ethyl 3-(1H-imidazol-4-yl)propanoate -Drug Synthesis Database

【结构式】

【分子编号】27422

【品名】ethyl 3-(1H-imidazol-4-yl)propanoate

【CA登记号】

【分子式】C₈H₁₂N₂O₂

【分子量】168.19556

【元素组成】C 57.13% H 7.19% N 16.66% O 19.02%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(III)

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).

参考文献中间体

合成目标

【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2

该中间体在本合成路线中的序号：(III)

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.

参考文献中间体

合成目标

【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3

该中间体在本合成路线中的序号：(III)

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.

参考文献中间体

合成目标

【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

Extended Information