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【结 构 式】 
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【药物名称】Naxifylline, BG-9719, CVT-124, Adentri 【化学名称】(1S,2R,3S,4S,6S)-8-[3-Oxatricyclo[3.2.1.0(2,4)]oct-6-yl]-1,3-dipropylxanthine 【CA登记号】166374-49-8, 166374-48-7 ((6R)-isomer), 166181-76-6 (undefined isomer) 【 分 子 式 】C18H24N4O3 【 分 子 量 】344.41698 |
【开发单位】University of Florida (Originator), Biogen Idec (Licensee), CV Therapeutics (Licensee) 【药理作用】CARDIOVASCULAR DRUGS, Heart Failure Therapy, IMMUNOMODULATING AGENTS, Treatment of Autoimmune Diseases, Adenosine A1 Antagonists |
合成路线1
The asymmetric Diels-Alder cycloaddition of cyclopentadiene (II) with the acrylic ester (I) of the chiral auxiliary D-pantolactone catalyzed by TiCl4 gives the chiral norbornene (III), which is treated with LiOH or NaOH to eliminate the auxiliary to yield the carboxylic acid (IV). The reaction of (IV) with oxalyl chloride affords the acyl chloride (V), which is condensed with 5,6-diamino-1,3-dipropyluracil (VI) by means of DMAP in pyridine to provide the amide (VII). The cyclization of (VII) by means of NaOH in dioxane gives the 1,3-dipropylxanthine derivative (VIII), which is finally epoxidated by means of magnesium monoperphthalate (MMPP) in aq. isopropanol to furnish the target xanthine derivative.
| 【1】 Pfister, J.R.; et al.; Synthesis and biological evaluation of the enantiomers of the potent and selective A1-adenosine antagonist 1, 3-dipropyl-8-[2-(5,6-epoxynorbonyl)]xanthine. J Med Chem 1997, 40, 12, 1773. |
| 【2】 Belardinelli, L.; Olsson, R.; Baker, S.; Scammells, P.J.; Milner, P.G.; Pfister, J.R.; Schreiner, G.F. (University of Florida); Novel A1 adenosine receptor agonists and antagonists. EP 0725782; JP 1997507052; US 5446046; WO 9511904 . |
| 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) | 54720 | (3R)-2,2-dimethyl-4-oxotetrahydro-3-furanyl acrylate | C9H12O4 | 详情 | 详情 | |
| (II) | 11183 | 1,3-Cyclopentadiene | C5H6 | 详情 | 详情 | |
| (III) | 54721 | (3R)-2,2-dimethyl-4-oxotetrahydro-3-furanyl (1S,2S,4S)bicyclo[2.2.1]hept-5-ene-2-carboxylate | C14H18O4 | 详情 | 详情 | |
| (IV) | 54722 | (1S,2S,4S)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid | C8H10O2 | 详情 | 详情 | |
| (V) | 54723 | (1S,2S,4S)bicyclo[2.2.1]hept-5-ene-2-carbonyl chloride | C8H9ClO | 详情 | 详情 | |
| (VI) | 14628 | 5,6-diamino-1,3-dipropyl-2,4(1H,3H)-pyrimidinedione | C10H18N4O2 | 详情 | 详情 | |
| (VII) | 54724 | (1S,2S,4S)-N-(6-amino-2,4-dioxo-1,3-dipropyl-1,2,3,4-tetrahydro-5-pyrimidinyl)bicyclo[2.2.1]hept-5-ene-2-carboxamide | C18H26N4O3 | 详情 | 详情 | |
| (VIII) | 54725 | 8-[(1S,2S,4S)bicyclo[2.2.1]hept-5-en-2-yl]-1,3-dipropyl-3,9-dihydro-1H-purine-2,6-dione | C18H24N4O2 | 详情 | 详情 |