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【结 构 式】

【分子编号】15502

【品名】10-methyl-7-[(E)-(5-methyl-1-trityl-1H-imidazol-4-yl)methylidene]-8,9-dihydropyrido[1,2-a]indol-6(7H)-one

【CA登记号】

【 分 子 式 】C37H31N3O

【 分 子 量 】533.67276

【元素组成】C 83.27% H 5.85% N 7.87% O 3%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(V)

The condensation of 10-methyl-6,7,8,9-tetrahydropyrido[1,2-a]indol-6-one (I) with 5-methyl-1-(triphenylmethyl)-1H-imidazole-4-carboxaldehyde (II) by means of BuLi in THF gives 7-[hydroxy[5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl]methyl]-10-methyl-6,7,8,9-tetrahydropyrido[1,2-a]indol-6-one (III), which is treated with acetic anhydride in pyridine, yielding the corresponding acetoxy derivative (IV). Elimination of acetic acid from (IV) in hot toluene affords the corresponding methylene derivative (V), which is hydrogenated with H2 over Pd/C in DMF/ethanol giving 10-methyl-7-[5-methyl-1-(triphenylmethyl)-1H-imidazol-4-ylmethyl]-6,7,8,9-tetrahydropyrido[1,2-a]indol-6-one (VI). Finally, this compound is deprotected in hot acetic acid/water. In order to obtain the (+)-enantiomer, the racemic mixture is treated with either (-)-di-p-toluyl-L-tartaric acid or (+)-di-p-toluyl-D-tartaric acid. The mixture of diastereomeric salts is separated by fractional crystallization. The pure (+)-enantiomer is obtained by treatment of the corresponding tartrate salt with NaHCO3 or NaOH in water. Finally, the (+)-free base is treated with HCl in methanol.

1 Kato, M.; Ito, K.; Takasugi, H. (Fujisawa Pharmaceutical Co., Ltd.); Use of pyridoindole derivs. in the treatment of ischemic disorders. EP 0451538; JP 1992270280 .
2 Kato, M.; Ito, K.; Takasugi, H. (Fujisawa Pharmaceutical Co., Ltd.); Pyridoindole and processes for preparation thereof. AU 8941406; EP 0361317; JP 1990117675; US 5141945; US 5173493; US 5290785 .
3 Prous, J.; Castaner, J.; Mealy, N.; FK-1052. Drugs Fut 1994, 19, 12, 1075.
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) 15498 10-methyl-8,9-dihydropyrido[1,2-a]indol-6(7H)-one C13H13NO 详情 详情
(II) 15499 5-methyl-1-trityl-1H-imidazole-4-carbaldehyde C24H20N2O 详情 详情
(III) 15500 7-[(Z)-1-hydroxy-2-(methyleneamino)-3-[methyl(trityl)amino]-2-butenyl]-10-methyl-8,9-dihydropyrido[1,2-a]indol-6(7H)-one C37H33N3O2 详情 详情
(IV) 15501 (10-methyl-6-oxo-6,7,8,9-tetrahydropyrido[1,2-a]indol-7-yl)(5-methyl-1-trityl-1H-imidazol-4-yl)methyl acetate C39H35N3O3 详情 详情
(V) 15502 10-methyl-7-[(E)-(5-methyl-1-trityl-1H-imidazol-4-yl)methylidene]-8,9-dihydropyrido[1,2-a]indol-6(7H)-one C37H31N3O 详情 详情
(VI) 15503 10-methyl-7-[(5-methyl-1-trityl-1H-imidazol-4-yl)methyl]-8,9-dihydropyrido[1,2-a]indol-6(7H)-one C37H33N3O 详情 详情

合成路线2

该中间体在本合成路线中的序号:(VII)

A new synthesis of FK-1052 has been described: The cyclization of 2-methylcyclohexane-1,3-dione (I) with phenylhydrazine (II) by means of sulfuric acid in toluene gives 10-methyl-6,7,8,9-tetrahydropyrido[1,2-a]indol-6-one (III), which is condensed with 5-methyl-1-(triphenylmethyl)imidazole-4-carbaldehyde (IV) by means of lithium diisopropylamide (LDA) in THF to yield 7-[hydroxy[5-methyl-1-(triphenylmethyl)imidazol-4-yl]methyl]-10-methyl-6,7,8,9-tetrahydropyrido[1,2-a]indol-6-one (V). The acylation of (V) with acetic anhydride in pyridine affords the corresponding acetate (VI), which by treatment with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) is converted to the methylene derivative (VII). Finally, this compound is hydrogenated and deprotected by hydrogenolysis with H2 over Pd/C in acetic acid. In order to obtain the (+)-enantiomer, the racemic mixture is treated with (+)-di-p-toluoyl-D-tartaric acid, and the mixture of diastereomeric salts is separated by fractional crystallization. The (+)-enantiomer is obtained by treatment of the corresponding tartrate salt with 2N NaOH. Finally, the (+)-free base is converted to the hydrochloride by treatment with HCl in EtOH and recrystallization from MeOH/ether.

1 Ito, K.; Kato, M.; Yamakuni, H.; Nishino, S.; Takasugi, H.; New 5-HT3 (serotonin-3) receptor antagonists. I. Synthesis and structure-activity relationships of pyrido[1,2-a]indoles. Chem Pharm Bull 1994, 42, 12, 2546.
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) 15504 2-methyl-1,3-cyclohexanedione 1193-55-1 C7H10O2 详情 详情
(II) 11818 Phenyl hydrazine; 1-Phenylhydrazine 100-63-0 C6H8N2 详情 详情
(III) 15498 10-methyl-8,9-dihydropyrido[1,2-a]indol-6(7H)-one C13H13NO 详情 详情
(IV) 15499 5-methyl-1-trityl-1H-imidazole-4-carbaldehyde C24H20N2O 详情 详情
(V) 15508 7-[hydroxy(5-methyl-1-trityl-1H-imidazol-4-yl)methyl]-10-methyl-8,9-dihydropyrido[1,2-a]indol-6(7H)-one C37H33N3O2 详情 详情
(VI) 15501 (10-methyl-6-oxo-6,7,8,9-tetrahydropyrido[1,2-a]indol-7-yl)(5-methyl-1-trityl-1H-imidazol-4-yl)methyl acetate C39H35N3O3 详情 详情
(VII) 15502 10-methyl-7-[(E)-(5-methyl-1-trityl-1H-imidazol-4-yl)methylidene]-8,9-dihydropyrido[1,2-a]indol-6(7H)-one C37H31N3O 详情 详情
Extended Information