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【结 构 式】

【分子编号】68957

【品名】1-benzyl-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione

【CA登记号】 

【 分 子 式 】C30H25N3O2

【 分 子 量 】459.548

【元素组成】C 78.41% H 5.48% N 9.14% O 6.96%

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:(VII)

Condensation of methyl 5,6-dihydropyrrolo[3,2,1-ij]quinolin-1-ylacetate (I) with methyl (3-indolyl)glyoxylate (II) in the presence of LDA in THF affords the butenedioate derivative (III), which can also be prepared by condensation of methyl 5,6-dihydropyrrolo[3,2,1-ij] quinoline-1-glyoxylate (IV) with methyl 3-indolylacetate (V) in the presence of LDA in THF. Hydrogenation of alkene (III) over Pd/C gives the saturated diester (VI), which upon cyclocondensation with benzylamine in THF yields the 1-benzyl-2,5-pyrrolidinedione derivative (VII). Debenzylation of compound (VII) by means of H2 over Pd/C then provides the 2,3-diarylsuccinimide (VIII) as a cis/trans mixture. Alternatively, succinimide (VIII) can be produced by the direct cyclocondensation of diester (VI) with NH3 in MeOH at elevated temperature. Isomerization of intermediate (VIII) with t-BuOK in t-BuOH or THF/t-BuOH leads to the (±)-trans-isomer, racemic tivantinib (IX) . Resolution of racemate (IX) can be effected by means of chiral preparative SFC or MCC , or by fractional crystallization with (1S,2S)-(+)-pseudoephedrine .
Racemic tivantinib (IX) can also be obtained by the following methods:
Reduction of the maleimide derivative (X) with Mg in refluxing MeOH produces the trans-succinimide (IX) . Alternatively, the reduction of maleimide (X) by catalytic hydrogenation over Pd/C in MeOH or Pd(OH)2/C in toluene provides the (±)-cis-succinimide (XI), which can be isomerized to the corresponding trans-succinimide (IX) by treatment with t-BuOK in t-BuOH at 50 °C . Similarly, reduction of the maleimide (X) with Zn(Hg) in HCl/EtOH leads to a mixture of cis- and trans-maleimides . The tricyclic compound (IX) can also be obtained by intramolecular Heck reaction of the 1-allyl-7-bromoindole derivative (XII) in the presence of 9-BBN and Pd(PPh3)4 . In a further method, condensation of 1-benzyl-3,4-dibromopyrrole-2,5-dione (XIII) with indole (XIV) using methyl magnesium bromide yields 1-benzyl-3-bromo-4-(3-indolyl)pyrrole-2,5-dione (XV), which by Suzuki coupling with 5,6-dihydropyrrolo[3,2,1-ij]quinolin-1-ylboronic acid (XVI) in the presence of Pd(PPh3)4 or by condensation with 5,6-dihydropyrrolo[3,2,1-ij]quinoline (XVII) by means of LiHMDS affords the maleimide (XVIII). Finally, adduct (XVIII) is reduced with Mg in refluxing MeOH, followed by debenzylation with H2 over Pd/C in MeOH (IX) .

1 Li, C.J., Ashwell, M.A., Hill, J., Moussa, M.M., Munshi, N. (ArQule, Inc.). Maleimide derivatives, pharmaceutical compositions and methods for treatment of cancer. CN 10194970, EP 1846406, EP 2289892, JP 2008530026, US 2006223760, US 7713969, WO 2006086484.
2 Chan, T.C.K., France, D.S., Ishii, K. (ArQule, Inc.; Kyowa Hakko Kirin Co., Ltd.). Combinational compositions and methods for treatment of cancer. KR 2011118817, US 2010297075, WO 2010093789.
3 Reed, D.P., Barnes, N.R., Kane, J.C., Lee, C.A., Chen, J.-X., Redmon, M.P.(ArQule, Inc.). Purified pyrroloquinolinyl-pyrrolidine-2,5-dione compositions and methods for preparing and using same. US 201116022, WO 2011079142.
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) 68951 methyl 2-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)acetate   C14H15NO2 详情 详情
(II) 68952 methyl (3-indolyl)glyoxylate;methyl 2-(1H-indol-3-yl)-2-oxoacetate;Methyl indolyl-3-glyoxylate;Indole-3-glyoxylic acid methyl ester 18372-22-0 C11H9NO3 详情 详情
(III) 68953 dimethyl 2-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-3-(1H-indol-3-yl)maleate   C25H22N2O4 详情 详情
(IV) 68954 methyl 2-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-2-oxoacetate   C14H13NO3 详情 详情
(V) 68955 methyl 3-indolylacetate;b-Indolylacetic acid methyl ester;Methyl b-indoleacetate;Methyl indole-3-acetate;Methylindol-3-ylacetate;Methyl 2-(1H-indol-3-yl)acetate;Methyl 1H-indole-3-acetate;Methyl 1H-indol-3-ylacetate;Indolyl-3-acetic acid methyl ester;IAAmethyl ester;(1H-Indol-3-yl)acetic acid methyl ester 1912-33-0 C11H11NO2 详情 详情
(VI) 68956 dimethyl 2-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-3-(1H-indol-3-yl)succinate   C25H24N2O4 详情 详情
(VII) 68957 1-benzyl-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione   C30H25N3O2 详情 详情
(VIII) 68958 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione   C23H19N3O2 详情 详情
(IX) 68959 (±)-trans-(3R,4R)-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione   C23H19N3O2 详情 详情
(X) 68960 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione   C23H17N3O2 详情 详情
(XI) 68961 (±)-cis-(3S,4S)-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-2,5-Pyrrolidinedione   C23H19N3O2 详情 详情
(XII) 68962 (±)-trans-(3R,4R)-3-(1-allyl-7-bromo-1H-indol-3-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione   C23H18BrN3O2 详情 详情
(XIII) 68963 1-benzyl-3,4-dibromopyrrole-2,5-dione;3,4-dibromo-1-(phenylmethyl)-1H-Pyrrole-2,5-dione;N-Benzyl-2,3-dibromomaleimide 91026-00-5 C11H7Br2NO2 详情 详情
(XIV) 15292 Indole; 1H-indole 120-72-9 C8H7N 详情 详情
(XV) 68964 1-benzyl-3-bromo-4-(3-indolyl)pyrrole-2,5-dione   C19H13BrN2O2 详情 详情
(XVI) 68965 5,6-dihydropyrrolo[3,2,1-ij]quinolin-1-ylboronic acid;(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)boronic acid   C11H12BNO2 详情 详情
(XVII) 68966 5,6-dihydropyrrolo[3,2,1-ij]quinoline;5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline;1,7-Trimethyleneindol;1,8-Trimethyleneindole 5840-01-7 C11H11N 详情 详情
(XVIII) 68967 1-benzyl-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione   C30H23N3O2 详情 详情
Extended Information