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【结 构 式】 
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【分子编号】12708 【品名】diethyl [[(1S)-2-[4-amino-2-oxo-1(2H)-pyrimidinyl]-1-(hydroxymethyl)ethyl]oxy]methylphosphonate 【CA登记号】 |
【 分 子 式 】C12H22N3O6P 【 分 子 量 】335.297062 【元素组成】C 42.99% H 6.61% N 12.53% O 28.63% P 9.24% |
合成路线1
该中间体在本合成路线中的序号：(XIV)2) The reaction of 2(R),3-O-isopropylideneglycerol (IV) with benzyl bromide by means of benzyltriethylammonium bromide (BTA) in refluxing aqueous NaOH gives (S)-3-O-benzylglycerol (V), which is monotritylated with 4-methoxytriphenylmethyl chloride (VI) and dimethylaminopyridine (DMAP) yielding the secondary alcohol (VII). The condensation of (VII) with diethyl tosyloxymethylphosphonate (VIII) by means of NaH in THF affords the fully protected phosphorylmethoxy derivative (IX), which is detritylated by treatment with aqueous acetic acid at 100 C to give 3-benzyloxy-2(S)-(diethoxyphosphorylmethoxy)-1-propanol (X). The reaction of (X) with methanesulfonyl chloride and triethylamine in dichloromethane yields the corresponding mesylate (XI), which is condensed with cytosine (XII) by means of cesium carbonate in hot DMF affording 1-[3-benzyloxy-2(S)-(diethoxyphosphorylmethoxy)propyl]cytosine (XIII). The debenzylation of (XIII) by treatment with Pd(OH)2 on carbon in refluxing ethanol/cyclohexene gives the corresponding alcohol (XIV), which is finally treated with bromotrimethylsilane in acetonitrile to eliminate the ethyl groups of the phosphonate.
| 【1】 Martin, J.C.; Webb, R.R. II, Wos, J.A.; Bronson, J.J.; Synthesis of (S)-N1-(3-hydroxy-2-phosphonylmethoxy)propylcytosine, (S)-HPMPC. Tetrahedron Lett 1988, 29, 5475-8. |
| 【2】 Fromtling, R.A.; Castaner, J.; Cidofovir. Drugs Fut 1996, 21, 10, 1003. |
| 【3】 Bronson, J.J.; Ghazzouli, I.; Hitchcock, M.J.M.; Webb, R.R. II, Martin, J.C.; Synthesis and antiviral activity of the nucleotide analogue (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine. J Med Chem 1989, 32, 7, 1457-63. |
| 【4】 Martin, J.C.; Bronson, J.J.; Webb, R.R. II, Hitchcock, M.J.M.; Ghazzouli, I.; Synthesis and antiherpesvirus activity of (S)-1-((3-hydroxy-2-phosphonylmethoxy)propyl)cytosine (HPMPC) and related nucleotide analogues. Nucleosides Nucleotides 1989, 8, 5-6, 923-6. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 12698 | [(4R)-2,2-Dimethyl-1,3-dioxolan-4-yl]methanol | 14347-78-5 | C6H12O3 | 详情 | 详情 |
| (V) | 12699 | (2S)-3-(Benzyloxy)-1,2-propanediol; (S)-(-)-1-Benzylglycerol | 17325-85-8 | C10H14O3 | 详情 | 详情 |
| (VI) | 12700 | 4-[Chloro(diphenyl)methyl]phenyl methyl ether; 1-[Chloro(diphenyl)methyl]-4-methoxybenzene; p-Anisylchlorodiphenylmethane | 14470-28-1 | C20H17ClO | 详情 | 详情 |
| (VII) | 12701 | (2R)-1-(Benzyloxy)-3-[(4-methoxyphenyl)(diphenyl)methoxy]-2-propanol | C30H30O4 | 详情 | 详情 | |
| (VIII) | 12702 | (diethoxyphosphoryl)methyl 4-methylbenzenesulfonate | 31618-90-3 | C12H19O6PS | 详情 | 详情 |
| (IX) | 12703 | diethyl [((1R)-2-(benzyloxy)-1-[[(4-methoxyphenyl)(diphenyl)methoxy]methyl]ethyl)oxy]methylphosphonate | C35H41O7P | 详情 | 详情 | |
| (X) | 12704 | diethyl [[(1S)-2-(benzyloxy)-1-(hydroxymethyl)ethyl]oxy]methylphosphonate | C15H25O6P | 详情 | 详情 | |
| (XI) | 12705 | (2R)-3-(benzyloxy)-2-[(diethoxyphosphoryl)methoxy]propyl methanesulfonate | C16H27O8PS | 详情 | 详情 | |
| (XII) | 12706 | Cytosine; 4-Amino-2(1H)-pyrimidinone | 71-30-7 | C4H5N3O | 详情 | 详情 |
| (XIII) | 12707 | diethyl ([(1S)-2-[4-amino-2-oxo-1(2H)-pyrimidinyl]-1-[(benzyloxy)methyl]ethyl]oxy)methylphosphonate | C19H28N3O6P | 详情 | 详情 | |
| (XIV) | 12708 | diethyl [[(1S)-2-[4-amino-2-oxo-1(2H)-pyrimidinyl]-1-(hydroxymethyl)ethyl]oxy]methylphosphonate | C12H22N3O6P | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIV)3) The reaction of 2(S),3-O-isopropylideneglycerol (XV) with methanesulfonyl chloride and triethylamine in dichloromethane gives the corresponding mesylate (XVI), which is condensed with cytosine (XII) by means of cesium carbonate as before yielding 1-[2(S),3-(isopropylidenedioxy)propyl]cytosine (XVII). The deprotection of (XVII) with aqueous acetic acid at 100 C affords the corresponding diol (XVIII), which is treated with trityl chloride, DMAP and triethylamine in DMF to give the monotrityl compound (XIX). The condensation of (XIX) with diethyl tosyloxymethylphosphonate (VIII) [obtained by reaction of diethylphosphite (XX) with paraformaldehyde, followed by tosylation with tosyl chloride] by a previous treatment of (XX) with DMF dimethylacetal, then condensation by means of NaH in DMF, and a final hydrolysis with hot aqueous acetic acid yields the 1-[2(S)-(diethoxyphosphorylmethoxy)-3-hydroxypropyl]cytosine (XIV) (already obtained), which is finally treated with bromotrimethylsilane as before. 4) The reaction of the acetonide (XVI) with N4-benzoylcytosine (XXI) by means of potassium tert-butoxide or cesium carbonate gives the condensation product (XXII), which is deprotected with HCl in acetic acid yielding the diol (XXIII). The reaction of (XXIII) with trityl chloride and DMAP in refluxing pyridine affords the monotritylated compound (XXIV), which is condensed with the phosphonate (VIII) by means of NaH in DMF to give the fully protected HPMPC compound (XXV). The successive deprotections of (XXV), first with HCl in dichloromethane to eliminate the trityl group yielding (XXVI), then with bromotrimethylsilane to obtain the free phosphono group giving (XXVII), and finally with concentrated aqueous NH4OH to eliminate the benzoyl group affords cidofovir. 5) The benzoylation of acetonide derivative (XVII) with benzoyl anhydride in refluxing pyridine gives the benzoyl citosine derivative (XXII) already obtained.
| 【1】 Fromtling, R.A.; Castaner, J.; Cidofovir. Drugs Fut 1996, 21, 10, 1003. |
| 【2】 Bronson, J.J.; Ferrara, L.M.; Howell, H.G.; Brodfuehrer, P.R.; Martin, J.C.; A new synthesis of the potent and selective anti-herpesvirus agent (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine. Nucleosides Nucleotides 1990, 9, 6, 745-69. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIII) | 12702 | (diethoxyphosphoryl)methyl 4-methylbenzenesulfonate | 31618-90-3 | C12H19O6PS | 详情 | 详情 |
| (XII) | 12706 | Cytosine; 4-Amino-2(1H)-pyrimidinone | 71-30-7 | C4H5N3O | 详情 | 详情 |
| (XIV) | 12708 | diethyl [[(1S)-2-[4-amino-2-oxo-1(2H)-pyrimidinyl]-1-(hydroxymethyl)ethyl]oxy]methylphosphonate | C12H22N3O6P | 详情 | 详情 | |
| (XV) | 12709 | [(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]methanol | 22323-82-6 | C6H12O3 | 详情 | 详情 |
| (XVI) | 12710 | [(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl methanesulfonate | C7H14O5S | 详情 | 详情 | |
| (XVII) | 12711 | 4-Amino-1-[[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl]-2(1H)-pyrimidinone | C10H15N3O3 | 详情 | 详情 | |
| (XVIII) | 12695 | 4-Amino-1-[(2S)-2,3-dihydroxypropyl]-2(1H)-pyrimidinone | C7H11N3O3 | 详情 | 详情 | |
| (XIX) | 12713 | 4-Amino-1-[(2S)-2-hydroxy-3-(trityloxy)propyl]-2(1H)-pyrimidinone | C26H25N3O3 | 详情 | 详情 | |
| (XX) | 12714 | diethyl phosphonate; diethyl phosphite | 762-04-9 | C4H11O3P | 详情 | 详情 |
| (XXI) | 12715 | N-(2-Oxo-1,2-dihydro-4-pyrimidinyl)benzamide; N-Benzoylcytosine | 26661-13-2 | C11H9N3O2 | 详情 | 详情 |
| (XXII) | 12716 | N-(1-[[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]methyl]-2-oxo-1,2-dihydro-4-pyrimidinyl)benzamide | C17H19N3O4 | 详情 | 详情 | |
| (XXIII) | 12717 | N-[1-[(2S)-2,3-Dihydroxypropyl]-2-oxo-1,2-dihydro-4-pyrimidinyl]benzamide | C14H15N3O4 | 详情 | 详情 | |
| (XXIV) | 12718 | N-[1-[(2S)-2-Hydroxy-3-(trityloxy)propyl]-2-oxo-1,2-dihydro-4-pyrimidinyl]benzamide | C33H29N3O4 | 详情 | 详情 | |
| (XXV) | 12719 | diethyl ([(1S)-2-[4-(benzoylamino)-2-oxo-1(2H)-pyrimidinyl]-1-[(trityloxy)methyl]ethyl]oxy)methylphosphonate | C38H40N3O7P | 详情 | 详情 | |
| (XXVI) | 12720 | diethyl [[(1S)-2-[4-(benzoylamino)-2-oxo-1(2H)-pyrimidinyl]-1-(hydroxymethyl)ethyl]oxy]methylphosphonate | C19H26N3O7P | 详情 | 详情 | |
| (XXVII) | 12721 | [[(1S)-2-[4-(Benzoylamino)-2-oxo-1(2H)-pyrimidinyl]-1-(hydroxymethyl)ethyl]oxy]methylphosphonic acid | C15H18N3O7P | 详情 | 详情 |