5-bromo-8-nitroisoquinoline -Drug Synthesis Database

【结构式】

【分子编号】22812

【品名】5-bromo-8-nitroisoquinoline

【CA登记号】

【分子式】C₉H₅BrN₂O₂

【分子量】253.05498

【元素组成】C 42.72% H 1.99% Br 31.58% N 11.07% O 12.64%

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：(II)

Nitration of 5-bromoisoquinoline (I) using KNO3 in H2SO4 gave 5-bromo-8-nitroisoquinoline (II), which upon methylation with dimethyl sulfate was converted to the isoquinolinium salt (III). Subsequent reduction of (III) with NaBH4 in AcOH provided tetrahydroisoquinoline (IV). This was coupled with phenylboronic acid (V) in the presence of Pd(PPh3)4 and NaHCO3 to yield the 5-phenylisoquinoline (VI). Further reduction of the nitro group of (VI) by catalytic hydrogenation over Pd/C afforded amine (VII). The pyrroloisoquinoline (VIII) was then formed by condensation of (VII) with chloral and hydroxylamine in boiling water, followed by cyclization of the intermediate (oxymino)acetamide in methanesulfonic acid at 120 C. After chlorosulfonation of (VIII), the sulfonyl chloride (IX) was condensed with dimethylamine in THF to afford sulfonamide (X). Hydroxylamine derivative (XIV) was prepared by O-alkylation of N-hydroxyphthalimide (XI) with alpha-bromo-gamma-butyrolactone (XII), followed by hydrolysis of the phthalimide (XIII) in boiling 1 M HCl. Hydroxylamine derivative (XIV) was then condensed with sulfonamide (X) to furnish oxime (XV). Finally, hydrolysis of the butyrolactone group of (XV) with aqueous NaOH gave the title compound.

参考文献中间体

合成目标

【1】 Watjen, F.; Drejer, J. (NeuroSearch A/S); Novel indole-2,3-dione-3-oxime derivs.. EP 0869958; JP 2000501432; US 6124285; WO 9814447 .

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)	22811	5-bromoisoquinoline		C₉H₆BrN	详情	详情
(II)	22812	5-bromo-8-nitroisoquinoline		C₉H₅BrN₂O₂	详情	详情
(III)	22813	5-bromo-2-methyl-8-nitro-2lambda(5)-isoquinoline		C₁₀H₈BrN₂O₂	详情	详情
(IV)	22814	5-bromo-2-methyl-8-nitro-1,2,3,4-tetrahydroisoquinoline		C₁₀H₁₁BrN₂O₂	详情	详情
(V)	16593	Phenylboronic acid；Benzeneboronic acid;Phenylboron dihydroxide	98-80-6	C₆H₇BO₂	详情	详情
(VI)	22816	2-methyl-8-nitro-5-phenyl-1,2,3,4-tetrahydroisoquinoline		C₁₆H₁₆N₂O₂	详情	详情
(VII)	22817	2-methyl-5-phenyl-1,2,3,4-tetrahydro-8-isoquinolinylamine; 2-methyl-5-phenyl-1,2,3,4-tetrahydro-8-isoquinolinamine		C₁₆H₁₈N₂	详情	详情
(VIII)	22818	8-methyl-5-phenyl-6,7,8,9-tetrahydro-1H-pyrrolo[3,2-h]isoquinoline-2,3-dione		C₁₈H₁₆N₂O₂	详情	详情
(IX)	22819	4-(8-methyl-2,3-dioxo-2,3,6,7,8,9-hexahydro-1H-pyrrolo[3,2-h]isoquinolin-5-yl)benzenesulfonyl chloride		C₁₈H₁₅ClN₂O₄S	详情	详情
(X)	22820	N,N-dimethyl-4-(8-methyl-2,3-dioxo-2,3,6,7,8,9-hexahydro-1H-pyrrolo[3,2-h]isoquinolin-5-yl)benzenesulfonamide		C₂₀H₂₁N₃O₄S	详情	详情
(XI)	13505	N-Hydroxyphthalimide; 2-Hydroxy-1H-isoindole-1,3(2H)-dione	524-38-9	C₈H₅NO₃	详情	详情
(XII)	22822	3-bromodihydro-2(3H)-furanone	5061-21-2	C₄H₅BrO₂	详情	详情
(XIII)	22823	2-[(2-oxotetrahydro-3-furanyl)oxy]-1H-isoindole-1,3(2H)-dione		C₁₂H₉NO₅	详情	详情
(XIV)	22824	3-(aminooxy)dihydro-2(3H)-furanone		C₄H₇NO₃	详情	详情
(XV)	22825	N,N-dimethyl-4-(8-methyl-2-oxo-3-[[(2-oxotetrahydro-3-furanyl)oxy]imino]-1,2,6,7,8,9-hexahydro-3H-pyrrolo[3,2-h]isoquinolin-5-yl)benzenesulfonamide		C₂₄H₂₆N₄O₆S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(II)

Nitration of 5-bromoisoquinoline (I) employing KNO3 in H2SO4 provides 5-bromo-8-nitroisoquinoline (II). Quaternization of isoquinoline (II) with dimethyl sulfate, followed by reduction of the resultant N-methyl isoquinolinium salt (III) with NaBH4 in cold HOAc furnishes the tetrahydroisoquinoline (IV). Subsequent Suzuki coupling between the bromotetrahydroisoquinoline (IV) and 4-chlorophenylboronic acid (V) yields the 5-aryl isoquinoline derivative (VI). The nitro group of (VI) is further reduced to amine (VII) by catalytic hydrogenation over Raney nickel. The key isatin compound (IX) is then obtained by condensation of amine (VII) with chloral (VIII) in the presence of hydroxylamine hydrochloride and sodium sulfate. Finally, isatin (IX) is converted to the desired oxime by treatment with hydroxylamine hydrochloride in EtOH.

参考文献中间体

合成目标

【1】 Watjen, F.; Drejer, J. (NeuroSearch A/S); AMPA antagonists and a method of treatment therewith. EP 0698025; JP 1996510221; US 5780493; US 5843945; WO 9426747 .
【2】 Moeller, A.; Peters, D.; Groenborg, M. (NeuroSearch A/S); Isatine derivs. with neurotrophic activity. EP 1255734; US 2003040518; WO 0155110 .

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)	22811	5-bromoisoquinoline		C₉H₆BrN	详情	详情
(II)	22812	5-bromo-8-nitroisoquinoline		C₉H₅BrN₂O₂	详情	详情
(III)	58406	5-bromo-2-methyl-8-nitroisoquinolinium methanesulfonate		C₁₁H₁₁BrN₂O₅S	详情	详情
(IV)	22814	5-bromo-2-methyl-8-nitro-1,2,3,4-tetrahydroisoquinoline		C₁₀H₁₁BrN₂O₂	详情	详情
(V)	17575	4-chlorophenylboronic acid	1679-18-1	C₆H₆BClO₂	详情	详情
(VI)	58407	5-(4-chlorophenyl)-2-methyl-8-nitro-1,2,3,4-tetrahydroisoquinoline		C₁₆H₁₅ClN₂O₂	详情	详情
(VII)	58408	5-(4-chlorophenyl)-2-methyl-1,2,3,4-tetrahydro-8-isoquinolinamine; 5-(4-chlorophenyl)-2-methyl-1,2,3,4-tetrahydro-8-isoquinolinylamine		C₁₆H₁₇ClN₂	详情	详情
(VIII)	58409	2,2,2-trichloroacetaldehyde	75-87-6	C₂HCl₃O	详情	详情
(IX)	58410	5-(4-chlorophenyl)-8-methyl-6,7,8,9-tetrahydro-1H-pyrrolo[3,2-h]isoquinoline-2,3-dione		C₁₈H₁₅ClN₂O₂	详情	详情

Extended Information