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【结 构 式】 
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【分子编号】27424 【品名】3-(1-trityl-1H-imidazol-4-yl)-1-propanol 【CA登记号】 |
【 分 子 式 】C25H24N2O 【 分 子 量 】368.47844 【元素组成】C 81.49% H 6.56% N 7.6% O 4.34% |
合成路线1
该中间体在本合成路线中的序号：(II)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2
该中间体在本合成路线中的序号：(II)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3
该中间体在本合成路线中的序号：(V)This compound can be obtained by two similar ways: 1) The hydrogenation of the double bond of 3-(4-imidazolyl)propenoic acid (I) with H2 over Pd/C in water gives the propionic acid (II), which is esterified with ethanol and sulfuric acid to the ethyl ester (III). The protection of (III) with triphenylmethyl chloride by means of triethylamine in DMF affords the trityl derivative (IV), which is reduced with LiAlH4 in THF yielding 3-(4-imidazolyl)propanol (V). The condensation of (V) with the phenol (VI) by means of triphenylphosphine and diethyl azodicarboxylate in THF provides the ether (VII), which deprotected with HCl in hot THF. 2) Alternatively, propanol (V) can be condensed with cyclopropyl 4-fluorophenyl ketone (VIII) by means of NaH in refluxing toluene to give the previously reported ether (VII).
| 【1】 Krause, M.; Stark, H.; Sadek, B.; et al.; Novel histamine H3-receptor antagonists with carbonyl-substituted 4-(3-(phenoxy) propyl)-1H-imidazole structures like ciproxifan and related compounds. J Med Chem 2000, 43, 21, 3987. |
| 【2】 Ligneau, X.; Stark, H.; Elz, S.; Teriuk, W.; Schwartz, J.-C.; Athmani, S.; Arrang, J.-M.; Hüls, A.; Schunack, W.; Ganellin, C.R.; Optimization of 4-(3-(phenoxy)propyl)-1H-imidazoles leading to ciproxifan, a novel potent histamine H3-receptor antagonist. 15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998, Edinburgh) 1998, Abst P.120. |
| 【3】 Imidazole derivs. as histamine receptor H3 (ant)agonists. EP 0760811; FR 2732017; JP 1998501001; WO 9629315 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIIII) | 27427 | cyclopropyl(4-fluorophenyl)methanone | 772-31-6 | C10H9FO | 详情 | 详情 |
| (I) | 27420 | Urocanic acid; (E)-3-(1H-imidazol-4-yl)-2-propenoic acid | 104-98-3 | C6H6N2O2 | 详情 | 详情 |
| (II) | 27421 | 3-(1H-imidazol-4-yl)propionic acid | C6H8N2O2 | 详情 | 详情 | |
| (III) | 27422 | ethyl 3-(1H-imidazol-4-yl)propanoate | C8H12N2O2 | 详情 | 详情 | |
| (IV) | 27423 | ethyl 3-(1-trityl-1H-imidazol-4-yl)propanoate | C27H26N2O2 | 详情 | 详情 | |
| (V) | 27424 | 3-(1-trityl-1H-imidazol-4-yl)-1-propanol | C25H24N2O | 详情 | 详情 | |
| (VI) | 27425 | cyclopropyl(4-hydroxyphenyl)methanone | C10H10O2 | 详情 | 详情 | |
| (VII) | 27426 | cyclopropyl[4-[3-(1-trityl-1H-imidazol-4-yl)propoxy]phenyl]methanone | C35H32N2O2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(V)Hydrogenation of urocanic acid (I) provided 3-(imidazol-4-yl)propionic acid (II), which was esterified with EtOH and H2SO4 to give ethyl ester (III). Tritylation of (III) with triphenylmethyl chloride afforded (IV), and subsequent reduction using LiAlH4 yielded alcohol (V). Acid cleavage of the trityl protecting group of (V) furnished imidazolylpropanol (VI). Isocyanate (VIII) was prepared from (S)-2-heptylamine (VII) by treatment with diphosgene and a catalytic amount of activated charcoal. Then, condensation between isocyanate (VIII) and alcohol (V) in refluxing acetonitrile generated the corresponding carbamate. The title compound was isolated after conversion to the corresponding hydrogen maleate salt Hydrogenation of urocanic acid (I) provided 3-(imidazol-4-yl)propionic acid (II), which was esterified with EtOH and H2SO4 to give ethyl ester (III). Tritylation of (III) with triphenylmethyl chloride afforded (IV), and subsequent reduction using LiAlH4 yielded alcohol (V). Acid cleavage of the trityl protecting group of (V) furnished imidazolylpropanol (VI). Isocyanate (VIII) was prepared from (S)-2-heptylamine (VII) by treatment with diphosgene and a catalytic amount of activated charcoal. Then, condensation between isocyanate (VIII) and alcohol (V) in refluxing acetonitrile generated the corresponding carbamate. The title compound was isolated after conversion to the corresponding hydrogen maleate salt.
| 【1】 Kiec-Kononowicz, K.; Sasse, A.; Stark, H.; et al.; Development of chiral N-alkylcarbamates as new leads for potent and selective H3-receptor antagonists: Synthesis, capillary electrophoresis, and in vitro and oral in vivo activity. J Med Chem 1999, 42, 4, 593. |
| 【2】 Imidazole derivs. as histamine receptor H3 (ant)agonists. EP 0760811; FR 2732017; JP 1998501001; WO 9629315 . |
| 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) | 27420 | Urocanic acid; (E)-3-(1H-imidazol-4-yl)-2-propenoic acid | 104-98-3 | C6H6N2O2 | 详情 | 详情 |
| (II) | 27421 | 3-(1H-imidazol-4-yl)propionic acid | C6H8N2O2 | 详情 | 详情 | |
| (III) | 27422 | ethyl 3-(1H-imidazol-4-yl)propanoate | C8H12N2O2 | 详情 | 详情 | |
| (IV) | 27423 | ethyl 3-(1-trityl-1H-imidazol-4-yl)propanoate | C27H26N2O2 | 详情 | 详情 | |
| (V) | 27424 | 3-(1-trityl-1H-imidazol-4-yl)-1-propanol | C25H24N2O | 详情 | 详情 | |
| (VI) | 21245 | 3-(1H-imidazol-4-yl)-1-propanol | C6H10N2O | 详情 | 详情 | |
| (VII) | 35809 | (1S)-1-methylhexylamine; (2S)-2-heptanamine | 44745-29-1 | C7H17N | 详情 | 详情 |
| (VIII) | 35810 | (2S)-2-isocyanatoheptane; (1S)-1-methylhexyl isocyanate | C8H15NO | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(V)Urocanic acid (I) was hydrogenated to imidazolepropionic acid (II) and then esterified with EtOH and H2SO4. The resulting imidazole ester (III) was protected as the N-trityl derivative (IV) and then reduced to alcohol (V) by means of LiAlH4 (1). Coupling of (V) with 4'-hydroxyacetophenone (VI) under Mitsunobu conditions furnished ether (VII). The trityl protecting group of (VII) was then cleaved by acidic treatment to give (VIII). Finally, condensation of (VIII) with hydroxylamine provided the target E-oxime.
| 【1】 Derrick, I.; et al.; 3-Deoxyclocinnamox: The first high-affinity, nonpeptide mu-opioid antagonist lacking a phenolic hydroxyl group. J Med Chem 2000, 43, 17, 3348. |
| 【2】 Imidazole derivs. as histamine receptor H3 (ant)agonists. EP 0760811; FR 2732017; JP 1998501001; WO 9629315 . |
| 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) | 27420 | Urocanic acid; (E)-3-(1H-imidazol-4-yl)-2-propenoic acid | 104-98-3 | C6H6N2O2 | 详情 | 详情 |
| (II) | 27421 | 3-(1H-imidazol-4-yl)propionic acid | C6H8N2O2 | 详情 | 详情 | |
| (III) | 27422 | ethyl 3-(1H-imidazol-4-yl)propanoate | C8H12N2O2 | 详情 | 详情 | |
| (IV) | 27423 | ethyl 3-(1-trityl-1H-imidazol-4-yl)propanoate | C27H26N2O2 | 详情 | 详情 | |
| (V) | 27424 | 3-(1-trityl-1H-imidazol-4-yl)-1-propanol | C25H24N2O | 详情 | 详情 | |
| (VI) | 18123 | 1-(4-hydroxyphenyl)-1-ethanone; 4'-Hydroxyacetophenone | 99-93-4 | C8H8O2 | 详情 | 详情 |
| (VII) | 44104 | 1-[4-[3-(1-trityl-1H-imidazol-4-yl)propoxy]phenyl]-1-ethanone | C33H30N2O2 | 详情 | 详情 | |
| (VIII) | 44105 | 1-[4-[3-(1H-imidazol-4-yl)propoxy]phenyl]-1-ethanone | C14H16N2O2 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(VI)Esterification of urocanic acid (I) by means of HCl in MeOH affords methyl ester (II), which is then hydrogenated over Pd/C in MeOH to provide compound (III). Protection of the imidazole ring of (III) with triphenylmethyl chloride (trityl chloride) (IV) and Et3N in acetonitrile yields derivative (V), whose carboxylate moiety is reduced with LiAlH4 in refluxing THF to give alcohol (VI). Trityl removal from compound (VI) with HCl in refluxing EtOH furnishes hydrochloride (VII), which is finally converted into the desired product by condensation in refluxing acetonitrile with isocyanate (VIII) (which in turn can be obtained either by treatment of carboxylic acid (IX) with diphenyl phosphorazidate (DPPA) and Et3N in refluxing dioxane or by reaction of amine (X) with diphosgene (XI) and catalytic charcoal in refluxing ethyl acetate).
| 【1】 Stark, H.; et al.; [125I]Iodoproxyfan and related compounds: A reversible radioligand and novel classes of antagonists with high affinity and selectivity for the histamine H3 receptor. J Med Chem 1996, 39, 6, 1220. |
| 【2】 Sasse, A.; Reidemeister, S.; Stark, H.; et al.; Novel partial agonists for the histamine H3 receptor with high in vitro and in vivo activity. J Med Chem 1999, 42, 20, 4269. |
| 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) | 27420 | Urocanic acid; (E)-3-(1H-imidazol-4-yl)-2-propenoic acid | 104-98-3 | C6H6N2O2 | 详情 | 详情 |
| (II) | 39976 | methyl (E)-3-(1H-imidazol-4-yl)-2-propenoate | C7H8N2O2 | 详情 | 详情 | |
| (III) | 39977 | methyl 3-(1H-imidazol-4-yl)propanoate | C7H10N2O2 | 详情 | 详情 | |
| (IV) | 28630 | Triphenylchloromethane; 1-[Chloro(diphenyl)methyl]benzene; Trityl chloride | 76-83-5 | C19H15Cl | 详情 | 详情 |
| (V) | 47602 | methyl 3-(1-trityl-1H-imidazol-4-yl)propanoate | C26H24N2O2 | 详情 | 详情 | |
| (VI) | 27424 | 3-(1-trityl-1H-imidazol-4-yl)-1-propanol | C25H24N2O | 详情 | 详情 | |
| (VII) | 21245 | 3-(1H-imidazol-4-yl)-1-propanol | C6H10N2O | 详情 | 详情 | |
| (VIII) | 47603 | (1S)-1,2,2-trimethylpropyl isocyanate; (3S)-3-isocyanato-2,2-dimethylbutane | C7H13NO | 详情 | 详情 | |
| (IX) | 47604 | (2S)-2,3,3-trimethylbutyric acid | C7H14O2 | 详情 | 详情 | |
| (X) | 47605 | (1S)-1,2,2-trimethylpropylamine; (2S)-3,3-dimethyl-2-butanamine | 22526-47-2 | C6H15N | 详情 | 详情 |
| (XI) | 42918 | Chloroformic acid trichloromethyl ester; di-Phosgene; Chloroformic Acid, Trichloromethyl Ester; Trichloromethyl chloroformate; Diphosgene | 503-38-8 | C2Cl4O2 | 详情 | 详情 |