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【结 构 式】 
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【分子编号】12699 【品名】(2S)-3-(Benzyloxy)-1,2-propanediol; (S)-(-)-1-Benzylglycerol 【CA登记号】17325-85-8 |
【 分 子 式 】C10H14O3 【 分 子 量 】182.21936 【元素组成】C 65.92% H 7.74% O 26.34% |
合成路线1
该中间体在本合成路线中的序号：(V)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：(I)Silylation of 1-O-benzylglycerol (I) with tert-butyldimethylsilyl chloride afforded the 1,3-diprotected glycerol (II). After methylation of the free secondary hydroxyl of (II) using MeI and NaH to yield (III), its O-benzyl protecting group was cleaved by hydrogenolysis, yielding (IV). Acylation of alcohol (IV) with oleoyl chloride (V) in the presence of pyridine provided the corresponding ester (VI). Desilylation of (VI) to give alcohol (VII) was carried out by treatment with tetrabutylammonium fluoride. Alcohol (VII) was then condensed with (2-cyanoethyl)-N,N,N',N'-tetraisopropylphosphorodiamidite (VIII) in the presence of 3-hydroxypropionitrile and tetrazole, followed by reaction with elemental sulfur to furnish the thiophosphate (IX). Finally, cleavage of the cyanoethyl ester groups with Et3N and bis(trimethylsilyl)acetamide provided the title compound.
| 【1】 Boyd, E.A.; Umansky, S.R.; Baxter, A.D.; Price, S.; Goddard, J.G.; Picker, D.H.; Wijkmans, J.C.H.M. (Evotec Biosystems AG; LXR Biotechnology Inc.); Compsns. containing lysophosphatidic acids which inhibit apoptosis and uses thereof. WO 9947101 . |
| 【2】 Vmansky, S.R.; Goddard, J.G.; Picker, D.H.; Bathurst, I.C.; Bradley, J.D.; Foehr, M.W. (LXR Biotechnology Inc.); Compsns. containing lysophosphatidic acids which inhibit apoptosis and uses thereof. WO 9841213 . |
| 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) | 12699 | (2S)-3-(Benzyloxy)-1,2-propanediol; (S)-(-)-1-Benzylglycerol | 17325-85-8 | C10H14O3 | 详情 | 详情 |
| (II) | 48651 | 1-(benzyloxy)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-propanol | C16H28O3Si | 详情 | 详情 | |
| (III) | 48652 | benzyl 3-[[tert-butyl(dimethyl)silyl]oxy]-2-methoxypropyl ether; [3-(benzyloxy)-2-methoxypropoxy](tert-butyl)dimethylsilane | C17H30O3Si | 详情 | 详情 | |
| (IV) | 48653 | 3-[[tert-butyl(dimethyl)silyl]oxy]-2-methoxy-1-propanol | C10H24O3Si | 详情 | 详情 | |
| (V) | 28280 | Oleoyl chloride; (E)-9-Octadecenoyl chloride | C18H33ClO | 详情 | 详情 | |
| (VI) | 48654 | 3-[[tert-butyl(dimethyl)silyl]oxy]-2-methoxypropyl (Z)-9-octadecenoate | C28H56O4Si | 详情 | 详情 | |
| (VII) | 48655 | 3-hydroxy-2-methoxypropyl (Z)-9-octadecenoate | C22H42O4 | 详情 | 详情 | |
| (VIII) | 48656 | 2-Cyanoethyl N,N,N',N'-tetraisopropylphosphoramidite; 2-Cyanoethyl N,N,N',N'-tetraisopropylphosphorodiamidite; Bis(diisopropylamino)-2-cyanoethoxyphosphine | 102691-36-1 | C15H32N3OP | 详情 | 详情 |
| (IX) | 48657 | 3-([(2-cyanoethoxy)[(2-cyanoethyl)sulfanyl]phosphoryl]oxy)-2-methoxypropyl (Z)-9-octadecenoate | C28H49N2O6PS | 详情 | 详情 |