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【结 构 式】 
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【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% |
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 |