8-(2,4-dichlorophenyl)-2-methyl-4-quinolinol -Drug Synthesis Database

【结构式】

【分子编号】60297

【品名】8-(2,4-dichlorophenyl)-2-methyl-4-quinolinol

【CA登记号】

【分子式】C₁₆H₁₁Cl₂NO

【分子量】304.17488

【元素组成】C 63.18% H 3.65% Cl 23.31% N 4.6% O 5.26%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(VI)

Suzuki coupling of 2-bromoaniline (I) with 2,4-dichlorophenylboronic acid (II) affords the biphenylyl amine (III). This is condensed with ethyl acetoacetate (IV) to produce enamine (V), which is further cyclized in hot diphenyl ether to furnish the hydroxyquinoline (VI). Treatment of the sodium salt of (VI) with N-phenyl trifluoromethanesulfonimide gives rise to the aryl triflate (VII). Finally, displacement of the sulfonate group of (VII) with 1,2,3,6-tetrahydropyridine-4-carboxamide (VIII) in hot DMF provides the title compound

参考文献中间体

合成目标

【1】 Nakazato, A.; et al.; Chemical modification of 4-carbamoyl-1,2,3,6-tetrahydropyridinopyrrolopyrimidine, CRA0316, for discovery CRH1 receptor antagonists. Drugs Fut 2002, 27, Suppl. A.
【2】 Kennis, L.; Kumagai, T.; Nakazato, A.; et al.; Synthesis, SAR and biological activities of CRH1 receptor: Novel 3- or 4-carbamoyl-1,2,5,6-tetrahydropyridinoquinoline derivative. 224th ACS Natl Meet (Aug 18 2002, Boston) 2002, Abst MEDI 258.
【3】 Kameo, K.; Kumagai, T.; Nakazato, A.; Okubo, T. (Taisho Pharmaceutical Co., Ltd.); Tetrahydropyridino or piperidino heterocyclic derivs.. EP 1299378; WO 0202549 .

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)	27739	2-bromoaniline	615-36-1	C₆H₆BrN	详情	详情
(II)	48912	2,4-Dichlorophenylboronic acid; 2,4-Dichlorobenzeneboronic acid	68716-47-2	C₆H₅BCl₂O₂	详情	详情
(III)	60295	2',4'-dichloro[1,1'-biphenyl]-2-amine; 2',4'-dichloro[1,1'-biphenyl]-2-ylamine		C₁₂H₉Cl₂N	详情	详情
(IV)	11819	ethyl acetoacetate; ethyl 3-oxobutanoate；Acetoacetic ester;Ethyl beta-ketobutyrate;ethyl 3-oxobutyrate	141-97-9	C₆H₁₀O₃	详情	详情
(V)	60296	ethyl 3-[(2',4'-dichloro[1,1'-biphenyl]-2-yl)amino]-2-butenoate		C₁₈H₁₇Cl₂NO₂	详情	详情
(VI)	60297	8-(2,4-dichlorophenyl)-2-methyl-4-quinolinol		C₁₆H₁₁Cl₂NO	详情	详情
(VII)	60298	8-(2,4-dichlorophenyl)-2-methyl-4-quinolinyl trifluoromethanesulfonate		C₁₇H₁₀Cl₂F₃NO₃S	详情	详情
(VIII)	60299	1,2,3,6-tetrahydro-4-pyridinecarboxamide		C₆H₁₀N₂O	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

Alternatively, hydroxyquinoline (I) is chlorinated in refluxing POCl3 to provide chloroquinoline (II). Substitution of (II) with 4-piperidone ethylene ketal (III) in boiling DMF furnishes the piperidinyl quinoline derivative (IV), which is further hydrolyzed to piperidone (V) under acidic conditions. Addition of cyanide to piperidone (V) gives rise to cyanohydrin (VI), and subsequent dehydration by means of POCl3/pyridine affords the unsaturated nitrile (VII). Finally, partial hydrolysis of nitrile (VII) with HCl in formic acid leads to the target amide compound

参考文献中间体

合成目标

【1】 Kameo, K.; Kumagai, T.; Nakazato, A.; Okubo, T. (Taisho Pharmaceutical Co., Ltd.); Tetrahydropyridino or piperidino heterocyclic derivs.. EP 1299378; WO 0202549 .

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)	60297	8-(2,4-dichlorophenyl)-2-methyl-4-quinolinol		C₁₆H₁₁Cl₂NO	详情	详情
(II)	60301	4-chloro-8-(2,4-dichlorophenyl)-2-methylquinoline		C₁₆H₁₀Cl₃N	详情	详情
(III)	11338	1,4-Dioxa-8-azaspiro[4.5]decane; 4-Piperidone ethylene ketal	177-11-7	C₇H₁₃NO₂	详情	详情
(IV)	60302	8-(2,4-dichlorophenyl)-4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-2-methylquinoline		C₂₃H₂₂Cl₂N₂O₂	详情	详情
(V)	60303	1-[8-(2,4-dichlorophenyl)-2-methyl-4-quinolinyl]-4-piperidinone		C₂₁H₁₈Cl₂N₂O	详情	详情
(VI)	60304	1-[8-(2,4-dichlorophenyl)-2-methyl-4-quinolinyl]-4-hydroxy-4-piperidinecarbonitrile		C₂₂H₁₉Cl₂N₃O	详情	详情
(VII)	60305	1-[8-(2,4-dichlorophenyl)-2-methyl-4-quinolinyl]-1,2,3,6-tetrahydro-4-pyridinecarbonitrile		C₂₂H₁₇Cl₂N₃	详情	详情

Extended Information