9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-1,2,3,9-tetrahydro-4H-carbazol-4-one -Drug Synthesis Database

【结构式】

【分子编号】53903

【品名】9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-1,2,3,9-tetrahydro-4H-carbazol-4-one

【CA登记号】n/a

【分子式】C₁₈H₁₉N₃O

【分子量】293.36848

【元素组成】C 73.7% H 6.53% N 14.32% O 5.45%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(IX)

Condensation of 2-iodoaniline (I) with cyclohexane-1,3-dione (II) at 120 C yields secondary amine (III), which is then methylated with iodomethane by means of sodium hydride in refluxing benzene to provide tertiary amine (IV). Treatment of (IV) with lithium diisopropylamide (LDA) and dimethylaminomethylene iodide (Eschenmoser's salt) (V) in THF yields dimethylaminomethyl derivative (VI), which is then coupled with 2-methylindole (VII) in DMF to give compound (VIII). Cyclization of cyclohexenone derivative (VIII) by means of palladium (II) acetate and triethylamine in acetonitrile provides carbazolone derivative (IX), which is finally converted into the desired hydrochloride salt by treatment with HCl.

参考文献中间体

合成目标

【1】 Bell, J.A.; Ewan, G.B.; Humber, D.C.; Costes, I.H.; Godfrey, N. (GlaxoSmithKline plc); Process for the preparation of 3-imidazolylmethyltetrahydrocarbazolones. EP 0221629 .

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)	27725	2-iodoaniline	615-43-0	C₆H₆IN	详情	详情
(II)	11244	1,3-Cyclohexanedione	504-02-9	C₆H₈O₂	详情	详情
(III)	53899	3-(2-iodoanilino)-2-cyclohexen-1-one	n/a	C₁₂H₁₂INO	详情	详情
(IV)	53900	3-[2-iodo(methyl)anilino]-2-cyclohexen-1-one	n/a	C₁₃H₁₄INO	详情	详情
(V)	48555	Eschenmoser's salt; N,N-Dimethylmethyleneimmonium chloride; N,N-Dimethylmethyleneimmonium iodide		C₃H₈IN	详情	详情
(VI)	53901	6-[(dimethylamino)methyl]-3-[2-iodo(methyl)anilino]-2-cyclohexen-1-one	n/a	C₁₆H₂₁IN₂O	详情	详情
(VII)	15670	2-Methylimidazole; 2-Methyl-1H-imidazole	693-98-1	C₄H₆N₂	详情	详情
(VIII)	53902	3-[2-iodo(methyl)anilino]-6-[(2-methyl-1H-imidazol-1-yl)methyl]-2-cyclohexen-1-one	n/a	C₁₈H₂₀IN₃O	详情	详情
(IX)	53903	9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-1,2,3,9-tetrahydro-4H-carbazol-4-one	n/a	C₁₈H₁₉N₃O	详情	详情

合成路线2

该中间体在本合成路线中的序号：(V)

Treatment of tetrahydrocarbazolone (I) with formaldehyde and dimethylamine in EtOH provides tertiary amine (II), which is then methylated with refluxing iodomethane to furnish methanaminium iodide (III). Condensation of (III) with 2-methylimidazole (IV) in DMF affords free base (V), which is converted into the desired product, the hydrochloride dihydrate, by treatment with HCl in isopropanol/water. Alternatively, free base (V) can be obtained by other related procedures: (a) treatment of methanaminium iodide (III) with sodium carbonate in water to furnish methylene derivative (VI) followed by condensation with 2-methylimidazole (IV) in refluxing water; (b) conversion of (VI) into chloromethyl derivative (VII) by treatment with ethereal HCl in CHCl3, followed by reaction of (VII) with 2-methylimidazole (IV) in DMF; (c) treatment of dimethylamino derivative (VIII) with 2-methylimidazole (IV) in refluxing water; or (d) methylation of carbazolone (IX) with dimethylsulfate and sodium hydride in DMF.

参考文献中间体

合成目标

【1】 Tyers, M.B. (GlaxoSmithKline plc); Ketone derivs.. EP 0275668; JP 1988253083; US 4845115 .
【2】 Coates, I.H.; Bell, J.A.; Ewan, G.B.; Humber, D.C. (GlaxoSmithKline plc); 1,2,3,9-Tetrahydro-3-imidazol-1-ylmethyl-4H-carbazol-4-ones, compsn. containing them, and method of using them to treat neuronal 5HT function disturbances. AU 8652614; EP 0191562; JP 1986210083; US 4695578 .
【3】 Coates, I.H.; Bell, J.A.; Hunber, D.C.; Ewan, G.B. (GlaxoSmithKline plc); Imidazolylmethyl substd. carbazoles. AU 8538097; BE 0901576; CH 664152; ES 8609309; ES 8708224; ES 8801247; FR 2561244; GB 2153821; JP 1985214784 .
【4】 Kraus, W.; Weisert, A.; Spies, J. (GlaxoSmithKline plc); Pharmaceutical product. DE 3740351 .
【5】 Kraus, W.; Weisert, A.; Spies, J. (GlaxoSmithKline plc); Pharmaceutical product. DE 3906883 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(II),(VIII)	53904	3-[(dimethylamino)methyl]-9-methyl-1,2,3,9-tetrahydro-4H-carbazol-4-one	n/a	C₁₆H₂₀N₂O	详情	详情
(I)	53889	9-methyl-1,2,3,9-tetrahydro-4H-carbazol-4-one	27387-31-1	C₁₃H₁₃NO	详情	详情
(III)	53905	N,N,N-trimethyl(9-methyl-4-oxo-2,3,4,9-tetrahydro-1H-carbazol-3-yl)methanaminium iodide	n/a	C₁₇H₂₃IN₂O	详情	详情
(IV)	15670	2-Methylimidazole; 2-Methyl-1H-imidazole	693-98-1	C₄H₆N₂	详情	详情
(V)	53903	9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-1,2,3,9-tetrahydro-4H-carbazol-4-one	n/a	C₁₈H₁₉N₃O	详情	详情
(VI)	53893	9-methyl-3-methylene-1,2,3,9-tetrahydro-4H-carbazol-4-one	n/a	C₁₄H₁₃NO	详情	详情
(VII)	53906	3-(chloromethyl)-9-methyl-1,2,3,9-tetrahydro-4H-carbazol-4-one	n/a	C₁₄H₁₄ClNO	详情	详情
(IX)	53907	3-[(2-methyl-1H-imidazol-1-yl)methyl]-1,2,3,9-tetrahydro-4H-carbazol-4-one	n/a	C₁₇H₁₇N₃O	详情	详情

合成路线3

该中间体在本合成路线中的序号：(VIII)

Treatment of 3-methoxy-2-cyclohexen-1-one (I) with n-butyllithium and diisopropylamine in THF, followed by addition of N,N-dimethylmethylene ammonium iodide (Eschenmoser's salt) (II) and precipitation with maleic acid, furnishes maleate (III). Methylation of (III) with iodomethane in DMF, followed by condensation with 2-methylimidazole (IV), affords compound (V), which is then converted into methylphenyl hydrazino derivative (VII) by first treatment with HCl in H2O followed by reaction with 1-methyl-1-phenylhydrazine (VI). Cyclization of (VII) is then performed by means of ZnCl2 in HOAc at 85 C to give carbazolone (VIII), and finally the target product is obtained by formation of the hydrochloride dihydrate salt.

参考文献中间体

合成目标

【1】 Bell, J.A.; Ewan, G.B.; Oxford, A.W.; Humber, D.C.; Eldred, C.D.; Costes, I.H. (GlaxoSmithKline plc); Process for the preparation of 3-imidazolylmethyltetrahydrocarbazolones. EP 0219929 .

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)	53908	3-Methoxy-2-cyclohexen-1-one	16807-60-6	C₇H₁₀O₂	详情	详情
(II)	48555	Eschenmoser's salt; N,N-Dimethylmethyleneimmonium chloride; N,N-Dimethylmethyleneimmonium iodide		C₃H₈IN	详情	详情
(III)	55373			C₁₄H₂₁NO₆	详情	详情
(IV)	15670	2-Methylimidazole; 2-Methyl-1H-imidazole	693-98-1	C₄H₆N₂	详情	详情
(V)	53910	3-methoxy-6-[(2-methyl-1H-imidazol-1-yl)methyl]-2-cyclohexen-1-one		C₁₂H₁₆N₂O₂	详情	详情
(VI)	53911	1-Methyl-1-phenylhydrazine; 1-Methylphenylhydrazine	618-40-6	C₇H₁₀N₂	详情	详情
(VII)	53912	6-[(2-methyl-1H-imidazol-1-yl)methyl]-3-(2-methyl-2-phenylhydrazino)-2-cyclohexen-1-one	n/a	C₁₈H₂₂N₄O	详情	详情
(VIII)	53903	9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-1,2,3,9-tetrahydro-4H-carbazol-4-one	n/a	C₁₈H₁₉N₃O	详情	详情

Extended Information