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【结 构 式】 
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【分子编号】21245 【品名】3-(1H-imidazol-4-yl)-1-propanol 【CA登记号】 |
【 分 子 式 】C6H10N2O 【 分 子 量 】126.15828 【元素组成】C 57.12% H 7.99% N 22.21% O 12.68% |
合成路线1
该中间体在本合成路线中的序号：(I)1) The condensation of 4-(3-hydroxypropyl)-1H-imidazole (I) with dimethylcarbamoyl chloride by means of triethylamine in refluxing acetonitrile followed by reaction with trimethylchlorosilane gives 1-(dimethylcarbamoyl)-4-[3-(trimethylsilyloxy)propyl]imidazole (II), which is condensed with 4-cyanobenzyl bromide (III) in refluxing acetonitrile yielding 1-(4-cyanobenzyl)-5-(3-hydroxypropyl)imidazole (IV). The reaction of (IV) with SOCl2 in refluxing dichloromethane affords the corresponding 3-chloropropyl derivative (V), which is finally cyclized by means of potassium tert-butoxide in THF.
| 【1】 Browne, L.J. (Ciba Geigy Corp.); Substituted imidazo[1,5-A]pyridine derivatives as aromatase inhibitors.. ES 8801262; JP 61012688; US 4617307 . |
| 【2】 Pento, J.T.; Prous, J.; Castaner, J.; CGS-16949A. Drugs Fut 1989, 14, 9, 843. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 13708 | N,N'-Dimethylcarbamoyl chloride; Dimethylcarbamoyl chloride; [(Chlorocarbonyl)(methyl)amino]methane | 79-44-7 | C3H6ClNO | 详情 | 详情 | |
| (I) | 21245 | 3-(1H-imidazol-4-yl)-1-propanol | C6H10N2O | 详情 | 详情 | |
| (II) | 21246 | N,N-dimethyl-4-[4-(trimethylsilyl)butyl]-1H-imidazole-1-carboxamide | C13H25N3OSi | 详情 | 详情 | |
| (III) | 14200 | 4-(Bromomethyl)benzonitrile; alpha-Bromo-p-tolunitrile | 17201-43-3 | C8H6BrN | 详情 | 详情 |
| (IV) | 21248 | 4-[[5-(3-hydroxypropyl)-1H-imidazol-1-yl]methyl]benzonitrile | C14H15N3O | 详情 | 详情 | |
| (V) | 21249 | 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：(IV)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3
该中间体在本合成路线中的序号：(IV)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4
该中间体在本合成路线中的序号：(I)The protection of 3-(1H-imidazol-4-yl)-1-propanol (I) according to known techniques gives (II), which is condensed with 4-iodobenzyl bromide (III) by means of ammonia in acetonitrile, yielding 3-[1-(4-iodobenzyl)-1H-imidazol-5-yl)-1-propanol (IV). The reaction of (IV) with SOCl2 in dichloromethane affords the corresponding chloro derivative (V), which is cyclized by means of LDA and TMEDA in THF, affording 5-(4-iodophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine (VI). Finally, this compound is treated with (14C)-KCN and palladium tetrakis(triphenylphosphine) in refluxing THF.
| 【1】 Markus, B.; Jones, L.; Duelfer, T.; Ray, T.; Wu, A.; Allentoff, A.J.; Ciszewska, G.; Palladium-catalyzed aryl cyanations with [C-14]KCN: Synthesis of C-14-labelled fadrozole, a potent aromatase inhibitor. J Label Compd Radiopharm 2000, 43, 11, 1075. |
| 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) | 21245 | 3-(1H-imidazol-4-yl)-1-propanol | C6H10N2O | 详情 | 详情 | |
| (II) | 47910 | N-(tert-butyl)-4-[3-[(trimethylsilyl)oxy]propyl]-1H-imidazole-1-carboxamide | C14H27N3O2Si | 详情 | 详情 | |
| (III) | 39980 | 1-(bromomethyl)-4-iodobenzene | 16004-15-2 | C7H6BrI | 详情 | 详情 |
| (IV) | 39979 | 3-[1-(4-iodobenzyl)-1H-imidazol-5-yl]-1-propanol | C13H15IN2O | 详情 | 详情 | |
| (V) | 39981 | 5-(3-chloropropyl)-1-(4-iodobenzyl)-1H-imidazole | C13H14ClIN2 | 详情 | 详情 | |
| (VI) | 39982 | 5-(4-iodophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine | C13H13IN2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(V)4-Iodophenol (I) was protected as the trimethylsilyl ether (II) with Me3SiCl and then coupled with (trimethylsilyl)acetylene (III) using palladium catalyst and CuI to afford the O-desilylated ethynylphenol (IV). This was condensed under Mitsunobu conditions with N-Boc-imidazolylpropanol (VI), prepared from imidazolylpropanol (V) and Boc2O, to afford ether (VII). Deprotection of the Boc group of (VII) with methanolic hydrazine at r.t. yielded a mixture of (VIII) and the fully desilylated analogue (IX), which was isolated by column chromatography and finally crystallized as the maleate salt from EtOH-Et2O.
| 【1】 Krause, M.; Ligneau, X.; Stark, H.; Garbarg, M.; Schwartz, J.C.; Schunack, W.; 4-Alkynylphenyl imidazolylpropyl ethers as selective histamine H3-receptor antagonists with high oral central nervous system activity. J Med Chem 1998, 41, 21, 4171. |
| 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) | 22242 | 4-iodophenol | 540-38-5 | C6H5IO | 详情 | 详情 |
| (II) | 22243 | (4-iodophenoxy)(trimethyl)silane; 4-iodophenyl trimethylsilyl ether | C9H13IOSi | 详情 | 详情 | |
| (III) | 23897 | ethynyl(trimethyl)silane；trimethylsilyl acetylene | 1066-54-2 | C5H10Si | 详情 | 详情 |
| (IV) | 22245 | 4-[2-(trimethylsilyl)ethynyl]phenol | C11H14OSi | 详情 | 详情 | |
| (V) | 21245 | 3-(1H-imidazol-4-yl)-1-propanol | C6H10N2O | 详情 | 详情 | |
| (VI) | 22247 | tert-butyl 4-(3-hydroxypropyl)-1H-imidazole-1-carboxylate | C11H18N2O3 | 详情 | 详情 | |
| (VII) | 22248 | tert-butyl 4-(3-[4-[2-(trimethylsilyl)ethynyl]phenoxy]propyl)-1H-imidazole-1-carboxylate | C22H30N2O3Si | 详情 | 详情 | |
| (VIII) | 22249 | 4-(3-[4-[2-(trimethylsilyl)ethynyl]phenoxy]propyl)-1H-imidazole; 3-(1H-imidazol-4-yl)propyl 4-[2-(trimethylsilyl)ethynyl]phenyl ether | C17H22N2OSi | 详情 | 详情 | |
| (IX) | 22250 | 4-ethynylphenyl 3-(1H-imidazol-4-yl)propyl ether; 4-[3-(4-ethynylphenoxy)propyl]-1H-imidazole | C14H14N2O | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(VI)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7
该中间体在本合成路线中的序号：(VII)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 |