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【结 构 式】 
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【分子编号】19235 【品名】diisopropyl [[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethyl]oxy]methylphosphonate 【CA登记号】 |
【 分 子 式 】C15H26N5O4P 【 分 子 量 】371.376502 【元素组成】C 48.51% H 7.06% N 18.86% O 17.23% P 8.34% |
合成路线1
该中间体在本合成路线中的序号：(X)1) The protection of isobutyl D-(+)-lactate (I) with dihydropyran (DHP)/HCl in DMF gives the tetrahydropyranyloxy derivative (II), which is reduced with bis(2-methoxyethoxy)aluminum hydride in refluxing ether/ toluene yielding 2(R)-(tetrahydropyranyloxy)-1-propanol (III). The tosylation of (III) with tosyl chloride as usual affords the expected tosylate (VI), which is condensed with adenine (V) by means of Cs2CO3 in hot DMF, affording 9-[2(R)-(tetrahydropyranyloxy)propyl]adenine (VI). The deprotection of (VI) with sulfuric acid affords 9-[2(R)-hydroxypropyl]adenine (VII), which is N-benzoylated with benzoyl chloride/chlorotrimethylsilane in pyridine to give the benzamide (VIII), which is condensed with tosyl-oxymethylphosphonic acid diisopropyl ester (IX) by means of NaH in DMF to yield 9-[2(R)-(diisopropoxyphosphorylmethoxy)propyl]adenine (X). Finally, this compound is hydrolyzed by means of bromotrimethylsilane in acetonotrile.
| 【1】 Masojídková, M.; Holý, A.; Synthesis of enantiomeric N-(2-phosphonomethoxypropyl) derivatives of purine and pyrimidine bases. I. The stepwise approach. Coll Czech Chem Commun 1995, 60, 7, 1196. |
| 【2】 Sorbera, L.A.; Castañer, J.; (R)-PMPA and Bis(POC)PMPA. Drugs Fut 1998, 23, 12, 1279. |
| 【3】 Holy, A.; Dvorakova, H.; DeClercq, E.D.A.; Balzarini, J.M.R. (Gilead Sciences Inc.; Stichting Rega Vzw); Antiretroviral enantiomeric nucleotide analogs. EP 0654037; JP 1996503927; US 6057305; WO 9403467 . |
| 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) | 19226 | isobutyl (2R)-2-hydroxypropanoate | 61597-96-4 | C7H14O3 | 详情 | 详情 |
| (II) | 19227 | isobutyl (2R)-2-(tetrahydro-2H-pyran-2-yloxy)propanoate | C12H22O4 | 详情 | 详情 | |
| (III) | 19228 | (2S)-2-(tetrahydro-2H-pyran-2-yloxy)-1-propanol | 76946-21-9 | C8H16O3 | 详情 | 详情 |
| (IV) | 19229 | (2S)-2-(tetrahydro-2H-pyran-2-yloxy)propyl 4-methylbenzenesulfonate | C15H22O5S | 详情 | 详情 | |
| (V) | 10343 | 9H-Purin-6-amine; 9H-Purin-6-ylamine; Adenine | 73-24-5 | C5H5N5 | 详情 | 详情 |
| (VI) | 19231 | 9-[(2S)-2-(tetrahydro-2H-pyran-2-yloxy)propyl]-9H-purin-6-amine; 9-[(2R)-2-(tetrahydro-2H-pyran-2-yloxy)propyl]-9H-purin-6-ylamine | C13H19N5O2 | 详情 | 详情 | |
| (VII) | 19232 | (2S)-1-(6-amino-9H-purin-9-yl)-2-propanol | C8H11N5O | 详情 | 详情 | |
| (VIII) | 19233 | N-[9-[(2S)-2-hydroxypropyl]-9H-purin-6-yl]benzamide | C15H15N5O2 | 详情 | 详情 | |
| (IX) | 19234 | (diisopropoxyphosphoryl)methyl 4-methylbenzenesulfonate | C14H23O6PS | 详情 | 详情 | |
| (X) | 19235 | diisopropyl [[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethyl]oxy]methylphosphonate | C15H26N5O4P | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(X)2) The reaction of the previously described (R)-2-(2-tetrahydropyranyloxy)-1-propanol (III) with benzyl bromide (XI) by means of NaH in DMF, followed by a treatment with Dowex 50X, gives 1-benzyloxy-2(R)-propanol (XII), which is condensed with tosyloxymethylphosphonic acid diisopropyl ester (IX) by means of NaH in THF, yielding 2-benzyloxy-1(R)-methylethoxymethylphosphonic acid diisopropyl ester (XIII). The hydrogenolysis of (XIII) over Pd/C in methanol affords 2-hydroxy-1(R)-methylethoxymethylphosphonic acid diisopropyl ester (XIV), which is tosylated with tosyl chloride/dimethyl-aminopyridine in pyridine to give the expected tosylate (XV). The condensation of (XV) with adenine (VI) by means of Cs2CO3 in hot DMF yields 9-[2(R)-(diisopropoxyphosphorylmethoxy)propyl]adenine (X), which is finally hydrolyzed as before.
| 【1】 Masojídková, M.; Holý, A.; Synthesis of enantiomeric N-(2-phosphonomethoxypropyl) derivatives of purine and pyrimidine bases. I. The stepwise approach. Coll Czech Chem Commun 1995, 60, 7, 1196. |
| 【2】 Sorbera, L.A.; Castañer, J.; (R)-PMPA and Bis(POC)PMPA. Drugs Fut 1998, 23, 12, 1279. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 19228 | (2S)-2-(tetrahydro-2H-pyran-2-yloxy)-1-propanol | 76946-21-9 | C8H16O3 | 详情 | 详情 |
| (V) | 10343 | 9H-Purin-6-amine; 9H-Purin-6-ylamine; Adenine | 73-24-5 | C5H5N5 | 详情 | 详情 |
| (IX) | 19234 | (diisopropoxyphosphoryl)methyl 4-methylbenzenesulfonate | C14H23O6PS | 详情 | 详情 | |
| (X) | 19235 | diisopropyl [[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethyl]oxy]methylphosphonate | C15H26N5O4P | 详情 | 详情 | |
| (XI) | 12912 | 1-(Bromomethyl)benzene; Alpha-bromotoluene | 100-39-0 | C7H7Br | 详情 | 详情 |
| (XII) | 19237 | (2R)-1-(benzyloxy)-2-propanol | C10H14O2 | 详情 | 详情 | |
| (XIII) | 19238 | diisopropyl [[(1S)-2-(benzyloxy)-1-methylethyl]oxy]methylphosphonate | C17H29O5P | 详情 | 详情 | |
| (XIV) | 19239 | diisopropyl [[(1S)-2-hydroxy-1-methylethyl]oxy]methylphosphonate | C10H23O5P | 详情 | 详情 | |
| (XV) | 19240 | (2S)-2-[(diisopropoxyphosphoryl)methoxy]propyl 4-methylbenzenesulfonate | C17H29O7PS | 详情 | 详情 |