[2-(benzyloxy)-4-methoxyphenyl](chloro)zinc -Drug Synthesis Database

【结构式】

【分子编号】27599

【品名】[2-(benzyloxy)-4-methoxyphenyl](chloro)zinc

【CA登记号】

【分子式】C₁₄H₁₃ClO₂Zn

【分子量】314.09872

【元素组成】C 53.54% H 4.17% Cl 11.29% O 10.19% Zn 20.82%

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：(LV)

In a further procedure, pyridine-2,3-dicarboxylic acid (L) was esterified with MeOH and SOCl2 and then oxidized to the N-oxide (LI), which by treatement with POCl3 gave chloropyridine (LII). Then, substitution of the halogen atom of (LII) for a butyl group using n-BuLi in the presence of ZnCl2 and palladium catalyst provided butylpyridine (LIII). Saponification of the methyl esters, followed by reaction with Ac2O gave cyclic anhydride (LIV). This was condensed with organozinc reagent (LV) to give ketone (LVI). After activation of (LVI) with carbonyl diimidazole, condensation with the lithium enolate of ethyl acetate, followed by cyclization produced cyclopentenone (LVII). This was condensed with Grignard reagent (XXIV) to give (LVIII) and then reduced with Zn and HCl and isomerized in the presence of EtONa to provide (LIX) as a racemic mixture.

参考文献中间体

合成目标

【1】 Niiyama, K.; et al.; A potent, orally active, most balanced ETA/ETB dual endothelin receptor antagonist. Discovery of J-104132. 15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998, Edinburgh) 1998, Abst P.297.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XXIV)	27570	1,3-benzodioxol-5-yl(bromo)magnesium		C₇H₅BrMgO₂	详情	详情
(L)	17246	2,3-pyridinedicarboxylic acid; Quinolinic Acid	89-00-9	C₇H₅NO₄	详情	详情
(LI)	27595	2,3-bis(methoxycarbonyl)-1-pyridiniumolate		C₉H₉NO₅	详情	详情
(LII)	27596	dimethyl 6-chloro-2,3-pyridinedicarboxylate		C₉H₈ClNO₄	详情	详情
(LIII)	27597	dimethyl 6-butyl-2,3-pyridinedicarboxylate		C₁₃H₁₇NO₄	详情	详情
(LIV)	27598	2-butylfuro[3,4-b]pyridine-5,7-dione		C₁₁H₁₁NO₃	详情	详情
(LV)	27599	[2-(benzyloxy)-4-methoxyphenyl](chloro)zinc		C₁₄H₁₃ClO₂Zn	详情	详情
(LVI)	27600	2-[2-(benzyloxy)-4-methoxybenzoyl]-6-butylnicotinic acid		C₂₅H₂₅NO₅	详情	详情
(LVII)	27601	ethyl 7-[2-(benzyloxy)-4-methoxyphenyl]-2-butyl-5-oxo-5H-cyclopenta[b]pyridine-6-carboxylate		C₂₅H₂₅NO₅	详情	详情
(LVIII)	27602	ethyl 5-(1,3-benzodioxol-5-yl)-7-[2-(benzyloxy)-4-methoxyphenyl]-2-butyl-5-hydroxy-5H-cyclopenta[b]pyridine-6-carboxylate		C₃₆H₃₅NO₇	详情	详情
(LIX)	27603	ethyl (5S,6R,7R)-5-(1,3-benzodioxol-5-yl)-7-[2-(benzyloxy)-4-methoxyphenyl]-2-butyl-6,7-dihydro-5H-cyclopenta[b]pyridine-6-carboxylate		C₃₆H₃₇NO₆	详情	详情

合成路线2

该中间体在本合成路线中的序号：(II)

Addition of the organozinc reagent (II) to the cyclic anhydride (I) produced keto acid (III). After activation of the carboxyl group of (III) with carbonyl diimidazole, condensation with the lithium enolate of tert-butyl acetate furnished keto ester (IV). This was subsequently cyclized to the cyclopentapyridine system (V) upon treatment with silica in CHCl3. Addition of 2,2-difluoro-1,3-benzodioxol-5-ylmagnesium bromide (VI) to the keto group of (V) gave carbinol (VII). After hydroxyl group acetylation, hydrogenation of the olefin and simultaneous hydrogenolysis of the O-benzyl groups of (VII) over Pd/C yielded (VIII). Further epimerization of the carboxylate group of (VIII) in the presence of potassium tert-butoxide afforded isomer (IX). After conversion of (IX) to the aryl triflate (X), palladium-catalyzed coupling of (X) with allylic alcohol (XI) produced (XII).

参考文献中间体

合成目标

【1】 Hayama, T.; Ohtake, N.; Niiyama, K.; et al.; New cyclopentenopyridine derivatives. A potent, orally active, selective endothelin ETA receptor antagonist. 16th Int Symp Med Chem (Sept 18 2000, Bologna) 2000, Abst PA-78.
【2】 Nishikibe, M.; Hayama, T.; Otake, N. (Banyu Pharmaceutical Co., Ltd.); Substd. 5-(2,2-difluoro-1,3-benzodioxol-5-yl) cyclopentenopyridine deriv.. EP 1049691; WO 9937639 .

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)	17247	furo[3,4-b]pyridine-5,7-dione; 2,3-Pyridinedicarboxylic anhydride	699-98-9	C₇H₃NO₃	详情	详情
(II)	27599	[2-(benzyloxy)-4-methoxyphenyl](chloro)zinc		C₁₄H₁₃ClO₂Zn	详情	详情
(III)	43947	2-[2-(benzyloxy)-4-methoxybenzoyl]nicotinic acid		C₂₁H₁₇NO₅	详情	详情
(IV)	43948	tert-butyl 3-[2-[2-(benzyloxy)-4-methoxybenzoyl]-3-pyridinyl]-3-oxopropanoate		C₂₇H₂₇NO₆	详情	详情
(V)	43949	tert-butyl 7-[2-(benzyloxy)-4-methoxyphenyl]-5-oxo-5H-cyclopenta[b]pyridine-6-carboxylate		C₂₇H₂₅NO₅	详情	详情
(VI)	43950	bromo(2,2-difluoro-1,3-benzodioxol-5-yl)magnesium		C₇H₃BrF₂MgO₂	详情	详情
(VII)	43951	tert-butyl 7-[2-(benzyloxy)-4-methoxyphenyl]-5-(2,2-difluoro-1,3-benzodioxol-5-yl)-5-hydroxy-5H-cyclopenta[b]pyridine-6-carboxylate		C₃₄H₂₉F₂NO₇	详情	详情
(VIII)	43952	tert-butyl (5S,6S,7R)-5-(2,2-difluoro-1,3-benzodioxol-5-yl)-7-(2-hydroxy-4-methoxyphenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-6-carboxylate		C₂₇H₂₅F₂NO₆	详情	详情
(IX)	43953	tert-butyl (5S,6R,7R)-5-(2,2-difluoro-1,3-benzodioxol-5-yl)-7-(2-hydroxy-4-methoxyphenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-6-carboxylate		C₂₇H₂₅F₂NO₆	详情	详情
(X)	43954	tert-butyl (5S,6R,7R)-5-(2,2-difluoro-1,3-benzodioxol-5-yl)-7-(4-methoxy-2-[[(trifluoromethyl)sulfonyl]oxy]phenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-6-carboxylate		C₂₈H₂₄F₅NO₈S	详情	详情
(XI)	43956	2-methyl-2-propen-1-ol	513-42-8	C₄H₈O	详情	详情
(XII)	43955	tert-butyl (5S,6R,7R)-5-(2,2-difluoro-1,3-benzodioxol-5-yl)-7-[2-(3-hydroxy-2-methylpropyl)-4-methoxyphenyl]-6,7-dihydro-5H-cyclopenta[b]pyridine-6-carboxylate		C₃₁H₃₃F₂NO₆	详情	详情

Extended Information