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【结 构 式】 
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【分子编号】17719 【品名】p-Toluoyl chloride; 4-methylbenzoyl chloride 【CA登记号】874-60-2 |
【 分 子 式 】C8H7ClO 【 分 子 量 】154.59568 【元素组成】C 62.15% H 4.56% Cl 22.93% O 10.35% |
合成路线1
该中间体在本合成路线中的序号：(A)The reaction of 3,4-dihydroxyphenyl-tert-butylaminomethyl ketone (I) with sodium ethoxide in DMF gives the corresponding disodium salt, which without isolation is condensed with p-toluyl chloride (A) to yield 3,4-bis(p-toluyloxy)phenyl-tert-butylaminomethyl ketone hydrochloride (II); this salt is then reduced with H2 over Pd/C in ethanol or with sodium borohydride in methanol.
| 【1】 Minatoya, H.; et al.; Ester von alpha-Aminomethyl-3-(hydroxy- oder hydroxymethyl)-4-hydroxybenzyl-alkoholen und Verfahren zu ihrer Herstellung. DE 2015573; FR 2042295; GB 1298771 . |
| 【2】 Castaner, J.; Weetman, D.F.; Bitolterol. Drugs Fut 1976, 1, 10, 454. |
合成路线2
该中间体在本合成路线中的序号：(XXXVI)The reaction of 2,3-O-isopropylidene-D-ribofuranose (XXXV) with 4-methylbenzoyl chloride (XXXVI) by means of pyridine in butyl acetate gives 2,3-O-isopropylidene-5-O-(4-methylbenzoyl)-D-ribofuranose (XXXVII), which is methylated by means of NaH and dimethylsulfate in THF to yield the expected methyl ribofuranoside (XXXVIII). The hydrolysis of the acetonide group of (XXXVIII) with trifluoromethanesulfonic acid in acetonitrile affords 1-O-methyl-5-O-(4-methylbenzoyl)-alpha-D-ribofuranose (XXXIX), which is treated with SO2Cl2/triethylamine in butyl acetate to give the cyclic sulfate (XL). The reduction of (XL) with NaBH4 in THF yields 3-deoxy-1-O-methyl-5-O-(4-methylbenzoyl)-alpha-D-ribofuranose (XLI), which is treated with trifluoromethanesulfonic anhydride and tetrabutylammonium fluoride in dichloromethane/pyridine to afford 2,3-dideoxy-2-fluoro-1-O-methyl-alpha-D-arabinofuranose (XLII). The reaction of (XLII) with HBr in acetic acid as before gives the bromosugar (XLIII), which is condensed with 6-chloro-9-(trimethylsilyl)purine (XLIV) in dichloromethane to yield 6-chloro-9-[2,3-dideoxy-2-fluoro-5-O-(4-methylbenzoyl)-beta-D-arabinofuranosyl]purine (XLV). Finally, this compound is treated with ammonia in methanol at 90 C.
| 【1】 Castaner, J.; Graul, A.; Silvestre, J.S.; Lodenosine. Drugs Fut 1998, 23, 11, 1176-1189. |
| 【2】 Saischek, E.; Dax, K.; Braun, W.; Fuchs, F.; Saischek, G. (Chevron Research Co.); D-Xylofuranose derivs., method of preparing them, their use, and novel intermediate compounds for the method. WO 9606851 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IXL) | 17722 | [(2R,3S,4R,5S)-3,4-dihydroxy-5-methoxytetrahydro-2-furanyl]methyl 4-methylbenzoate | C14H18O6 | 详情 | 详情 | |
| (XXXV) | 17718 | (3aR,6R,6aR)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-ol | C8H14O5 | 详情 | 详情 | |
| (XXXVI) | 17719 | p-Toluoyl chloride; 4-methylbenzoyl chloride | 874-60-2 | C8H7ClO | 详情 | 详情 |
| (XXXVII) | 17720 | [(3aR,4R,6aR)-6-hydroxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl 4-methylbenzoate | C16H20O6 | 详情 | 详情 | |
| (XXXVIII) | 17721 | [(3aR,4R,6S,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl 4-methylbenzoate | C17H22O6 | 详情 | 详情 | |
| (XL) | 17723 | [(3aR,4R,6S,6aR)-6-methoxy-2,2-dioxotetrahydro-2lambda(6)-furo[3,4-d][1,3,2]dioxathiol-4-yl]methyl 4-methylbenzoate | C14H16O8S | 详情 | 详情 | |
| (XLI) | 17724 | [(2S,4R,5S)-4-hydroxy-5-methoxytetrahydro-2-furanyl]methyl 4-methylbenzoate | C14H18O5 | 详情 | 详情 | |
| (XLII) | 17725 | [(2S,4S,5S)-4-fluoro-5-methoxytetrahydro-2-furanyl]methyl 4-methylbenzoate | C14H17FO4 | 详情 | 详情 | |
| (XLIII) | 17726 | [(2S,4S,5S)-5-bromo-4-fluorotetrahydro-2-furanyl]methyl 4-methylbenzoate | C13H14BrFO3 | 详情 | 详情 | |
| (XLIV) | 17727 | 6-chloro-9-(trimethylsilyl)-9H-purine | C8H11ClN4Si | 详情 | 详情 | |
| (XLV) | 17728 | [(2S,4S,5R)-5-(6-chloro-9H-purin-9-yl)-4-fluorotetrahydro-2-furanyl]methyl 4-methylbenzoate | C18H16ClFN4O3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)A practical synthetic approach to lodenosine has been developed: Acylation of the chiral carbinol (I) with 4-methylbenzoyl chloride (II) and pyridine in dichloromethane gives the ester (III), which is diastereoselectively hydrogenated with H2 over Pd/C in ethyl acetate to yield the tetrahydrofuranone (IV). Surprisingly, the diastereoselectivity of this reaction depends on the hydrogen pressure: while at 40 psi it is very poor, at 10 psi it increases to 98%. The reduction of lactone (IV) with red-Al and 2-hydroxypyridine in THF at -30 C affords the lactol (V), which is treated with Ac2O and catalytic concentrated H2SO4 to provide the acetate ester (VI). Reaction of compound (VI) with HBr in AcOH gives the bromo derivative (VII), which is condensed with N6-benzoyl adenine (VIII) by means of NaH in refluxing THF to give the acylated adenosine derivative (IX). Finally, this compound is deprotected with NaOMe in refluxing methanol.
| 【1】 Xu, G.Y.; Wang, D.J.; Pierce, M.E.; Choudhury, A.; Nguyen, D.; Jin, F.Q.; Confalona, P.N.; Wang, Z.; (2R,3S,5S)-2-Acetoxy-3-fluoro-5-(p-toluoyloxymethyl)tetrahydrofuran: A key intermediate for the practical synthesis of 9-(2,3-dideoxy-2-fluoro-beta-D-threo-pentofuranosyl)adenine (FddA). Tetrahedron Lett 2001, 42, 29, 4787. |
| 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) | 48723 | (5S)-3-fluoro-5-(hydroxymethyl)-2(5H)-furanone | C5H5FO3 | 详情 | 详情 | |
| (II) | 17719 | p-Toluoyl chloride; 4-methylbenzoyl chloride | 874-60-2 | C8H7ClO | 详情 | 详情 |
| (III) | 48724 | [(2S)-4-fluoro-5-oxo-2,5-dihydro-2-furanyl]methyl 4-methylbenzoate | C13H11FO4 | 详情 | 详情 | |
| (IV) | 48725 | [(2S,4S)-4-fluoro-5-oxotetrahydro-2-furanyl]methyl 4-methylbenzoate | C13H13FO4 | 详情 | 详情 | |
| (V) | 48726 | [(2S,4S)-4-fluoro-5-hydroxytetrahydro-2-furanyl]methyl 4-methylbenzoate | C13H15FO4 | 详情 | 详情 | |
| (VI) | 48727 | [(2S,4S,5R)-5-(acetoxy)-4-fluorotetrahydro-2-furanyl]methyl 4-methylbenzoate | C15H17FO5 | 详情 | 详情 | |
| (VII) | 48728 | [(2S,4S,5R)-5-bromo-4-fluorotetrahydro-2-furanyl]methyl 4-methylbenzoate | C13H14BrFO3 | 详情 | 详情 | |
| (VIII) | 10035 | N-(9H-Purin-6-yl)benzamide; N6-Benzoyladenine | 4005-49-6 | C12H9N5O | 详情 | 详情 |
| (IX) | 48729 | [(2S,4S,5R)-5-[6-(benzoylamino)-9H-purin-9-yl]-4-fluorotetrahydro-2-furanyl]methyl 4-methylbenzoate | C25H22FN5O4 | 详情 | 详情 |