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【结 构 式】

【分子编号】19252

【品名】[[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethyl]oxy]methylphosphonic acid

【CA登记号】

【 分 子 式 】C9H14N5O4P

【 分 子 量 】287.215222

【元素组成】C 37.64% H 4.91% N 24.38% O 22.28% P 10.78%

与该中间体有关的原料药合成路线共 3 条

合成路线1

该中间体在本合成路线中的序号:(IV)

The reaction of chloromethyl chloroformate (I) with isopropyl alcohol (II) by means of pyridine or triethylamine in ether gives the mixed carbonate (III), which is then condensed with (R)-PMPA (IV) by means of diisopropyl ethyl-amine in DMF.

1 Oliyai, R.; Dougherty, J.; Bischofberger, N.; Kim, C.U.; Mulato, A.; Shaw, J.P.; Cundy, K.C.; Arimilli, M.N.; Synthesis, in vitro biological evaluation and oral bioavailability of 9-[2-(phosphonomethoxy)propyl]adenine (PMPA) prodrugs. Antivir Chem Chemother 1997, 8, 6, 557.
2 Sorbera, L.A.; Castañer, J.; (R)-PMPA and Bis(POC)PMPA. Drugs Fut 1998, 23, 12, 1279.
3 Arimilli, M.N.; Cundy, K.C.; Dougherty, J.P.; Kim, C.U.; Oliyai, R.; Stella, V.J. (Gilead Sciences Inc.); Nucleotide analogs. US 5922695; WO 9804569 .
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) 19249 Chloromethyl chloroformate; Chloro[(chlorocarbonyl)oxy]methane 22128-62-7 C2H2Cl2O2 详情 详情
(II) 19250 2-propanol 67-63-0 C3H8O 详情 详情
(III) 19251 chloromethyl isopropyl carbonate C5H9ClO3 详情 详情
(IV) 19252 [[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethyl]oxy]methylphosphonic acid C9H14N5O4P 详情 详情

合成路线2

该中间体在本合成路线中的序号:(VI)

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

合成路线3

该中间体在本合成路线中的序号:(I)

 

1 Parthasaradhi Reddy B, Rathnakar Reddy K. Raji Reddy R,et aL. 2007. Process for the prrparation of acyclic phosphonate nucleotide analogs. W0 2007013085
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) 19252 [[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethyl]oxy]methylphosphonic acid C9H14N5O4P 详情 详情
(II) 66828 (R,Z)-(((1-(6-(((dimethylamino)methylene)amino)-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonic acid   C12H19N6O4P 详情 详情
Extended Information