5,8-dibromo-7,10-dihydroxy-2-methyl-6H-pyrazolo[4,5,1-de]acridin-6-one -Drug Synthesis Database

【结构式】

【分子编号】60007

【品名】5,8-dibromo-7,10-dihydroxy-2-methyl-6H-pyrazolo[4,5,1-de]acridin-6-one

【CA登记号】

【分子式】C₁₅H₈Br₂N₂O₃

【分子量】424.0482

【元素组成】C 42.49% H 1.9% Br 37.69% N 6.61% O 11.32%

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：(X)

Copper-catalyzed arylation of 3-methyl-6-nitroindazole (I) with 2-bromo-6-methoxybenzoic acid (II) furnished (III). Subsequent reduction of the nitro group of (III) to (IV) was effected by transfer hydrogenation with hydrazine hydrate in the presence of Pd/C. Intramolecular cyclization of carboxylic acid (IV) in hot PPA gave rise to the pyrazoloacridine system (V). The amino group of (V) was then converted to the bromide (VI) using a Sandmeyer reaction (1). Methyl ether cleavage in (VI) with HBr in hot AcOH provided phenol (VII), which was brominated with elemental bromine at low temperature to give (VIII). A formyl group was subsequently introduced in (VIII) by treatment with dichloromethyl methyl ether and TiCl4, yielding (IX). Oxidative cleavage of aldehyde (IX) under Baeyer-Villiger rearrangement conditions furnished the diphenol compound (X). Selective acetylation of one hydroxyl group of (X) affording (XI), followed by methylation of the remaining hydroxyl afforded (XII). Benzylic bromination of the side-chain methyl group of (XII) with NBS gave the bromomethyl derivative (XIII)

参考文献中间体

合成目标

【1】 Mimura, T.; Kato, N.; Sugaya, T.; Ikuta, M.; Kato, S.; Kuge, Y.; Tomioka, S.; Kasai, M.; An efficient synthesis of a new class of DNA intercalating antitumor 7,10-dihydroxy-6H-pyrazolo[4,5,1-de]acridin-6-ones. Synthesis (Stuttgart) 1999, 6, 947.
【2】 Mimura, Y.; Shida, Y.; Kasai, M.; Ashizawa, T.; Gomi, K. (Kyowa Hakko Kogyo Co., Ltd.); Pyrazoloacridone derivs.. EP 0487097; JP 1993001064; US 5220026 .

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)	59941	2-bromo-6-methoxybenzoic acid		C₈H₇BrO₃	详情	详情
(II)	59942	3-methyl-6-nitro-1H-indazole	6494-19-5	C₈H₇N₃O₂	详情	详情
(III)	60000	2-methoxy-6-(3-methyl-6-nitro-1H-indazol-1-yl)benzoic acid		C₁₆H₁₃N₃O₅	详情	详情
(IV)	60001	2-(6-amino-3-methyl-1H-indazol-1-yl)-6-methoxybenzoic acid		C₁₆H₁₅N₃O₃	详情	详情
(V)	60002	5-amino-7-methoxy-2-methyl-6H-pyrazolo[4,5,1-de]acridin-6-one		C₁₆H₁₃N₃O₂	详情	详情
(VI)	60003	5-bromo-7-methoxy-2-methyl-6H-pyrazolo[4,5,1-de]acridin-6-one		C₁₆H₁₁BrN₂O₂	详情	详情
(VII)	60004	5-bromo-7-hydroxy-2-methyl-6H-pyrazolo[4,5,1-de]acridin-6-one		C₁₅H₉BrN₂O₂	详情	详情
(VIII)	60005	5,8-dibromo-7-hydroxy-2-methyl-6H-pyrazolo[4,5,1-de]acridin-6-one		C₁₅H₈Br₂N₂O₂	详情	详情
(IX)	60006	5,8-dibromo-7-hydroxy-2-methyl-6-oxo-6H-pyrazolo[4,5,1-de]acridine-10-carbaldehyde		C₁₆H₈Br₂N₂O₃	详情	详情
(X)	60007	5,8-dibromo-7,10-dihydroxy-2-methyl-6H-pyrazolo[4,5,1-de]acridin-6-one		C₁₅H₈Br₂N₂O₃	详情	详情
(XI)	60008	5,8-dibromo-7-hydroxy-2-methyl-6-oxo-6H-pyrazolo[4,5,1-de]acridin-10-yl acetate		C₁₇H₁₀Br₂N₂O₄	详情	详情
(XII)	60009	5,8-dibromo-7-methoxy-2-methyl-6-oxo-6H-pyrazolo[4,5,1-de]acridin-10-yl acetate		C₁₈H₁₂Br₂N₂O₄	详情	详情
(XIII)	60010	5,8-dibromo-2-(bromomethyl)-7-methoxy-6-oxo-6H-pyrazolo[4,5,1-de]acridin-10-yl acetate		C₁₈H₁₁Br₃N₂O₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XXVI)

An improved synthesis of the title compound has been developed. Methyl ester (XX) was prepared from the known indazolylbenzoate sodium salt (XIX) by alkylation with iodomethane and K2CO3. Benzylic bromination of (XX) using NBS in the presence of AIBN as the radical initiator furnished the bromomethyl derivative (XXI). The brominated ester (XXI) was cyclized with trifluoromethanesulfonic acid at 100 C to provide the pyrazoloacridone (XXII) along with some phenol analogue (XXIII). Complete cleavage of the methyl ether of (XXII) was then accomplished with HBr in AcOH at 70 C. Further bromination of (XXIII) with elemental bromine in dichloroethane gave the ortho-bromophenol (XXIV). Introduction of the hydroxy group at C-10 was carried out by a two step sequence involving oxidation of (XXIV) to quinone (XXV) with (diacetoxy)iodobenzene, followed by its reduction to the corresponding hydroquinone (XXVI) with tetrabutylammonium triacetoxyborohydride. Condensation of (XXVI) with N-benzylethanolamine (XXVII) yielded the tertiary amine (XXVIII). Further bromine displacement in (XXVIII) with 1,3-propanediamine (XVI) provided (XXIX). The remaining bromine and the N-benzyl protecting groups of (XXIX) were finally subjected to hydrogenolysis in the presence of Pd/C

参考文献中间体

合成目标

【1】 Mimura, T.; Kato, N.; Sugaya, T.; Ikuta, M.; Kato, S.; Kuge, Y.; Tomioka, S.; Kasai, M.; An efficient synthesis of a new class of DNA intercalating antitumor 7,10-dihydroxy-6H-pyrazolo[4,5,1-de]acridin-6-ones. Synthesis (Stuttgart) 1999, 6, 947.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XVI)	19331	3-aminopropylamine; 1,3-propanediamine	109-76-2	C₃H₁₀N₂	详情	详情
(XIX)	60014	2-(6-bromo-3-methyl-1H-indazol-1-yl)-6-methoxybenzoate		C₁₆H₁₂BrN₂O₃	详情	详情
(XX)	60015	methyl 2-(6-bromo-3-methyl-1H-indazol-1-yl)-6-methoxybenzoate		C₁₇H₁₅BrN₂O₃	详情	详情
(XXI)	60016	methyl 2-[6-bromo-3-(bromomethyl)-1H-indazol-1-yl]-6-methoxybenzoate		C₁₇H₁₄Br₂N₂O₃	详情	详情
(XXII)	60017	5-bromo-2-(bromomethyl)-7-methoxy-6H-pyrazolo[4,5,1-de]acridin-6-one		C₁₆H₁₀Br₂N₂O₂	详情	详情
(XXIII)	60018	5-bromo-2-(bromomethyl)-7-hydroxy-6H-pyrazolo[4,5,1-de]acridin-6-one		C₁₅H₈Br₂N₂O₂	详情	详情
(XXIV)	60019	5,8-dibromo-2-(bromomethyl)-7-hydroxy-6H-pyrazolo[4,5,1-de]acridin-6-one		C₁₅H₇Br₃N₂O₂	详情	详情
(XXV)	60005	5,8-dibromo-7-hydroxy-2-methyl-6H-pyrazolo[4,5,1-de]acridin-6-one		C₁₅H₈Br₂N₂O₂	详情	详情
(XXVI)	60007	5,8-dibromo-7,10-dihydroxy-2-methyl-6H-pyrazolo[4,5,1-de]acridin-6-one		C₁₅H₈Br₂N₂O₃	详情	详情
(XXVII)	25630	2-(benzylamino)-1-ethanol	104-63-2	C₉H₁₃NO	详情	详情
(XXVIII)	60020	2-{[benzyl(butyl)amino]methyl}-5,8-dibromo-7,10-dihydroxy-6H-pyrazolo[4,5,1-de]acridin-6-one		C₂₆H₂₃Br₂N₃O₃	详情	详情
(XXIX)	60021	5-[(3-aminopropyl)amino]-2-{[benzyl(butyl)amino]methyl}-8-bromo-7,10-dihydroxy-6H-pyrazolo[4,5,1-de]acridin-6-one		C₂₉H₃₂BrN₅O₃	详情	详情

Extended Information