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【结 构 式】 
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【分子编号】68960 【品名】3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione 【CA登记号】 |
【 分 子 式 】C23H17N3O2 【 分 子 量 】367.407 【元素组成】C 75.19% H 4.66% N 11.44% O 8.71% |
合成路线1
该中间体在本合成路线中的序号：(X)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 |
合成路线2
该中间体在本合成路线中的序号：(X)The 2,3-disubstituted maleimide intermediate (X) is prepared by N-alkylation of 1,2,3,4-tetrahydroquinoline (XIX) with ethyl 3-bromopyruvate (XX) in THF to give ethyl 3-(3,4-dihydro-2H-quinolin-1-yl)-2-oxopropionate (XXI), which by intramolecular cyclocondensation by means of MgCl2 in 2-methoxyethanol at 125 °C affords ethyl 5,6-dihydropyrrolo[3,2,1-ij]quinoline-1-carboxylate (XXII). Hydrolysis of ethyl ester (XXII) with NaOH in EtOH/H2O provides the corresponding carboxylic acid (XXIII), which is then decarboxylated to 5,6-dihydropyrrolo[3,2,1-ij]quinoline (lilolidine) (XVII) by heating to 185 °C in quinoline in the presence of CuO·Cr2O3 . Acylation of lilolidine (XVII) with (COCl)2 in Et2O, and subsequent quenching of the resulting glyoxylyl chloride with MeOH or NaOMe/MeOH affords the oxoester (XXIV), which is finally cyclocondensed with indole-3-acetamide (XXV) in the presence of t-BuOK in THF .
| 【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 |
|---|---|---|---|---|---|---|
| (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 | |
| (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 |
| (XIX) | 23859 | 1,2,3,4-tetrahydroquinoline | 635-46-1 | C9H11N | 详情 | 详情 |
| (XX) | 25183 | ethyl 3-bromo-2-oxopropanoate;ethyl 3-bromopyruvate;Bromopyruvic acid ethyl ester;ethyl 3-bromopyruvate;ethyl bromopyruvate | 70-23-5 | C5H7BrO3 | 详情 | 详情 |
| (XXI) | 68968 | ethyl 3-(3,4-dihydro-2H-quinolin-1-yl)-2-oxopropionate | C14H17NO3 | 详情 | 详情 | |
| (XXII) | 68969 | ethyl 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1-carboxylate | C14H15NO2 | 详情 | 详情 | |
| (XXIII) | 68970 | 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1-carboxylic acid | C12H11NO2 | 详情 | 详情 | |
| (XXIV) | 68971 | methyl 2-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-2-oxoacetate | C14H13NO3 | 详情 | 详情 | |
| (XXV) | 48682 | Indole-3-acetamide;3-Indoleacetamide;2-(1H-indol-3-yl) | 879-37-8 | C10H10N2O | 详情 | 详情 |