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【结 构 式】 
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【分子编号】11875 【品名】1-[(2R,4S,5R)-4-Hydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-2,4(1H,3H)-pyrimidinedione; 2'-Deoxyuridine 【CA登记号】951-78-0 |
【 分 子 式 】C9H12N2O5 【 分 子 量 】228.20476 【元素组成】C 47.37% H 5.3% N 12.28% O 35.05% |
合成路线1
该中间体在本合成路线中的序号：(I)5-Chloromercuri-2'-deoxyuridine (II) is prepared from 2'-deoxyuridine (I) by reaction with mercuriacetate and natrium chloride (1). Condensation of (II) with ethylacrylate (A) and lithium palladium chloride gives (E)-5-(2-carbethoxyvinyl)-2'-deoxyuridine (III), which is readily hydrozyled to (E)-5-(2-carboxyvinyl)-2'-deoxyuridine (IV) under basic conditions (0.5M NaOH). The final step involves the reaction of (IV) with N-bromosuccinimide to produce (E)-5-(2-bromovinyl)-2'-deoxyuridine.
| 【1】 Bergstrom, D.E.; Ruth, J.L.; Preparation of C-5 mercurated pyrimidine nucleosides. J Carbohydates Nucleosides Nucleotides 1977, 4, 5, 4415. |
| 【2】 De Clercq, E.; Bromovinyldeoxyuridine. Drugs Fut 1980, 5, 7, 334. |
| 【3】 Jones, A.S.; et al.; The synthesis of the potent antiherpes virus agent, E-5(2-bromovinyl)-2'-deoxyuridine and related compounds. Tetrahedron Lett 1979, 45, 4415-8. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 10164 | ethyl acrylate | 140-88-5 | C5H8O2 | 详情 | 详情 |
| (I) | 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 |
| (II) | 39186 | chloro[1-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]mercury | C9H11ClHgN2O5 | 详情 | 详情 | |
| (III) | 39187 | ethyl (E)-3-[1-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]-2-propenoate | C14H18N2O7 | 详情 | 详情 | |
| (IV) | 39188 | (E)-3-[1-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]-2-propenoic acid | C12H14N2O7 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IX)The benzoylation of 2'-deoxy-5-iodouridine (I) with benzoyl chloride by means of pyridine in dichloromethane gives 5'-O-benzoyl-2'-deoxy-5-iodouridine (II), which is treated with benzyl trichloroacetimidate (III) and trifluoromethanesulfonic acid in dichloromethane - THF to afford the 3'-O-benzyl derivative (IV). The hydrolysis of (IV) with sodium ethoxide in ethanol yields 3'-O-benzyl-2'-deoxy-5-iodouridine (V), which is finally trifluoromethylated with bromotrifluoromethane and copper in pyridine-DMF by means of dimethylaminopyridine. The tritylation of 2'-deoxyuridine (IX) with trityl chloride in hot pyridine gives 2'-deoxy-5'-O-trityluridine (X), which is benzylated with benzyl chloride and NaH in THF yielding 3'-O-benzyl-2'-deoxy-5'-O-trityluridine (XI). The photochemical trifluoromethylation of (XI) with N-nitroso-N-(trifluoromethyl)trifluoromethanesulfonamide and biacetyl in acetonitrile irradiated with a high-pressure Hg lamp in a glass tube at room temperature affords 3'-O-benzyl-2'-deoxy-5-(trifluoromethyl-5'-O-trityluridine (XII), which is finally deprotected with HCl in methanol.
| 【1】 Fujii, S.; Yamashita, J.; Matsumoto, H.; Takeda, S.; Terada, T.; Yasumoto, M.; Unemi, N. (Taiho Pharmaceutical Co., Ltd.); Novel 2'-deoxy-5-substd. uridine derivs., processes for preparing the same and antitumor agent containing the same. EP 0129984; ES 8606381; ES 8606382; ES 8607982; ES 8706715; JP 1984216899; JP 1985061591 . |
| 【2】 Yasumoto, M.; Matsumoto, H.; Tada, Y.; Kobayashi, K.; Noguchi, K. (Taiho Pharmaceutical Co., Ltd.); Method for the preparation of 3'-O-benzyl-2'-deoxy-beta-uridines. JP 1987187484 . |
| 【3】 Yamashita, J.-I.; Takeda, S.; Matsumoto, H.; Unemi, N.; Yasumoto, M.; Studies on antitumor agents. 8. Antitumor activities of O-alkyl derivatives of 2'-deoxy-5-(trifluoromethyl)uridine and 2'-deoxy-5-fluorouridine. J Med Chem 1989, 32, 1, 136-139. |
| 【4】 Hoshi, A.; Prous, J.; Castaner, J.; FTC-092. Drugs Fut 1990, 15, 8, 790. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10463 | Benzoyl chloride | 98-88-4 | C7H5ClO | 详情 | 详情 | |
| 19171 | 1-(Chloromethyl)benzene; Benzyl chloride | 100-44-7 | C7H7Cl | 详情 | 详情 | |
| (I) | 31154 | 1-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-iodo-2,4(1H,3H)-pyrimidinedione | 54-42-2 | C9H11IN2O5 | 详情 | 详情 |
| (II) | 31155 | [(2R,3S,5R)-3-hydroxy-5-[5-iodo-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl]methyl benzoate | C16H15IN2O6 | 详情 | 详情 | |
| (III) | 31156 | benzyl 2,2,2-trichloroethanimidoate | 81927-55-1 | C9H8Cl3NO | 详情 | 详情 |
| (IV) | 31157 | [(2R,3S,5R)-3-(benzyloxy)-5-[5-iodo-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl]methyl benzoate | C23H21IN2O6 | 详情 | 详情 | |
| (V) | 31158 | 1-[(2R,4S,5R)-4-(benzyloxy)-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-iodo-2,4(1H,3H)-pyrimidinedione | C16H17IN2O5 | 详情 | 详情 | |
| (IX) | 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 |
| (X) | 31159 | 1-[(2R,4S,5R)-4-hydroxy-5-[(trityloxy)methyl]tetrahydro-2-furanyl]-2,4(1H,3H)-pyrimidinedione | C28H26N2O5 | 详情 | 详情 | |
| (XI) | 31160 | 1-[(2R,4S,5R)-4-(benzyloxy)-5-[(trityloxy)methyl]tetrahydro-2-furanyl]-2,4(1H,3H)-pyrimidinedione | C35H32N2O5 | 详情 | 详情 | |
| (XII) | 31161 | 1-[(2R,4S,5R)-4-(benzyloxy)-5-[(trityloxy)methyl]tetrahydro-2-furanyl]-5-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione | C36H31F3N2O5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IX)Idoxuridine can be obtained by several related ways: 1) The reaction of 5-iodouracil (I) with refluxing POCl3 and dimethylaniline gives 2,4-dichloro-5-iodopyrimidine (II), which by reaction with NaOCH3 in refluxing methanol, is converted into 2,4-dimethoxy-5-iodopyrimidine (III). The reaction of (III) with 2-deoxy-3,6-di-O-p-toluoyl-D-ribofuranosyl chloride (IV) in acetonitrile yields the ribofuranosyl pyridone (V), which is demethylated with acetic anhydride - dry HCl to afford 2'-deoxy-5-iodo-3',6'-di-O-p-toluoyluridine (VI). Finally, this compound is hydrolyzed with NaOCH3 in methanol. 2) The acetylation of 5-iodouracil (I) with refluxing acetic anhydride gives 1-acetyl-5-iodouracil (VII), which by reaction with mercuric acetate in refluxing methanol is converted into the corresponding mercurium salt (VIII). The condensation of (VIII) with the ribofuranosyl chloride (IV) in chloroform affords the protected 2'-deoxy-5-iodouridine (VI), already obtained. 3) The iodination of 2'-deoxyuridine (IX) with iodine, iodic acid, acetic anhydride, CCl4 and water gives 2'-deoxy-5,6-diiodo-5,6-dihydrouridine (X), which is then treated with NaOH to eliminate HI. 4) By direct iodination of 2'-deoxyuridine (IX) with iodine and nitric acid in refluxing chloroform.
| 【1】 Castaner, J.; Robinson, C.; Idoxuridine. Drugs Fut 1995, 20, 7, 670. |
| 【2】 Prystas, M.; Sorm, F.; Nucleic acid components and their analogues.XLIII. Synthesis of anomeric 5-iodo-2'-deoxyuridines. Coll Czech Chem Commun 1964, 29, 121-9. |
| 【3】 Chang, P.K.; Welch, A.D.; Iodination of 2'-deoxycytidine and related substances. J Med Chem 1963, 6, 428-30. |
| 【4】 Cheong, L.; Rich, M.A.; Eidinoff, M.L.; Introduction of the 5-halogenated uracil moiety into deoxyribonucleic acid of mammalian cells in culture. J Biol Chem 1960, 235, 5, 1441-7. |
| 【5】 Prusoff, W.H.; Synthesis and biological activities of iododeoxyuridine, an analog of thymidine. Biochim Biophys Acta 1959, 32, 295-6. |
| 【6】 Amiard, G.; Torelli, V. (Aventis Pharma SA); New method for the preparation of a uridine deriv. and products used in this method. FR 1336866; GB 1024156 . |
| 【7】 Trivedi, M.A.; A rapid method for the synthesis of 5-iodo-2'-deoxyuridine (IDR) and optimisation of the parameters. J Label Compd Radiopharm 1993, 33, 7, 607-12. |
| 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) | 11867 | 5-Iodo-2,4(1H,3H)-pyrimidinedione | 696-07-1 | C4H3IN2O2 | 详情 | 详情 |
| (II) | 11868 | 2,4-Dichloro-5-iodopyrimidine | C4HCl2IN2 | 详情 | 详情 | |
| (III) | 11869 | 5-Iodo-2-methoxy-4-pyrimidinyl methyl ether; 5-Iodo-2,4-dimethoxypyrimidine | 52522-99-3 | C6H7IN2O2 | 详情 | 详情 |
| (IV) | 11870 | (2R,3S,5S)-5-Chloro-2-[[(4-methylbenzoyl)oxy]methyl]tetrahydro-3-furanyl 4-methylbenzoate | C21H21ClO5 | 详情 | 详情 | |
| (V) | 11871 | (2R,3S,5R)-5-[5-iodo-4-methoxy-2-oxo-1(2H)-pyrimidinyl]-2-[[(4-methylbenzoyl)oxy]methyl]tetrahydro-3-furanyl 4-methylbenzoate | C26H25IN2O7 | 详情 | 详情 | |
| (VI) | 11872 | (2R,3S,5R)-5-[5-iodo-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-2-[[(4-methylbenzoyl)oxy]methyl]tetrahydro-3-furanyl 4-methylbenzoate | C25H23IN2O7 | 详情 | 详情 | |
| (VII) | 11873 | 1-Acetyl-5-iodo-2,4(1H,3H)-pyrimidinedione | C6H5IN2O3 | 详情 | 详情 | |
| (VIII) | 11874 | 6-Iodo-8,8a-dihydro-7H-[1,4,2]oxazamercurolo[4,5-a]pyrimidin-7-one | C5H5HgIN2O2 | 详情 | 详情 | |
| (IX) | 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 |
| (X) | 11876 | 1-[(2R,4S,5R)-4-Hydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-5,6-diiododihydro-2,4(1H,3H)-pyrimidinedione | C9H12I2N2O5 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(V)The reaction of 1-(2-deoxy-beta-D-ribofuranosyl)uracil (V) with CH2O and KOH gives 1-(2-deoxy-beta-D-ribofuranosyl)-5-hydroxymethyluracil (VI), which is treated with methanolic-HCl. Chromatography on silica gel yields the target compound.
| 【1】 Gupta, V.S.; Bubbar, G.L.; Synthesis of 5-substituted ether derivatives of 5-hydroxymethyl deoxyuridine and their 'alpha-anomers'. Can J Chem 1970, 48, 20, 3147. |
| 【2】 Gupta, V.S.; Methoxymethyl-2'-deoxyuridine. Drugs Fut 1981, 6, 1, 32. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 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 |
| (VI) | 37193 | 1-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-(hydroxymethyl)-2,4(1H,3H)-pyrimidinedione | C10H14N2O6 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XXI)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 |