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【结 构 式】 
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【分子编号】17692 【品名】6-Chloropurine; 6-chloro-9H-purine 【CA登记号】87-42-3 |
【 分 子 式 】C5H3ClN4 【 分 子 量 】154.55848 【元素组成】C 38.86% H 1.96% Cl 22.94% N 36.25% |
合成路线1
该中间体在本合成路线中的序号：(I)A new enantioselective synthesis of neplanocin A has been reported: The enantiocontrolled condensation of the 6-chloropurine (I) with cis-1,3-bis(benzoyloxy)-4-cyclopentene (II) catalyzed by a chiral Pd catalyst gives the alkylated purine (III), which is condensed with the nitrosulfone (IV) by means of PPh3 and TEA yielding the intermediate (V). Epoxidation of (V) with MCPBA in dichloromethane affords the epoxide (VI), which is oxidized with O3 and DBU in methanol/THF giving the cyclopentenecarboxylate (VII). The esterification of the beta-OH group of (VII) with 4-nitrobenzoic acid (VIII), PPh3 and DEAD in THF, using a Mitsunobu reaction to invert the OH group, yields the ester (IX), with the desired alpha-OH configuration. The reduction of (IX) with DIBAL in THF/dichloromethane affords the unsaturated the diol (X), which is dihydroxylated with OsO4 and NMO in acetone/water providing the tetraol (XI). The reaction of (XI) with 2,2-dimethoxypropane and TsOH gives the diacetonide (XII), which is selectively monodeprotected with FeCl3 on silica gel yielding the dihydroxylated acetonide (XIII). The regioselective hydroxylation of the primary OH of (XIII) with pivaloyl chloride (Piv-Cl) in pyridine yields the pivalate (XIV), which is dehydrated with SOCl2 in DMF/pyridine affording the fully protected 6-chloropurine derivative (XV). Compound (XV) is treated with ammonia in order to eliminate the pivaloyl group and to form the adenine derivative (XVI), which is finally treated with hot aqueous HCl to eliminate the acetonide group.
| 【1】 Madsen, R.; Brown, B.; Guile, S.D.; Trost, B.M.; Palladium-catalyzed enantioselective synthesis of carbanucleosides. J Am Chem Soc 2000, 122, 25, 5947. |
| 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) | 17692 | 6-Chloropurine; 6-chloro-9H-purine | 87-42-3 | C5H3ClN4 | 详情 | 详情 |
| (II) | 37776 | (1R,4S)-4-(benzoyloxy)-2-cyclopenten-1-yl benzoate | C19H16O4 | 详情 | 详情 | |
| (III) | 41036 | (1S,4R)-4-(6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl benzoate | C17H13ClN4O2 | 详情 | 详情 | |
| (IV) | 37778 | (nitromethyl)(dioxo)phenyl-lambda(6)-sulfane; nitromethyl phenyl sulfone | 21272-85-5 | C7H7NO4S | 详情 | 详情 |
| (V) | 41037 | 6-chloro-9-[(1R,4S)-4-[(S)-nitro(phenylsulfonyl)methyl]-2-cyclopenten-1-yl]-9H-purine; (S)-[(1S,4R)-4-(6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl](nitro)methyl phenyl sulfone | C17H14ClN5O4S | 详情 | 详情 | |
| (VI) | 41038 | (S)-[(1S,2S,4R,5R)-4-(6-chloro-9H-purin-9-yl)-6-oxabicyclo[3.1.0]hex-2-yl](nitro)methyl phenyl sulfone; 6-chloro-9-[(1R,2R,4S,5S)-4-[(S)-nitro(phenylsulfonyl)methyl]-6-oxabicyclo[3.1.0]hex-2-yl]-9H-purine | C17H14ClN5O5S | 详情 | 详情 | |
| (VII) | 41039 | methyl (3S,4R)-4-(6-chloro-9H-purin-9-yl)-3-hydroxy-1-cyclopentene-1-carboxylate | C12H11ClN4O3 | 详情 | 详情 | |
| (VIII) | 18119 | 4-nitrobenzoic acid; p-nitrobenzoic acid | 62-23-7 | C7H5NO4 | 详情 | 详情 |
| (IX) | 41040 | (1R,5R)-5-(6-chloro-9H-purin-9-yl)-3-(methoxycarbonyl)-2-cyclopenten-1-yl 4-nitrobenzoate | C19H14ClN5O6 | 详情 | 详情 | |
| (X) | 41041 | (1R,5R)-5-(6-chloro-9H-purin-9-yl)-3-(hydroxymethyl)-2-cyclopenten-1-ol | C11H11ClN4O2 | 详情 | 详情 | |
| (XI) | 41042 | (1S,2S,3S,4R)-4-(6-chloro-9H-purin-9-yl)-1-(hydroxymethyl)-1,2,3-cyclopentanetriol | C11H13ClN4O4 | 详情 | 详情 | |
| (XII) | 41043 | C17H21ClN4O4 | 详情 | 详情 | ||
| (XIII) | 41044 | (3aS,4S,6R,6aS)-6-(6-chloro-9H-purin-9-yl)-4-(hydroxymethyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-ol | C14H17ClN4O4 | 详情 | 详情 | |
| (XIV) | 41045 | [(3aS,4S,6R,6aS)-6-(6-chloro-9H-purin-9-yl)-4-hydroxy-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]methyl pivalate | C19H25ClN4O5 | 详情 | 详情 | |
| (XV) | 41046 | [(3aR,6R,6aS)-6-(6-chloro-9H-purin-9-yl)-2,2-dimethyl-6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]methyl pivalate | C19H23ClN4O4 | 详情 | 详情 | |
| (XVI) | 41047 | [(3aR,6R,6aS)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyl-6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]methanol | C14H17N5O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XII)The reaction of D-ribose (I) with 2,2-dimethoxypropane (II) by means of HClO4 in methanol gives the isopropylidene derivative (III), which is oxidized with PCC in benzene to yield the tetrahydrofuranone (IV). The reaction of (IV) with the lithium salt of dimethyl methylphosphonate (V) affords the chiral cyclopentenone (VI), which is condensed with tert-butyl methyl ether (VII) by means of tBu-OK and sec-BuLi in THF to provide the cyclopentenol derivative (VIII). The reaction of (VIII) with Ac2O, TEA and DMAP in dichloromethane gives the corresponding acetate (IX), which is submitted to rearrangement catalyzed by PdCl2(acetonitrile)2 and benzoquinone in refluxing THF to yield the regioisomeric acetate (X). The hydrolysis of (X) by means of K2CO3 in methanol yields the corresponding alcohol (XI), which is condensed with 6-chloropurine (XII) by means of PPh3 and DIEA to afford the adduct (XIII). The reaction of (XIII) with ammonia in ethanol at 80 C in a steel bomb affords the protected adenine nucleoside (XIV), which is finally deprotected with aqueous TFA to provide the target cyclopentenyl nucleoside.
| 【1】 Ali, S.M.; et al.; Efficient enantioselective syntheses of carbocyclic nucleoside and prostaglandin synthons. Tetrahedron Lett 1990, 31, 11, 1509. |
| 【2】 Song, G.Y.; et al.; Enantiomeric synthesis of D-and L-cyclopentenyl nucleosides and their antiviral activity against HIV and West Nile virus. J Med Chem 2001, 44, 23, 3985. |
| 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) | 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) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (III) | 49594 | Methyl 2,3-O-Isopropylidene-beta-D-Ribofuranoside | C9H16O5 | 详情 | 详情 | |
| (IV) | 49585 | (3aS,6aR)-6-methoxy-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxol-4(3aH)-one | C8H12O5 | 详情 | 详情 | |
| (V) | 29720 | [(dimethoxyphosphoryl)methyl]lithium | C3H8LiO3P | 详情 | 详情 | |
| (VI) | 49586 | (3aS,6aS)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-one | C8H10O3 | 详情 | 详情 | |
| (VII) | 49587 | 2-methoxy-2-methylpropane; tert-butyl methyl ether | C5H12O | 详情 | 详情 | |
| (VIII) | 49588 | tert-Butylmethyl ether; Methyl tert-butyl ether | 1634-04-4 | C13H22O4 | 详情 | 详情 |
| (IX) | 49589 | (3aS,4S,6aS)-4-(tert-butoxymethyl)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl acetate | C15H24O5 | 详情 | 详情 | |
| (X) | 49590 | (3aR,4S,6aR)-6-(tert-butoxymethyl)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl acetate | C15H24O5 | 详情 | 详情 | |
| (XI) | 49591 | (3aS,4S,6aR)-6-(tert-butoxymethyl)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ol | C13H22O4 | 详情 | 详情 | |
| (XII) | 17692 | 6-Chloropurine; 6-chloro-9H-purine | 87-42-3 | C5H3ClN4 | 详情 | 详情 |
| (XIII) | 49592 | 9-[(3aS,4R,6aR)-6-(tert-butoxymethyl)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-6-chloro-9H-purine; [(3aR,6R,6aS)-6-(6-chloro-9H-purin-9-yl)-2,2-dimethyl-6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]methyl tert-butyl ether | C18H23ClN4O3 | 详情 | 详情 | |
| (XIV) | 49593 | 9-[(3aS,4R,6aR)-6-(tert-butoxymethyl)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-9H-purin-6-amine; 9-[(3aS,4R,6aR)-6-(tert-butoxymethyl)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-9H-purin-6-ylamine | C18H25N5O3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XII)The esterification of 1H-imidazole-4,5-dicarboxylic acid (I) with EtOH and sulfuric acid gives the diethyl ester (II), which is brominated with NBS in acetonitrile, yielding the 2-bromo derivative (III). The hydrolysis of (III) by means of hot aqueous Na2CO3 affords the 2-bromo-1H-imidazole-4,5-dicarboxylic acid (IV), which is diazocoupled with the labeled diazonium ion (V) to provide the monolabeled azo acid (VI). The reaction of acid (VI) with 15NH4Cl and DEC in acetonitrile gives the doubly labeled azoamide (VII), which is reduced with H2 over Pd/C in methanol to yield the doubly labeled 5-amino-1H-imidazole-4-carboxamide (VIII). The cyclization of (VIII) with sodium 13C-ethylxanthate (IX) in DMF affords the mercaptoxanthine (X), which is reduced to the hypoxanthine (XI) with Raney Ni and formic acid. The reaction of (XI) with POCl3 in hot N,N-dimethylaniline provides the triply labeled chloropurine (XII), which is submitted to enzymatic trans-glycosylation with 7-methylguanosine or thymidine and purine nucleoside phosphorylase (PNP) and thymidine phosphorylase (TP) to give the glycosylated chloropurine (XIII). Finally, this compound is treated with 15NH4Cl and KHCO3 in hot anhydrous DMSO to afford the target tetralabeled adenine nucleoside.
| 【1】 Abad, J.-L.; Gaffney B.L.; Jones R.A.; 15N-multilabeled adenine and guanine nucleosides syntheses of [1,3,NH2-15N3]- and [2-13C-1,3NH2-15N3]-labeled adenosine, guanosine , 2'-deoxyadenosine, and 2'-deoxyguanosine. J Org Chem 1999, 64, 18, 6575. |
| 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) | 31951 | 1H-imidazole-4,5-dicarboxylic acid | 570-22-9 | C5H4N2O4 | 详情 | 详情 |
| (II) | 27424 | 3-(1-trityl-1H-imidazol-4-yl)-1-propanol | C25H24N2O | 详情 | 详情 | |
| (III) | 51896 | diethyl 2-bromo-1H-imidazole-4,5-dicarboxylate | C9H11BrN2O4 | 详情 | 详情 | |
| (IV) | 51897 | 2-bromo-1H-imidazole-4,5-dicarboxylic acid | C5H3BrN2O4 | 详情 | 详情 | |
| (V) | 51898 | 4-bromobenzenediazonium | C6H4BrN2 | 详情 | 详情 | |
| (V) | 51907 | 4-bromobenzenediazonium | C6H4BrN2 | 详情 | 详情 | |
| (VI) | 51899 | 2-bromo-5-[(E)-2-phenyldiazenyl]-1H-imidazole-4-carboxylic acid | C10H7BrN4O2 | 详情 | 详情 | |
| (VI) | 51908 | 2-bromo-5-[(E)-2-phenyldiazenyl]-1H-imidazole-4-carboxylic acid | C10H7BrN4O2 | 详情 | 详情 | |
| (VII) | 51900 | 2-bromo-5-[(E)-2-phenyldiazenyl]-1H-imidazole-4-carboxamide | C10H8BrN5O | 详情 | 详情 | |
| (VII) | 51909 | 2-bromo-5-[(E)-2-phenyldiazenyl]-1H-imidazole-4-carboxamide | C10H8BrN5O | 详情 | 详情 | |
| (VIII) | 11015 | 5-Amino-1H-imidazole-4-carboxamide | 360-97-4 | C4H6N4O | 详情 | 详情 |
| (VIII) | 51901 | 5-amino-1H-imidazole-4-carboxamide | C4H6N4O | 详情 | 详情 | |
| (IX) | 51902 | C3H5NaOS2 | 详情 | 详情 | ||
| (IX) | 51910 | C3H5NaOS2 | 详情 | 详情 | ||
| (X) | 51903 | C5H3N4NaOS | 详情 | 详情 | ||
| (X) | 51911 | C5H3N4NaOS | 详情 | 详情 | ||
| (XI) | 51904 | 1,9-dihydro-6H-purin-6-one | C5H4N4O | 详情 | 详情 | |
| (XI) | 51912 | 1,9-dihydro-6H-purin-6-one | C5H4N4O | 详情 | 详情 | |
| (XII) | 17692 | 6-Chloropurine; 6-chloro-9H-purine | 87-42-3 | C5H3ClN4 | 详情 | 详情 |
| (XII) | 51905 | 6-chloro-9H-purine | C5H3ClN4 | 详情 | 详情 | |
| (XIII) | 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 |
| (XIII) | 51906 | (2R,3R,4S,5R)-2-(6-chloro-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3,4-furandiol | C10H11ClN4O4 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XII)The esterification of 1H-imidazole-4,5-dicarboxylic acid (I) with EtOH and sulfuric acid gives the diethyl ester (II), which is brominated with NBS in acetonitrile, yielding the 2-bromo derivative (III). The hydrolysis of (III) by means of hot aqueous Na2CO3 affords the 2-bromo-1H-imidazole-4,5-dicarboxylic acid (IV), which is diazocoupled with the labeled diazonium ion (V) to provide the monolabeled azo acid (VI). The reaction of acid (VI) with 15NH4Cl and DEC in acetonitrile gives the doubly labeled azoamide (VII), which is reduced with H2 over Pd/C in methanol to yield the doubly labeled 5-amino-1H-imidazole-4-carboxamide (VIII). The cyclization of (VIII) with sodium ethylxanthate (IX) in DMF affords the mercaptoxanthine (X), which is reduced to the hypoxanthine (XI) with Raney Ni and formic acid. The reaction of (XI) with POCl3 in hot N,N-dimethylaniline provides the doubly labeled chloropurine (XII), which is submitted to enzymatic trans-glycosylation with 7-methylguanosine or thymidine and purine nucleoside phosphorylase (PNP) and thymidine phosphorylase (TP) to give the glycosylated chloropurine (XIII). Finally, this compound is treated with 15NH4Cl and KHCO3 in hot anhydrous DMSO to afford the target triply labeled adenine nucleoside. Alternatively, the intermediate hypoxanthine (XI) can also be obtained directly by cyclization of the doubly labeled 5-amino-1H-imidazole-4-carboxamide (VIII) with formic acid and diethoxymethyl acetate (DEMA) in DMF.
| 【1】 Abad, J.-L.; Gaffney B.L.; Jones R.A.; 15N-multilabeled adenine and guanine nucleosides syntheses of [1,3,NH2-15N3]- and [2-13C-1,3NH2-15N3]-labeled adenosine, guanosine , 2'-deoxyadenosine, and 2'-deoxyguanosine. J Org Chem 1999, 64, 18, 6575. |
| 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) | 31951 | 1H-imidazole-4,5-dicarboxylic acid | 570-22-9 | C5H4N2O4 | 详情 | 详情 |
| (II) | 27424 | 3-(1-trityl-1H-imidazol-4-yl)-1-propanol | C25H24N2O | 详情 | 详情 | |
| (III) | 51896 | diethyl 2-bromo-1H-imidazole-4,5-dicarboxylate | C9H11BrN2O4 | 详情 | 详情 | |
| (IV) | 51897 | 2-bromo-1H-imidazole-4,5-dicarboxylic acid | C5H3BrN2O4 | 详情 | 详情 | |
| (V) | 51898 | 4-bromobenzenediazonium | C6H4BrN2 | 详情 | 详情 | |
| (V) | 51907 | 4-bromobenzenediazonium | C6H4BrN2 | 详情 | 详情 | |
| (VI) | 51899 | 2-bromo-5-[(E)-2-phenyldiazenyl]-1H-imidazole-4-carboxylic acid | C10H7BrN4O2 | 详情 | 详情 | |
| (VI) | 51908 | 2-bromo-5-[(E)-2-phenyldiazenyl]-1H-imidazole-4-carboxylic acid | C10H7BrN4O2 | 详情 | 详情 | |
| (VII) | 51900 | 2-bromo-5-[(E)-2-phenyldiazenyl]-1H-imidazole-4-carboxamide | C10H8BrN5O | 详情 | 详情 | |
| (VII) | 51909 | 2-bromo-5-[(E)-2-phenyldiazenyl]-1H-imidazole-4-carboxamide | C10H8BrN5O | 详情 | 详情 | |
| (VIII) | 11015 | 5-Amino-1H-imidazole-4-carboxamide | 360-97-4 | C4H6N4O | 详情 | 详情 |
| (VIII) | 51901 | 5-amino-1H-imidazole-4-carboxamide | C4H6N4O | 详情 | 详情 | |
| (IX) | 51910 | C3H5NaOS2 | 详情 | 详情 | ||
| (X) | 51911 | C5H3N4NaOS | 详情 | 详情 | ||
| (X) | 51913 | C5H3N4NaOS | 详情 | 详情 | ||
| (XI) | 51912 | 1,9-dihydro-6H-purin-6-one | C5H4N4O | 详情 | 详情 | |
| (XI) | 51914 | 1,9-dihydro-6H-purin-6-one | C5H4N4O | 详情 | 详情 | |
| (XII) | 17692 | 6-Chloropurine; 6-chloro-9H-purine | 87-42-3 | C5H3ClN4 | 详情 | 详情 |
| (XII) | 51915 | 6-chloro-9H-purine | C5H3ClN4 | 详情 | 详情 | |
| (XIII) | 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 |
| (XIII) | 51916 | (2R,3R,4S,5R)-2-(6-chloro-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3,4-furandiol | C10H11ClN4O4 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(V)The TLC monitored reaction of 1,3-di-O-acetyl-5-O-benzoyl-2-deoxy-2-fluoro-D-arabinofuranose (III) with 30% HBr in acetic acid gives the bromosugar (IV), which is condensed with 6-chloropurine (V) in refluxing dichloromethane, yielding the chloropurine derivative (VI). The reaction of (VI) with methanolic NH3 at 100 C in a steel bomb affords 9-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)adenine (VII), which is selectively silylated with tert-butyldimethylsilyl chloride (TBDMS-Cl) and imidazole in DMF, giving the 5'-O-silyl derivative (VIII). The reaction of (VIII) with phenyl chlorothioformate by means of dimethylaminopyridine in DMF yields the thiocarbonate (IX), which is reduced with tributyltin hydride and AIBN in hot toluene, affording 9-[2,3-dideoxy-2-fluoro-5-O-(tert-butyldimethylsilyl)-beta-D-arabinofuranosyl]adenine (X). Finally, this compound is desilylated with tetrabutylammonium fluoride in THF.
| 【1】 Castaner, J.; Graul, A.; Silvestre, J.S.; Lodenosine. Drugs Fut 1998, 23, 11, 1176-1189. |
| 【2】 Ford, H. Jr.; Driscoll, J.S.; Aoki, S.; Kelley, J.A.; Johns, D.G.; Roth, J.S.; Tseng, C.K.-H.; Broder, S.; Marquez, V.E.; Mitsuya, H.; Acid-stable 2'-fluoro purine dideoxynucleosides as active agents against HIV. J Med Chem 1990, 33, 3, 978-85. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 17690 | [(2R,3R,4S)-5-(acetoxy)-4-fluoro-3-[(1-hydroxyvinyl)oxy]tetrahydro-2-furanyl]methyl benzoate | C16H17FO7 | 详情 | 详情 | |
| (IV) | 17691 | [(2R,3R,4S)-3-(acetoxy)-5-bromo-4-fluorotetrahydro-2-furanyl]methyl benzoate | C14H14BrFO5 | 详情 | 详情 | |
| (V) | 17692 | 6-Chloropurine; 6-chloro-9H-purine | 87-42-3 | C5H3ClN4 | 详情 | 详情 |
| (VI) | 17693 | [(2R,3R,4S,5R)-3-(acetoxy)-5-(6-chloro-9H-purin-9-yl)-4-fluorotetrahydro-2-furanyl]methyl benzoate | C19H16ClFN4O5 | 详情 | 详情 | |
| (VII) | 17694 | (2R,3R,4S,5R)-5-(6-amino-9H-purin-9-yl)-4-fluoro-2-(hydroxymethyl)tetrahydro-3-furanol | C10H12FN5O3 | 详情 | 详情 | |
| (VIII) | 17695 | (2R,3R,4S,5R)-5-(6-amino-9H-purin-9-yl)-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4-fluorotetrahydro-3-furanol | C16H26FN5O3Si | 详情 | 详情 | |
| (IX) | 17696 | O-[(2R,3R,4S,5R)-5-(6-amino-9H-purin-9-yl)-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4-fluorotetrahydro-3-furanyl] O-phenyl carbonothioate | C23H30FN5O4SSi | 详情 | 详情 | |
| (X) | 17697 | 9-[(2R,3S,5S)-5-([[tert-butyl(dimethyl)silyl]oxy]methyl)-3-fluorotetrahydro-2-furanyl]-9H-purin-6-ylamine; 9-[(2R,3S,5S)-5-([[tert-butyl(dimethyl)silyl]oxy]methyl)-3-fluorotetrahydro-2-furanyl]-9H-purin-6-amine | C16H26FN5O2Si | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(V)The reaction of 1,3,5-tri-O-benzoyl-2-deoxy-2-fluoro-alpha-D-arabinofuranose (XI) with HBr in acetic acid gives the bromosugar (XII), which is methylated with methanol/K2CO3 in THF, yielding the 1-O-methyl glucoside (XIII). The selective benzoylation of (XIII) with benzoyl chloride in pyridine at -30 C affords the 5-O-benzoyl glucoside (XIV), which is treated with CS2/methyl iodide and NaH in DMF, giving compound (XV). The reduction of (XV) with tributyltin hydride and AIBN in refluxing toluene yields the 3-deoxy glucoside (XVI), which is condensed with 6-chloropurine (V) in refluxing hexamethyldisylazane, affording 9-(5-O-benzoyl-2,3-dideoxy-2-fluoro-beta-D-arabinofuranosyl)adenine (XVII). Finally, this compound is debenzoylated with methanolic ammonia at 100 C in a sealed tube.
| 【1】 Siddiqui, M.A.; Marquez, V.E.; Driscoll, J.S.; Barchi, J.J. Jr.; Wysocki, R.J. Jr.; A more expedient approach to the synthesis of anti-HIV-active 2,3-dideoxy-2-fluoro-beta-D-threo-pentofuranosyl nucleosides. Synthesis 1991, 11, 11, 1005-8. |
| 【2】 Castaner, J.; Graul, A.; Silvestre, J.S.; Lodenosine. Drugs Fut 1998, 23, 11, 1176-1189. |
| 【3】 Driscoll, J.S.; Roth, J.S.; Broder, S.; Kelley, J.A.; Tseng, C.K.-H.; Mitsuya, H.; Marquez, V.E.; 2',3'-Dideoxy-2'-fluoro-ara-A, an acid-stable purine nucleoside active against human immunodeficiency virus (HIV). Biochem Pharmacol 1987, 36, 17, 2719-22. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 17692 | 6-Chloropurine; 6-chloro-9H-purine | 87-42-3 | C5H3ClN4 | 详情 | 详情 |
| (XI) | 17698 | [(2R,3R,4S,5R)-3,5-bis(benzoyloxy)-4-fluorotetrahydro-2-furanyl]methyl benzoate | C26H21FO7 | 详情 | 详情 | |
| (XII) | 17699 | (2R,3R,4S)-5-bromo-4-fluoro-2-(hydroxymethyl)tetrahydro-3-furanol | C5H8BrFO3 | 详情 | 详情 | |
| (XIII) | 17700 | (2R,3R,4S,5R)-4-fluoro-2-(hydroxymethyl)-5-methoxytetrahydro-3-furanol | C6H11FO4 | 详情 | 详情 | |
| (XIV) | 17701 | [(2R,3R,4S,5R)-4-fluoro-3-hydroxy-5-methoxytetrahydro-2-furanyl]methyl benzoate | C13H15FO5 | 详情 | 详情 | |
| (XV) | 17702 | ((2R,3R,4S,5R)-4-fluoro-5-methoxy-3-[[(methylsulfanyl)carbothioyl]oxy]tetrahydro-2-furanyl)methyl benzoate | C15H17FO5S2 | 详情 | 详情 | |
| (XVI) | 17703 | [(2S,4S,5R)-4-fluoro-5-methoxytetrahydro-2-furanyl]methyl benzoate | C13H15FO4 | 详情 | 详情 | |
| (XVII) | 17704 | [(2S,4S,5R)-5-(6-chloro-9H-purin-9-yl)-4-fluorotetrahydro-2-furanyl]methyl benzoate | C17H14ClFN4O3 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(V)The controlled reaction of 1,3,5-tri-O-benzoyl-2-deoxy-2-fluoro-alpha-D-arabinofuranose (XI) with HBr in acetic acid gives the bromosugar (XXII), which is condensed with 6-chloropurine (V) as before, yielding 6-chloro-9-(3,5-di-O-benzoyl-2-deoxy-2-fluoro-beta-D-arabinofuranosyl)purine (XXIII). Finally, this compound is treated with ammonia in methanol as before to afford intermediate 9-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)adenine (VII).
| 【1】 Castaner, J.; Graul, A.; Silvestre, J.S.; Lodenosine. Drugs Fut 1998, 23, 11, 1176-1189. |
| 【2】 Marquez, V.E.; Design, synthesis, and antiviral activity of nucleoside and nucleotide analogs. ACS Symp Ser 1989, 401, 140-55. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 17692 | 6-Chloropurine; 6-chloro-9H-purine | 87-42-3 | C5H3ClN4 | 详情 | 详情 |
| (VII) | 17694 | (2R,3R,4S,5R)-5-(6-amino-9H-purin-9-yl)-4-fluoro-2-(hydroxymethyl)tetrahydro-3-furanol | C10H12FN5O3 | 详情 | 详情 | |
| (XI) | 17698 | [(2R,3R,4S,5R)-3,5-bis(benzoyloxy)-4-fluorotetrahydro-2-furanyl]methyl benzoate | C26H21FO7 | 详情 | 详情 | |
| (XXII) | 17705 | [(2R,3R,4S,5R)-3-(benzoyloxy)-5-bromo-4-fluorotetrahydro-2-furanyl]methyl benzoate | C19H16BrFO5 | 详情 | 详情 | |
| (XXIII) | 17706 | [(2R,3R,4S,5R)-3-(benzoyloxy)-5-(6-chloro-9H-purin-9-yl)-4-fluorotetrahydro-2-furanyl]methyl benzoate | C24H18ClFN4O5 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(VII)Treatment of alkenyl iodide (I) with the organozinc reagent (II) in the presence of CuBr afforded the unsaturated alpha,alpha-difluorophosphonate (III), which was condensed with diazomethane to give the cyclopropane derivative (IV). Acid hydrolysis of the tetrahydropyranyl ether of (IV) provided alcohol (V), which was converted into tosylate (VI) with p-TsCl and Et3N. Coupling of (VI) with 6-chloropurine (VII) gave the 9-alkylated purine (VIII). Finally, hydrolysis of both phosphonate esters and the chloro atom of purine (VIII) was carried out upon treatment with bromotrimethylsilane, followed by aqueous hydrolysis to yield the title compound.
| 【1】 Yokomatsu, T.; Abe, H.; Sato, M.; Suemune, K.; Kihara, T.; Soeda, S.; Shimeno, H.; Shibuya, S.; Synthesis of 1,1-difluoro-5-(1H-9-purinyl)-2-pentenylphosphonic acids and the related methano analogues. Remarkable effect of the nucleobases and the cyclopropane rings on inhibitory activity toward purine nucleoside phosphorylase. Bioorg Med Chem 1998, 6, 12, 2495. |
| 【2】 Shimeno, H.; Suemune, K.; Abe, H.; Yokomatsu, T.; Kihara, T.; Sato, M.; Soeda, S.; Shibuya, S.; Synthesis of novel nucleotide analogues possessing difluoromethylene phosphonate pharmacophore. Evaluation of the inhibitory activities of PNPases. Symp Med Chem 1998, Abst 1-P-06. |
| 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) | 30269 | (E)-4-iodo-3-butenyl tetrahydro-2H-pyran-2-yl ether; 2-[[(E)-4-iodo-3-butenyl]oxy]tetrahydro-2H-pyran | C9H15IO2 | 详情 | 详情 | |
| (II) | 30270 | bromo[(diethoxyphosphoryl)(difluoro)methyl]zinc | C5H10BrF2O3PZn | 详情 | 详情 | |
| (III) | 30271 | diethyl (E)-1,1-difluoro-5-(tetrahydro-2H-pyran-2-yloxy)-2-pentenylphosphonate | C14H25F2O5P | 详情 | 详情 | |
| (IV) | 30272 | diethyl difluoro[(1R,2S)-2-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]cyclopropyl]methylphosphonate | C15H27F2O5P | 详情 | 详情 | |
| (V) | 30273 | diethyl difluoro[(1R,2S)-2-(2-hydroxyethyl)cyclopropyl]methylphosphonate | C10H19F2O4P | 详情 | 详情 | |
| (VI) | 30274 | 2-[(1S,2R)-2-[(diethoxyphosphoryl)(difluoro)methyl]cyclopropyl]ethyl 4-methylbenzenesulfonate | C17H25F2O6PS | 详情 | 详情 | |
| (VII) | 17692 | 6-Chloropurine; 6-chloro-9H-purine | 87-42-3 | C5H3ClN4 | 详情 | 详情 |
| (VIII) | 30275 | diethyl [(1R,2S)-2-[2-(6-chloro-9H-purin-9-yl)ethyl]cyclopropyl](difluoro)methylphosphonate | C15H20ClF2N4O3P | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(XVII)Hydrolysis of (XIIIa-b) to the carboxylic acid (XIVa-b), and further iodo decarboxylation yielded a mixture of epimeric iodides (XVa-b). From hydrolysis of the iodide group of (XVa-b) with NaHCO3 only the alpha-alcohol (XVI) was isolated. This was condensed with 6-chloropurine (XVII) under Mitsunobu conditions to give adduct (XVIII). The 6-chloro derivative (XVIII) was converted into the protected adenosine analogue (XIX) by treatment with methanolic ammonia in a steel bomb at 100 C. Finally, desilylation of (XIX) employing tetrabutylammonium fluoride furnished the title compound.
| 【1】 Gumina, G.; et al.; Stereoselective synthesis of carbocyclic L-4'-fluoro-2',3'-dideoxyadenosine. Org Lett 2000, 2, 9, 1229. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIIIa) | 36757 | ethyl (1S,3S)-3-([[tert-butyl(dimethyl)silyl]oxy]methyl)-3-fluorocyclopentanecarboxylate | C15H29FO3Si | 详情 | 详情 | |
| (XIIIb) | 36758 | ethyl (1R,3S)-3-([[tert-butyl(dimethyl)silyl]oxy]methyl)-3-fluorocyclopentanecarboxylate | C15H29FO3Si | 详情 | 详情 | |
| (XIVa) | 36763 | (1S,3S)-3-([[tert-butyl(dimethyl)silyl]oxy]methyl)-3-fluorocyclopentanecarboxylic acid | C13H25FO3Si | 详情 | 详情 | |
| (XIVb) | 36764 | (1R,3S)-3-([[tert-butyl(dimethyl)silyl]oxy]methyl)-3-fluorocyclopentanecarboxylic acid | C13H25FO3Si | 详情 | 详情 | |
| (XVa) | 36765 | tert-butyl[[(1S,3S)-1-fluoro-3-iodocyclopentyl]methoxy]dimethylsilane; tert-butyl(dimethyl)silyl [(1S,3S)-1-fluoro-3-iodocyclopentyl]methyl ether | C12H24FIOSi | 详情 | 详情 | |
| (XVb) | 36766 | tert-butyl[[(1S,3R)-1-fluoro-3-iodocyclopentyl]methoxy]dimethylsilane; tert-butyl(dimethyl)silyl [(1S,3R)-1-fluoro-3-iodocyclopentyl]methyl ether | C12H24FIOSi | 详情 | 详情 | |
| (XVI) | 36767 | (1R,3S)-3-([[tert-butyl(dimethyl)silyl]oxy]methyl)-3-fluorocyclopentanol | C12H25FO2Si | 详情 | 详情 | |
| (XVII) | 17692 | 6-Chloropurine; 6-chloro-9H-purine | 87-42-3 | C5H3ClN4 | 详情 | 详情 |
| (XVIII) | 36768 | 9-[(1S,3S)-3-([[tert-butyl(dimethyl)silyl]oxy]methyl)-3-fluorocyclopentyl]-6-chloro-9H-purine; tert-butyl(dimethyl)silyl [(1S,3S)-3-(6-chloro-9H-purin-9-yl)-1-fluorocyclopentyl]methyl ether | C17H26ClFN4OSi | 详情 | 详情 | |
| (XIX) | 36769 | 9-[(1S,3S)-3-([[tert-butyl(dimethyl)silyl]oxy]methyl)-3-fluorocyclopentyl]-9H-purin-6-amine; 9-[(1S,3S)-3-([[tert-butyl(dimethyl)silyl]oxy]methyl)-3-fluorocyclopentyl]-9H-purin-6-ylamine | C17H28FN5OSi | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(VIII)Treatment of 1,2,5,6-diisopropylidene-D-glucofuranose (I) with trifluoromethanesulfonic anhydride and pyridine provides triflate (II), which is then displaced with sodium azide to furnish the 3-azido derivative (III). Oxidative cleavage of the 5,6-diol acetonide of (III) by means of periodic acid leads to aldehyde (IV). Further oxidation of (IV) with a catalytic amount of ruthenium trichloride in the presence of sodium periodate affords carboxylic acid (V). After activation of acid (V) with oxalyl chloride, coupling with methylamine provides amide (VI). Acidic hydrolysis of the remaining 1,2-acetonide of (VI) in the presence of acetic anhydride gives rise to diacetate (VII). Silylation of 6-chloropurine (VIII), followed by coupling with the diacetyl ribofuranuronic acid derivative (VII) in the presence of trimethylsilyl triflate yields the purine glycoside (IX). The acetate ester group of (IX) is then removed by methanolysis in the presence of either methylamine or triethylamine, to produce alcohol (X). Subsequent azido group reduction in (X) by means of triphenylphosphine leads to amine (XI), which is then protected as the N-Boc derivative (XII) employing di-t-butyl dicarbonate.
| 【1】 Masamune, H.; Scott, R.W.; Deninno, M.P. (Pfizer Products Inc.); Cpds. for the treatment of ischemia. EP 1216257; JP 2003510331; WO 0123399 . |
| 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) | 29141 | (3aR,5S,6S,6aR)-5-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol | 582-52-5 | C12H20O6 | 详情 | 详情 |
| (II) | 61299 | (3aR,5R,6S,6aR)-5-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-yl trifluoromethanesulfonate | C13H19F3O8S | 详情 | 详情 | |
| (III) | 61300 | (3aR,5S,6R,6aR)-5-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-yl azide; (3aR,5S,6R,6aR)-6-azido-5-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole | C12H19N3O5 | 详情 | 详情 | |
| (IV) | 61363 | (3aR,5S,6R,6aR)-6-azido-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole-5-carbaldehyde | C8H11N3O4 | 详情 | 详情 | |
| (V) | 31364 | (5E)-2-[(Z,4E)-6-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-methyl-4-hexenylidene]-6,10-dimethyl-5,9-undecadienal | C28H35NO3 | 详情 | 详情 | |
| (VI) | 31365 | tert-butyl[[(2E,6Z,10E)-7-(diethoxymethyl)-3,11,15-trimethyl-2,6,10,14-hexadecatetraenyl]oxy]dimethylsilane; tert-butyl(dimethyl)silyl (2E,6Z,10E)-7-(diethoxymethyl)-3,11,15-trimethyl-2,6,10,14-hexadecatetraenyl ether | C30H56O3Si | 详情 | 详情 | |
| (VII) | 31366 | 2-[(2E,6Z,10E)-7-(hydroxymethyl)-3,11,15-trimethyl-2,6,10,14-hexadecatetraenyl]-1H-isoindole-1,3(2H)-dione | C28H37NO3 | 详情 | 详情 | |
| (VIII) | 17692 | 6-Chloropurine; 6-chloro-9H-purine | 87-42-3 | C5H3ClN4 | 详情 | 详情 |
| (IX) | 61367 | (2R,3R,4R,5S)-4-azido-2-(6-chloro-9H-purin-9-yl)-5-[(methylamino)carbonyl]tetrahydro-3-furanyl acetate | C13H13ClN8O4 | 详情 | 详情 | |
| (X) | 61368 | (2S,3S,4R,5R)-3-azido-5-(6-chloro-9H-purin-9-yl)-4-hydroxy-N-methyltetrahydro-2-furancarboxamide | C11H11ClN8O3 | 详情 | 详情 | |
| (XI) | 61369 | (2S,3S,4R,5R)-3-amino-5-(6-chloro-9H-purin-9-yl)-4-hydroxy-N-methyltetrahydro-2-furancarboxamide | C11H13ClN6O3 | 详情 | 详情 | |
| (XII) | 61370 | tert-butyl (2S,3S,4R,5R)-5-(6-chloro-9H-purin-9-yl)-4-hydroxy-2-[(methylamino)carbonyl]tetrahydro-3-furanylcarbamate | C16H21ClN6O5 | 详情 | 详情 |