 子 量 】147.1308 【元素组成】C 40.82% H 6.17% N 9.52% O 43.5% |
合成路线1
该中间体在本合成路线中的序号：(I)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
该中间体在本合成路线中的序号：(I)D-Glutamic acid (I) is treated with SOCl2 in EtOH to produce ethyl D-pyroglutamate (II). Further protection of (II) with di-tert-butyl dicarbonate yields the N-Boc pyroglutamate (III) (1). The lithiated derivative of (III) is alkylated with 2-(bromomethyl)benzothiophene (IV) to afford the trans alkylated isomer (V). Basic hydrolysis of (V) produces the N-Boc amino diacid (VI). Then, acidic Boc group cleavage in (VI), followed by treatment of the resultant hydrochloride salt with propylene oxide in MeOH leads to the free aminoacid (1,2).
| 【1】 De Dios, A.; Prieto, L.; Martin, J.A.; Rubio, A.; Ezquerra, J.; Tebbe, M.; López de Uralde, B.; Martín, J.; Sánchez, A.; LeTourneu, D.L.; McGee, J.E.; Boylan, C.; Parr, T.R.; Smith, M.C.; 4-Substituted D-glutamic acid analogues: The first potent inhibitors of glutamate racemase (MurI) enzyme with antibacterial activity. J Med Chem 2002, 45, 20, 4559. |
| 【2】 Martin, J.A.; Ezquerra-Carrera, J.; Tebbe, M.J.; De Dios, A.; Prieto, L.; McGee, J.E.; Rubio-Esteban, A.; Smith, M.C. (Eli Lilly and Company); Chemical cpds.. WO 0214261 . |
| 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) | 64464 | ethyl (2R)-5-oxo-2-pyrrolidinecarboxylate | C7H11NO3 | 详情 | 详情 | |
| (III) | 43914 | 1-(tert-butyl) 2-ethyl (2S)-5-oxo-1,2-pyrrolidinedicarboxylate | 144978-35-8 | C12H19NO5 | 详情 | 详情 |
| (IV) | 64465 | 2-(bromomethyl)-1-benzothiophene | C9H7BrS | 详情 | 详情 | |
| (V) | 64466 | 1-(tert-butyl) 2-ethyl (2R,4R)-4-(1-benzothiophen-2-ylmethyl)-5-oxo-1,2-pyrrolidinedicarboxylate | C21H25NO5S | 详情 | 详情 | |
| (VI) | 64467 | (2R,4R)-2-(1-benzothiophen-2-ylmethyl)-4-[(tert-butoxycarbonyl)amino]pentanedioic acid | C19H23NO6S | 详情 | 详情 |