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【结 构 式】 
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【药物名称】Tenofovir, GS-1278, PMPA-(R), (R)-PMPA 【化学名称】(R)-9-[2-(Phosphonomethoxy)propyl]adenine 【CA登记号】147127-20-6, 147127-19-3 ((S)-isomer), 206184-49-8 (monohydrate) 【 分 子 式 】C9H14N5O4P 【 分 子 量 】287.21683 |
【开发单位】Gilead (Originator), Nat. Inst. Allergy & Infectious Dis. (Codevelopment) 【药理作用】AIDS Medicines, Anti-HIV Agents, ANTIINFECTIVE THERAPY, Reverse Transcriptase Inhibitors |
合成路线1
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
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 |
合成路线3
3) The catalytic hydrogenation of (S)-glycidol (XVI) over Pd/C gives the (R)-1,2-propanediol (XVII), which is esterified with diethyl carbonate (XVIII)/NaOEt, yielding the cyclic carbonate (XIX). The reaction of (XIX) with adenine (V) by means of NaOH in DMF affords 9-[2(R)-hydroxypropyl]adenine (VII), which is condensed with tosyloxymethylphosphonic acid diethyl ester (XX) by means of lithium tert-butoxide in THF, giving 9-[2(R)-(diethoxyphosphorylmethoxy)propyl]adenine (XXI). Finally, this compound is hydrolyzed with bromotrimethylsilane as before. Compound (XX) is obtained by reaction of diethyl phosphite (XXII) with paraformaldehyde, yielding hydroxy- methylphosphonic acid diethyl ester (XXIII), which is finally tosylated as usual.
| 【1】 Leone-Bay, A.; et al.; 4-(4-Salicyloylaminophenyl)butyric acid as a novel oral delivery agent for recombinant human growth hormone. 211th ACS Natl Meet (March 24-28, New Orleans) 1996, Abst MEDI 006. |
| 【2】 Schultze, L.M.; Chapman, H.H.; Dubree, N.J.P.; et al.; Practical synthesis of the anti-HIV drug, PMPA. Tetrahedron Lett 1998, 39, 14, 1853. |
| 【3】 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 |
|---|---|---|---|---|---|---|
| (V) | 10343 | 9H-Purin-6-amine; 9H-Purin-6-ylamine; Adenine | 73-24-5 | C5H5N5 | 详情 | 详情 |
| (VII) | 19232 | (2S)-1-(6-amino-9H-purin-9-yl)-2-propanol | C8H11N5O | 详情 | 详情 | |
| (XVI) | 19241 | (2S)oxiranylmethanol | 60456-23-7 | C3H6O2 | 详情 | 详情 |
| (XVII) | 19242 | (2S)-1,2-propanediol | 4254-15-3 | C3H8O2 | 详情 | 详情 |
| (XVIII) | 17470 | diethyl carbonate; diethylcarbonate | 105-58-8 | C5H10O3 | 详情 | 详情 |
| (XIX) | 19244 | (4S)-4-methyl-1,3-dioxolan-2-one | C4H6O3 | 详情 | 详情 | |
| (XX) | 12702 | (diethoxyphosphoryl)methyl 4-methylbenzenesulfonate | 31618-90-3 | C12H19O6PS | 详情 | 详情 |
| (XXI) | 19246 | diethyl [[(1S)-2-(6-amino-9H-purin-9-yl)-1-methylethyl]oxy]methylphosphonate | C13H22N5O4P | 详情 | 详情 | |
| (XXII) | 12714 | diethyl phosphonate; diethyl phosphite | 762-04-9 | C4H11O3P | 详情 | 详情 |
| (XXIII) | 19248 | diethyl hydroxymethylphosphonate | 3084-40-0 | C5H13O4P | 详情 | 详情 |