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【结 构 式】 
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【分子编号】23623 【品名】Chlorophosphoric acid ethyl ester；Phosphorochloridic acid diethyl ester；Diethyl chlorophosphate;diethyl phosphorochloridate 【CA登记号】814-49-3 |
【 分 子 式 】C4H10ClO3P 【 分 子 量 】172.548062 【元素组成】C 27.84% H 5.84% Cl 20.55% O 27.82% P 17.95% |
合成路线1
该中间体在本合成路线中的序号：(C)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
该中间体在本合成路线中的序号：(B)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
该中间体在本合成路线中的序号：(C)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
该中间体在本合成路线中的序号：(B)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
该中间体在本合成路线中的序号：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6
该中间体在本合成路线中的序号：(II)Treatment of carboxylic acid (I) with diethyl chlorophosphate (II) in the presence of Et3N furnished the corresponding mixed anhydride (III). This was then condensed with the sodium salt of alpha-mercapto-gamma-butyrolactone (IV) to produce the title thioester.
| 【1】 Biggadike, K.; Procopiou, P.A. (Glaxo Wellcome plc); Lactone derivs. of 17beta-carboxy, carbothio and amide androstane derivs.. JP 1999501675; US 6197761; WO 9724365 . |
| 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) | 47372 | (4aS,4bR,5S,6aS,8R,9aR,10aS,10bS,12S)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-8-propyl-2,3,4,4a,4b,5,6,6a,9a,10,10a,10b,11,12-tetradecahydro-6bH-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxole-6b-carboxylic acid | C24H32F2O6 | 详情 | 详情 | |
| (II) | 23623 | Chlorophosphoric acid ethyl ester；Phosphorochloridic acid diethyl ester；Diethyl chlorophosphate;diethyl phosphorochloridate | 814-49-3 | C4H10ClO3P | 详情 | 详情 |
| (III) | 47373 | [(4aS,4bR,5S,6aS,8R,9aR,10aS,10bS,12S)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-8-propyl-2,3,4,4a,4b,5,6,6a,9a,10,10a,10b,11,12-tetradecahydro-6bH-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-6-yl]carbonyl diethyl phosphate | C28H41F2O9P | 详情 | 详情 | |
| (IV) | 46294 | 3-sulfanyldihydro-2(3H)-furanone | C4H6O2S | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(V)N-Boc-Homophenylalanine (I) was coupled to N,O-dimethyl hydroxylamine using DCC, and the resulting N-methoxy amide (II) was reduced to aldehyde (III) with LiAlH4. Sulfonyl phosphonate (VI), (prepared from methyl phenyl sulfone (IV) and diethyl chlorophosphate (V)), was then condensed with aldehyde (III) in the presence of NaH to provide the vinylogous sulfone (VII). Subsequent acid deprotection of the Boc group of (VII) yielded amine (VIII). This was finally coupled with mixed anhydride (X), (obtained from morpholinocarbonyl-phenylalanine (IX) and isobutyl chloroformate in the presence of N-methylmorpholine), to furnish the target amide.
| 【1】 Rasnick, D.; Klaus, J.L.; Palmer, J.T. (Khepri Pharmaceuticals Inc.); Irreversible cysteine protease inhibitors containi. WO 9523222 . |
| 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) | 23619 | (2S)-2-[(tert-butoxycarbonyl)amino]-4-phenylbutyric acid | 100564-78-1 | C15H21NO4 | 详情 | 详情 |
| (II) | 23620 | tert-butyl (1S)-1-[[methoxy(methyl)amino]carbonyl]-3-phenylpropylcarbamate | C17H26N2O4 | 详情 | 详情 | |
| (III) | 23621 | tert-butyl (1S)-1-formyl-3-phenylpropylcarbamate | C15H21NO3 | 详情 | 详情 | |
| (IV) | 23622 | methyl phenyl sulfone; methyl(dioxo)phenyl-lambda(6)-sulfane | 3112-85-4 | C7H8O2S | 详情 | 详情 |
| (V) | 23623 | Chlorophosphoric acid ethyl ester；Phosphorochloridic acid diethyl ester；Diethyl chlorophosphate;diethyl phosphorochloridate | 814-49-3 | C4H10ClO3P | 详情 | 详情 |
| (VI) | 23624 | diethyl (phenylsulfonyl)methylphosphonate | C11H17O5PS | 详情 | 详情 | |
| (VII) | 23625 | tert-butyl (1S,2E)-1-phenethyl-3-(phenylsulfonyl)-2-propenylcarbamate | C22H27NO4S | 详情 | 详情 | |
| (VIII) | 23626 | (1S,2E)-1-phenethyl-3-(phenylsulfonyl)-2-propenylamine; (E,3S)-5-phenyl-1-(phenylsulfonyl)-1-penten-3-amine | C17H19NO2S | 详情 | 详情 | |
| (IX) | 23627 | (2S)-2-[(4-morpholinylcarbonyl)amino]-3-phenylpropionic acid | C14H18N2O4 | 详情 | 详情 | |
| (X) | 23628 | N-(4-Morpholinylcarbonyl)-L-phenylalanine ethoxycarbonyl anhydride | C17H22N2O6 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(LXXV)Rearrangement of 5-bromo-2-methylpyridine 1-oxide (LXVII) with trifluoroacetic anhydride gives (5-bromopyridin-2-yl)methyl trifluoroacetate (LXVIII), which, without isolation, is hydrolyzed in MeOH solution, yielding (5-bromopyridin-2-yl)methanol trifluoroacetate salt (LXIX). Basification of compound (LXIX) with K2CO3 followed by chlorination with SOCl2 affords 5-bromo-2-(chloromethyl)pyridine (LXX), which is subsequently condensed with diethyl phosphite in the presence of LiHMDS, affording phosphonate (LXXI). Finally, Suzuki coupling of bromopyridine derivative (LXXI) with 3-fluorophenylboronic acid (V) by means of Na2CO3 and Pd/C in H2O at 75 °C provides the phenylpyridine compound (XII) .
O-Protection of 6-methyl-3-pyridinol (LXXII) with TIPSCl in DMF gives the corresponding silyl ether (LXXIII), which is then condensed with diethyl chlorophosphate (LXXIV) in the presence of BuLi and DIEA in THF, yielding diethyl phosphonate (II) .
| 【1】 Chackalamannil, S., Wang, Y., Greenlee, W.J. et al. Discovery of a novel, orally active himbacine-based thrombin receptor antagonist (SCH 530348) with potent antiplatelet activity. J Med Chem 2008, 51(11): 3061-4. |
| 【2】 Wu, G., Sudhakar, A.R., Wang, T. et al. (Schering Corp.). Exo- and diastereo- selective synthesis of himbacine analogs. CA 2594871, EP 1848705, EP 2196454, EP 2196468, EP 2206697, JP 2008526972, US 2006247450, WO 2006076415. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 68703 | diethyl ((5-((triisopropylsilyl)oxy)pyridin-2-yl)methyl)phosphonate | C19H36NO4PSi | 详情 | 详情 | |
| (V) | 68704 | 3-fluorophenylboronic acid;3-Fluorobenzeneboronic acid | 768-35-4 | C6H6BFO2 | 详情 | 详情 |
| (XII) | 68705 | diethyl ((5-(3-fluorophenyl)pyridin-2-yl)methyl)phosphonate | C16H19FNO3P | 详情 | 详情 | |
| (LXVII) | 68760 | 5-bromo-2-methylpyridine 1-oxide；5-bromo-2-Picoline-1-oxide；3-Bromo-6-methylpyridine 1-oxide;5-bromo-2-methylpyridine N-oxide;5-Bromo-2-picoline N-oxide | 31181-64-3 | C6H6BrNO | 详情 | 详情 |
| (LXVIII) | 68761 | (5-bromopyridin-2-yl)methyl trifluoroacetate；(5-bromopyridin-2-yl)methyl 2,2,2-trifluoroacetate | C8H5BrF3NO2 | 详情 | 详情 | |
| (LXIX) | 68762 | (5-bromopyridin-2-yl)methanol 2,2,2-trifluoroacetate | C6H6BrNO.C2HF3O2 | 详情 | 详情 | |
| (LXX) | 68763 | 5-bromo-2-(chloromethyl)pyridine | 168823-76-5 | C6H5BrClN | 详情 | 详情 |
| (LXXI) | 68764 | diethyl ((5-bromopyridin-2-yl)methyl)phosphonate | C10H15BrNO3P | 详情 | 详情 | |
| (LXXII) | 25748 | 6-methyl-3-pyridinol; 5-Hydroxy-2-methylpyridine | 1121-78-4 | C6H7NO | 详情 | 详情 |
| (LXXIV) | 68765 | 2-methyl-5-((triisopropylsilyl)oxy)pyridine | C15H27NOSi | 详情 | 详情 | |
| (LXXV) | 23623 | Chlorophosphoric acid ethyl ester；Phosphorochloridic acid diethyl ester；Diethyl chlorophosphate;diethyl phosphorochloridate | 814-49-3 | C4H10ClO3P | 详情 | 详情 |