HAK-2701, -Drug Synthesis Database

【结构式】

【药物名称】HAK-2701

【化学名称】5'(R)-Ethynyladenosine
　　　　　　9-(6,7-Dideoxy-beta-D-allo-hept-5-ynofuranosyl)adenine

【CA登记号】

【分子式】C₁₂H₁₃N₅O₄

【分子量】291.26851

【开发单位】Hokkaido University (Originator), Tokyo Metropolitan Institute of Medical (Originator)

【药理作用】PHARMACOLOGICAL TOOLS, Drugs Acting on Adenosine Receptors

合成路线1 合成路线2

合成路线1

The Grignard condensation of the protected adenosine derivative (I) with trimethylsilylethynyl magnesium bromide (II) in THF gives the diastereomeric mixture (III), which is separated by column chromatography. The desired isomer (IV) is treated with ammonia in methanol to yield the isopropylidene derivative of the target compound (V), which is finally deprotected with 90% aqueous TFA.

参考文献中间体

【1】 Matsuda, A.; Saitoh, Y.; Nakata, H.; Minakawa, N.; Yoshimura, Y.; Kosaki, H.; Nucleosides and nucleotides. 177. 9-(6,7-dideoxy-beta-D-allo-hept-5-ynofuranosyl)adenine: A selective and potent ligand for P3 purinoceptor-like protein. J Med Chem 1998, 41, 15, 2676.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	31054	N-[9-[(3aR,4R,6S,6aR)-6-formyl-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-9H-purin-6-yl]benzamide	C₂₀H₁₉N₅O₅	详情	详情
(II)	31055	bromo[2-(trimethylsilyl)ethynyl]magnesium	C₅H₉BrMgSi	详情	详情
(III)	31056	N-(9-[(3aR,4R,6R,6aR)-6-[(1S)-1-hydroxy-3-(trimethylsilyl)-2-propynyl]-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-9H-purin-6-yl)benzamide	C₂₅H₂₉N₅O₅Si	详情	详情
(IV)	31057	N-(9-[(3aR,4R,6R,6aR)-6-[1-hydroxy-3-(trimethylsilyl)-2-propynyl]-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-9H-purin-6-yl)benzamide	C₂₅H₂₉N₅O₅Si	详情	详情
(V)	31058	1-[(3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-2-propyn-1-ol	C₁₅H₁₇N₅O₄	详情	详情

合成路线2

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.

参考文献中间体

【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

Extended Information