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【结 构 式】 
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【分子编号】10035 【品名】N-(9H-Purin-6-yl)benzamide; N6-Benzoyladenine 【CA登记号】4005-49-6 |
【 分 子 式 】C12H9N5O 【 分 子 量 】239.23656 【元素组成】C 60.25% H 3.79% N 29.27% O 6.69% |
合成路线1
该中间体在本合成路线中的序号：(XIX)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 |
合成路线2
该中间体在本合成路线中的序号：(VIII)A practical synthetic approach to lodenosine has been developed: Acylation of the chiral carbinol (I) with 4-methylbenzoyl chloride (II) and pyridine in dichloromethane gives the ester (III), which is diastereoselectively hydrogenated with H2 over Pd/C in ethyl acetate to yield the tetrahydrofuranone (IV). Surprisingly, the diastereoselectivity of this reaction depends on the hydrogen pressure: while at 40 psi it is very poor, at 10 psi it increases to 98%. The reduction of lactone (IV) with red-Al and 2-hydroxypyridine in THF at -30 C affords the lactol (V), which is treated with Ac2O and catalytic concentrated H2SO4 to provide the acetate ester (VI). Reaction of compound (VI) with HBr in AcOH gives the bromo derivative (VII), which is condensed with N6-benzoyl adenine (VIII) by means of NaH in refluxing THF to give the acylated adenosine derivative (IX). Finally, this compound is deprotected with NaOMe in refluxing methanol.
| 【1】 Xu, G.Y.; Wang, D.J.; Pierce, M.E.; Choudhury, A.; Nguyen, D.; Jin, F.Q.; Confalona, P.N.; Wang, Z.; (2R,3S,5S)-2-Acetoxy-3-fluoro-5-(p-toluoyloxymethyl)tetrahydrofuran: A key intermediate for the practical synthesis of 9-(2,3-dideoxy-2-fluoro-beta-D-threo-pentofuranosyl)adenine (FddA). Tetrahedron Lett 2001, 42, 29, 4787. |
| 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) | 48723 | (5S)-3-fluoro-5-(hydroxymethyl)-2(5H)-furanone | C5H5FO3 | 详情 | 详情 | |
| (II) | 17719 | p-Toluoyl chloride; 4-methylbenzoyl chloride | 874-60-2 | C8H7ClO | 详情 | 详情 |
| (III) | 48724 | [(2S)-4-fluoro-5-oxo-2,5-dihydro-2-furanyl]methyl 4-methylbenzoate | C13H11FO4 | 详情 | 详情 | |
| (IV) | 48725 | [(2S,4S)-4-fluoro-5-oxotetrahydro-2-furanyl]methyl 4-methylbenzoate | C13H13FO4 | 详情 | 详情 | |
| (V) | 48726 | [(2S,4S)-4-fluoro-5-hydroxytetrahydro-2-furanyl]methyl 4-methylbenzoate | C13H15FO4 | 详情 | 详情 | |
| (VI) | 48727 | [(2S,4S,5R)-5-(acetoxy)-4-fluorotetrahydro-2-furanyl]methyl 4-methylbenzoate | C15H17FO5 | 详情 | 详情 | |
| (VII) | 48728 | [(2S,4S,5R)-5-bromo-4-fluorotetrahydro-2-furanyl]methyl 4-methylbenzoate | C13H14BrFO3 | 详情 | 详情 | |
| (VIII) | 10035 | N-(9H-Purin-6-yl)benzamide; N6-Benzoyladenine | 4005-49-6 | C12H9N5O | 详情 | 详情 |
| (IX) | 48729 | [(2S,4S,5R)-5-[6-(benzoylamino)-9H-purin-9-yl]-4-fluorotetrahydro-2-furanyl]methyl 4-methylbenzoate | C25H22FN5O4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IX)The reaction of the protected carbohydrate (I) with trimethylsilylacetylene (II) gives adduct (III) with no stereoselectivity at the reaction point. The oxidation of the OH group of (III) with DMP gives the corresponding oxo compound (IV), which is stereoselectively reduced with N-Selectride to yield the (R)-diastereomer (V) in a 33:1 ratio. The desilylation of (V) with TBAF in THF affords the free compound (VI), which is benzoylated with Bz2O, TEA and DMAP in acetonitrile to provide the tribenzoate (VII). The reaction of (VII) with Ac2O, H2SO4 and AcOH gives the 1-acetoxy compound (VIII), which is condensed with N6-benzoyladenine (IX) by means of Tms-OTf and TEA in acetonitrile, yielding the adenosine derivative (X). Finally, this compound is debenzoylated with ammonia in methanol.
| 【1】 Umino, T.; et al.; Nucleosides and nucleotides. Part 201: Alternative method to synthesize 9-(6,7-dideoxy-beta-D-allo-hept-5-ynofuranosyl)adenine, a selective and potent ligand for P-3 purinoceptor-like protein: A stereoselective reduction based on sugar puckering of the fu. Tetrahedron Lett 2000, 41, 33, 6419. |
| 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) | 42083 | (2S,3R,4R,5R)-3,4-bis[[tert-butyl(dimethyl)silyl]oxy]-5-methoxytetrahydro-2-furancarbaldehyde | C18H38O5Si2 | 详情 | 详情 | |
| (II) | 23897 | ethynyl(trimethyl)silane；trimethylsilyl acetylene | 1066-54-2 | C5H10Si | 详情 | 详情 |
| (III) | 42084 | (1R)-1-((2R,3R,4R,5R)-3,4-bis[[tert-butyl(dimethyl)silyl]oxy]-5-methoxytetrahydro-2-furanyl)-3-(trimethylsilyl)-2-propyn-1-ol | C23H48O5Si3 | 详情 | 详情 | |
| (IV) | 42085 | 1-((2S,3R,4R,5R)-3,4-bis[[tert-butyl(dimethyl)silyl]oxy]-5-methoxytetrahydro-2-furanyl)-3-(trimethylsilyl)-2-propyn-1-one | C23H46O5Si3 | 详情 | 详情 | |
| (V) | 42086 | 1-((2R,3R,4R,5R)-3,4-bis[[tert-butyl(dimethyl)silyl]oxy]-5-methoxytetrahydro-2-furanyl)-3-(trimethylsilyl)-2-propyn-1-ol | C23H48O5Si3 | 详情 | 详情 | |
| (VI) | 42087 | (2R,3S,4R,5R)-2-(1-hydroxy-2-propynyl)-5-methoxytetrahydro-3,4-furandiol | C8H12O5 | 详情 | 详情 | |
| (VII) | 42088 | (2R,3R,4R,5R)-4-(benzoyloxy)-2-[1-(benzoyloxy)-2-propynyl]-5-methoxytetrahydro-3-furanyl benzoate | C29H24O8 | 详情 | 详情 | |
| (VIII) | 42089 | (3R,4R,5R)-2-(acetoxy)-4-(benzoyloxy)-5-[1-(benzoyloxy)-2-propynyl]tetrahydro-3-furanyl benzoate | C30H24O9 | 详情 | 详情 | |
| (IX) | 10035 | N-(9H-Purin-6-yl)benzamide; N6-Benzoyladenine | 4005-49-6 | C12H9N5O | 详情 | 详情 |
| (X) | 42090 | 1-[(2R,3R,4R,5R)-5-[6-(benzoylamino)-9H-purin-9-yl]-3,4-bis(benzoyloxy)tetrahydro-2-furanyl]-2-propynyl benzoate | C40H29N5O8 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)The condensation of the cyclic sulfite (I) with N6-benzoyladenine (II) gives the isoadenosine (III), which is condensed with 2-chlorophenylphosphono-bis-triazolide (ClPTr) to yield the phosphate diester (IV). The condensation of (IV) with the deoxycytidine (V) by means of triisopropylbenzenesulfonyl tetrazolide (TPS-TAZ) affords the phosphoric ester (VI), which is treated with dichloroacetic acid (Cl2HOAc) in order to eliminate the dimethoxytrityl protecting group and provide the hydroxymethyl derivative (VII). The phosphorylation of (VII) by means of 2-cyanoethyl phosphate (VIII) gives the protected intermediate (IX), which is finally treated with hot NH4OH to yield the target bis nucleoside phosphate.
| 【1】 Taktakishvili, M.; Nair, V.; Pal, s.; Neamati, N.; Pommier, Y.; Recognition and inhibition of HIV integrase by novel dinucleotides. J Am Chem Soc 2000, 122, 24, 5671. |
| 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) | 50021 | (3aR,4R)-4-[[bis(4-methoxyphenyl)(phenyl)methoxy]methyl]tetrahydrofuro[3,4-d][1,3]dioxol-2-one | C27H26O7 | 详情 | 详情 | |
| (II) | 10035 | N-(9H-Purin-6-yl)benzamide; N6-Benzoyladenine | 4005-49-6 | C12H9N5O | 详情 | 详情 |
| (III) | 46816 | N-[9-((3R,4S,5R)-5-[[bis(4-methoxyphenyl)(phenyl)methoxy]methyl]-4-hydroxytetrahydro-3-furanyl)-9H-purin-6-yl]benzamide | C38H35N5O6 | 详情 | 详情 | |
| (IV) | 46817 | sodium [((2R,3S,4R)-4-[6-(benzoylamino)-9H-purin-9-yl]-2-[[bis(4-methoxyphenyl)(phenyl)methoxy]methyl]tetrahydro-3-furanyl)oxy](2-chlorophenoxy)oxophosphoranolate | C44H38ClN5NaO9P | 详情 | 详情 | |
| (V) | 46818 | (2R,3S,5R)-5-[4-(benzoylamino)-2-oxo-1(2H)-pyrimidinyl]-2-(hydroxymethyl)tetrahydro-3-furanyl acetate | C18H19N3O6 | 详情 | 详情 | |
| (VI) | 46819 | (2R,3S,5R)-5-[4-(benzoylamino)-2-oxo-1(2H)-pyrimidinyl]-2-([[[((2R,3S,4R)-4-[6-(benzoylamino)-9H-purin-9-yl]-2-[[bis(4-methoxyphenyl)(phenyl)methoxy]methyl]tetrahydro-3-furanyl)oxy](2-chlorophenoxy)phosphoryl]oxy]methyl)tetrahydro-3-furanyl acetate | C62H56ClN8O14P | 详情 | 详情 | |
| (VII) | 46820 | (2R,3S,5R)-5-[4-(benzoylamino)-2-oxo-1(2H)-pyrimidinyl]-2-([[[[(2R,3S,4R)-4-[6-(benzoylamino)-9H-purin-9-yl]-2-(hydroxymethyl)tetrahydro-3-furanyl]oxy](2-chlorophenoxy)phosphoryl]oxy]methyl)tetrahydro-3-furanyl acetate | C41H38ClN8O12P | 详情 | 详情 | |
| (VIII) | 50022 | 2-cyanoethyl dihydrogen phosphate | C3H6NO4P | 详情 | 详情 | |
| (IX) | 50023 | (2R,3S,5R)-5-[4-(benzoylamino)-2-oxo-1(2H)-pyrimidinyl]-2-([[([(2R,3S,4R)-4-[6-(benzoylamino)-9H-purin-9-yl]-2-[(phosphonooxy)methyl]tetrahydro-3-furanyl]oxy)(2-chlorophenoxy)phosphoryl]oxy]methyl)tetrahydro-3-furanyl acetate | C41H39ClN8O15P2 | 详情 | 详情 |