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【结 构 式】 
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【分子编号】12700 【品名】4-[Chloro(diphenyl)methyl]phenyl methyl ether; 1-[Chloro(diphenyl)methyl]-4-methoxybenzene; p-Anisylchlorodiphenylmethane 【CA登记号】14470-28-1 |
【 分 子 式 】C20H17ClO 【 分 子 量 】308.80708 【元素组成】C 77.79% H 5.55% Cl 11.48% O 5.18% |
合成路线1
该中间体在本合成路线中的序号：(VI)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：(IX)The regioselective reaction of cyclopentadiene (I) and sodium or commercial sodium cyclopentadienide (II) with benzyl chloromethyl ether (III) by means of the chiral catalyst (-)-diisopinocampheylborane in THF, followed by hydroxylation with H2O2/NaOH, gives (1S-trans)-2-(benzyloxymethyl)-3-cyclopenten-1-ol (IV), which is regioselectively epoxidized with tert-butyl hydroperoxide and vanadyl acetylacetonate in 2,2,4-trimethylpentane, yielding [1S-(1alpha,2alpha,3beta,5alpha)-2-(benzyloxymethyl)-6-oxabicyclo[3.1.0]hexan-3-ol (V). The protection of (V) with benzyl bromide and NaH affords the corresponding ether (VI), which is condensed with 6-O-benzylguanine (VII) by means of LiH in DMF to give the guanine derivative (VIII). The protection of the amino group of (VIII) with 4-methoxyphenyl(diphenyl)chloromethane (IX), TEA and DMAP in dichloromethane gives intermediate (X), which is oxidized at the free hydroxyl group with methylphosphonic acid, DCC and oxalic acid in DMSO or Dess Martin periodinane in dichloromethane, yielding the cyclopentanone derivative (XI). The reaction of (XI) with (i) Zn/TiCl4/CH2Br2 complex in THF/CH2Cl2, (ii) activated Zn/PbCl2/CH2I2/TiCl4 in THF/CH2Cl2 (2), (iii) Nysted reagent/TiCl4 in THF/CH2Cl2 or (iv) Tebbe reagent in toluene affords the corresponding methylene derivative (XII), which is partially deprotected with 3N HCl in hot THF, providing the dibenzylated compound (XI). Finally, this compound is treated with BCl3 in dichloromethane. (Scheme 18263401a)
| 【1】 Bisacchi, G.S.; Chao, S.T.; Bachard, C.; et al.; BMS-200475. A novel carbocyclic 2'-deoxyguanosine analog with potent and selective anti-hepatitis B virus activity in vitro. Bioorg Med Chem Lett 1997, 7, 2, 127. |
| 【2】 Castaner, J.; Graul, A.; BMS-200475. Drugs Fut 1999, 24, 111, 1173. |
| 【3】 Zahler, R.; Slusarchyk, W.A. (Bristol-Myers Squibb Co.); Hydroxymethyl(methylenecyclopentyl)purines and pyrimidines. EP 0481754; JP 1992282373; US 5206244 . |
| 【4】 Bisacchi, G.S.; Sundeen, J.E. (Bristol-Myers Squibb Co.); Improved process for preparing the antiviral agent [1S-(1alpha, 3alpha, 4beta)]-2-amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6H-purin-6-one. WO 9809964 . |
| 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) | 11183 | 1,3-Cyclopentadiene | C5H6 | 详情 | 详情 | |
| (II) | 29887 | Sodium cyclopentadienide | 4984-82-1 | C5H5Na | 详情 | 详情 |
| (III) | 14560 | Benzyl chloromethyl ether; 1-[(chloromethoxy)methyl]benzene | 3587-60-8 | C8H9ClO | 详情 | 详情 |
| (IV) | 29888 | (1S,2R)-2-[(benzyloxy)methyl]-3-cyclopenten-1-ol | C13H16O2 | 详情 | 详情 | |
| (V) | 29889 | (1S,2R,3S,5R)-2-[(benzyloxy)methyl]-6-oxabicyclo[3.1.0]hexan-3-ol | C13H16O3 | 详情 | 详情 | |
| (VI) | 29890 | (1S,2R,3S,5R)-3-(benzyloxy)-2-[(benzyloxy)methyl]-6-oxabicyclo[3.1.0]hexane; benzyl (1S,2R,3S,5R)-2-[(benzyloxy)methyl]-6-oxabicyclo[3.1.0]hex-3-yl ether | C20H22O3 | 详情 | 详情 | |
| (VII) | 14383 | 6-(benzyloxy)-9H-purin-2-ylamine; 6-(benzyloxy)-9H-purin-2-amine | 19916-73-5 | C12H11N5O | 详情 | 详情 |
| (VIII) | 29891 | (1S,2S,3S,5S)-5-[2-amino-6-(benzyloxy)-9H-purin-9-yl]-3-(benzyloxy)-2-[(benzyloxy)methyl]cyclopentanol | C32H33N5O4 | 详情 | 详情 | |
| (IX) | 12700 | 4-[Chloro(diphenyl)methyl]phenyl methyl ether; 1-[Chloro(diphenyl)methyl]-4-methoxybenzene; p-Anisylchlorodiphenylmethane | 14470-28-1 | C20H17ClO | 详情 | 详情 |
| (X) | 29892 | (1S,2S,3S,5S)-3-(benzyloxy)-5-(6-(benzyloxy)-2-[[(4-methoxyphenyl)(diphenyl)methyl]amino]-9H-purin-9-yl)-2-[(benzyloxy)methyl]cyclopentanol | C52H49N5O5 | 详情 | 详情 | |
| (XI) | 29893 | (2R,3S,5S)-3-(benzyloxy)-5-(6-(benzyloxy)-2-[[(4-methoxyphenyl)(diphenyl)methyl]amino]-9H-purin-9-yl)-2-[(benzyloxy)methyl]cyclopentanone | C52H47N5O5 | 详情 | 详情 | |
| (XII) | 29894 | 6-(benzyloxy)-9-[(1S,3R,4S)-4-(benzyloxy)-3-[(benzyloxy)methyl]-2-methylenecyclopentyl]-N-[(4-methoxyphenyl)(diphenyl)methyl]-9H-purin-2-amine; N-(6-(benzyloxy)-9-[(1S,3R,4S)-4-(benzyloxy)-3-[(benzyloxy)methyl]-2-methylenecyclopentyl]-9H-purin-2-yl)-N-[(4-methoxyphenyl)(diphenyl)methyl]amine | 142217-80-9 | C53H49N5O4 | 详情 | 详情 |
| (XIII) | 29895 | 2-amino-9-[(1S,3R,4S)-4-(benzyloxy)-3-[(benzyloxy)methyl]-2-methylenecyclopentyl]-1,9-dihydro-6H-purin-6-one | 142217-81-0 | C26H27N5O3 | 详情 | 详情 |