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【结 构 式】

【分子编号】15515

【品名】1-(2-[[bromo(triphenyl)phosphoranyl]methyl]phenyl)dihydro-2,6(1H,3H)-pyridinedione

【CA登记号】

【 分 子 式 】C30H27BrNO2P

【 分 子 量 】544.427682

【元素组成】C 66.19% H 5% Br 14.68% N 2.57% O 5.88% P 5.69%

与该中间体有关的原料药合成路线共 1 条

合成路线1

该中间体在本合成路线中的序号:(V)

A new synthesis of FK-1052 has been performed by two closely related ways: 1) The reaction of 2-methylaniline (I) with glutaric anhydride (II) gives the corresponding glutarimide (III), which is brominated with N-bromosuccinimide (NBS) and benzoyl peroxide in CCl4 to the bromomethyl derivative (IV). The reaction of (IV) with triphenylphosphine yields the phosphonium bromide (V), which, by an intramolecular Wittig reaction with 1,8 diazabicyclo[5.4.0]undec-7-ene (DBU) in DMF affords 6,7,8,9-tetrahydropyrido[1,2-a]indol-6-one (VI). The condensation of (VI) with 5-methyl-1-(triphenylmethyl)imidazole-4-carbaldehyde (VII) by means of lithium diisopropylamide (LDA) in THF gives the condensed methanol derivative (VIII), which is acetylated with acetic anhydride and pyridine to the acetoxy compound (IX), and converted into the olefine (X) by reaction with DBU in toluene. Elimination of the triphenylmethyl group of (X) with aqueous acetic acid gives 7-(5-methyl-1H-imidazol-4-ylmethylene)-6,7,8,9-tetrahydropyrido[1,2-a]indol-6-one (XI), which is hydrogenated over Pd/C and ammonium formate in THF/water to afford the saturated compound (XII). Optical resolution of (XII) with di-p-toluyl-D-tartaric acid as usual, gives the (+)-enantiomer (XIII), which is treated with paraformaldehyde and dimethylamine in aqueous acetic acid to yield the (+)-dimethylaminomethyl compound (XIV). Finally, the dimethylamino group is eliminated with Pd/C and ammonium formate in THF/ethanol/water. 2) The final steps of the preceding sequence can also be performed in reverse order: The racemic compound (XII) is first treated with paraformaldehyde and dimethylamine as before to give the racemic dimethylaminomethyl compound (XVI), which is deaminated with Pd/C and ammonium formate as before to the racemic FK-1052 (XVI). Finally, this compound is submitted to optical resolution with di-p-toluyl-D-tartaric acid as before.

1 Takasugi, H.; Ito, K.; Kato, M.; Nishino, S.; New 5-HT3 (serotonin-3) receptor antagonists. III. An efficient synthesis of carbon 14-labeled (+)-8,9-dihydro-10-methyl-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one hydrochloride (FK 1052). Chem Pharm Bull 1995, 43, 8, 1346.
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) 15511 o-toluidine; 2-methylphenylamine;2-Methylaniline;2-Aminotoluene;1-Amino-2-methylbenzene;1-Methyl-2-aminobenzene; ortho-Toluidine 95-53-4 C7H9N 详情 详情
(II) 15512 Glutaric Anhydride; dihydro-2H-pyran-2,6(3H)-dione 108-55-4 C5H6O3 详情 详情
(III) 15513 1-(2-methylphenyl)dihydro-2,6(1H,3H)-pyridinedione C12H13NO2 详情 详情
(IV) 15514 1-[2-(bromomethyl)phenyl]dihydro-2,6(1H,3H)-pyridinedione C12H12BrNO2 详情 详情
(V) 15515 1-(2-[[bromo(triphenyl)phosphoranyl]methyl]phenyl)dihydro-2,6(1H,3H)-pyridinedione C30H27BrNO2P 详情 详情
(VI) 15516 8,9-dihydropyrido[1,2-a]indol-6(7H)-one C12H11NO 详情 详情
(VII) 15499 5-methyl-1-trityl-1H-imidazole-4-carbaldehyde C24H20N2O 详情 详情
(VIII) 15518 7-[hydroxy(5-methyl-1-trityl-1H-imidazol-4-yl)methyl]-8,9-dihydropyrido[1,2-a]indol-6(7H)-one C36H31N3O2 详情 详情
(IX) 15519 (5-methyl-1-trityl-1H-imidazol-4-yl)(6-oxo-6,7,8,9-tetrahydropyrido[1,2-a]indol-7-yl)methyl acetate C38H33N3O3 详情 详情
(X) 15520 7-[(E)-(1-benzyl-5-methyl-1H-imidazol-4-yl)methylidene]-8,9-dihydropyrido[1,2-a]indol-6(7H)-one C24H21N3O 详情 详情
(XI) 15521 7-[(E)-(5-methyl-1H-imidazol-4-yl)methylidene]-8,9-dihydropyrido[1,2-a]indol-6(7H)-one C17H15N3O 详情 详情
(XII) 15522 (rac)-(7-[(5-methyl-1H-imidazol-4-yl)methyl]-8,9-dihydropyrido[1,2-a]indol-6(7H)-one) C17H17N3O 详情 详情
(XIII) 64681 7-[(5-methyl-1H-imidazol-4-yl)methyl]-8,9-dihydropyrido[1,2-a]indol-6(7H)-one C17H17N3O 详情 详情
(XIV) 64682 10-[(dimethylamino)methyl]-7-[(5-methyl-1H-imidazol-4-yl)methyl]-8,9-dihydropyrido[1,2-a]indol-6(7H)-one C20H24N4O 详情 详情
(XV) 15524 (rac)-(10-[(dimethylamino)methyl]-7-[(5-methyl-1H-imidazol-4-yl)methyl]-8,9-dihydropyrido[1,2-a]indol-6(7H)-one) C20H24N4O 详情 详情
(XVI) 15526 10-methyl-7-[(5-methyl-1H-imidazol-4-yl)methyl]-8,9-dihydropyrido[1,2-a]indol-6(7H)-one C18H19N3O 详情 详情
Extended Information