diisopropyl ({1-[(6-amino-4-chloro-1H-benzimidazol-1-yl)methyl]cyclopropyl}oxy)methylphosphonate -Drug Synthesis Database

【结构式】

【分子编号】60573

【品名】diisopropyl ({1-[(6-amino-4-chloro-1H-benzimidazol-1-yl)methyl]cyclopropyl}oxy)methylphosphonate

【CA登记号】

【分子式】C₁₈H₂₇ClN₃O₄P

【分子量】415.856662

【元素组成】C 51.99% H 6.54% Cl 8.53% N 10.1% O 15.39% P 7.45%

与该中间体有关的原料药合成路线共 1 条

合成路线1

该中间体在本合成路线中的序号：(VIII)

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

参考文献中间体

合成目标

【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

Extended Information