J-112287, -Drug Synthesis Database

【结构式】

【药物名称】J-112287

【化学名称】5(S)-(2,2-Difluoro-1,3-benzodioxol-5-yl)-7(R)-[2-(3-hydroxy-2-methylpropyl)-4-methoxyphenyl]-2-(isopropylamino)-6,7-dihydro-5H-cyclopenta[b]pyridine-6(R)-carboxylic acid

【CA登记号】232954-22-2, 232953-87-6 (diastereomer)

【分子式】C₃₀H₃₂F₂N₂O₆

【分子量】554.59614

【开发单位】Banyu (Originator)

【药理作用】CARDIOVASCULAR DRUGS, Hypertension, Treatment of, Endothelin ETA Receptor Antagonists

合成路线1 合成路线2

合成路线1

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

【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

合成路线2

Resolution of (XII) by chiral HPLC and then acetylation of the hydroxyl group gave the chiral acetate (XIII). The pyridine ring of (XIII) was converted to the corresponding N-oxide (XIV) by means of meta-chloroperbenzoic acid. Subsequent displacement of the N-oxide of (XIV) with N-isopropyl-benzimidoyl chloride (XV) introduced the N-benzoyl-N-isopropylamino group into the pyridine to afford (XVI). After tert-butyl ester cleavage with trifluoroacetic acid, yielding (XVIII), basic hydrolysis of the benzamido group provided the title compound.

参考文献中间体

【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	分子式	供应商	用于合成
(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
(XIII)	43957	tert-butyl (5S,6R,7R)-7-[2-[3-(acetoxy)-2-methylpropyl]-4-methoxyphenyl]-5-(2,2-difluoro-1,3-benzodioxol-5-yl)-6,7-dihydro-5H-cyclopenta[b]pyridine-6-carboxylate	C₃₃H₃₅F₂NO₇	详情	详情
(XIV)	43958	(5S,6R,7R)-7-[2-[3-(acetoxy)-2-methylpropyl]-4-methoxyphenyl]-6-(tert-butoxycarbonyl)-5-(2,2-difluoro-1,3-benzodioxol-5-yl)-6,7-dihydro-5H-cyclopenta[b]pyridinium-1-olate	C₃₃H₃₅F₂NO₈	详情	详情
(XV)	43959	N-isopropylbenzenecarboximidoyl chloride	C₁₀H₁₂ClN	详情	详情
(XVI)	43960	tert-butyl (5S,6R,7R)-2-[benzoyl(isopropyl)amino]-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	C₄₁H₄₄F₂N₂O₇	详情	详情
(XVII)	43961	(5S,6R,7R)-2-[benzoyl(isopropyl)amino]-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-carboxylic acid	C₃₇H₃₆F₂N₂O₇	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)