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【结 构 式】 
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【药物名称】Sinefungin, Compound-57926, A-9145, Antibiotic 32232RP 【化学名称】6,9-Diamino-1-(6-amino-9H-purin-9-yl)-1,5,6,7,8,9-hexadeoxy-beta-D-ribo-decofuranuroic acid 【CA登记号】58944-73-3 【 分 子 式 】C15H23N7O5 【 分 子 量 】381.39446 |
【开发单位】Lilly (Originator) 【药理作用】Antifungal Agents, ANTIINFECTIVE THERAPY, Antileishmanials, Antiviral Drugs, Treatment of Protozoal Diseases |
合成路线1
A total synthesis of (+)-sinefungin has been reported: The reaction of D-ribose (I) with acetone and methanol by means of CuSO4 and a catalytic amount of H2SO4 gives methyl 2,3-O-isopropylidene-beta-D-ribofuranoside (II), which is oxidized to the aldehyde (III) with oxalyl chloride in DMSO/dichloromethane. The Wittig condensation of (III) with triethyl phosphonoacetate (IV) by means of NaH in THF affords the unsaturated ester (V), which is hydrogenated with H2 over Pd/C in ethyl acetate and saponified with LiOH in methanol/water to give the propionic acid (VI). The condensation of (VI) with the chiral oxazolidone (VII) by means of pivaloyl chloride and triethylamine in THF yields the oxalidone (VIII). The stereoselective alkylation of (VIII) with allyl bromide by means of lithium hexamethyldisylazide in THF affords the 2(S)-allyl derivative (IX), which is hydrolyzed with LiOH in THF/water to the corresponding free acid (X). The Curtius degradation of the acid (X) by means of diphenyl phosphorazidate and benzyl alcohol gives the corresponding benzyloxycarbonylamino derivative (XI), which is benzylated with benzyl bromide to the fully protected compound (XII). The ozonolysis of the allyl double bond of (XII) with O3 in methanol/dichloromethane yields the aldehyde (XIII).
| 【1】 Ghosh, A.K.; Liu, W.M.; Total synthesis of (+)-sinefungin. J Org Chem 1996, 61, 18, 6175. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 32112 | 3-iodo-1-propene;3-iodo-propen;allyl iodide | 556-56-9 | C3H5I | 详情 | 详情 | |
| (I) | 10016 | D-Ribose; (3R,4S,5R)-5-(Hydroxymethyl)tetrahydro-2,3,4-furantriol; (2R,3R,4R)-2,3,4,5-Tetrahydroxypentanal | 50-69-1 | C5H10O5 | 详情 | 详情 |
| (II) | 10017 | [(3aR,4R,6R,6aR)-6-Methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methanol | 4099-85-8 | C9H16O5 | 详情 | 详情 |
| (III) | 10018 | (3aR,4S,6R,6aR)-6-Methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbaldehyde | C9H14O5 | 详情 | 详情 | |
| (IV) | 10019 | Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate | 867-13-0 | C8H17O5P | 详情 | 详情 |
| (V) | 10020 | Ethyl (E)-3-[(3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-2-propenoate | C13H20O6 | 详情 | 详情 | |
| (VI) | 10021 | 3-[(3aR,4R,6R,6aR)-6-Methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]propionic acid | C11H18O6 | 详情 | 详情 | |
| (VII) | 10022 | [(3aS,8aR)-2-Oxo-8,8a-dihydro-2H-indeno[1,2-d][1,3]oxazol-3(3aH)-yl]lithium | C10H8LiNO2 | 详情 | 详情 | |
| (VIII) | 10023 | (3aS,8aR)-3-[3-[(3aR,4R,6R,6aR)-6-Methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]propanoyl]-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d][1,3]oxazol-2-one | C21H25NO7 | 详情 | 详情 | |
| (IX) | 10024 | (3aS,8aR)-3-((2S)-2-[[(3aR,4R,6R,6aR)-6-Methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl]-4-pentenoyl)-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d][1,3]oxazol-2-one | C24H29NO7 | 详情 | 详情 | |
| (X) | 10025 | (2S)-2-[[(3aR,4R,6R,6aR)-6-Methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl]-4-pentenoic acid | C14H22O6 | 详情 | 详情 | |
| (XI) | 10026 | Benzyl N-((1S)-1-[[(3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl]-3-butenyl)carbamate | 180776-29-8 | C21H29NO6 | 详情 | 详情 |
| (XII) | 10027 | Benzyl (1S)-1-[[(3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl]-3-butenyl(benzyl)carbamate | C28H35NO6 | 详情 | 详情 | |
| (XIII) | 10028 | Benzyl (1R)-1-[[(3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl]-3-oxopropyl(benzyl)carbamate | C27H33NO7 | 详情 | 详情 |
合成路线2
The aldehyde (XIII) is submitted to a Wittig condensation with N-acetyl-2-(diphenylphosphoryl)glycine (XIV) and potassium tert-butoxide in dichloromethane giving a mixture of the (Z)- and (E)-isomers (XV) and (XVI), respectively. The regiocontrolled hydrogenation of this mixture with H2 over a chiral rhodium catalyst in methanol yields the saturated (S,S)-isomer (XVII), which is submitted to a selective deprotection of its sugar moiety, followed by acetylation of the resulting free hydroxy groups with acetic anhydride in dioxane to afford the triacetoxy compound (XVIII). The condensation of (XVIII) with N6-benzoyladenine (XIX) by means of trimethylsilyl trifluoromethanesulfonate gives the adenosine derivative (XX), which is treated with K2CO3 and hydrazine to eliminate the acetyl and benzoyl groups yielding (XXI). Finally, this compound is debenzylated by hydrogenation with H2 over Pd/C in methanol.
| 【1】 Ghosh, A.K.; Liu, W.M.; Total synthesis of (+)-sinefungin. J Org Chem 1996, 61, 18, 6175. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIII) | 10028 | Benzyl (1R)-1-[[(3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl]-3-oxopropyl(benzyl)carbamate | C27H33NO7 | 详情 | 详情 | |
| (XIV) | 10030 | Ethyl 2-(acetamido)-2-(diphenoxyphosphino)acetate | C18H20NO5P | 详情 | 详情 | |
| (XV) | 10031 | Ethyl (E,5S)-6-[(3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-2-(acetamido)-5-[benzyl[(benzyloxy)carbonyl]amino]-2-hexenoate | C33H42N2O9 | 详情 | 详情 | |
| (XVI) | 10032 | Ethyl (Z,5S)-6-[(3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-2-(acetamido)-5-[benzyl[(benzyloxy)carbonyl]amino]-2-hexenoate | C33H42N2O9 | 详情 | 详情 | |
| (XVII) | 10033 | Ethyl (2S,5S)-6-[(3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-2-(acetamido)-5-[benzyl[(benzyloxy)carbonyl]amino]hexanoate | C33H44N2O9 | 详情 | 详情 | |
| (XVIII) | 10034 | Ethyl (2S,5S)-2-(acetamido)-5-[benzyl[(2-phenylacetyl)oxy]amino]-6-[(2R,3R,4R)-3,4,5-tris(acetoxy)tetrahydro-2-furanyl]hexanoate | C35H44N2O12 | 详情 | 详情 | |
| (XIX) | 10035 | N-(9H-Purin-6-yl)benzamide; N6-Benzoyladenine | 4005-49-6 | C12H9N5O | 详情 | 详情 |
| (XX) | 10036 | ethyl (2S,5S)-2-(acetamido)-5-[benzyl[(2-phenylacetyl)oxy]amino]-6-[(2R,3R,4R,5R)-3,4-bis(acetoxy)-5-[6-(benzoylamino)-9H-purin-9-yl]tetrahydro-2-furanyl]hexanoate | C45H49N7O11 | 详情 | 详情 | |
| (XXI) | 10037 | (2S,5S)-2-Amino-6-[(2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydro-2-furanyl]-5-[benzyl[(2-phenylacetyl)oxy]amino]hexanoic acid | C30H35N7O7 | 详情 | 详情 |