T-1032, -Drug Synthesis Database

【结构式】

【药物名称】T-1032

【化学名称】2-(4-Aminophenyl)-1-oxo-7-(pyridin-2-ylmethoxy)-4-(3,4,5-trimethoxyphenyl)-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester sulfate

【CA登记号】212500-03-3, 212498-37-8 (diHCl), 212500-05-5 (dimethanesulfonate), 212500-02-2 (free base)

【分子式】C₃₂H₃₁N₃O₁₁S

【分子量】665.68137

【开发单位】Tanabe Seiyaku (Originator)

【药理作用】CARDIOVASCULAR DRUGS, Hypertension, Treatment of, Pulmonary Hypertension, Treatment of, RENAL-UROLOGIC DRUGS, Treatment of Erectile Dysfunction, Treatment of Male Sexual Dysfunction, Phosphodiesterase V (PDE5A) Inhibitors

合成路线1 合成路线2

合成路线1

Lithiation of 5-benzyloxy-2-bromobenzaldehyde dimethyl acetal (I), followed by addition to N,N-dimethyl-3,4,5-trimethoxybenzamide (II), gave rise to benzophenone (III). After acetal hydrolysis using an acidic ion exchange resin, the resulting aldehyde (IV) was oxidized to carboxylic acid (V) by means of sodium chlorite. Condensation of this keto acid (V) with diethyl bromomalonate (VI), followed by acidic treatment, furnished the isocoumarin derivative (VII). Subsequent addition of water to the double bond upon treatment with NaOH in aqueous methanol produced (VIII). This compound was condensed with N-Boc-p-phenylenediamine (IX) in the presence of N-methylmorpholine in hot 1,3-dimethyl-2-imidazolinone to afford the isoquinolinone (X). The methyl ester (XI) was prepared by reaction of carboxylic acid (X) with iodomethane and K2CO3.

参考文献中间体

【1】 Ikeo, T.; Ukita, T.; Omori, K. (Tanabe Seiyaku Co., Ltd.); Isoquinolinone derivs., process for preparing the same, and their use as phosphodiesterase inhibitors. JP 1998298164; WO 9838168 .

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)	43965	4-(benzyloxy)-1-bromo-2-(dimethoxymethyl)benzene; benzyl 4-bromo-3-(dimethoxymethyl)phenyl ether		C₁₆H₁₇BrO₃	详情	详情
(II)	43966	3,4,5-trimethoxy-N,N-dimethylbenzamide		C₁₂H₁₇NO₄	详情	详情
(III)	43967	[4-(benzyloxy)-2-(dimethoxymethyl)phenyl](3,4,5-trimethoxyphenyl)methanone		C₂₆H₂₈O₇	详情	详情
(IV)	43968	5-(benzyloxy)-2-(3,4,5-trimethoxybenzoyl)benzaldehyde		C₂₄H₂₂O₆	详情	详情
(V)	43969	5-(benzyloxy)-2-(3,4,5-trimethoxybenzoyl)benzoic acid		C₂₄H₂₂O₇	详情	详情
(VI)	35647	diethyl 2-bromomalonate	685-87-0	C₇H₁₁BrO₄	详情	详情
(VII)	43970	7-(benzyloxy)-1-oxo-4-(3,4,5-trimethoxyphenyl)-1H-isochromene-3-carboxylic acid		C₂₆H₂₂O₈	详情	详情
(VIII)	43971	7-(benzyloxy)-3-hydroxy-1-oxo-4-(3,4,5-trimethoxyphenyl)-3,4-dihydro-1H-isochromene-3-carboxylic acid		C₂₆H₂₄O₉	详情	详情
(IX)	43972	4-(N-Boc-aminomethyl)aniline;tert-butyl (4-aminophenyl)carbamate;tert-butyl 4-aminophenylcarbamate		C₁₁H₁₆N₂O₂	详情	详情
(X)	43973	7-(benzyloxy)-2-[4-[(tert-butoxycarbonyl)amino]phenyl]-1-oxo-4-(3,4,5-trimethoxyphenyl)-1,2-dihydro-3-isoquinolinecarboxylic acid		C₃₇H₃₆N₂O₉	详情	详情
(XI)	43974	methyl 7-(benzyloxy)-2-[4-[(tert-butoxycarbonyl)amino]phenyl]-1-oxo-4-(3,4,5-trimethoxyphenyl)-1,2-dihydro-3-isoquinolinecarboxylate		C₃₈H₃₈N₂O₉	详情	详情

合成路线2

Hydrogenolytic removal of the O-benzyl group provided phenol (XII), which was subsequently alkylated with 2-picolyl chloride (XIII) to produce ether (XIV). The Boc protecting group of (XIV) was finally cleaved by treatment with HCl in EtOAc.

参考文献中间体

【1】 Ikeo, T.; Ukita, T.; Omori, K. (Tanabe Seiyaku Co., Ltd.); Isoquinolinone derivs., process for preparing the same, and their use as phosphodiesterase inhibitors. JP 1998298164; WO 9838168 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XI)	43974	methyl 7-(benzyloxy)-2-[4-[(tert-butoxycarbonyl)amino]phenyl]-1-oxo-4-(3,4,5-trimethoxyphenyl)-1,2-dihydro-3-isoquinolinecarboxylate		C₃₈H₃₈N₂O₉	详情	详情
(XII)	43975	methyl 2-[4-[(tert-butoxycarbonyl)amino]phenyl]-7-hydroxy-1-oxo-4-(3,4,5-trimethoxyphenyl)-1,2-dihydro-3-isoquinolinecarboxylate		C₃₁H₃₂N₂O₉	详情	详情
(XIII)	26187	2-(Chloromethyl)pyridine	4377-33-7	C₆H₆ClN	详情	详情
(XIV)	43976	methyl 2-[4-[(tert-butoxycarbonyl)amino]phenyl]-1-oxo-7-(2-pyridinylmethoxy)-4-(3,4,5-trimethoxyphenyl)-1,2-dihydro-3-isoquinolinecarboxylate		C₃₇H₃₇N₃O₉	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)