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【结 构 式】

【分子编号】27420

【品名】Urocanic acid; (E)-3-(1H-imidazol-4-yl)-2-propenoic acid

【CA登记号】104-98-3

【 分 子 式 】C6H6N2O2

【 分 子 量 】138.12592

【元素组成】C 52.17% H 4.38% N 20.28% O 23.17%

与该中间体有关的原料药合成路线共 6 条

合成路线1

该中间体在本合成路线中的序号:(I)

14C-Radiolabeled fadrozole has been obtained by two similar ways: 1) The condensation of 4-[3-(methanesulfonyloxy)propyl]-N,N-dimethylimidazole-1-carboxamide (VI) with 14C-labeled 4-(bromomethyl)benzonitrile (IX) by means of NH3 followed by hydrolysis with HCl gives radiolabeled 4-[5-(3-hydroxypropyl)imidazol-1-ylmethyl]benzonitrile (X), which is treated with SOCl2 yielding the chloropropyl derivative (XI). Finally, this compound is cyclized to the target compound by means of potassium tert-butoxide. The intermediate compounds imidazole (VI) and radiolabeled benzonitrile (IX) have been obtained as follows: a) Imidazole (VI): The esterification of 3-(4-imidazolyl)-2(E)-propenoic acid (I) with SOCl2 and methanol gives the methyl ester (II), which is reduced with H2 over Pd/C yielding the propionic ester (III). The reduction of (III) with LiAlH4 affords 3-(4-imidazolyl)-1-propanol (IV), which is treated with N,N-dimethyl chloroformamide to afford 4-(3-hydroxypropyl)-N,N-dimethylimidazole-1-carboxamide (V). Finally, this compound is mesylated with methanesulfonyl chloride to give the desired intermediate (VI). b) Radiolabeled benzonitrile (IX): The reaction of 4-bromotoluene (VII) with radiolabeled potassium cyanide gives the radiolabeled 4-methylbenzonitrile (VIII), which is brominated with NBS and benzoylperoxide yielding intermediate (IX).

1 Allentoff, A.J.; et al.; Palladium-catalyzed aryl cynations in radiosynthesis: Synthesis of 14C-labeled fadrozole, a potent aromatase inhibitor. 218th ACS Natl Meet (Aug 22 1999, New Orleans) 1999, Abst MEDI 49.
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) 21245 3-(1H-imidazol-4-yl)-1-propanol C6H10N2O 详情 详情
(V) 39978 4-(3-hydroxypropyl)-N,N-dimethyl-1H-imidazole-1-carboxamide C9H15N3O2 详情 详情
(VI) 27902 N,N-dimethyl-4-[3-[(trimethylsilyl)oxy]propyl]-1H-imidazole-1-carboxamide C12H23N3O2Si 详情 详情
(VII) 14044 4-Bromotoluene; 1-Bromo-4-methylbenzene 106-38-7 C7H7Br 详情 详情
(VIII) 15458 4-methylbenzonitrile; p-tolunitrile 104-85-8 C8H7N 详情 详情
(VIII) 45171 4-methylbenzonitrile C8H7N 详情 详情
(IX) 14200 4-(Bromomethyl)benzonitrile; alpha-Bromo-p-tolunitrile 17201-43-3 C8H6BrN 详情 详情
(IX) 45172 4-(bromomethyl)benzonitrile C8H6BrN 详情 详情
(X) 21248 4-[[5-(3-hydroxypropyl)-1H-imidazol-1-yl]methyl]benzonitrile C14H15N3O 详情 详情
(X) 45173 4-[[5-(3-hydroxypropyl)-1H-imidazol-1-yl]methyl]benzonitrile C14H15N3O 详情 详情
(XI) 21249 4-[[5-(3-chloropropyl)-1H-imidazol-1-yl]methyl]benzonitrile C14H14ClN3 详情 详情
(XI) 45174 4-[[5-(3-chloropropyl)-1H-imidazol-1-yl]methyl]benzonitrile C14H14ClN3 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 esterification of 3-(4-imidazolyl)-2(E)-propenoic acid (I) with SOCl2 and methanol gives the methyl ester (II), which is reduced with H2 over Pd/C yielding the propionic ester (III). The reduction of (III) with LiAlH4 affords 3-(4-imidazolyl)-1-propanol (IV), which is treated with N,N-dimethyl chloroformamide to afford 4-(3-hydroxypropyl)-N,N-dimethylimidazole-1-carboxamide (V). The mesylation of (V) with methanesulfonyl chloride to give the corresponding methanesulfonate (VI), which is condensed with alpha-bromo-4-iodotoluene (XII) by means of NH3 and treated with HCl yielding 3-[1-(4-iodobenzyl)imidazol-5-yl]-1-propanol (XIII). The reaction of (XIII) with SOCl2 affords the 3-chloropropyl derivative (XIV), which is cyclized by means of potassium tert-butoxide to give 5-(4-iodobenzyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine (XV). Finally, this compound is condensed with radiolabeled potassium cyanide by means of palladium tetrakis(triphenylphosphine).

1 Allentoff, A.J.; et al.; Palladium-catalyzed aryl cynations in radiosynthesis: Synthesis of 14C-labeled fadrozole, a potent aromatase inhibitor. 218th ACS Natl Meet (Aug 22 1999, New Orleans) 1999, Abst MEDI 49.
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) 21245 3-(1H-imidazol-4-yl)-1-propanol C6H10N2O 详情 详情
(V) 39978 4-(3-hydroxypropyl)-N,N-dimethyl-1H-imidazole-1-carboxamide C9H15N3O2 详情 详情
(VI) 27902 N,N-dimethyl-4-[3-[(trimethylsilyl)oxy]propyl]-1H-imidazole-1-carboxamide C12H23N3O2Si 详情 详情
(XII) 39980 1-(bromomethyl)-4-iodobenzene 16004-15-2 C7H6BrI 详情 详情
(XIII) 39979 3-[1-(4-iodobenzyl)-1H-imidazol-5-yl]-1-propanol C13H15IN2O 详情 详情
(XIV) 39981 5-(3-chloropropyl)-1-(4-iodobenzyl)-1H-imidazole C13H14ClIN2 详情 详情
(XV) 39982 5-(4-iodophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine C13H13IN2 详情 详情

合成路线3

该中间体在本合成路线中的序号:(I)

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:(I)

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:(I)

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:(I)

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
Extended Information