【结 构 式】 |
【分子编号】20668 【品名】diisopropyl (2S,4R)-4-[(2-amino-6-chloro-9H-purin-9-yl)methyl]-1,3-dioxolan-2-ylphosphonate 【CA登记号】 |
【 分 子 式 】C15H23ClN5O5P 【 分 子 量 】419.804782 【元素组成】C 42.92% H 5.52% Cl 8.45% N 16.68% O 19.06% P 7.38% |
合成路线1
该中间体在本合成路线中的序号:(VIII)(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 |