Tivantinib；ARQ-197, -Drug Synthesis Database

【结构式】

【药物名称】Tivantinib；ARQ-197

【化学名称】(–)-3(R)-(5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4(R)-(1H-indol-3-yl)pyrrolidine-2,5-dione

【CA登记号】905854-02-6

【分子式】C₂₃H₁₉N₃O₂

【分子量】369.4159

【开发单位】Developed by ArQule, Inc. (US) in partnership with Daiichi Sankyo Co., Ltd. (JP) and Asian licensee Kyowa Hakko Kogyo Co., Ltd. (JP)

【药理作用】Proto-oncogene c-Met Inhibitor；Hepatocyte Growth Factor Receptor Inhibitor；Oncolytic

合成路线1 合成路线2 合成路线3

合成路线1

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) .

参考文献中间体

【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

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 .

参考文献中间体

【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

合成路线3

The allyl-indole intermediate (XII) is obtained by acylation of 1-allyl-7-bromoindole (XXVI) with (COCl)2 in CH2Cl2, followed by treatment with NaOMe to afford the oxoester (XXVII), which upon cyclocondensation with (3-indolyl)acetamide (XXV) in the presence of t-BuOK in THF furnishes the pyrrole-2,5-dione derivative (XXVIII). Finally, the maleimide derivative (XXVIII) is reduced by means of Mg in refluxing MeOH .

参考文献中间体

【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.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(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
(XXV)	48682	Indole-3-acetamide;3-Indoleacetamide;2-(1H-indol-3-yl)	879-37-8	C₁₀H₁₀N₂O	详情	详情
(XXVI)	68972	1-allyl-7-bromoindole;1-allyl-7-bromo-1H-indole		C₁₁H₁₀BrN	详情	详情
(XXVII)	68973	methyl 2-(1-allyl-7-bromo-1H-indol-3-yl)-2-oxoacetate		C₁₄H₁₂BrNO₃	详情	详情
(XXVIII)	68974	3-(1-allyl-7-bromo-1H-indol-3-yl)-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione		C₂₃H₁₆BrN₃O₂	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(2)