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【结 构 式】 
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【分子编号】27920 【品名】Cytidine; 4-amino-1-((2S,3S,4S,5S)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidin-2(1H)-one;4-amino-1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-2(1H)-pyrimidinone 【CA登记号】65-46-3 |
【 分 子 式 】C9H13N3O5 【 分 子 量 】243.21944 【元素组成】C 44.45% H 5.39% N 17.28% O 32.89% |
合成路线1
该中间体在本合成路线中的序号：(XII)Reaction of cytidine (XII) with benzoyl anhydride in DMF gives Nbenzoylcytidine (XIII), which is selectively protected with 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane (TIPDSCl2) in pyridine to yield the silylated cytidine (XIV). Oxidation of the remaining OH group of (XIV) by means of DMSO, TFAA and TEA produces the ketone (XV), which by a Grignard condensation with MeLi, followed by a desilylation with AcOH provides the tertiary alcohol (XVI). Selective benzoylation of the primary and secondary OH groups of compound (XVI) with benzoyl chloride and pyridine results in tribenzoate (XVII) with a remaining free tertiary OH group. Finally, benzoate (XVII) is fluorinated with DAST to yield the tribenzoylated fluorocytidine (II) .
| 【1】 Clark, J. (Pharmasset, Inc.). Modified fluorinated nucleoside analogues, WO 2005003147. |
| 【2】 Clark, J.L., Hollecker, L., Mason, J.C. et al. Design, synthesis, and antiviral activity of 2’-deoxy-2’-fluoro-2’-C-methylcytidine, a potent inhibitor of hepatitis C virus replication. J Med Chem 2005, 45(17): 5504-8. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVII) | 65909 | N-Benzoyl-3',5'-di-O-benzoyl-2'-C-methyl-D-cytidine | C31H27N3O8 | 详情 | 详情 | |
| (II) | 65910 | (2'R)-N-Benzoyl-2'-deoxy-2'-fluoro-2'-methylcytidine 3',5'-dibenzoate | 817204-32-3 | C31H26FN3O7 | 详情 | 详情 |
| (XII) | 27920 | Cytidine; 4-amino-1-((2S,3S,4S,5S)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidin-2(1H)-one;4-amino-1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-2(1H)-pyrimidinone | 65-46-3 | C9H13N3O5 | 详情 | 详情 |
| (XIII) | 61580 | N-Benzoylcytidine;N-[1-[3,4-Dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-2-oxopyrimidin-4-yl]benzamide;N-{1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-2-oxo-1,2-dihydro-4-pyrimidinyl}benzamide | 13089-48-0 | C16H17N3O6 | 详情 | 详情 |
| (XIV) | 65906 | N-Benzoyl-3',5'-O-[1,1,3,3-tetrakis(1-methylethyl)-1,3-disiloxanediyl]cytidine; N-[1-[(6aR,8R,9R,9aS)-9-hydroxy-2,2,4,4-tetra(propan-2-yl)-6a,8,9,9a-tetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8-yl]-2-oxopyrimidin-4-yl]benzamide | 69304-43-4 | C28H43N3O7Si2 | 详情 | 详情 |
| (XV) | 65907 | N-Benzoyl-2'-deoxy-2'-oxo-3',5'-O-[1,1,3,3-tetrakis(1-methylethyl)-1,3-disiloxanediyl]cytidine | 119411-03-9 | C28H41N3O7Si2 | 详情 | 详情 |
| (XVI) | 65908 | N-Benzoyl-2'-C-methyl-D-cytidine | C17H19N3O6 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(III)This compound can be obtained in two different ways: 1) By condensation of 1-beta-D-arabinofuranosylcytosine (I) with palmitic anhydride (II) in hot dioxane. 2) By acylation of cytidine (III) with palmitic anhydride (II) in hot dioxane to yield N4-palmitoylcytidine (IV), which is then isomerized by treatment with POCl3 in ethyl acetate.
| 【1】 Ishida, T.; et al.; JP 7626884 . |
| 【2】 Ishida, T.; et al.; JP 7707974 . |
| 【3】 Ishida, T.; et al.; JP 7632573 . |
| 【4】 Akiyama, M.; et al.; The synthesis of new derivatives of 1-beta-D-arabinofuranosylcytosine. Chem Pharm Bull 1978, 26, 3, 981-984. |
| 【5】 Ishida, T.; et al.; JP 7648679 . |
| 【6】 Ishida, T.; et al. (Asahi Chemical Industry Co., Ltd.); N4-Acylarabinonucleosides. DE 2461862 . |
| 【7】 Ishida, T.; et al. (Asahi Chemical Industry Co., Ltd.); N4-Acylarabinonucleosides and the preparation thereof. DE 2426304 . |
| 【8】 Cabanillas, F.; Castaner, J.; Palmitoyl/Stearoyl Ara-C. Drugs Fut 1980, 5, 12, 617. |
| 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) | 32709 | Cytarabine; Cytosine Beta-D-Arabinofuranoside; 4-amino-1-[(2R,3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-2(1H)-pyrimidinone | 147-94-4 | C9H13N3O5 | 详情 | 详情 |
| (II) | 39214 | acetic hexadecanoic anhydride | C18H34O3 | 详情 | 详情 | |
| (III) | 27920 | Cytidine; 4-amino-1-((2S,3S,4S,5S)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidin-2(1H)-one;4-amino-1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-2(1H)-pyrimidinone | 65-46-3 | C9H13N3O5 | 详情 | 详情 |
| (IV) | 27921 | N-[1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-2-oxo-1,2-dihydro-4-pyrimidinyl]hexadecanamide | C25H43N3O6 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)Compound can be prepared in three different ways: 1) The reduction of cytidine (I) with H2 over Rh/Al2O3 in water in a Parr apparatus at 2.8 bar gives 3,4,5,6-tetrahydrocytidine (II), which is then hydrolyzed with water at pH 5.5. 2) The reduction of uridine (III) with H2 over Rh/Al2O3 as before gives 5,6-dihydrouridine (IV), which is then reduced again with NaBH4 in water or with H2 over Rh/Al2O3 in water containing ammonia. 3) The reduction of (III) can also be performed in a single step with H2 over Rh/Al2O3 in water containing NH3, in a Parr apparatus at 2.94 bar.
| 【1】 Woodman, R.J.; Tetrahydrouridine. Drugs Fut 1979, 4, 4, 283. |
| 【2】 Hanze, A.R.; Nucleic acids. IV. The catalytic reduction of pyrimidine nucleosides (human liver deaminase inhibitors). J Am Chem Soc 1967, 89, 25, 6720-25. |
| 【3】 Hanze, A.R.; Camiener, G.W.; US 3462416 . |
| 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) | 27920 | Cytidine; 4-amino-1-((2S,3S,4S,5S)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidin-2(1H)-one;4-amino-1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-2(1H)-pyrimidinone | 65-46-3 | C9H13N3O5 | 详情 | 详情 |
| (II) | 39509 | 4-amino-1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]tetrahydro-2(1H)-pyrimidinone | C9H17N3O5 | 详情 | 详情 | |
| (III) | 11996 | 1-[(2R,3R,4S,5R)-3,4-Dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-2,4(1H,3H)-pyrimidinedione; Uridine | 58-96-8 | C9H12N2O6 | 详情 | 详情 |
| (IV) | 39510 | 1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]dihydro-2,4(1H,3H)-pyrimidinedione | C9H14N2O6 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(III)This compound can be obtained in two different ways: 1) By condensation of 1-beta-D-arabinofuranosylcytosine (I) with docosanoyl anhydride (II) in hot dioxane. 2) By acylation of cytidine (III) with docosanoyl anhydride (II) as before to give N4-docosanoylcytidine (IV), which is then isomerized by treatment with POCl3 in ethyl acetate.
| 【1】 Akiyama, M.; et al.; The synthesis of new derivatives of 1-beta-D-arabinofuranosylcytosine. Chem Pharm Bull 1978, 26, 3, 981-984. |
| 【2】 Ishida, T.; et al.; JP 7626884 . |
| 【3】 Ishida, T.; et al.; JP 7648679 . |
| 【4】 Ishida, T.; et al.; JP 7632573 . |
| 【5】 Ishida, T.; et al.; N4-Acylarabinonucleosides apparatus for handling articles. DE 2461862; FR 2342070; JP 51019777 . |
| 【6】 Ishida, T.; et al.; N4-Acylarabinonucleosides and the preparation thereof. DE 426304; FR 2231388; GB 1449708; JP 50018482 . |
| 【7】 Serradell, M.N.; Cabanillas, F.; Castaner, J.; Blancafort, P.; Behenoyl Ara-C. Drugs Fut 1980, 5, 12, 603. |
| 【8】 Ishida, T.; et al. (Asahi Chemical Industry Co., Ltd.); Process for preparing N4-acylcytarabines. JP 52007974 . |
| 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) | 32709 | Cytarabine; Cytosine Beta-D-Arabinofuranoside; 4-amino-1-[(2R,3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-2(1H)-pyrimidinone | 147-94-4 | C9H13N3O5 | 详情 | 详情 |
| (II) | 32710 | docosanoic anhydride | 55726-23-3 | C44H86O3 | 详情 | 详情 |
| (III) | 27920 | Cytidine; 4-amino-1-((2S,3S,4S,5S)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidin-2(1H)-one;4-amino-1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-2(1H)-pyrimidinone | 65-46-3 | C9H13N3O5 | 详情 | 详情 |
| (IV) | 31711 | 1-(2-diazo-1-phenylethyl)benzene | C14H12N2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)The protection of cytidine (I) with 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane (II) and dimethylformamide dimethylacetal (A) in pyridine gives the fully protected cytidine (III), which is oxidized with oxalyl chloride in DMSO/dichloromethane yielding the 2'-deoxy-2'-oxo derivative (IV). The reaction of (IV) with fluoromethyl phenyl sulfone (B) by means of diethyl chlorophosphate and lithium hexamethyldisylazide in THF affords the fluorovinyl sulfone (V) as a mixture of (E) and (Z) isomers that is separated by flash chromatography. The (Z)-isomer (V) is treated with tributyl tin hydride and AIBN in refluxing benzene to give the fluorovinyl stannane (VI), which is finally treated with KF in refluxing methanol to afford the target compound.
| 【1】 Donaldson, R.E. (Aventis Pharmaceuticals, Inc.); Monohydrate of (E)-2'-deoxy-2'-(fluoromethylene)cytidine. WO 9518815 . |
| 【2】 Mathews, D.P.; McCarthy, J.R.; Sabol, J.S. (Aventis Pharmaceuticals, Inc.); A process for the preparation of ribonucleotide reductase inhibitors. WO 9323414 . |
| 【3】 Snyder, R.D. (Aventis Pharmaceuticals, Inc.); Method of treating a neoplastic disease state by conjunctive therapy with 2'-fluoromethylidene derivs. and radioation or chemotherapy. WO 9601638 . |
| 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) | 11984 | N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine； Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal | 4637-24-5 | C5H13NO2 | 详情 | 详情 |
| (B) | 29245 | (fluoromethyl)(dioxo)phenyl-lambda(6)-sulfane | 20808-12-2 | C7H7FO2S | 详情 | 详情 |
| (I) | 27920 | Cytidine; 4-amino-1-((2S,3S,4S,5S)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidin-2(1H)-one;4-amino-1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-2(1H)-pyrimidinone | 65-46-3 | C9H13N3O5 | 详情 | 详情 |
| (II) | 29242 | 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane | 69304-37-6 | C12H28Cl2OSi2 | 详情 | 详情 |
| (III) | 29243 | N'-[1-[(6aR,8R,9R,9aS)-9-hydroxy-2,2,4,4-tetraisopropyltetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8-yl]-2-oxo-1,2-dihydro-4-pyrimidinyl]-N,N-dimethyliminoformamide | C24H44N4O6Si2 | 详情 | 详情 | |
| (IV) | 29244 | N'-[1-[(6aR,8R,9aR)-2,2,4,4-tetraisopropyl-9-oxotetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8-yl]-2-oxo-1,2-dihydro-4-pyrimidinyl]-N,N-dimethyliminoformamide | C24H42N4O6Si2 | 详情 | 详情 | |
| (V) | 29246 | 1-[(6aR,8R,9aS)-9-[(Z)-fluoro(phenylsulfonyl)methylidene]-2,2,4,4-tetraisopropyldihydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8(8H)-yl]-4-amino-2(1H)-pyrimidinone | C28H42FN3O7SSi2 | 详情 | 详情 | |
| (VI) | 29247 | 1-[(6aR,8R,9aS)-9-[(Z)-fluoro(tributylstannyl)methylidene]-2,2,4,4-tetraisopropyldihydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8(8H)-yl]-4-amino-2(1H)-pyrimidinone | C34H64FN3O5Si2Sn | 详情 | 详情 | |
| (C) | 23623 | Chlorophosphoric acid ethyl ester；Phosphorochloridic acid diethyl ester；Diethyl chlorophosphate;diethyl phosphorochloridate | 814-49-3 | C4H10ClO3P | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(I)The protection of labeled cytidine (I) with 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane (II) and dimethylformamide dimethylacetal (A) in pyridine gives the fully protected cytidine (III), which is oxidized with oxalyl chloride in DMSO/dichloromethane yielding the 2'-deoxy-2'-oxo derivative (IV). The reaction of (IV) with fluoromethyl phenyl sulfone (B) by means of diethyl chlorophosphate and lithium hexamethyldisylazide in THF affords the fluorovinyl sulfone (V) as a mixture of (E) and (Z) isomers that is separated by flash chromatography. The (Z)-isomer (V) is treated with tributyl tin hydride and AIBN in refluxing benzene to give the fluorovinyl stannane (VI), which is finally treated with KF in refluxing methanol to afford the labeled target compound.
| 【1】 Wagner, E.R.; et al.; Radiolabeling of ribonucleotide diphosphate reductase inhibitor (E)-2'-deoxy-2'-(fluoromethylene)cytidine. Synthesis and Applications of Isotopically Labelled Compounds 1994, 659 (paper 118). |
| 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) | 11984 | N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine； Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal | 4637-24-5 | C5H13NO2 | 详情 | 详情 |
| (B) | 29245 | (fluoromethyl)(dioxo)phenyl-lambda(6)-sulfane | 20808-12-2 | C7H7FO2S | 详情 | 详情 |
| (I) | 27920 | Cytidine; 4-amino-1-((2S,3S,4S,5S)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidin-2(1H)-one;4-amino-1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-2(1H)-pyrimidinone | 65-46-3 | C9H13N3O5 | 详情 | 详情 |
| (I) | 45211 | 4-amino-1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-2(1H)-pyrimidinone | C9H13N3O5 | 详情 | 详情 | |
| (II) | 29242 | 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane | 69304-37-6 | C12H28Cl2OSi2 | 详情 | 详情 |
| (III) | 29243 | N'-[1-[(6aR,8R,9R,9aS)-9-hydroxy-2,2,4,4-tetraisopropyltetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8-yl]-2-oxo-1,2-dihydro-4-pyrimidinyl]-N,N-dimethyliminoformamide | C24H44N4O6Si2 | 详情 | 详情 | |
| (III) | 45212 | N'-[1-[(6aR,8R,9R,9aS)-9-hydroxy-2,2,4,4-tetraisopropyltetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8-yl]-2-oxo-1,2-dihydro-4-pyrimidinyl]-N,N-dimethyliminoformamide | C24H44N4O6Si2 | 详情 | 详情 | |
| (IV) | 29244 | N'-[1-[(6aR,8R,9aR)-2,2,4,4-tetraisopropyl-9-oxotetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8-yl]-2-oxo-1,2-dihydro-4-pyrimidinyl]-N,N-dimethyliminoformamide | C24H42N4O6Si2 | 详情 | 详情 | |
| (IV) | 45213 | N'-[1-[(6aR,8R,9aR)-2,2,4,4-tetraisopropyl-9-oxotetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8-yl]-2-oxo-1,2-dihydro-4-pyrimidinyl]-N,N-dimethyliminoformamide | C24H42N4O6Si2 | 详情 | 详情 | |
| (V) | 29246 | 1-[(6aR,8R,9aS)-9-[(Z)-fluoro(phenylsulfonyl)methylidene]-2,2,4,4-tetraisopropyldihydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8(8H)-yl]-4-amino-2(1H)-pyrimidinone | C28H42FN3O7SSi2 | 详情 | 详情 | |
| (V) | 45214 | 1-[(6aR,8R,9aS)-9-[(Z)-fluoro(phenylsulfonyl)methylidene]-2,2,4,4-tetraisopropyldihydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8(8H)-yl]-4-amino-2(1H)-pyrimidinone | C28H42FN3O7SSi2 | 详情 | 详情 | |
| (VI) | 29247 | 1-[(6aR,8R,9aS)-9-[(Z)-fluoro(tributylstannyl)methylidene]-2,2,4,4-tetraisopropyldihydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8(8H)-yl]-4-amino-2(1H)-pyrimidinone | C34H64FN3O5Si2Sn | 详情 | 详情 | |
| (VI) | 45215 | 1-[(6aR,8R,9aS)-9-[(Z)-fluoro(tributylstannyl)methylidene]-2,2,4,4-tetraisopropyldihydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8(8H)-yl]-4-amino-2(1H)-pyrimidinone | C34H64FN3O5Si2Sn | 详情 | 详情 | |
| (C) | 23623 | Chlorophosphoric acid ethyl ester；Phosphorochloridic acid diethyl ester；Diethyl chlorophosphate;diethyl phosphorochloridate | 814-49-3 | C4H10ClO3P | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(I)The protection of cytidine (I) with 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane (II) and dimethylformamide dimethylacetal (A) in pyridine gives the fully protected cytidine (III), which is oxidized with oxalyl chloride in DMSO/dichloromethane yielding the 2'-deoxy-2'-oxo derivative (IV). The reaction of (IV) with labeled fluoromethyl phenyl sulfone (V) by means of diethyl chlorophosphate (B) and lithium hexamethyldisylazide in THF affords the fluorovinyl sulfone (VI) as a mixture of (E) and (Z) isomers that is separated by flash chromatography. The (Z)-isomer (VI) is treated with tributyl tin hydride and AIBN in refluxing benzene to give the fluorovinyl stannane (VII), which is finally treated with KF in refluxing methanol to afford the labeled target compound.
| 【1】 Wagner, E.R.; et al.; Radiolabeling of ribonucleotide diphosphate reductase inhibitor (E)-2'-deoxy-2'-(fluoromethylene)cytidine. Synthesis and Applications of Isotopically Labelled Compounds 1994, 659 (paper 118). |
| 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) | 11984 | N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine； Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal | 4637-24-5 | C5H13NO2 | 详情 | 详情 |
| (B) | 23623 | Chlorophosphoric acid ethyl ester；Phosphorochloridic acid diethyl ester；Diethyl chlorophosphate;diethyl phosphorochloridate | 814-49-3 | C4H10ClO3P | 详情 | 详情 |
| (I) | 27920 | Cytidine; 4-amino-1-((2S,3S,4S,5S)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidin-2(1H)-one;4-amino-1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-2(1H)-pyrimidinone | 65-46-3 | C9H13N3O5 | 详情 | 详情 |
| (II) | 29242 | 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane | 69304-37-6 | C12H28Cl2OSi2 | 详情 | 详情 |
| (III) | 29243 | N'-[1-[(6aR,8R,9R,9aS)-9-hydroxy-2,2,4,4-tetraisopropyltetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8-yl]-2-oxo-1,2-dihydro-4-pyrimidinyl]-N,N-dimethyliminoformamide | C24H44N4O6Si2 | 详情 | 详情 | |
| (IV) | 29244 | N'-[1-[(6aR,8R,9aR)-2,2,4,4-tetraisopropyl-9-oxotetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8-yl]-2-oxo-1,2-dihydro-4-pyrimidinyl]-N,N-dimethyliminoformamide | C24H42N4O6Si2 | 详情 | 详情 | |
| (V) | 29245 | (fluoromethyl)(dioxo)phenyl-lambda(6)-sulfane | 20808-12-2 | C7H7FO2S | 详情 | 详情 |
| (V) | 45218 | fluoromethyl phenyl sulfone; (fluoromethyl)(dioxo)phenyl-lambda(6)-sulfane | C7H7FO2S | 详情 | 详情 | |
| (VI) | 29246 | 1-[(6aR,8R,9aS)-9-[(Z)-fluoro(phenylsulfonyl)methylidene]-2,2,4,4-tetraisopropyldihydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8(8H)-yl]-4-amino-2(1H)-pyrimidinone | C28H42FN3O7SSi2 | 详情 | 详情 | |
| (VI) | 45219 | 1-[(6aR,8R,9aS)-9-[(Z)-fluoro(phenylsulfonyl)methylidene]-2,2,4,4-tetraisopropyldihydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8(8H)-yl]-4-amino-2(1H)-pyrimidinone | C28H42FN3O7SSi2 | 详情 | 详情 | |
| (VII) | 29247 | 1-[(6aR,8R,9aS)-9-[(Z)-fluoro(tributylstannyl)methylidene]-2,2,4,4-tetraisopropyldihydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8(8H)-yl]-4-amino-2(1H)-pyrimidinone | C34H64FN3O5Si2Sn | 详情 | 详情 | |
| (VII) | 45220 | 1-[(6aR,8R,9aS)-9-[(Z)-fluoro(tributylstannyl)methylidene]-2,2,4,4-tetraisopropyldihydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8(8H)-yl]-4-amino-2(1H)-pyrimidinone | C34H64FN3O5Si2Sn | 详情 | 详情 | |
| (VIII) | 29254 | methyl(oxo)phenyl-lambda(4)-sulfane | 1193-82-4 | C7H8OS | 详情 | 详情 |
| (VIII) | 45216 | methyl phenyl sulfoxide; methyl(oxo)phenyl-lambda(4)-sulfane | C7H8OS | 详情 | 详情 | |
| (IX) | 29255 | fluoromethyl phenyl sulfide | C7H7FS | 详情 | 详情 | |
| (IX) | 45217 | 1-[(fluoromethyl)sulfanyl]benzene; fluoromethyl phenyl sulfide | C7H7FS | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(I)A new synthesis of tezacitabine has been described: Protection of cytidine (I) with 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane (II) in pyridine gives the protected cytidine (III), which is oxidized with trifluoroacetic anhydride (TFAA)/DMSO in THF and treated with TEA to yield the 2'-deoxy-2'-oxocytidine derivative (IV). Condensation of (IV) with fluoromethyl phenyl sulfone (V) by means of diethyl chlorophosphate and lithium hexamethyldisilazide in THF affords the fluorovinyl sulfone (VI) as a mixture of (E)- and (Z)-isomers that is separated by flash chromatography. The desired (Z)-isomer (VI) is treated with tributyl tin hydride and AIBN in refluxing benzene to give the fluorovinyl stannane (VII), which is finally treated with KF in refluxing methanol.
| 【1】 Duguid, R.J.; Appell, R.B.; New synthesis of protected ketonucleoside by a non-cryogenic oxidation with TFAA/DMSO. Org Process Res Dev 2000, 4, 3, 172. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 23623 | Chlorophosphoric acid ethyl ester；Phosphorochloridic acid diethyl ester；Diethyl chlorophosphate;diethyl phosphorochloridate | 814-49-3 | C4H10ClO3P | 详情 | 详情 | |
| (I) | 27920 | Cytidine; 4-amino-1-((2S,3S,4S,5S)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidin-2(1H)-one;4-amino-1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-2(1H)-pyrimidinone | 65-46-3 | C9H13N3O5 | 详情 | 详情 |
| (II) | 29242 | 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane | 69304-37-6 | C12H28Cl2OSi2 | 详情 | 详情 |
| (III) | 46713 | 1-[(6aR,8R,9R,9aS)-9-hydroxy-2,2,4,4-tetraisopropyltetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8-yl]-4-amino-2(1H)-pyrimidinone | C21H39N3O6Si2 | 详情 | 详情 | |
| (IV) | 46714 | 1-[(6aR,8R,9aR)-2,2,4,4-tetraisopropyl-9-oxotetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8-yl]-4-amino-2(1H)-pyrimidinone | C21H37N3O6Si2 | 详情 | 详情 | |
| (V) | 29245 | (fluoromethyl)(dioxo)phenyl-lambda(6)-sulfane | 20808-12-2 | C7H7FO2S | 详情 | 详情 |
| (VI) | 29246 | 1-[(6aR,8R,9aS)-9-[(Z)-fluoro(phenylsulfonyl)methylidene]-2,2,4,4-tetraisopropyldihydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8(8H)-yl]-4-amino-2(1H)-pyrimidinone | C28H42FN3O7SSi2 | 详情 | 详情 | |
| (VII) | 29247 | 1-[(6aR,8R,9aS)-9-[(Z)-fluoro(tributylstannyl)methylidene]-2,2,4,4-tetraisopropyldihydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8(8H)-yl]-4-amino-2(1H)-pyrimidinone | C34H64FN3O5Si2Sn | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(VII)4) The acylation of cytidine (VII) with hexadecanoyl anhydride (III) in hot DMF gives N-4-hexadecanoylcytidine (VIII), which is protected with 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane in pyridine, yielding the 3',5'-cyclic disiloxane (IX). The oxidation of (IX) with pyridinium dichromate in dichloromethane affords the ketonic derivative (X), which is treated with NaCN in ethyl acetate/phosphate buffer to give 2'-C-cyano-N4-hexadecanoyl-3',5'-O-(1,1,3,3-tetraisopropyldisiloxane-1,3-diyl)cytidine (XI). The reaction of (XI) with phenoxythiocarbonyl chloride and DMAP in triethylamine provides the thiocarbonate (XII), which is reduced with AIBN and tributyltin in refluxing toluene to give the 2'-deoxy compound (VI). Finally, this compound is desilylated with TBAF in acetic acid.
| 【1】 Castaner, J.; Hoshi, A.; CS-682. Drugs Fut 1999, 24, 9, 957. |
| 【2】 Kaneko, M.; Hotoda, H.; Shibata, T.; Kobayashi, T.; Mitsuhashi, Y.; Matsuda, A.; Sasaki, T. (Sankyo Co., Ltd.); Pyrimidine nucleoside derivs. having anti-tumor activity, their preparation and use. EP 0536936; JP 1993194497; US 5691319 . |
| 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) | 27919 | N-[1-[(6aR,8R,9S,9aS)-9-cyano-2,2,4,4-tetraisopropyltetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8-yl]-2-oxo-1,2-dihydro-4-pyrimidinyl]hexadecanamide | C38H68N4O6Si2 | 详情 | 详情 | |
| (VII) | 27920 | Cytidine; 4-amino-1-((2S,3S,4S,5S)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidin-2(1H)-one;4-amino-1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-2(1H)-pyrimidinone | 65-46-3 | C9H13N3O5 | 详情 | 详情 |
| (VIII) | 27916 | hexadecanoic anhydride | 623-65-4 | C32H62O3 | 详情 | 详情 |
| (IX) | 27921 | N-[1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-2-oxo-1,2-dihydro-4-pyrimidinyl]hexadecanamide | C25H43N3O6 | 详情 | 详情 | |
| (X) | 27922 | N-[1-[(6aR,8R,9R,9aS)-9-hydroxy-2,2,4,4-tetraisopropyltetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8-yl]-2-oxo-1,2-dihydro-4-pyrimidinyl]hexadecanamide | C37H69N3O7Si2 | 详情 | 详情 | |
| (XI) | 27923 | N-[1-[(6aR,8R,9aR)-2,2,4,4-tetraisopropyl-9-oxotetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8-yl]-2-oxo-1,2-dihydro-4-pyrimidinyl]hexadecanamide | C37H67N3O7Si2 | 详情 | 详情 | |
| (XII) | 27924 | N-[1-[(6aR,8R,9R,9aR)-9-cyano-9-hydroxy-2,2,4,4-tetraisopropyltetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8-yl]-2-oxo-1,2-dihydro-4-pyrimidinyl]hexadecanamide | C38H68N4O7Si2 | 详情 | 详情 | |
| (XIII) | 27925 | O-[(6aR,8R,9R,9aR)-9-cyano-2,2,4,4-tetraisopropyl-8-[2-oxo-4-(palmitoylamino)-1(2H)-pyrimidinyl]tetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-9-yl] O-phenyl carbonothioate | C45H72N4O8SSi2 | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(I)The reaction of cytidine (I) with benzoyl anhydride in dioxane gives N-benzoylcytidine (II), which is selectively monoprotected at the primary OH group by means of 4-methoxytrityl chloride and pyridine to yield N-benzoyl-5'O-(monomethoxytrityl)cytidine (III). The monosilylation of (III) by means of Tbdms-Cl and AgNO3 in pyridine/THF affords a mixture of the 3'-O-silyl (IV) and the desired 2'-O-silyl (V) derivative which is easily separated by flash chromatography. (The yield of the desired 2'-O-silyl isomer (V) can be improved by isomerization of the 3'-O-silyl isomer (IV) by means of pyridine in methanol at 70 C). The oxidation of (V) by means of CrO3 and Ac2O provides the 3'-oxonucleoside (VI), which is selectively deprotected by means of TsOH in chloroform/methanol to give compound (VII). The reaction of (VII) with trimethylsilylacetylene (VIII) by means of BuLi and CeCl3 in THF yields the protected ethynyl nucleoside (IX), which is debenzoylated by means of NH3 in methanol to afford the silylated nucleoside (X). Finally, this compound is treated with TBAF in THF to obtain the target ethynyl cytidine.
| 【1】 Ludwig, P.S.; Schwender, R.A.; Schott, H.; A new laboratory scale synthesis for the anticancer drug 3'-C.ethynylcytidine. Synthesis (Stuttgart) 2002, 16, 2387. |
| 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) | 27920 | Cytidine; 4-amino-1-((2S,3S,4S,5S)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidin-2(1H)-one;4-amino-1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-2(1H)-pyrimidinone | 65-46-3 | C9H13N3O5 | 详情 | 详情 |
| (II) | 61580 | N-Benzoylcytidine;N-[1-[3,4-Dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-2-oxopyrimidin-4-yl]benzamide;N-{1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-2-oxo-1,2-dihydro-4-pyrimidinyl}benzamide | 13089-48-0 | C16H17N3O6 | 详情 | 详情 |
| (III) | 61581 | N-[1-((2R,3R,4S,5R)-3,4-dihydroxy-5-{[tris(4-methoxyphenyl)methoxy]methyl}tetrahydro-2-furanyl)-2-oxo-1,2-dihydro-4-pyrimidinyl]benzamide | C38H37N3O9 | 详情 | 详情 | |
| (IV) | 61582 | N-[1-((2R,3R,4S,5R)-4-{[tert-butyl(dimethyl)silyl]oxy}-3-hydroxy-5-{[tris(4-methoxyphenyl)methoxy]methyl}tetrahydro-2-furanyl)-2-oxo-1,2-dihydro-4-pyrimidinyl]benzamide | C44H51N3O9Si | 详情 | 详情 | |
| (V) | 61583 | N-[1-((2R,3R,4R,5R)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-hydroxy-5-{[tris(4-methoxyphenyl)methoxy]methyl}tetrahydro-2-furanyl)-2-oxo-1,2-dihydro-4-pyrimidinyl]benzamide | C44H51N3O9Si | 详情 | 详情 | |
| (VI) | 61584 | N-[1-((2R,3S,5R)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-oxo-5-{[tris(4-methoxyphenyl)methoxy]methyl}tetrahydro-2-furanyl)-2-oxo-1,2-dihydro-4-pyrimidinyl]benzamide | C44H49N3O9Si | 详情 | 详情 | |
| (VII) | 61585 | N-{1-[(2R,3S,5R)-3-{[tert-butyl(dimethyl)silyl]oxy}-5-(hydroxymethyl)-4-oxotetrahydro-2-furanyl]-2-oxo-1,2-dihydro-4-pyrimidinyl}benzamide | C22H29N3O6Si | 详情 | 详情 | |
| (VIII) | 23897 | ethynyl(trimethyl)silane；trimethylsilyl acetylene | 1066-54-2 | C5H10Si | 详情 | 详情 |
| (IX) | 61586 | N-(1-{(2R,3R,4R,5R)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-hydroxy-5-(hydroxymethyl)-4-[2-(trimethylsilyl)ethynyl]tetrahydro-2-furanyl}-2-oxo-1,2-dihydro-4-pyrimidinyl)benzamide | C27H39N3O6Si2 | 详情 | 详情 | |
| (X) | 61587 | 4-amino-1-{(2R,3R,4R,5R)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-hydroxy-5-(hydroxymethyl)-4-[2-(trimethylsilyl)ethynyl]tetrahydro-2-furanyl}-2(1H)-pyrimidinone | C20H35N3O5Si2 | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(I)Acylation of cytidine (I) with benzoic anhydride in DMF provides N4-benzoylcytidine (II), which is regioselectively protected at the 3’- and 5’-hydroxyl groups with 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane in pyridine, giving the cyclic siloxane derivative (III). Subsequent Swern oxidation of the 2’-alcohol group of compound (III) using DMSO, TFAA and Et3N followed by addition of methyllithium to the obtained ketone (IV) and desilylation with AcOH leads to the 2’-C-methylcytidine derivative (V). After reprotection of the primary and secondary hydroxyl groups of the cytidine (V) with benzoyl chloride in pyridine, the tertiary hydroxyl of compound (VI) is fluorinated using DAST in cold toluene to give the benzoyl-protected 2’-deoxy-2’-fluoro-2’-methylcytidine (VII) (1-3). In a different strategy, the nucleoside derivative (VII) is prepared by coupling of the methyl (VIIIa) (1-3) or acetyl (VIIIb) glycosides (4) or the glycosyl chloride (VIIIc) (5) with silylated N4-benzoylcytosine (IX) by means of either trimethylsilyl triflate or tin tetrachloride. The tribenzoylated precursor (VII) is then deprotected with methanolic NaOMe (1, 2) or ammonia (3, 4) to obtain PSI-6130 (X), which is finally esterified with isobutyryl chloride (XI) in the presence of DMAP and Et3N in THF/H2O (6). Scheme 1.
| 【1】 Clark, J. (Pharmasset Ltd.). Modified fluorinated nucleoside analogues. WO 2005003147. |
| 【2】 Clark, J.L., Hollecker, L., Mason, J.C. Design, synthesis, and antiviral activity of 2’-deoxy-2’-fluoro-2’-C-methylcytidine, a potent inhibitor of hepatitis C virus replication. J Med Chem 2005, 48(17): 5504-8. |
| 【3】 Clark, J. (Pharmasset, Inc.). Modified fluorinated nucleoside analogues. US 20080070861. |
| 【4】 Chun, B.-K., Wang, P. (Pharmasset, Inc.). Preparation of 2’-fluoro-2’-alkyl-substituted or other optionally substituted ribofuranosyl pyrimidines and purines and their derivatives. WO 2006031725. |
| 【5】 Axt, S.D., Sarma, K., Vitale, J. et al. (Pharmasset, Inc.; F. Hoffmann La Roche AG). Preparation of nucleosides ribofuranosyl pyrimidines. WO 2008045419. |
| 【6】 Chun, B.-K., Clark, J., Sarma, K., Wang, P. (F. Hoffmann-La Roche AG; Pharmasset, Inc.). Antiviral nucleosides. WO 2007065829. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIIIA) | 65911 | ((2S,3S,4S)-3-(benzoyloxy)-4-fluoro-5-methoxy-4-methyltetrahydrofuran-2-yl)methyl benzoate | C21H21FO6 | 详情 | 详情 | |
| (VIIIB) | 65912 | C22H21FO6 | 详情 | 详情 | ||
| (VIIIC) | 65913 | C20H17ClFO5 | 详情 | 详情 | ||
| (I) | 27920 | Cytidine; 4-amino-1-((2S,3S,4S,5S)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidin-2(1H)-one;4-amino-1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-2(1H)-pyrimidinone | 65-46-3 | C9H13N3O5 | 详情 | 详情 |
| (II) | 61580 | N-Benzoylcytidine;N-[1-[3,4-Dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-2-oxopyrimidin-4-yl]benzamide;N-{1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-2-oxo-1,2-dihydro-4-pyrimidinyl}benzamide | 13089-48-0 | C16H17N3O6 | 详情 | 详情 |
| (III) | 65906 | N-Benzoyl-3',5'-O-[1,1,3,3-tetrakis(1-methylethyl)-1,3-disiloxanediyl]cytidine; N-[1-[(6aR,8R,9R,9aS)-9-hydroxy-2,2,4,4-tetra(propan-2-yl)-6a,8,9,9a-tetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8-yl]-2-oxopyrimidin-4-yl]benzamide | 69304-43-4 | C28H43N3O7Si2 | 详情 | 详情 |
| (IV) | 65907 | N-Benzoyl-2'-deoxy-2'-oxo-3',5'-O-[1,1,3,3-tetrakis(1-methylethyl)-1,3-disiloxanediyl]cytidine | 119411-03-9 | C28H41N3O7Si2 | 详情 | 详情 |
| (V) | 65908 | N-Benzoyl-2'-C-methyl-D-cytidine | C17H19N3O6 | 详情 | 详情 | |
| (VI) | 65909 | N-Benzoyl-3',5'-di-O-benzoyl-2'-C-methyl-D-cytidine | C31H27N3O8 | 详情 | 详情 | |
| (VII) | 65910 | (2'R)-N-Benzoyl-2'-deoxy-2'-fluoro-2'-methylcytidine 3',5'-dibenzoate | 817204-32-3 | C31H26FN3O7 | 详情 | 详情 |
| (IX) | 12715 | N-(2-Oxo-1,2-dihydro-4-pyrimidinyl)benzamide; N-Benzoylcytosine | 26661-13-2 | C11H9N3O2 | 详情 | 详情 |
| (X) | 65914 | 2'-Deoxy-2'-fluoro-2'-C-methylcytidine | 817204-33-4 | C10H14FN3O4 | 详情 | 详情 |
| (XI) | 14932 | isobutyryl chloride; 2-methylpropanoyl chloride | 79-30-1 | C4H7ClO | 详情 | 详情 |