|
【结 构 式】 
|
【药物名称】Tezacitabine, KW-2331, FMdC, MDL-101731 【化学名称】(E)-2'-Deoxy-2'-(fluoromethylene)cytidine 【CA登记号】130306-02-4, 171176-43-5 (hydrate) 【 分 子 式 】C10H12FN3O4 【 分 子 量 】257.22324 |
【开发单位】Aventis Pharma (Originator), Chiron (Licensee), Kyowa Hakko (Licensee), Matrix Pharmaceutical (Licensee) 【药理作用】ANTIINFECTIVE THERAPY, Antiviral Drugs, Colorectal Cancer Therapy, Gastric Cancer Therapy, Leukemia Therapy, Liver Cancer Therapy, Lung Cancer Therapy, Lymphoma Therapy, Myeloid Leukemia Therapy, Non-Hodgkin's Lymphoma Therapy, Non-Small Cell Lung Cancer Therapy, Oncolytic Drugs, Antimetabolites, Ribonucleoside-Diphosphate Reductase Inhibitors |
合成路线1
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2
The acetylation of uridine (I) with acetic anhydride gives the 2',3',5'-triacetyl derivative (II), which is treated with SOCl2 and sodium ethoxide yielding the 4-ethoxypyrimidinone (III). The partial protection of (III) with 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane (IV) yields the silylated compound (V), which is oxidized with oxalyl chloride to the silylated furanone (VI). The reaction of (VI) with fluoromethyl phenyl sulfone (A) by means of diethyl chlorophosphate (B) and lithium hexamethyldisylazide in THF affords the fluorovinyl sulfone (VII) as a mixture of (E) and (Z) isomers that is separated by flash chromatography. The (Z)-isomer (VII) is treated with tributyl tin hydride and AIBN in refluxing benzene to give the fluorovinyl stannane (VIII), which is finally treated with CsF and NH3 in refluxing methanol to afford the target compound.
| 【1】 Sunkara, P.S.; McCarthy, J.R.; Matthews, D.P.; et al.; Design of a fluoro-olefin cytidine nucleoside as a bioprecursor of a mechanism-based inhibitor of ribonucleotide reductase. ACS Symp Ser 1996, 639, 246. |
| 【2】 McCarthy, J.R.; et al.; Stereospecific synthesis of 1-fluoro olefins via (fluorovinyl)stannanes and an unequivocal NMR method for the assignment of fluoro olefin geometry. Tetrahedron 1996, 52, 1, 45. |
| 【3】 Matthews, D.P.; et al.; Improved synthesis of (E)-2'-deoxy-2'-(fluoromethylene)cytidine - A potent inhibitor of ribonucleotide diphosphate reductase. Nucleosides Nucleotides 1993, 12, 2, 115. |
| 【4】 McCarthy, J.R.; Edwards, M.L.; Matthews, D.P. (Merrell Pharmaceuticals, Inc.); Novel 2'-halomethylidene, 2'-ethenylidene and 2'-ethynyl cytidine, uridine and guanosine derivs.. EP 0372268; JP 1990178272; US 5378693 . |
| 【5】 McCarthy, J.R.; Matthews, D.P.; Bitonti, A.J.; Edwards, M.L. (Merrell Pharmaceuticals, Inc.); Treatment of carcinoma by administration of 2'-halomethylidenyl-2'-deoxynucleosides. US 5607925 . |
| 【6】 McCarthy, J.R.; Matthews, D.P.; Edwards, M.L. (Merrell Pharmaceuticals, Inc.); 2'-Ethenylidene cytidine, uridine and guanosine derivs.. US 5616702 . |
| 【7】 McCarthy, J.R.; et al.; Stereospecific method to E and Z terminal fluoro olefins and its application to the synthesis of 2'-deoxy-2'-fluoromethylene nucleosides as potential inhibitors of ribonucleoside diphosphate reductase. J Am Chem Soc 1991, 113, 19, 7439. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (B) | 23623 | Chlorophosphoric acid ethyl ester；Phosphorochloridic acid diethyl ester；Diethyl chlorophosphate;diethyl phosphorochloridate | 814-49-3 | C4H10ClO3P | 详情 | 详情 |
| (A) | 29245 | (fluoromethyl)(dioxo)phenyl-lambda(6)-sulfane | 20808-12-2 | C7H7FO2S | 详情 | 详情 |
| (I) | 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 |
| (II) | 29248 | (2R,3R,4R,5R)-4-(acetoxy)-2-[(acetoxy)methyl]-5-[2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-3-furanyl acetate | C15H18N2O9 | 详情 | 详情 | |
| (III) | 29249 | 1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-4-ethoxy-2(1H)-pyrimidinone | C11H16N2O6 | 详情 | 详情 | |
| (IV) | 29242 | 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane | 69304-37-6 | C12H28Cl2OSi2 | 详情 | 详情 |
| (V) | 29250 | 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-ethoxy-2(1H)-pyrimidinone | C23H42N2O7Si2 | 详情 | 详情 | |
| (VI) | 29251 | 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-ethoxy-2(1H)-pyrimidinone | C23H40N2O7Si2 | 详情 | 详情 | |
| (VII) | 29252 | 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-ethoxy-2(1H)-pyrimidinone | C30H45FN2O8SSi2 | 详情 | 详情 | |
| (VIII) | 29253 | 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-ethoxy-2(1H)-pyrimidinone | C36H67FN2O6Si2Sn | 详情 | 详情 |
合成路线3
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4
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5
The acetylation of (E)-2'-deoxy-2'-(fluoromethylene)cytidine (I) with acetyl chloride gives the diacetate (II), which is iodinated with iodine and silver trifluoroacetate in dioxane yielding the 5-iodo derivative (III). The hydrogenation of (III) with tritium over Rh/Al2O3 affords the tritiated diacetyl target compound (IV), which is finally hydrolyzed with K2CO3 in methanol.
| 【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 |
|---|---|---|---|---|---|---|
| (I) | 29256 | 4-amino-1-[(2R,4S,5R)-3-[(E)-fluoromethylidene]-4-hydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-2(1H)-pyrimidinone | C10H12FN3O4 | 详情 | 详情 | |
| (II) | 29257 | [(2R,3S,5R)-3-(acetoxy)-5-[4-amino-2-oxo-1(2H)-pyrimidinyl]-4-[(E)-fluoromethylidene]tetrahydro-2-furanyl]methyl acetate | C14H16FN3O6 | 详情 | 详情 | |
| (III) | 29258 | [(2R,3S,5R)-3-(acetoxy)-5-[4-amino-5-iodo-2-oxo-1(2H)-pyrimidinyl]-4-[(E)-fluoromethylidene]tetrahydro-2-furanyl]methyl acetate | C14H15FIN3O6 | 详情 | 详情 | |
| (IV) | 53834 | {(2R,3S,5R)-3-(acetyloxy)-5-[4-amino-2-oxo-1(2H)-pyrimidinyl]-4-[(E)-fluoromethylidene]tetrahydro-2-furanyl}methyl acetate | n/a | C14H16FN3O6 | 详情 | 详情 |
合成路线6
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 |