5-quinolinol -Drug Synthesis Database

【结构式】

【分子编号】23805

【品名】5-quinolinol

【CA登记号】578-67-6

【分子式】C₉H₇NO

【分子量】145.16072

【元素组成】C 74.47% H 4.86% N 9.65% O 11.02%

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：(VI)

N-(2,2-Diphenylacetyl)piperazine (IV) was prepared by acylation of N-formylpiperazine (II) with 2,2-diphenylacetyl chloride (I), followed by acid-promoted formyl deprotection of the resulting amide (III). Condensation of 5-hydroxyquinoline (VI) with epichlorohydrin (V) in the presence of potassium tert-butoxide in DMF at 90 C provided 5-(2,3-epoxypropoxy)quinoline (VII), which was subsequently coupled with acylpiperazine (IV) in boiling isopropanol to yield (VIII). This was finally treated with fumaric acid (IX) in MeOH to furnish the title sesquifumarate salt.

参考文献中间体

合成目标

【1】 Suzuki, T.; et al.; Structure-activity relationship of newly synthesiz. J Med Chem 1997, 40, 13, 2047.

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)	23800	Diphenylacetyl chloride; 2,2-diphenylacetyl chloride	1871-76-7	C₁₄H₁₁ClO	详情	详情
(II)	23801	1-piperazinecarbaldehyde; N-Formylpiperazine	7755-92-2	C₅H₁₀N₂O	详情	详情
(III)	23802	4-(2,2-diphenylacetyl)-1-piperazinecarbaldehyde		C₁₉H₂₀N₂O₂	详情	详情
(IV)	23803	2,2-diphenyl-1-(1-piperazinyl)-1-ethanone		C₁₈H₂₀N₂O	详情	详情
(V)	10146	Epichlorohydrin; 2-(Chloromethyl)oxirane	106-89-8	C₃H₅ClO	详情	详情
(VI)	23805	5-quinolinol	578-67-6	C₉H₇NO	详情	详情
(VII)	23806	5-(2-oxiranylmethoxy)quinoline; 2-oxiranylmethyl 5-quinolinyl ether		C₁₂H₁₁NO₂	详情	详情
(VIII)	23807	1-[4-[2-hydroxy-3-(5-quinolinyloxy)propyl]-1-piperazinyl]-2,2-diphenyl-1-ethanone		C₃₀H₃₁N₃O₃	详情	详情
(IX)	23808	Fumaric acid; (E)-2-butenedioic acid	110-17-8	C₄H₄O₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(X)

Condensation of dibenzosuberenone (I) with sodium 2-chloro-2,2-difluoroacetate (II) in diglyme at 165 C gives 10,11-(difluoromethano)benzosuberone (III), which is reduced with NaBH4 in THF/methanol to yield the corresponding syn-alcohol (IV). Reaction of alcohol (IV) with hot SOCl2 affords a mixture of the syn- and anti-chloro derivatives (V). This mixture (V) is treated with 1-for-mylpiperazine (VI) in refluxing acetonitrile to provide a mixture of syn- and anti-4-[10,11-(difluoromethano)dibenzosuber-5-yl]piperazine-1-carbaldehyde (VI), which is separated by chromatography. The desired anti-isomer (VII) is then treated with KOH in refluxing ethanol/water to give the piperazine derivative (VIII), which is finally condensed with 5-[2(R),3-epoxypropoxy]quinoline (IX) in refluxing isopranol. 5-[2(R),3-Epoxypropoxy]quinoline (IX) is obtained by reaction of 5-hydroxyquinoline (X) with (R)-glycidyl tosylate (XI) by means of NaH in DMF.

参考文献中间体

合成目标

【1】 Sorbera, L.A.; Castaner, J.; Silvestre, J.S.; Bayes, M.; Zosuquidar Trihydrochloride.. Drugs Fut 2003, 28, 2, 125-136.
【2】 Knaus, E.E.; Vo, D.; Wolowyk, M.W.; Synthesis and cardioselective beta-adrenergic antagonist activity of quinolyloxypropanolamines. Drug Des Discov 1992, 9, 1, 69.
【3】 Bruno, N.A.; Nelson, J.T.; Wu, H.; Muehldorf, A.V.; Makra, F.; Cheung, P.; Slate, D.L.; Zutshi, N.; Casey, S.M.; Pfister, J.R.; Methanodibenzosuberylpiperazines as potent multidrug resistance reversal agents. Bioorg Med Chem Lett 1995, 5, 21, 2473.
【4】 Pfister, J.R.; Slate, D.L. (Syntex (USA) LLC); 10,11-Methanodibenzosuberane derivs. used as chemosensitizing agents. EP 0695293; EP 0866063; JP 1996509223; WO 9424107 .

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)	29151	5H-dibenzo[a,d]cyclohepten-5-one; Dibenzosuberenone	2222-33-5	C₁₅H₁₀O	详情	详情
(II)	59522	sodium 2-chloro-2,2-difluoroacetate		C₂ClF₂NaO₂	详情	详情
(III)	56203	1,1-difluoro-1a,10b-dihydrodibenzo[a,e]cyclopropa[c]cyclohepten-6(1H)-one		C₁₆H₁₀F₂O	详情	详情
(IV)	56204	(1aR,10bS)-1,1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-ol		C₁₆H₁₂F₂O	详情	详情
(V)	56205	6-chloro-1,1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cycloheptene		C₁₆H₁₁ClF₂	详情	详情
(VI)	23801	1-piperazinecarbaldehyde; N-Formylpiperazine	7755-92-2	C₅H₁₀N₂O	详情	详情
(VII)	56206	4-[(1aR,10bS)-1,1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-yl]-1-piperazinecarbaldehyde		C₂₁H₂₀F₂N₂O	详情	详情
(VIII)	56207	1-[(1aR,10bS)-1,1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-yl]piperazine		C₂₀H₂₀F₂N₂	详情	详情
(IX)	56211	(2R)oxiranylmethyl 5-quinolinyl ether; 5-[(2R)oxiranylmethoxy]quinoline		C₁₂H₁₁NO₂	详情	详情
(X)	23805	5-quinolinol	578-67-6	C₉H₇NO	详情	详情
(XI)	16242	(2R)oxiranylmethyl 4-methylbenzenesulfonate; (2R)-(-)-Glycidyl tosylate	113826-06-5	C₁₀H₁₂O₄S	详情	详情

合成路线3

该中间体在本合成路线中的序号：(X)

Reaction of alcohol (IV) with 48% HBr or with PBr3 affords the anti-bromo derivative (XII), which is condensed with pyrazine (XIII) in refluxing acetonitrile to give anti-1-[10,11-(difluoromethano)dibenzosuber-5-yl]pyrazinium bromide (XIV). Reduction of compound (XIV) with NaBH4 in ethyl acetate provides the piperazine derivative (VIII), which is finally condensed with 5-[2(R),3-epoxypropoxy]quinoline (IX) obtained by reaction of 5-hydroxyquinoline (X) with (R)-glycidyl 4-nitrobenzene- sulfonate (XV) by means of K2CO3 in DMF in hot ethanol.

参考文献中间体

合成目标

【1】 Sorbera, L.A.; Castaner, J.; Silvestre, J.S.; Bayes, M.; Zosuquidar Trihydrochloride.. Drugs Fut 2003, 28, 2, 125-136.
【2】 Le Tourneau, M.E.; Wilson, T.M.; Huff, B.E.; Bush, J.K.; Reutzel-Edens, S.M. (Eli Lilly and Company); Process for preparing 10,11-methanobenzosuberane derivs.. WO 0075121 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IV)	56204	(1aR,10bS)-1,1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-ol		C₁₆H₁₂F₂O	详情	详情
(VIII)	56207	1-[(1aR,10bS)-1,1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-yl]piperazine		C₂₀H₂₀F₂N₂	详情	详情
(IX)	56211	(2R)oxiranylmethyl 5-quinolinyl ether; 5-[(2R)oxiranylmethoxy]quinoline		C₁₂H₁₁NO₂	详情	详情
(X)	23805	5-quinolinol	578-67-6	C₉H₇NO	详情	详情
(XII)	56208	(1aR,10bS)-6-bromo-1,1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cycloheptene		C₁₆H₁₁BrF₂	详情	详情
(XIII)	56209	pyrazine		C₄H₄N₂	详情	详情
(XIV)	56210	1-[(1aR,10bS)-1,1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-yl]pyrazin-1-ium bromide		C₂₀H₁₅BrF₂N₂	详情	详情
(XV)	56212	(2R)oxiranylmethyl 3-nitrobenzenesulfonate		C₉H₉NO₆S	详情	详情

Extended Information