【结 构 式】 |
【药物名称】GS-7340 【化学名称】N-[[S(P)]-[2-(Adenin-9-yl)-1(R)-methylethoxymethyl](phenoxy)phosphoryl]-L-alanine isopropyl ester 【CA登记号】379270-37-8, 379270-38-9 (fumarate) 【 分 子 式 】C21H29N6O5P 【 分 子 量 】476.47628 |
【开发单位】Gilead (Originator) 【药理作用】AIDS Medicines, Anti-Hepatitis B Virus Drugs, Anti-Hepatitis Virus Drugs, Anti-HIV Agents, ANTIINFECTIVE THERAPY, Antiviral Drugs, Chemical Delivery Systems, DRUG DELIVERY, Drug Delivery Systems, Reverse Transcriptase Inhibitors |
合成路线1
Alkylation of adenine (I) by means of (R)-propylene carbonate (II) in the presence of NaOH in hot DMF provided (R)-9-(2-hydroxypropyl)adenine (III). This was condensed with tosylate (IV) using magnesium tert-butoxide to furnish the alkoxymethylphosphonate (V). Phosphonic acid (VI) was then obtained by hydrolysis of the phosphate ester groups with bromotrimethylsilane. Monophenyl phosphonate (IX) was prepared by either coupling of acid (VI) with phenol (VII) in the presence of DCC or by previous activation of (VI) with SOCl2, and then coupling with phenoxytrimethylsilane (VIII). Further activation of (IX) with SOCl2 to give (X), followed by its condensation with L-alanine isopropyl ester (XI), yielded phosphonamide (XII) as a mixture of diastereomers. The title isomer was then isolated by several alternative procedures, including column chromatography over various supports and fractional crystallization.
【1】 Prisbe, E.J.; Lee, W.A.; Rohloff, J.C.; Becker, M.W.; Chapman, H.H.; Cihlar, T.; Eisenberg, E.J.; He, G.-X.; Kernan, M.R.; Sparacino, M.L. (Gilead Sciences Inc.); Prodrugs of phosphonate nucleotide analogues and methods for selecting and making same. WO 0208241 . |
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) | 10343 | 9H-Purin-6-amine; 9H-Purin-6-ylamine; Adenine | 73-24-5 | C5H5N5 | 详情 | 详情 |
(II) | 19244 | (4S)-4-methyl-1,3-dioxolan-2-one | C4H6O3 | 详情 | 详情 | |
(III) | 19232 | (2S)-1-(6-amino-9H-purin-9-yl)-2-propanol | C8H11N5O | 详情 | 详情 | |
(IV) | 12072 | Dibromoneopentyl glycol; 2,2-Bis(bromomethyl)-1,3-propanediol | 3296-90-0 | C5H10Br2O2 | 详情 | 详情 |
(V) | 19246 | diethyl [[(1S)-2-(6-amino-9H-purin-9-yl)-1-methylethyl]oxy]methylphosphonate | C13H22N5O4P | 详情 | 详情 | |
(VI) | 19252 | [[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethyl]oxy]methylphosphonic acid | C9H14N5O4P | 详情 | 详情 | |
(VII) | 23540 | Phenol | 108-95-2 | C6H6O | 详情 | 详情 |
(VIII) | 58583 | Trimethylsilylphenoxide; Phenoxytrimethylsilane | 1529-17-5 | C9H14OSi | 详情 | 详情 |
(IX) | 58584 | phenyl hydrogen {[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethyl]oxy}methylphosphonate | C15H18N5O4P | 详情 | 详情 | |
(X) | 58585 | phenyl {[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethyl]oxy}methylphosphonate chloride | C15H17ClN5O3P | 详情 | 详情 | |
(XI) | 58586 | isopropyl (2S)-2-aminopropanoate | C6H13NO2 | 详情 | 详情 | |
(XII) | 58587 | isopropyl (2S)-2-{[({[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethyl]oxy}methyl)(phenoxy)phosphoryl]amino}propanoate | C21H29N6O5P | 详情 | 详情 |