cyclopropyl(4-hydroxyphenyl)methanone -Drug Synthesis Database

【结构式】

【分子编号】27425

【品名】cyclopropyl(4-hydroxyphenyl)methanone

【CA登记号】

【分子式】C₁₀H₁₀O₂

【分子量】162.1882

【元素组成】C 74.06% H 6.21% O 19.73%

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：(VI)

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：(II)

Intramolecular cyclization of p-hydroxy-4-chlorobutyrophenone (I) under alkaline conditions yields cyclopropyl(4-hydroxyphenyl) ketone (II). The phenolic hydroxyl group is then alkylated by 1-bromo-3-chloropropane (III) to furnish the chloropropyl ether (IV). Subsequent condensation of alkyl chloride (IV) with piperazine (V) gives rise to the N-substituted piperazine (VI). This is then coupled with N-Boc-L-alanine (VII) in the presence of EDC/DMAP to afford amide (VIII) (1, 2). After acidic cleavage of the N-Boc protecting group, the resultant monosubstituted piperazine (IX) is acylated by furanoyl chloride (X) to furnish the target furamide derivative

参考文献中间体

合成目标

【1】 Black, L.A.; Faghih, R.; Liu, H.; et al.; Acyl-D-alanine amides: Selective histamine H3 receptor antagonists. 224th ACS Natl Meet (Aug 18 2002, Boston) 2002, Abst MEDI 323.
【2】 Black, L.A.; Faghih, R.; Bennani, Y.L.; Liu, H.; Zhang, H.Q.; Dwight, W.J.; Gentles, R.G.; Phelan, K.M.; Vasudevan, A. (Abbott Laboratories Inc.); Cyclic and bicyclic diamino histamine-3 receptor antagonists. WO 0166534 .
【3】 Black, L.A.; Faghih, R.; Bennani, Y.L.; Liu, H.; Zhang, H.Q.; Dwight, W.J.; Gentles, R.G.; Phelan, K.M.; Vasudevan, A. (Abbott Laboratories Inc.); Cyclic and bicyclic diamino histamine-3 receptor antagonists. US 2001049367; US 6559140 .

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)	62995			C₁₀H₁₁ClO₂	详情	详情
(II)	27425	cyclopropyl(4-hydroxyphenyl)methanone		C₁₀H₁₀O₂	详情	详情
(III)	10358	1-Bromo-3-chloropropane	109-70-6	C₃H₆BrCl	详情	详情
(IV)	62988	5-bromo-N-(1H-imidazol-2-yl)-6-quinoxalinamine; N-(5-bromo-6-quinoxalinyl)-N-(1H-imidazol-2-yl)amine		C₁₁H₈BrN₅	详情	详情
(V)	10355	Diethylenediamine; Piperazine	110-85-0	C₄H₁₀N₂	详情	详情
(VI)	62996			C₁₇H₂₄N₂O₂	详情	详情
(VII)	15859	Boc-D-Alanine; (2R)-2-[(tert-butoxycarbonyl)amino]propionic acid	7764-95-6	C₈H₁₅NO₄	详情	详情
(VIII)	63042			C₂₈H₂₃ClN₂O₂	详情	详情
(IX)	63043			C₁₇H₁₅ClN₂O₂	详情	详情
(X)	26093	2-Furoyl chloride	527-69-5	C₅H₃ClO₂	详情	详情

合成路线3

该中间体在本合成路线中的序号：(II)

Cyclization of 4-chloro-4'-hydroxybutyrophenone (I) in the presence of 50% aqueous NaOH produces cyclopropyl (4-hydroxyphenyl) ketone (II). This is then alkylated with 1-bromo-3-chloropropane (III) to afford the chloropropyl ether (IV). Chloride displacement in (IV) with an excess of piperazine (V) in the presence of KI and K2CO3 furnishes the monosubstituted piperazine (VI). Subsequent coupling of piperazine (VI) with N-Boc-L-alanine (VII) leads to amide (VIII). Finally, Boc group cleavage in (VIII) employing trifluoroacetic acid yields the title compound (1-3).

参考文献中间体

合成目标

【1】 Faghih, R.; Dwight, W.; Black, L.; Liu, H.; Gentles, R.; Phelan, K.; Esbenshade, T.A.; Ireland, L.; Miller, T.R.; Kang, C.-H.; Krueger, K.M.; Fox, G.B.; Hancock; Bennani, Y.L.; Structure-activity relationships of non-imidazole H(3) receptor ligands. Part 2: Binding preference for D-amino acids motifs. Bioorg Med Chem Lett 2002, 12, 15, 2035.
【2】 Black, L.A.; Faghih, R.; Bennani, Y.L.; Liu, H.; Zhang, H.Q.; Dwight, W.J.; Gentles, R.G.; Phelan, K.M.; Vasudevan, A. (Abbott Laboratories Inc.); Cyclic and bicyclic diamino histamine-3 receptor antagonists. WO 0166534 .
【3】 Black, L.A.; Faghih, R.; Bennani, Y.L.; Liu, H.; Zhang, H.Q.; Dwight, W.J.; Gentles, R.G.; Phelan, K.M.; Vasudevan, A. (Abbott Laboratories Inc.); Cyclic and bicyclic diamino histamine-3 receptor antagonists. US 2001049367; US 6559140 .

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)	62995			C₁₀H₁₁ClO₂	详情	详情
(II)	27425	cyclopropyl(4-hydroxyphenyl)methanone		C₁₀H₁₀O₂	详情	详情
(III)	10358	1-Bromo-3-chloropropane	109-70-6	C₃H₆BrCl	详情	详情
(IV)	62998	[4-(3-chloropropoxy)phenyl](cyclopropyl)methanone		C₁₃H₁₅ClO₂	详情	详情
(V)	10355	Diethylenediamine; Piperazine	110-85-0	C₄H₁₀N₂	详情	详情
(VI)	62996			C₁₇H₂₄N₂O₂	详情	详情
(VII)	15859	Boc-D-Alanine; (2R)-2-[(tert-butoxycarbonyl)amino]propionic acid	7764-95-6	C₈H₁₅NO₄	详情	详情
(VIII)	64059	tert-butyl (1R)-2-(4-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}-1-piperazinyl)-1-methyl-2-oxoethylcarbamate		C₂₅H₃₇N₃O₅	详情	详情

Extended Information