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【结 构 式】

【分子编号】38013

【品名】9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-1,9-dihydro-6H-purin-6-one

【CA登记号】

【 分 子 式 】C10H12N4O5

【 分 子 量 】268.22924

【元素组成】C 44.78% H 4.51% N 20.89% O 29.82%

与该中间体有关的原料药合成路线共 4 条

合成路线1

该中间体在本合成路线中的序号:(I)

The reaction of inosine (I) with trimethyl orthoacetate and AcOH, followed by a treatment with acetyl bromide, gives 3'-beta-bromo-3'-deoxyinosine (II), which is debrominated by means of Bu3SnH and AIBN in toluene to yield 3'-deoxyinosine (III). The reaction of (III) with SOCl2 /DMF in refluxing dichloromethane or with POCl3 /TEA in refluxing acetonitrile yields the 6-chloropurine (IV), which is deacetylated with NaOMe in methanol to afford the dihydroxy compound (V). The selective tritylation of the primary OH group of (V) with Tr-Cl and collidine in acetonitrile provides the trityl ether (VI), which is fluorinated with diethylaminosulfur trifluoride (DAST) and pyridine in dichloromethane to give the 3'-beta-fluoro derivative (VII). The reaction of (VII) with ammonia in THF gives the tritylated fluoroadenosine (VIII), which is finally deprotected with HCl in methanol/water to provide the target lodenosine. Alternatively, conversion of (VII) into lodenosine can be performed by first removal of the trityl protecting group with HCl in MeOH/toluene yielding compound (IX), whose chlorine atom is finally displaced with ammonia in MeOH/toluene

1 Takamatsu, S.; et al.; 9-(2,3-Dideoxy-2-fluoro-beta-D-threo-pentofuranosyl)adenine (FddA) via a purine 3'-deoxynucleoside. J Org Chem 2001, 66, 22, 7469.
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
(II) 55505 [(2R,3S,4S,5R)-4-(acetyloxy)-3-bromo-5-(6-oxo-1,6-dihydro-9H-purin-9-yl)tetrahydro-2-furanyl]methyl acetate C14H15BrN4O6 详情 详情
(III) 55506 (2R,3R,5S)-5-[(acetyloxy)methyl]-2-(6-oxo-1,6-dihydro-9H-purin-9-yl)tetrahydro-3-furanyl acetate C14H16N4O6 详情 详情
(IV) 55507 [(2S,4R,5R)-4-(acetyloxy)-5-(6-chloro-9H-purin-9-yl)tetrahydro-2-furanyl]methyl acetate C14H15ClN4O5 详情 详情
(V) 48720 (2R,3R,5S)-2-(6-chloro-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3-furanol C10H11ClN4O3 详情 详情
(VI) 48721 (2R,3R,5S)-2-(6-chloro-9H-purin-9-yl)-5-[(trityloxy)methyl]tetrahydro-3-furanol C29H25ClN4O3 详情 详情
(VII) 48722 [(2S,4S,5R)-5-(6-chloro-9H-purin-9-yl)-4-fluorotetrahydro-2-furanyl]methyl trityl ether; 6-chloro-9-[(2R,3S,5S)-3-fluoro-5-[(trityloxy)methyl]tetrahydro-2-furanyl]-9H-purine C29H24ClFN4O2 详情 详情
(VIII) 29876 9-[(2R,3S,5S)-3-fluoro-5-[(trityloxy)methyl]tetrahydro-2-furanyl]-9H-purin-6-ylamine; 9-[(2R,3S,5S)-3-fluoro-5-[(trityloxy)methyl]tetrahydro-2-furanyl]-9H-purin-6-amine C29H26FN5O2 详情 详情
(IX) 17712 [(2S,4S,5R)-5-(6-chloro-9H-purin-9-yl)-4-fluorotetrahydro-2-furanyl]methanol C10H10ClFN4O2 详情 详情

合成路线2

该中间体在本合成路线中的序号:(I)

The reaction of inosine (I) with trimethyl orthoacetate and HOAc, followed by a treatment with acetyl bromide, gives 3'-beta-bromo-3'-deoxyinosine (II), which is debrominated by means of Bu3SnH and AIBN in toluene to yield 3'-deoxyinosine (III). The reaction of (III) with SOCl2 /DMF in refluxing dichloromethane or with POCl3 /TEA in refluxing acetonitrile yields the 6-chloropurine (IV), which is regioselectively monodeacetylated with TEA in methanol to afford the hydroxy compound (V). The fluorination of (V) with morpholinosulfur trifluoride (MOST) and pyridine in dichloromethane gives the 3'-beta-fluoro derivative (VI), which is finally deprotected with ammonia in THF to provide the target lodenosine.

1 Takamatsu, S.; et al.; 9-(2,3-Dideoxy-2-fluoro-beta-D-threo-pentofuranosyl)adenine (FddA) via a purine 3'-deoxynucleoside. J Org Chem 2001, 66, 22, 7469.
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
(II) 55505 [(2R,3S,4S,5R)-4-(acetyloxy)-3-bromo-5-(6-oxo-1,6-dihydro-9H-purin-9-yl)tetrahydro-2-furanyl]methyl acetate C14H15BrN4O6 详情 详情
(III) 55506 (2R,3R,5S)-5-[(acetyloxy)methyl]-2-(6-oxo-1,6-dihydro-9H-purin-9-yl)tetrahydro-3-furanyl acetate C14H16N4O6 详情 详情
(IV) 55507 [(2S,4R,5R)-4-(acetyloxy)-5-(6-chloro-9H-purin-9-yl)tetrahydro-2-furanyl]methyl acetate C14H15ClN4O5 详情 详情
(V) 55509 [(2S,4R,5R)-5-(6-chloro-9H-purin-9-yl)-4-hydroxytetrahydro-2-furanyl]methyl acetate C12H13ClN4O4 详情 详情
(VI) 55508 [(2S,4S,5R)-5-(6-chloro-9H-purin-9-yl)-4-fluorotetrahydro-2-furanyl]methyl acetate C12H12ClFN4O3 详情 详情

合成路线3

该中间体在本合成路线中的序号:(III)

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.

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4

该中间体在本合成路线中的序号:(I)

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.

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
Extended Information