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【结 构 式】

【药物名称】GR-79236

【化学名称】N6-[(1S-trans)-2-Hydroxycyclopentyl]adenosine

【CA登记号】124555-18-6, 124600-57-3 (fumarate salt (1:1))

【 分 子 式 】C15H21N5O5

【 分 子 量 】351.36512

【开发单位】GlaxoSmithKline (Originator)

【药理作用】Antidiabetic Drugs, Cardioprotectants, ENDOCRINE DRUGS, Lipoprotein Disorders, Treatment of , METABOLIC DRUGS, TREATMENT OF POISONING, DRUG ABUSE & DEPENDENCY, Adenosine A1 Agonists

合成路线1合成路线2合成路线3合成路线4

合成路线1

This compound has been obtained by two similar ways: 1) By condensation of the chloropurine (I) with (1S-trans)-2-aminocyclopentanol (1S-trans)-(II) by means of DEA in refluxing isopropanol. 2) The condensation of chloropurine (I) with (rac-trans)-2-aminocyclopentanol (rac-trans)-(II) (obtained by reaction of cyclopentene oxide (III) with ammonia) give a diastereomeric mixture, from which the target compound can be isolated by flash chromatography.

参考文献 中间体
【1】 Evans, B. (Glaxo Wellcome plc); Adenosine derivs.. AU 8827401; BE 1002167; CH 677495; DE 3843609; EP 0322242; FR 2663936; US 5032583 .
【2】 Knutsen, L.J.S.; Lau, J. (Novo Nordisk A/S); Purine derivs.. US 5672588 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(1S-trans)-(II) 38010 (1S,2S)-2-aminocyclopentanol C5H11NO 详情 详情
(rac)-(II) 63649 2-aminocyclopentanol C5H11NO 详情 详情
(I) 18716 6-chloropurine riboside; (2R,3R,4S,5R)-2-(6-chloro-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3,4-furandiol 2004-06-0 C10H11ClN4O4 详情 详情
(III) 38011 6-oxabicyclo[3.1.0]hexane 285-67-6 C5H8O 详情 详情

合成路线2

The cyclization of the imidazolyl riboside (I) with [13C]-formic acid ethyl ester (II) by means of sodium ethoxide in refluxing ethanol gives labeled inosine (III), which is acetylated with Ac2O and pyridine yielding the triacetate (IV). The nitration of (IV) with ammonium nitrate and trifluoroacetic anhydride affords the 1-nitroinosine (V), which is rearranged with 15NH4Cl in acetonitrile/water to provide the doubly labeled inosine (VI). The reaction of (VI) with SOCl2 gives the chloropurine (VII), which is condensed with the dideuterated 2-aminocyclopentanol (rac-trans)-(VIII) (obtained by hydrogenation of the unsaturated analogue (rac-trans)-(IX)) by means of NaHCO3 in isopropanol providing a diastereomeric mixture (X). The deacetylation of (X) with tert-butylamine in methanol furnishes a mixture of the target compound along with its diastereomer, which is separated by preparative HPLC.

参考文献 中间体
【1】 Wadsworth, A.H.; et al.; Synthesis of isotopically labelled versions of adenosine agonist GR79236. J Label Compd Radiopharm 2000, 43, 1, 11.
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),(VI) 38014 (2R,3R,4R,5R)-4-(acetoxy)-2-[(acetoxy)methyl]-5-(6-oxo-1,6-dihydro-9H-purin-9-yl)tetrahydro-3-furanyl acetate C16H18N4O8 详情 详情
(I) 37427 5-amino-1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-1H-imidazole-4-carboxamide C9H14N4O5 详情 详情
(II) 16602 ethyl formate 109-94-4 C3H6O2 详情 详情
(II) 45175 ethyl formate C3H6O2 详情 详情
(III) 38013 9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-1,9-dihydro-6H-purin-6-one C10H12N4O5 详情 详情
(III) 45176 9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-1,9-dihydro-6H-purin-6-one C10H12N4O5 详情 详情
(IV) 45177 (2R,3R,4R,5R)-4-(acetoxy)-2-[(acetoxy)methyl]-5-(6-oxo-1,6-dihydro-9H-purin-9-yl)tetrahydro-3-furanyl acetate C16H18N4O8 详情 详情
(V) 38015 (2R,3R,4R,5R)-4-(acetoxy)-2-[(acetoxy)methyl]-5-(1-nitro-6-oxo-1,6-dihydro-9H-purin-9-yl)tetrahydro-3-furanyl acetate C16H17N5O10 详情 详情
(V) 45178 (2R,3R,4R,5R)-4-(acetoxy)-2-[(acetoxy)methyl]-5-(1-nitro-6-oxo-1,6-dihydro-9H-purin-9-yl)tetrahydro-3-furanyl acetate C16H17N5O10 详情 详情
(VI) 45179 (2R,3R,4R,5R)-4-(acetoxy)-2-[(acetoxy)methyl]-5-(6-oxo-1,6-dihydro-9H-purin-9-yl)tetrahydro-3-furanyl acetate C16H18N4O8 详情 详情
(VII) 38016 (2R,3R,4R,5R)-4-(acetoxy)-2-[(acetoxy)methyl]-5-(6-chloro-9H-purin-9-yl)tetrahydro-3-furanyl acetate C16H17ClN4O7 详情 详情
(VII) 45180 (2R,3R,4R,5R)-4-(acetoxy)-2-[(acetoxy)methyl]-5-(6-chloro-9H-purin-9-yl)tetrahydro-3-furanyl acetate C16H17ClN4O7 详情 详情
(VIII) 38010 (1S,2S)-2-aminocyclopentanol C5H11NO 详情 详情
(VIII) 45181 (1S,2S)-2-aminocyclopentanol C5H11NO 详情 详情
(IX) 38017 (1S,2S)-2-amino-3-cyclopenten-1-ol C5H9NO 详情 详情
(X) 38018 (2R,3R,4R,5R)-4-(acetoxy)-2-[(acetoxy)methyl]-5-(6-[[(1S,2S)-2-hydroxycyclopentyl]amino]-9H-purin-9-yl)tetrahydro-3-furanyl acetate C21H27N5O8 详情 详情
(X) 45182 (2R,3R,4R,5R)-4-(acetoxy)-2-[(acetoxy)methyl]-5-(6-[[(1S,2S)-2-hydroxycyclopentyl]amino]-9H-purin-9-yl)tetrahydro-3-furanyl acetate C21H27N5O8 详情 详情

合成路线3

The commercially available 8-[14C]-inosine (I) with Ac2O in hot pyridine gives the triacetate (II), which is treated with SOCl2 and DMF in dichloromethane yielding the chloropurine (III). The condensation of (III) with (1S-trans)-2-aminocyclopentanol by means of NaHCO3 in hot isopropanol affords the acetylated target compound (V), which is finally deacetylated with t-Bu-NH2 in methanol.

参考文献 中间体
【1】 Wadsworth, A.H.; et al.; Synthesis of isotopically labelled versions of adenosine agonist GR79236. J Label Compd Radiopharm 2000, 43, 1, 11.
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) 38013 9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-1,9-dihydro-6H-purin-6-one C10H12N4O5 详情 详情
(I) 63751 9-[3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-1,9-dihydro-6H-purin-6-one C10H12N4O5 详情 详情
(II) 38014 (2R,3R,4R,5R)-4-(acetoxy)-2-[(acetoxy)methyl]-5-(6-oxo-1,6-dihydro-9H-purin-9-yl)tetrahydro-3-furanyl acetate C16H18N4O8 详情 详情
(II) 63752 4-(acetyloxy)-2-[(acetyloxy)methyl]-5-(6-oxo-1,6-dihydro-9H-purin-9-yl)tetrahydro-3-furanyl acetate C16H18N4O8 详情 详情
(III) 38015 (2R,3R,4R,5R)-4-(acetoxy)-2-[(acetoxy)methyl]-5-(1-nitro-6-oxo-1,6-dihydro-9H-purin-9-yl)tetrahydro-3-furanyl acetate C16H17N5O10 详情 详情
(III) 63753 4-(acetyloxy)-2-[(acetyloxy)methyl]-5-(6-chloro-9H-purin-9-yl)tetrahydro-3-furanyl acetate C16H17ClN4O7 详情 详情
(IV) 38017 (1S,2S)-2-amino-3-cyclopenten-1-ol C5H9NO 详情 详情
(V) 38018 (2R,3R,4R,5R)-4-(acetoxy)-2-[(acetoxy)methyl]-5-(6-[[(1S,2S)-2-hydroxycyclopentyl]amino]-9H-purin-9-yl)tetrahydro-3-furanyl acetate C21H27N5O8 详情 详情
(V) 63754 4-(acetyloxy)-2-[(acetyloxy)methyl]-5-{6-[(2-hydroxycyclopentyl)amino]-9H-purin-9-yl}tetrahydro-3-furanyl acetate C21H27N5O8 详情 详情

合成路线4

The condensation of the ribosyl chloropurine (I) with (rac-trans)-2-amino-3-cyclopentenol (II) by means of NaHCO3 in isopropanol gives a diastereomeric mixture of adenosine derivatives (III) + (IV) that is separated by HPLC. The desired isomer (III) is acetylated with Ac2O and pyridine yielding the tetraacetate (V), which is hydrogenated with tritium over Pt in THF to afford the tetraacetate (VI) of the target compound. Finally, (VI) is deacetylated by means of t-BuNH2 in methanol.

参考文献 中间体
【1】 Wadsworth, A.H.; et al.; Synthesis of isotopically labelled versions of adenosine agonist GR79236. J Label Compd Radiopharm 2000, 43, 1, 11.
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) 18716 6-chloropurine riboside; (2R,3R,4S,5R)-2-(6-chloro-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3,4-furandiol 2004-06-0 C10H11ClN4O4 详情 详情
(II) 38017 (1S,2S)-2-amino-3-cyclopenten-1-ol C5H9NO 详情 详情
(III) 38019 (2R,3R,4S,5R)-2-(6-[[(1S,5S)-5-hydroxy-2-cyclopenten-1-yl]amino]-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3,4-furandiol C15H19N5O5 详情 详情
(IV) 38020 (2R,3R,4S,5R)-2-(6-[[(1R,5R)-5-hydroxy-2-cyclopenten-1-yl]amino]-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3,4-furandiol C15H19N5O5 详情 详情
(V) 38021 (2R,3R,4R,5R)-4-(acetoxy)-2-[(acetoxy)methyl]-5-(6-[[(1S,5S)-5-hydroxy-2-cyclopenten-1-yl]amino]-9H-purin-9-yl)tetrahydro-3-furanyl acetate C21H25N5O8 详情 详情
(VI) 38018 (2R,3R,4R,5R)-4-(acetoxy)-2-[(acetoxy)methyl]-5-(6-[[(1S,2S)-2-hydroxycyclopentyl]amino]-9H-purin-9-yl)tetrahydro-3-furanyl acetate C21H27N5O8 详情 详情
Extended Information