|
【结 构 式】 
|
【分子编号】27919 【品名】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 【CA登记号】 |
【 分 子 式 】C38H68N4O6Si2 【 分 子 量 】733.15228 【元素组成】C 62.25% H 9.35% N 7.64% O 13.09% Si 7.66% |
合成路线1
该中间体在本合成路线中的序号：(VI)CS-682 has been synthesized by several related ways: 1) By acylation of 2'-cyano-2'-deoxy-1-(beta-D-arabinofuranosyl)cytosine (I) with hexadecanoyl chloride (II) and trimethylsilyl chloride in pyridine. 2) By acylation of 2'-cyano-2'-deoxy-1-(beta-D-arabinofuranosyl)cytosine (I) with hexadecanoyl anhydride (III) in hot DMF. 3) The protection of the OH groups of 2'-cyano-2'-deoxy-1-(beta-D-arabinofuranosyl)cytosine (I) with 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane in pyridine gives the 3',5'-cyclic disiloxane (IV), which is acylated by means of hexadecanoic acid (V) and DCC in THF, yielding the silylated compound (VI). Finally, this compound is deprotected with tetrabutylammonium fluoride (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 |
|---|---|---|---|---|---|---|
| (I) | 27915 | (2R,3S,4S,5R)-2-[4-amino-2-oxo-1(2H)-pyrimidinyl]-4-hydroxy-5-(hydroxymethyl)tetrahydro-3-furancarbonitrile | C10H12N4O4 | 详情 | 详情 | |
| (II) | 16480 | Palmitoyl Chloride; hexadecanoyl chloride | 112-67-4 | C16H31ClO | 详情 | 详情 |
| (III) | 27916 | hexadecanoic anhydride | 623-65-4 | C32H62O3 | 详情 | 详情 |
| (IV) | 27917 | (6aR,8R,9S,9aS)-8-[4-amino-2-oxo-1(2H)-pyrimidinyl]-2,2,4,4-tetraisopropyltetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocine-9-carbonitrile | C22H38N4O5Si2 | 详情 | 详情 | |
| (V) | 27918 | palmitic acid | 57-10-3 | C16H32O2 | 详情 | 详情 |
| (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 |
合成路线2
该中间体在本合成路线中的序号：(VI)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 |