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【结 构 式】 
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【分子编号】27916 【品名】hexadecanoic anhydride 【CA登记号】623-65-4 |
【 分 子 式 】C32H62O3 【 分 子 量 】494.84248 【元素组成】C 77.67% H 12.63% O 9.7% |
合成路线1
该中间体在本合成路线中的序号：(III)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：(VIII)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3
该中间体在本合成路线中的序号：(II)The target compound is obtained by esterification of Taxol (paclitaxel) (I) with hexadecanoic anhydride (II) by means of DCC in dichloromethane.
| 【1】 Ali, S.; et al.; Hydrolyzable hydrophobic taxanes: Synthesis and anti-cancer activities. Anti-Cancer Drugs 2001, 12, 2, 117. |
| 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) | 10595 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-[[(2R,3S)-3-(benzoylamino)-2-hydroxy-3-phenylpropanoyl]oxy]-1,9-dihydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | 33069-62-4 | C47H51NO14 | 详情 | 详情 |
| (II) | 27916 | hexadecanoic anhydride | 623-65-4 | C32H62O3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(IX)The reaction of the epoxy-glucoside (I) with Tms-N3 in DMF gives the azido-glucoside (II), which is treated with Pmb-Cl and NaH in DMF to yield the aryl ether protected glucoside (III). The cleavage of the acetonide group of (III) by means of HOAc/water affords the dihydroxy compound (IV), which is acylated by means of Ac2O and pyridine to provide the diacetate (V). The condensation of (V) with uracil (VI) by means of BSA and Tms-Br in acetonitrile gives the uridine derivative (VII), which is reduced at its azido group by means of H2 over Pd/C in ethyl acetate to yield the amino derivative (VIII). The condensation of (VIII) with palmitic anhydride (IX) affords the corresponding amide (X), which is selectively deprotected by means of TFA to provide the alcohol (XI). The condensation of (XI) with 5-azido-5-deoxy-1,2,3-O-triacetyl-alpha-D-ribofuranose (XII) by means of SnCl4 in dichloromethane provides the uridine derivative (XIII), which is deacetylated by means of MeONa in methanol to give the azido precursor (XIV). Finally, the azido group of (XIV) is reduced by means of H2 over Pd/C in methanol to yield the target compound.
| 【1】 Dini, C.; et al.; Synthesis and in vitro evaluation of riburamycin RU75411: Activity against MraY, antibacterial profile, and mechanism of action (MOA) on whole cells. 42nd Intersci Conf Antimicrob Agents Chemother (Sept 27 2002, San Diego) 2002, Abst F-361. |
| 【2】 Aszodi, J.; Didierlaurent, S.; Dini, C.; Zhang, J.; Drochon, N.; Guillot, J.-C. (Aventis Pharma SA); Uridine derivs. as antibiotics. EP 1284984; WO 0185750 . |
| 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) | 58679 | (3aR,5S,6aR)-2,2-dimethyl-5-[(2S)oxiranyl]tetrahydrofuro[2,3-d][1,3]dioxole | C9H14O4 | 详情 | 详情 | |
| (II) | 58680 | (1S)-1-[(3aR,5S,6aR)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl]-2-azido-1-ethanol | C9H15N3O4 | 详情 | 详情 | |
| (III) | 58681 | (3aR,5S,6aR)-5-{(1S)-2-azido-1-[(4-methoxybenzyl)oxy]ethyl}-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole; (1S)-1-[(3aR,5S,6aR)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl]-2-azidoethyl 4-methoxybenzyl ether | C17H23N3O5 | 详情 | 详情 | |
| (IV) | 58682 | (2S,3R,5S)-5-{(1S)-2-azido-1-[(4-methoxybenzyl)oxy]ethyl}tetrahydro-2,3-furandiol | C14H19N3O5 | 详情 | 详情 | |
| (V) | 58683 | (2R,3R,5S)-2-(acetyloxy)-5-{(1S)-2-azido-1-[(4-methoxybenzyl)oxy]ethyl}tetrahydro-3-furanyl acetate | C18H23N3O7 | 详情 | 详情 | |
| (VI) | 30921 | 2,4(1H,3H)-pyrimidinedione; Uracil | 66-22-8 | C4H4N2O2 | 详情 | 详情 |
| (VII) | 58684 | (2R,3R,5S)-5-{(1S)-2-azido-1-[(4-methoxybenzyl)oxy]ethyl}-2-[2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-3-furanyl acetate | C20H23N5O7 | 详情 | 详情 | |
| (VIII) | 58685 | (2R,3R,5S)-5-{(1S)-2-amino-1-[(4-methoxybenzyl)oxy]ethyl}-2-[2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-3-furanyl acetate | C20H25N3O7 | 详情 | 详情 | |
| (IX) | 27916 | hexadecanoic anhydride | 623-65-4 | C32H62O3 | 详情 | 详情 |
| (X) | 58686 | (2R,3R,5S)-2-[2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-5-[(1S)-1-[(4-methoxybenzyl)oxy]-2-(palmitoylamino)ethyl]tetrahydro-3-furanyl acetate | C36H55N3O8 | 详情 | 详情 | |
| (XI) | 58687 | (2R,3R,5S)-2-[2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-5-[(1S)-1-hydroxy-2-(palmitoylamino)ethyl]tetrahydro-3-furanyl acetate | C28H47N3O7 | 详情 | 详情 | |
| (XII) | 58688 | (2R,3R,4R,5R)-2,4-bis(acetyloxy)-5-(azidomethyl)tetrahydro-3-furanyl acetate | C11H15N3O7 | 详情 | 详情 | |
| (XIII) | 58689 | (2R,3R,4R,5S)-4-(acetyloxy)-5-{[(1S)-1-{(2S,4R,5R)-4-(acetyloxy)-5-[2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl}-2-(palmitoylamino)ethyl]oxy}-2-(azidomethyl)tetrahydro-3-furanyl acetate | C37H58N6O12 | 详情 | 详情 | |
| (XIV) | 58690 | N-((2S)-2-{[(2R,3R,4S,5R)-5-(azidomethyl)-3,4-dihydroxytetrahydro-2-furanyl]oxy}-2-{(2S,4R,5R)-5-[2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-4-hydroxytetrahydro-2-furanyl}ethyl)hexadecanamide | C31H52N6O9 | 详情 | 详情 |