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【结 构 式】 
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【分子编号】60570 【品名】diisopropyl {[1-(hydroxymethyl)cyclopropyl]oxy}methylphosphonate 【CA登记号】 |
【 分 子 式 】C11H23O5P 【 分 子 量 】266.274382 【元素组成】C 49.62% H 8.71% O 30.04% P 11.63% |
合成路线1
该中间体在本合成路线中的序号：(V)The key intermediate, cyclopropanol (I), was prepared by titanium-mediated Kulinkovich cyclopropanation in over 80% yield as a white solid. Etherification of compound (I) with diisopropyl bromomethylphosphonate, followed by sequential desilylation, mesylation and coupling reaction with 6-chloroguanine (VII), gave compound (VIII). Finally, hydrolysis of compound (VIII) in the presence of TMSBr afforded LB-80317.
| 【1】 Hwang, J.-T.; Choi, J.-R.; Novel phosphonate nucleosides as antiviral agents. Drugs Fut 2004, 29, 2, 163. |
| 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) | 60566 | ethyl 2-{[tert-butyl(diphenyl)silyl]oxy}acetate | C20H26O3Si | 详情 | 详情 | |
| (II) | 60567 | 1-({[tert-butyl(diphenyl)silyl]oxy}methyl)cyclopropanol | C20H26O2Si | 详情 | 详情 | |
| (III) | 60568 | diisopropyl bromomethylphosphonate | C7H16BrO3P | 详情 | 详情 | |
| (IV) | 60569 | diisopropyl {[1-({[tert-butyl(diphenyl)silyl]oxy}methyl)cyclopropyl]oxy}methylphosphonate | C27H41O5PSi | 详情 | 详情 | |
| (V) | 60570 | diisopropyl {[1-(hydroxymethyl)cyclopropyl]oxy}methylphosphonate | C11H23O5P | 详情 | 详情 | |
| (VI) | 63954 | diisopropyl {[1-({[methyl(dimethylene)-lambda~6~-sulfanyl]oxy}methyl)cyclopropyl]oxy}methylphosphonate | C14H29O5PS | 详情 | 详情 | |
| (VII) | 63955 | 6,9-dichloro-9H-purin-2-ylamine; 6,9-dichloro-9H-purin-2-amine | C5H3Cl2N5 | 详情 | 详情 | |
| (VIII) | 63956 | diisopropyl ({1-[(2-amino-6-chloro-9H-purin-9-yl)methyl]cyclopropyl}oxy)methylphosphonate | C16H25ClN5O4P | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)The silylated ethyl glycolate (I) is transformed into the cyclopropyl alcohol (II) by using the Kulinkovich reaction in the presence of ethylmagnesium bromide and titanium isopropoxide. Alcohol (II) is then condensed with diisopropyl (bromomethyl)phosphonate (III) to produce the alkoxymethyl phosphonate (IV). After desilylation of (IV) with ammonium fluoride, the free alcohol (V) is treated with methanesulfonyl chloride and triethylamine to provide mesylate (VI). Condensation of (VI) with 2-amino-6-chloropurine (VII) leads to the 9-substituted purine (VIII) as the major reaction product. Removal of the 6-chloro group of (VIII) by catalytic hydrogenolysis furnishes purine (IX). The phosphonate ester of (IX) is hydrolyzed to phosphonic acid (X) employing bromotrimethylsilane. Finally, condensation of (X) with chloromethyl pivalate (XI) in the presence of either N,N'-dicyclohexyl-4-morpholine-carboxamidine (DCMC) or triethylamine gives rise to the title compound
| 【1】 Hwang, J.-T.; Choi, J.-R.; Novel phosphonate nucleosides as antiviral agents. Drugs Fut 2004, 29, 2, 163. |
| 【2】 Choi, J.; Hwang, J.; Cho, D.G.; et al.; Synthesis and determination of oral bioavailability of prodrugs of a novel phosphonate nucleotide, LB80317. 42nd Intersci Conf Antimicrob Agents Chemother (Sept 27 2002, San Diego) 2002, Abst F-1689. |
| 【3】 Pavie, J.; Lefort, A.; Zarrouk, V.; Chau, F.; Garry, L.; Leclercq, R.; Fantin, B.; Efficacies of quinupristin-dalfopristin combined with vancomycin in vitro and in experimental endocarditis due to methicillin-resistant Staphylococcus aureus in relation to cross-resistance to macrolides, lincosamides, and streptogramin B- type antibiotic. Antimicrob Agents Chemother 2002, 46, 9, 3061. |
| 【4】 Lee, C.-H.; Kim, Y.-Z.; Kim, J.-H.; Choi, T.-S.; Kim, C.-M.; Kim, J.-M.; Choi, J.-R.; Roh, K.-Y.; Cho, D.-G.; Hwang, J.-T.; Cho, W.-Y.; Jang, H.-S.; Kim, T.-K.; Cho, S.-J.; Kim, G.-W. (LG Chem Ltd.); Novel acyclic nucleoside phosphonate derivs., salts thereof and process for the preparation of the same. WO 0257288 . |
| 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) | 60566 | ethyl 2-{[tert-butyl(diphenyl)silyl]oxy}acetate | C20H26O3Si | 详情 | 详情 | |
| (II) | 60567 | 1-({[tert-butyl(diphenyl)silyl]oxy}methyl)cyclopropanol | C20H26O2Si | 详情 | 详情 | |
| (III) | 60568 | diisopropyl bromomethylphosphonate | C7H16BrO3P | 详情 | 详情 | |
| (IV) | 60569 | diisopropyl {[1-({[tert-butyl(diphenyl)silyl]oxy}methyl)cyclopropyl]oxy}methylphosphonate | C27H41O5PSi | 详情 | 详情 | |
| (V) | 60570 | diisopropyl {[1-(hydroxymethyl)cyclopropyl]oxy}methylphosphonate | C11H23O5P | 详情 | 详情 | |
| (VI) | 60571 | {1-[(diisopropoxyphosphoryl)methoxy]cyclopropyl}methyl methanesulfonate | C12H25O7PS | 详情 | 详情 | |
| (VII) | 60572 | 4-chloro-1H-benzimidazol-6-amine; 4-chloro-1H-benzimidazol-6-ylamine | C7H6ClN3 | 详情 | 详情 | |
| (VIII) | 60573 | diisopropyl ({1-[(6-amino-4-chloro-1H-benzimidazol-1-yl)methyl]cyclopropyl}oxy)methylphosphonate | C18H27ClN3O4P | 详情 | 详情 | |
| (IX) | 60574 | diisopropyl ({1-[(2-amino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methylphosphonate | C16H26N5O4P | 详情 | 详情 | |
| (X) | 60575 | ({1-[(2-amino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methylphosphonic acid | C10H14N5O4P | 详情 | 详情 | |
| (XI) | 16166 | chloromethyl pivalate | 18997-19-8 | C6H11ClO2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(V)The key intermediate, cyclopropanol (I), was prepared by titanium-mediated Kulinkovich cyclopropanation in over 80% yield as a white solid. Etherification of compound (I) with diisopropyl bromomethylphosphonate, followed by sequential desilylation, mesylation and coupling reaction with 6-chloroguanine (VII), gave compound (VIII). Finally, hydrogenation of compound (VIII) in the presence of TMSBr afforded LB-80331.
| 【1】 Hwang, J.-T.; Choi, J.-R.; Novel phosphonate nucleosides as antiviral agents. Drugs Fut 2004, 29, 2, 163. |
| 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) | 60566 | ethyl 2-{[tert-butyl(diphenyl)silyl]oxy}acetate | C20H26O3Si | 详情 | 详情 | |
| (II) | 60567 | 1-({[tert-butyl(diphenyl)silyl]oxy}methyl)cyclopropanol | C20H26O2Si | 详情 | 详情 | |
| (III) | 60568 | diisopropyl bromomethylphosphonate | C7H16BrO3P | 详情 | 详情 | |
| (IV) | 60569 | diisopropyl {[1-({[tert-butyl(diphenyl)silyl]oxy}methyl)cyclopropyl]oxy}methylphosphonate | C27H41O5PSi | 详情 | 详情 | |
| (V) | 60570 | diisopropyl {[1-(hydroxymethyl)cyclopropyl]oxy}methylphosphonate | C11H23O5P | 详情 | 详情 | |
| (VI) | 63954 | diisopropyl {[1-({[methyl(dimethylene)-lambda~6~-sulfanyl]oxy}methyl)cyclopropyl]oxy}methylphosphonate | C14H29O5PS | 详情 | 详情 | |
| (VII) | 63955 | 6,9-dichloro-9H-purin-2-ylamine; 6,9-dichloro-9H-purin-2-amine | C5H3Cl2N5 | 详情 | 详情 | |
| (VIII) | 63956 | diisopropyl ({1-[(2-amino-6-chloro-9H-purin-9-yl)methyl]cyclopropyl}oxy)methylphosphonate | C16H25ClN5O4P | 详情 | 详情 |