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【结 构 式】

【药物名称】

【化学名称】(2S,4R)-4-(2-Amino-6-oxo-1,6-dihydro-9H-purin-9-ylmethyl)-1,3-dioxolan-2-ylphosphonic acid ammonium salt
      9-[2(S)-Phosphono-1,3-dioxolan-4(R)-ylmethyl]guanine ammonium salt

【CA登记号】

【 分 子 式 】C9H15N6O6P

【 分 子 量 】334.2303

【开发单位】Shire BioChem (Originator)

【药理作用】ANTIINFECTIVE THERAPY, Antiviral Drugs

合成路线1

(S)-Glycidol (I) was selectively opened by Li2NiBr4 at 0 C to provide (S)-3-bromo-1,2-propanediol (II). Subsequent reaction of (II) with trimethyl orthoformate in the presence of p-toluenesulfonic acid generated the dioxolane (III) as a 1:1 mixture of cis and trans orthoesters. The methoxy orthoester (III) was further converted to the isopropoxy analogue (IV) by treatement with isopropanol under acidic conditions. Introduction of the phosphonate group in (IV) was achieved by means of a ZnCl2-catalyzed Arbuzov reaction with triisopropyl phosphite and phosphorus trichloride to give a 2:5 mixture of cis (V) and trans (VI) phosphonates, which were separated by flash chromatography. Displacement of cis bromide (V) with 2-amino-6-chloropurine (VII) in the presence of Cs2CO3 in DMF at 60 C provided compound (VIII). The phosphonate ester of (VIII) was then deprotected by treatment with ISiMe3, followed by aqueous hydrolysis of the intermediate silyl phosphonate (IX) and concomitant hydrolysis of the 6-chloropurine to guanine (X). Finally, absorption on a Sephadex DEAE A-25 column, followed by elution with ammonium bicarbonate solution, provided the title ammonium salt.

1 Nguyen-Ba, P.; Lee, N.; Mitchell, H.; Chan, L.; Quimpere, M.; Design and synthesis of a novel class of nucleotide analogs with anti-HCMV activity. Bioorg Med Chem Lett 1998, 8, 24, 3555.
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) 19241 (2S)oxiranylmethanol 60456-23-7 C3H6O2 详情 详情
(II) 20662 (2S)-3-bromo-1,2-propanediol C3H7BrO2 详情 详情
(III) 20663 (4S)-4-(bromomethyl)-2-methoxy-1,3-dioxolane; (4S)-4-(bromomethyl)-1,3-dioxolan-2-yl methyl ether C5H9BrO3 详情 详情
(IV) 20664 (4S)-4-(bromomethyl)-2-isopropoxy-1,3-dioxolane; (4S)-4-(bromomethyl)-1,3-dioxolan-2-yl isopropyl ether C7H13BrO3 详情 详情
(V) 20665 diisopropyl (2S,4S)-4-(bromomethyl)-1,3-dioxolan-2-ylphosphonate C10H20BrO5P 详情 详情
(VI) 20666 diisopropyl (2R,4S)-4-(bromomethyl)-1,3-dioxolan-2-ylphosphonate C10H20BrO5P 详情 详情
(VII) 11644 6-Chloro-9H-purin-2-amine; 6-Chloro-9H-purin-2-ylamine; 2-Amino-6-chloropurine 10310-21-1 C5H4ClN5 详情 详情
(VIII) 20668 diisopropyl (2S,4R)-4-[(2-amino-6-chloro-9H-purin-9-yl)methyl]-1,3-dioxolan-2-ylphosphonate C15H23ClN5O5P 详情 详情
(IX) 20669 bis(trimethylsilyl) (2S,4R)-4-[(2-amino-6-chloro-9H-purin-9-yl)methyl]-1,3-dioxolan-2-ylphosphonate C15H27ClN5O5PSi2 详情 详情
(X) 20670 (2S,4R)-4-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methyl]-1,3-dioxolan-2-ylphosphonic acid C9H12N5O6P 详情 详情
Extended Information