4-(2-Quinolinylmethoxy)phenol -Drug Synthesis Database

【结构式】

【分子编号】13164

【品名】4-(2-Quinolinylmethoxy)phenol

【CA登记号】

【分子式】C₁₆H₁₃NO₂

【分子量】251.28476

【元素组成】C 76.48% H 5.21% N 5.57% O 12.73%

与该中间体有关的原料药合成路线共 4 条

合成路线1 合成路线2 合成路线3 合成路线4

合成路线1

该中间体在本合成路线中的序号：(IV)

A synthesis of RG-12525 has been published: The reaction of 2-methylquinoline (I) with chlorine gas gives 2-(chloromethyl)quinoline (II), which is condensed with an excess of hydroquinone (III) yielding 4-(quinolin-2-ylmethoxy)phenol (IV). The reaction of (IV) with an excess of alpha,alpha'-dichloro-o-xylene (V) affords the monoaddition compound (VI), which is treated with sodium cyanide giving the phenylacetonitrile derivative (VII). Finally, this compound is submitted to cyclization with sodium azide.

参考文献中间体

合成目标

【1】 Bridge, A.W.; et al.; The process development of RG 12525 (2-'{[4-(tetrazol-5-ylmethylphenyl)-methoxy]phenoxymethyl}quinoline). Org Process Res Dev 2001, 5, 1, 9.
【2】 O'Brien, M.; Sledeski, A.W.; Truesdale, L.K.; Approaches to p-hydroxyphenoxymethylquinolines which avoid intermediate chloromethylquinolines for the synthesis of the LTD4 antagonist, RG 12525. Tetrahedron Lett 1997, 38, 4, 509.
【3】 Huang, F.-C.; Galemmo Jr., R.A.; Campbell, H.F. (Aventis Pharma SA); Quinoline derivs. as antagonists of leukotriene D4, compsns. containing the same and processes for their preparation. EP 0348155; EP 0784052; US 4920131 .

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)	13161	Quinaldine; 2-Methylquinoline	91-63-4	C₁₀H₉N	详情	详情
(II)	13162	2-(Chloromethyl)quinoline; alpha-Chloroquinaldine	4377-41-7	C₁₀H₈ClN	详情	详情
(III)	13163	p-Dihydrobenzene; Hydroquinone	123-31-9	C₆H₆O₂	详情	详情
(IV)	13164	4-(2-Quinolinylmethoxy)phenol		C₁₆H₁₃NO₂	详情	详情
(V)	13165	1,2-Bis(chloromethyl)benzene	612-12-4	C₈H₈Cl₂	详情	详情
(VI)	13166	2-(Chloromethyl)benzyl 4-(2-quinolinylmethoxy)phenyl ether; 2-[(4-[[2-(Chloromethyl)benzyl]oxy]phenoxy)methyl]quinoline		C₂₄H₂₀ClNO₂	详情	详情
(VII)	13167	2-(2-[[4-(2-Quinolinylmethoxy)phenoxy]methyl]phenyl)acetonitrile		C₂₅H₂₀N₂O₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(V)

Synthesis of intermediate 4-(2-quinolinylmethoxy)phenol (V): The oxidation of 2-methylquinoline with urea and H2O2 in dichloromethane gives the N-oxide (II), which is treated with TsCl and K2CO3 in acetonitrile to yield the tosylate (III). Finally this compound is condensed with an excess of hydroquinone by means of NaOH in methanol/acetonitrile to afford the target intermediate (V).

参考文献中间体

合成目标

【1】 Sledeski, A.W.; et al.; A convergent synthesis of an LTD4 antagonist, RG12525. Tetrahedron Lett 1997, 38, 7, 1129.

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)	13161	Quinaldine; 2-Methylquinoline	91-63-4	C₁₀H₉N	详情	详情
(II)	43890	2-methyl-1-quinoliniumolate		C₁₀H₉NO	详情	详情
(III)	43891	2-quinolinylmethyl 4-methylbenzenesulfonate		C₁₇H₁₅NO₃S	详情	详情
(IV)	13163	p-Dihydrobenzene; Hydroquinone	123-31-9	C₆H₆O₂	详情	详情
(V)	13164	4-(2-Quinolinylmethoxy)phenol		C₁₆H₁₃NO₂	详情	详情

合成路线3

该中间体在本合成路线中的序号：(V)

Synthesis of the target compound 147690: This compound has been obtained by two similar ways: 1. The condensation of intermediate 4-(2-quinolinylmethoxy)phenol (V) with intermediate 5-[2-(bromomethyl)benzyl]-2-(triphenylmethyl)-2H-tetrazole (X) by means of KF/alumina in acetonitrile gives the adduct (XIII), which is finally deprotected to the target compound by means of HCl in methanol/THF. 2. The condensation of intermediate 4-(2-quinolinylmethoxy)phenol (V) with intermediate 5-[2-(bromomethyl)benzyl]-2-(tetrahydropyran-2-yl)-2H-tetrazole (XII) by means of KF/alumina in acetonitrile gives the adduct (XIV), which is finally deprotected to the target compound by means of HCl in methanol/THF.

参考文献中间体

合成目标

【1】 Sledeski, A.W.; et al.; A convergent synthesis of an LTD4 antagonist, RG12525. Tetrahedron Lett 1997, 38, 7, 1129.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(V)	13164	4-(2-Quinolinylmethoxy)phenol	C₁₆H₁₃NO₂	详情	详情
(X)	43896	5-[2-(bromomethyl)benzyl]-2-trityl-2H-1,2,3,4-tetraazole	C₂₈H₂₃BrN₄	详情	详情
(XII)	43898	5-[2-(bromomethyl)benzyl]-2-tetrahydro-2H-pyran-2-yl-2H-1,2,3,4-tetraazole	C₁₄H₁₇BrN₄O	详情	详情
(XIII)	43899	4-(2-quinolinylmethoxy)phenyl 2-[(2-trityl-2H-1,2,3,4-tetraazol-5-yl)methyl]benzyl ether; 2-[[4-([2-[(2-trityl-2H-1,2,3,4-tetraazol-5-yl)methyl]benzyl]oxy)phenoxy]methyl]quinoline	C₄₄H₃₅N₅O₂	详情	详情
(XIV)	43900	2-[[4-([2-[(2-tetrahydro-2H-pyran-2-yl-2H-1,2,3,4-tetraazol-5-yl)methyl]benzyl]oxy)phenoxy]methyl]quinoline; 4-(2-quinolinylmethoxy)phenyl 2-[(2-tetrahydro-2H-pyran-2-yl-2H-1,2,3,4-tetraazol-5-yl)methyl]benzyl ether	C₃₀H₂₉N₅O₃	详情	详情

合成路线4

该中间体在本合成路线中的序号：(IV)

The condensation of 2-(chloromethyl)quinoline (I) with hydroquinone monobenzoate (II) by means of K2CO3 in refluxing acetone/DMF gives 4-(2-quinolylmethoxy)phenyl benzoate (III), which is treated with sodium ethoxide in ethanol to yield 4-(2-quinolylmethoxy)phenol (IV). The condensation of (IV) with alpha,alpha'-dichloro-o-xylene (V) by means of NaH in THF affords the benzyl chloride derivative (VI), which is treated with NaCN in toluene/water with a phase-transfer catalyst to provide the benzyl cyanide derivative (VII). Finally, this compound is cyclized with sodium azide in hot DMF to afford the target tetrazole derivative.

参考文献中间体

合成目标

【1】 Huang, F.-C.; (2-Quinolinylmethoxy)phenyl-containing compounds as leukotriene receptor antagonists: A brief review of structure-activity relationships and the biological profile of RG 12525. Drugs Fut 1991, 16, 12, 1121.
【2】 Huang, F.-C.; et al.; Development of a novel series of (2-quinolinylmethoxy)phenyl-containing compounds as high-affinity leukotriene D4 receptor antagonists. 2. Effects of an additional phenyl ring on receptor affinity. J Med Chem 1990, 33, 4, 1194.
【3】 Youssefyeh, R.D.; et al.; Development of a novel series of (2-quinolinylmethoxy)phenyl-containing compounds as high-affinity leukotriene receptor antagonists. 1. Initial structure-activity relationships. J Med Chem 1990, 33, 4, 1186.

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)	13162	2-(Chloromethyl)quinoline; alpha-Chloroquinaldine	4377-41-7	C₁₀H₈ClN	详情	详情
(II)	44042	4-hydroxyphenyl benzoate		C₁₃H₁₀O₃	详情	详情
(III)	44043	4-(2-quinolinylmethoxy)phenyl benzoate		C₂₃H₁₇NO₃	详情	详情
(IV)	13164	4-(2-Quinolinylmethoxy)phenol		C₁₆H₁₃NO₂	详情	详情
(V)	13165	1,2-Bis(chloromethyl)benzene	612-12-4	C₈H₈Cl₂	详情	详情
(VI)	13166	2-(Chloromethyl)benzyl 4-(2-quinolinylmethoxy)phenyl ether; 2-[(4-[[2-(Chloromethyl)benzyl]oxy]phenoxy)methyl]quinoline		C₂₄H₂₀ClNO₂	详情	详情
(VII)	13167	2-(2-[[4-(2-Quinolinylmethoxy)phenoxy]methyl]phenyl)acetonitrile		C₂₅H₂₀N₂O₂	详情	详情

Extended Information