905854-02-6

Basic information

• Product Name: 3-(5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-pyrrolidine-2,5-dione
• Synonyms: 3-(5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-pyrrolidine-2,5-dione Tivantinib;(3R,4R)-3-(5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dio;3-(5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-pyrrolidine-2,5-dione;Tivantinib;(-)-3(R),4(R)-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione, (-)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione;(3R,4R)-3-(5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-2,5-pyrrolidinedione;Tivantinib/ARQ197/ARQ-197;2,5-Pyrrolidinedione,3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-, (3R,4R)-
• CAS NO: 905854-02-6
• Molecular Formula: C₂₃H₁₉N₃O₂
• Molecular Weight: 369.422
• Product Categories: Inhibitors
• Mol File: 905854-02-6.mol
• Article Data: 4

Chemical Properties

• Boiling Point: 715.95°C at 760 mmHg
• Flash Point: 386.793°C
• Appearance: /
• Density: 1.49
• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: 1.797
• Storage Temp.: -20°C Freezer, Under inert atmosphere
• Solubility: DMSO (Slightly), Methanol (Slightly)
• PKA: 9.28±0.70(Predicted)
• CAS DataBase Reference: 3-(5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-pyrrolidine-2,5-dione(CAS DataBase Reference)
• NIST Chemistry Reference: 3-(5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-pyrrolidine-2,5-dione(905854-02-6)
• EPA Substance Registry System: 3-(5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-pyrrolidine-2,5-dione(905854-02-6)

Safety Data

• Hazardous Substances Data: 905854-02-6(Hazardous Substances Data)

Usage

Description

3-(5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-pyrrolidine-2,5-dione is a complex organic compound with a unique molecular structure. It is characterized by the presence of a pyrroloquinoline ring fused with an indole ring, connected through a pyrrolidine-2,5-dione moiety. 3-(5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-pyrrolidine-2,5-dione has potential applications in various fields due to its unique chemical properties and interactions with biological targets.

Uses

Used in Pharmaceutical Industry:
3-(5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-pyrrolidine-2,5-dione is used as a potent c-MET inhibitor for the treatment of c-Met-associated cancers. It selectively inhibits the human c-Met receptor tyrosine kinase, making it a promising therapeutic option for patients with this type of cancer.
Used in Drug Development:
3-(5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-pyrrolidine-2,5-dione is used as a lead compound in drug development for the discovery of new therapeutic agents targeting the c-Met receptor. Its unique structure and inhibitory properties provide a foundation for further optimization and development of more effective and selective c-MET inhibitors.
Used in Cancer Research:
3-(5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-pyrrolidine-2,5-dione is used as a research tool in cancer biology to study the role of the c-Met receptor in tumor growth and progression. Its ability to selectively inhibit the c-Met receptor tyrosine kinase allows researchers to investigate the molecular mechanisms underlying c-Met-associated cancers and identify potential therapeutic targets for intervention.

Biological Activity

tivantinib (arq 197) is an oral, non–adenosine triphosphate-competitive, selective, small-molecule met proto-oncogene (c-met) inhibitor. the calculated inhibitory constant (ki) for tivantinib to inhibit recombinant human c-met was approximately 355 nmol/l.c-met, a type of receptor tyrosine kinase, is a high-affinity receptor of the hepatocyte growth factor (hgf). dysregulated hgf/c-met-signaling pathway frequently occurs in human cancer [1].tivantinib had weak inhibitory effects on vegf receptor-3 (flt4), p21-activated kinase 3, calmodulin-dependent kinase ii delta, and pim-1 [1]. tivantinib displayed cytotoxic activity against a wide panel of human tumor cell lines with an ec50 ranging from 300-600 nmol/l [4]. remarkably, a549, h3122, pc9 (del e746_a750), pc9 gr4 (del e746_a750/t790m), hcc827, hcc827 gr6, h1993 and ebc-1 cell lines showed some degree of sensitivity to tivantinib, with ic50s ranging between 0.36 and 0.8 μm [5]. in tumor cell lines, gtl-16, mkn-45, hs746t, snu-5, ebc-1, h1993, nci-h441, a549, hct-116, u87-mg, a2780, and tov-112d, tivantinib indiscriminately inhibited cell proliferation independently of c-met gene amplification and met protein expression with an ec50 ranging from 60 to 600 nmol/l. further research showed that tivantinib promotes mitotic arrest, prevents cells from re-entering g1, and drives them to apoptosis, and induces programmed cell death regardless of the presence or absence of a functional met kinase [4].tivantinib has demonstrated antitumor activity in a wide range of human tumor cell lines and in xenograft models of human lung, colon, prostate, pancreas, and breast cancer [1] [2] [3]. female 4-week-old athymic nude (nu/nu) mice were used as experimental animals. tivantinib at a dose of 120 mg/kg significantly inhibited tumor burden in the bone of treated animals compared with the controls, starting from 14 to 21 days after cell injection. increasing doses of tivantinib decreased the number and the extent of osteolytic lesions [6].

references

[1]. ryohei katayama, aki aoyama, takao yamori, et al. cytotoxic activity of tivantinib (arq 197) is not due solely to c-met inhibition. cancer research, 2013, 73(10): 3087-3097.[2]. andrew j.wagner, john m. goldberg, steven g. dubois, et al. tivantinib (arq 197), a selective inhibitor of met, in patients with microphthalmia transcription factor–associated tumors. cancer, 2012: 5894-5902.[3]. n. yamamoto, h. murakami, t. nishina, et al. the effect of cyp2c19 polymorphism on the safety, tolerability, and pharmacokinetics of tivantinib (arq 197): results from a phase i trial in advanced solid tumors. annals of oncology, 2013, 00: 1–7.[4]. cristina basilico, selma pennacchietti, elisa vigna, et al. tivantinib (arq197) displays cytotoxic activity that is independent of its ability to bind met. clin cancer res, 2013, 19(9):2381-92.[5]. cristina basilico, selma pennacchietti, elisa vigna, et al. tivantinib (arq197) displays cytotoxic activity that is independent of its ability to bind met. clinical cancer research, 2013, 19(9): 2381–92.[6]. sara previdi, giovanni abbadessa, francesca dalò, et al. breast cancer–derived bone metastasis can be effectively reduced through specific c-met inhibitor tivantinib (arq 197) and shrna c-met knockdown. mol cancer ther, 2011, 11(1):214-23.

InChI:InChI=1/C23H19N3O2/c27-22-19(16-11-24-18-9-2-1-7-14(16)18)20(23(28)25-22)17-12-26-10-4-6-13-5-3-8-15(17)21(13)26/h1-3,5,7-9,11-12,19-20,24H,4,6,10H2,(H,25,27,28)/t19-,20-/m0/s1

Synthetic route

(±)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione → (+)-3(S),4(S)-3-(5,6-dihydro-4H-pyrrolo[3,2,1-j]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione (905854-03-7) + Tivantinib (905854-02-6)

Conditions	Yield
Purification / work up; Resolution of racemate;
With Chiralpak AZ column In methanol; dichloromethane; acetonitrile Resolution of racemate; Multicolumn chromatography;	A n/a B n/a
With CHIRALPAK AD column In methanol; carbon dioxide liquid CO2;

5,6-dihydro-4H-pyrrolo-[3,2,1-ij]quinoline (5840-01-7) → Tivantinib (905854-02-6)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: tert-butyl methyl ether / 2.17 h / 15 - 32 °C / Industry scale 1.2: 2 h / Industry scale 2.1: potassium tert-butylate / tetrahydrofuran / 3 h / 20 - 32 °C / Industry scale 2.2: 0.5 h / 40 - 50 °C / Industry scale 2.3: 40 °C / pH 8 - 9 / Industry scale 3.1: hydrogen; potassium tert-butylate / 20 % Pd(OH)2/C / tetrahydrofuran / 45 - 55 °C / 3361.55 - 4137.29 Torr / Industry scale 4.1: hydrogenchloride / water; Isopropyl acetate / Industry scale 5.1: Chiralpak AZ column / dichloromethane; acetonitrile; methanol / Resolution of racemate; Multicolumn chromatography View Scheme
Multi-step reaction with 6 steps 1.1: tert-butyl methyl ether / 2.17 h / 15 - 32 °C / Industry scale 1.2: 2 h / Industry scale 2.1: potassium tert-butylate / tetrahydrofuran / 3 h / 20 - 32 °C / Industry scale 2.2: 0.5 h / 40 - 50 °C / Industry scale 2.3: 40 °C / pH 8 - 9 / Industry scale 3.1: hydrogen; potassium tert-butylate / 20 % Pd(OH)2/C / tetrahydrofuran / 45 - 55 °C / 3361.55 - 4137.29 Torr / Industry scale 4.1: hydrogenchloride / water; Isopropyl acetate / Industry scale 5.1: acetonitrile / 50 °C 6.1: hydrogenchloride / 3-methyltetrahydrofuran; water / 50 °C / pH 1.6 View Scheme
Multi-step reaction with 5 steps 1.1: tert-butyl methyl ether / 0.1 h / 20 - 32 °C / Inert atmosphere 1.2: 0.1 h / 25 °C / Inert atmosphere 2.1: potassium tert-butylate / tetrahydrofuran / 2.5 h / 20 - 32 °C / Inert atmosphere 2.2: 0.1 h / 0.4 - 0.5 °C 2.3: 0.01 h / 20 - 32 °C 3.1: potassium tert-butylate; 10 wt% Pd(OH)2 on carbon; hydrogen / tetrahydrofuran / 12 h / 0.45 - 0.5 °C / 3360.34 Torr 4.1: water; methanol / 3 h / 0.55 - 20 °C / Inert atmosphere 5.1: hydrogenchloride / methanol / 0.45 - 0.55 °C View Scheme

(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)oxoacetic acid methyl ester (345264-02-0) → Tivantinib (905854-02-6)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: potassium tert-butylate / tetrahydrofuran / 3 h / 20 - 32 °C / Industry scale 1.2: 0.5 h / 40 - 50 °C / Industry scale 1.3: 40 °C / pH 8 - 9 / Industry scale 2.1: hydrogen; potassium tert-butylate / 20 % Pd(OH)2/C / tetrahydrofuran / 45 - 55 °C / 3361.55 - 4137.29 Torr / Industry scale 3.1: hydrogenchloride / water; Isopropyl acetate / Industry scale 4.1: Chiralpak AZ column / dichloromethane; acetonitrile; methanol / Resolution of racemate; Multicolumn chromatography View Scheme
Multi-step reaction with 5 steps 1.1: potassium tert-butylate / tetrahydrofuran / 3 h / 20 - 32 °C / Industry scale 1.2: 0.5 h / 40 - 50 °C / Industry scale 1.3: 40 °C / pH 8 - 9 / Industry scale 2.1: hydrogen; potassium tert-butylate / 20 % Pd(OH)2/C / tetrahydrofuran / 45 - 55 °C / 3361.55 - 4137.29 Torr / Industry scale 3.1: hydrogenchloride / water; Isopropyl acetate / Industry scale 4.1: acetonitrile / 50 °C 5.1: hydrogenchloride / 3-methyltetrahydrofuran; water / 50 °C / pH 1.6 View Scheme
Multi-step reaction with 4 steps 1.1: potassium tert-butylate / tetrahydrofuran / 2.5 h / 20 - 32 °C / Inert atmosphere 1.2: 0.1 h / 0.4 - 0.5 °C 1.3: 0.01 h / 20 - 32 °C 2.1: potassium tert-butylate; 10 wt% Pd(OH)2 on carbon; hydrogen / tetrahydrofuran / 12 h / 0.45 - 0.5 °C / 3360.34 Torr 3.1: water; methanol / 3 h / 0.55 - 20 °C / Inert atmosphere 4.1: hydrogenchloride / methanol / 0.45 - 0.55 °C View Scheme

3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dion (345261-20-3) → Tivantinib (905854-02-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: hydrogen; potassium tert-butylate / 20 % Pd(OH)2/C / tetrahydrofuran / 45 - 55 °C / 3361.55 - 4137.29 Torr / Industry scale 2: hydrogenchloride / water; Isopropyl acetate / Industry scale 3: Chiralpak AZ column / dichloromethane; acetonitrile; methanol / Resolution of racemate; Multicolumn chromatography View Scheme
Multi-step reaction with 4 steps 1: hydrogen; potassium tert-butylate / 20 % Pd(OH)2/C / tetrahydrofuran / 45 - 55 °C / 3361.55 - 4137.29 Torr / Industry scale 2: hydrogenchloride / water; Isopropyl acetate / Industry scale 3: acetonitrile / 50 °C 4: hydrogenchloride / 3-methyltetrahydrofuran; water / 50 °C / pH 1.6 View Scheme
Multi-step reaction with 3 steps 1: potassium tert-butylate; 10 wt% Pd(OH)2 on carbon; hydrogen / tetrahydrofuran / 12 h / 0.45 - 0.5 °C / 3360.34 Torr 2: water; methanol / 3 h / 0.55 - 20 °C / Inert atmosphere 3: hydrogenchloride / methanol / 0.45 - 0.55 °C View Scheme

(+)-3(S),4(S)-3-(5,6-dihydro-4H-pyrrolo[3,2,1-j]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione (905854-03-7) → Tivantinib (905854-02-6)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: sodium hydroxide / ethanol / 13 h / 65 °C / Industry scale 1.2: 60 °C 2.1: acetonitrile / 50 °C 3.1: hydrogenchloride / 3-methyltetrahydrofuran; water / 50 °C / pH 1.6 View Scheme

(±)-cis-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione → Tivantinib (905854-02-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: hydrogenchloride / water; Isopropyl acetate / Industry scale 2: Chiralpak AZ column / dichloromethane; acetonitrile; methanol / Resolution of racemate; Multicolumn chromatography View Scheme
Multi-step reaction with 3 steps 1: hydrogenchloride / water; Isopropyl acetate / Industry scale 2: acetonitrile / 50 °C 3: hydrogenchloride / 3-methyltetrahydrofuran; water / 50 °C / pH 1.6 View Scheme

(3R,4R)-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione pseudoephedrine complex (1313508-66-5) → Tivantinib (905854-02-6)

Conditions	Yield
With hydrogenchloride In 3-methyltetrahydrofuran; water at 50℃; pH=1.6; Product distribution / selectivity;
With hydrogenchloride In methanol at 0.45 - 0.55℃;

1,2,3,4-tetrahydroisoquinoline (635-46-1) → (+)-3(S),4(S)-3-(5,6-dihydro-4H-pyrrolo[3,2,1-j]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione (905854-03-7) + Tivantinib (905854-02-6)

Conditions	Yield
Multi-step reaction with 8 steps 1.1: tetrahydrofuran / 24.5 h / 20 °C 2.1: magnesium chloride / 2-methoxy-ethanol / 6 h / 125 °C / Reflux 3.1: sodium hydroxide; water / ethanol / 2 h / Reflux 4.1: copper chromite / quinoline / 2 h / 185 °C 5.1: diethyl ether / 0 °C 5.2: -78 - 20 °C 6.1: potassium tert-butylate / tetrahydrofuran / 2.5 h / 0 °C 7.1: magnesium; methanol / 0.67 h / Inert atmosphere; Reflux 8.1: CHIRALPAK® AD column / methanol; carbon dioxide / liquid CO2 View Scheme
Multi-step reaction with 8 steps 1.1: tetrahydrofuran / 24.5 h / 20 °C 2.1: magnesium chloride / 2-methoxy-ethanol / 6 h / 125 °C / Reflux 3.1: sodium hydroxide; water / ethanol / 2 h / Reflux 4.1: copper chromite / quinoline / 2 h / 185 °C 5.1: diethyl ether / 0 °C 5.2: -78 - 20 °C 6.1: potassium tert-butylate / tetrahydrofuran / 2.5 h / 0 °C 7.1: zinc; mercury dichloride; hydrogenchloride / ethanol / Reflux 8.1: CHIRALPAK® AD column / methanol; carbon dioxide / liquid CO2 View Scheme
Multi-step reaction with 9 steps 1.1: tetrahydrofuran / 24.5 h / 20 °C 2.1: magnesium chloride / 2-methoxy-ethanol / 6 h / 125 °C / Reflux 3.1: sodium hydroxide; water / ethanol / 2 h / Reflux 4.1: copper chromite / quinoline / 2 h / 185 °C 5.1: diethyl ether / 0 °C 5.2: -78 - 20 °C 6.1: potassium tert-butylate / tetrahydrofuran / 2.5 h / 0 °C 7.1: palladium 10% on activated carbon; hydrogen / methanol / 48 h / 20 °C / 760.05 Torr 8.1: potassium tert-butylate / tert-butyl alcohol / 16 h / 50 °C 9.1: CHIRALPAK® AD column / methanol; carbon dioxide / liquid CO2 View Scheme
Multi-step reaction with 9 steps 1.1: tetrahydrofuran / 24.5 h / 20 °C 2.1: magnesium chloride / 2-methoxy-ethanol / 6 h / 125 °C / Reflux 3.1: sodium hydroxide; water / ethanol / 2 h / Reflux 4.1: copper chromite / quinoline / 2 h / 185 °C 5.1: diethyl ether / 0 °C 5.2: -78 - 20 °C 6.1: potassium tert-butylate / tetrahydrofuran / 2.5 h / 0 °C 7.1: zinc; mercury dichloride; hydrogenchloride / ethanol / Reflux 8.1: potassium tert-butylate / tert-butyl alcohol / 16 h / 50 °C 9.1: CHIRALPAK® AD column / methanol; carbon dioxide / liquid CO2 View Scheme

3-(3,4-dihydro-2H-quinolin-1-yl)-2-oxopropionic acid ethyl ester (152712-44-2) → (+)-3(S),4(S)-3-(5,6-dihydro-4H-pyrrolo[3,2,1-j]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione (905854-03-7) + Tivantinib (905854-02-6)

Conditions	Yield
Multi-step reaction with 7 steps 1.1: magnesium chloride / 2-methoxy-ethanol / 6 h / 125 °C / Reflux 2.1: sodium hydroxide; water / ethanol / 2 h / Reflux 3.1: copper chromite / quinoline / 2 h / 185 °C 4.1: diethyl ether / 0 °C 4.2: -78 - 20 °C 5.1: potassium tert-butylate / tetrahydrofuran / 2.5 h / 0 °C 6.1: zinc; mercury dichloride; hydrogenchloride / ethanol / Reflux 7.1: CHIRALPAK® AD column / methanol; carbon dioxide / liquid CO2 View Scheme
Multi-step reaction with 7 steps 1.1: magnesium chloride / 2-methoxy-ethanol / 6 h / 125 °C / Reflux 2.1: sodium hydroxide; water / ethanol / 2 h / Reflux 3.1: copper chromite / quinoline / 2 h / 185 °C 4.1: diethyl ether / 0 °C 4.2: -78 - 20 °C 5.1: potassium tert-butylate / tetrahydrofuran / 2.5 h / 0 °C 6.1: magnesium; methanol / 0.67 h / Inert atmosphere; Reflux 7.1: CHIRALPAK® AD column / methanol; carbon dioxide / liquid CO2 View Scheme
Multi-step reaction with 8 steps 1.1: magnesium chloride / 2-methoxy-ethanol / 6 h / 125 °C / Reflux 2.1: sodium hydroxide; water / ethanol / 2 h / Reflux 3.1: copper chromite / quinoline / 2 h / 185 °C 4.1: diethyl ether / 0 °C 4.2: -78 - 20 °C 5.1: potassium tert-butylate / tetrahydrofuran / 2.5 h / 0 °C 6.1: palladium 10% on activated carbon; hydrogen / methanol / 48 h / 20 °C / 760.05 Torr 7.1: potassium tert-butylate / tert-butyl alcohol / 16 h / 50 °C 8.1: CHIRALPAK® AD column / methanol; carbon dioxide / liquid CO2 View Scheme
Multi-step reaction with 8 steps 1.1: magnesium chloride / 2-methoxy-ethanol / 6 h / 125 °C / Reflux 2.1: sodium hydroxide; water / ethanol / 2 h / Reflux 3.1: copper chromite / quinoline / 2 h / 185 °C 4.1: diethyl ether / 0 °C 4.2: -78 - 20 °C 5.1: potassium tert-butylate / tetrahydrofuran / 2.5 h / 0 °C 6.1: zinc; mercury dichloride; hydrogenchloride / ethanol / Reflux 7.1: potassium tert-butylate / tert-butyl alcohol / 16 h / 50 °C 8.1: CHIRALPAK® AD column / methanol; carbon dioxide / liquid CO2 View Scheme

5,6-dihydro-4H-pyrrolo [3,2,1-ij]quinoline-1-carboxylic acid ethyl ester (124730-53-6) → (+)-3(S),4(S)-3-(5,6-dihydro-4H-pyrrolo[3,2,1-j]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione (905854-03-7) + Tivantinib (905854-02-6)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: sodium hydroxide; water / ethanol / 2 h / Reflux 2.1: copper chromite / quinoline / 2 h / 185 °C 3.1: diethyl ether / 0 °C 3.2: -78 - 20 °C 4.1: potassium tert-butylate / tetrahydrofuran / 2.5 h / 0 °C 5.1: zinc; mercury dichloride; hydrogenchloride / ethanol / Reflux 6.1: CHIRALPAK® AD column / methanol; carbon dioxide / liquid CO2 View Scheme
Multi-step reaction with 6 steps 1.1: sodium hydroxide; water / ethanol / 2 h / Reflux 2.1: copper chromite / quinoline / 2 h / 185 °C 3.1: diethyl ether / 0 °C 3.2: -78 - 20 °C 4.1: potassium tert-butylate / tetrahydrofuran / 2.5 h / 0 °C 5.1: magnesium; methanol / 0.67 h / Inert atmosphere; Reflux 6.1: CHIRALPAK® AD column / methanol; carbon dioxide / liquid CO2 View Scheme
Multi-step reaction with 7 steps 1.1: sodium hydroxide; water / ethanol / 2 h / Reflux 2.1: copper chromite / quinoline / 2 h / 185 °C 3.1: diethyl ether / 0 °C 3.2: -78 - 20 °C 4.1: potassium tert-butylate / tetrahydrofuran / 2.5 h / 0 °C 5.1: palladium 10% on activated carbon; hydrogen / methanol / 48 h / 20 °C / 760.05 Torr 6.1: potassium tert-butylate / tert-butyl alcohol / 16 h / 50 °C 7.1: CHIRALPAK® AD column / methanol; carbon dioxide / liquid CO2 View Scheme
Multi-step reaction with 7 steps 1.1: sodium hydroxide; water / ethanol / 2 h / Reflux 2.1: copper chromite / quinoline / 2 h / 185 °C 3.1: diethyl ether / 0 °C 3.2: -78 - 20 °C 4.1: potassium tert-butylate / tetrahydrofuran / 2.5 h / 0 °C 5.1: zinc; mercury dichloride; hydrogenchloride / ethanol / Reflux 6.1: potassium tert-butylate / tert-butyl alcohol / 16 h / 50 °C 7.1: CHIRALPAK® AD column / methanol; carbon dioxide / liquid CO2 View Scheme

3-(1-allyl-7-bromo-1H-indol-3-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione → (+)-3(S),4(S)-3-(5,6-dihydro-4H-pyrrolo[3,2,1-j]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione (905854-03-7) + Tivantinib (905854-02-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: tetrakis(triphenylphosphine) palladium(0); 9-bora-bicyclo[3.3.1]nonane 2: CHIRALPAK® AD column / methanol; carbon dioxide / liquid CO2 View Scheme

5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1-carboxylic acid (124730-56-9) → (+)-3(S),4(S)-3-(5,6-dihydro-4H-pyrrolo[3,2,1-j]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione (905854-03-7) + Tivantinib (905854-02-6)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: copper chromite / quinoline / 2 h / 185 °C 2.1: diethyl ether / 0 °C 2.2: -78 - 20 °C 3.1: potassium tert-butylate / tetrahydrofuran / 2.5 h / 0 °C 4.1: magnesium; methanol / 0.67 h / Inert atmosphere; Reflux 5.1: CHIRALPAK® AD column / methanol; carbon dioxide / liquid CO2 View Scheme
Multi-step reaction with 5 steps 1.1: copper chromite / quinoline / 2 h / 185 °C 2.1: diethyl ether / 0 °C 2.2: -78 - 20 °C 3.1: potassium tert-butylate / tetrahydrofuran / 2.5 h / 0 °C 4.1: zinc; mercury dichloride; hydrogenchloride / ethanol / Reflux 5.1: CHIRALPAK® AD column / methanol; carbon dioxide / liquid CO2 View Scheme
Multi-step reaction with 6 steps 1.1: copper chromite / quinoline / 2 h / 185 °C 2.1: diethyl ether / 0 °C 2.2: -78 - 20 °C 3.1: potassium tert-butylate / tetrahydrofuran / 2.5 h / 0 °C 4.1: palladium 10% on activated carbon; hydrogen / methanol / 48 h / 20 °C / 760.05 Torr 5.1: potassium tert-butylate / tert-butyl alcohol / 16 h / 50 °C 6.1: CHIRALPAK® AD column / methanol; carbon dioxide / liquid CO2 View Scheme
Multi-step reaction with 6 steps 1.1: copper chromite / quinoline / 2 h / 185 °C 2.1: diethyl ether / 0 °C 2.2: -78 - 20 °C 3.1: potassium tert-butylate / tetrahydrofuran / 2.5 h / 0 °C 4.1: zinc; mercury dichloride; hydrogenchloride / ethanol / Reflux 5.1: potassium tert-butylate / tert-butyl alcohol / 16 h / 50 °C 6.1: CHIRALPAK® AD column / methanol; carbon dioxide / liquid CO2 View Scheme

5,6-dihydro-4H-pyrrolo-[3,2,1-ij]quinoline (5840-01-7) → (+)-3(S),4(S)-3-(5,6-dihydro-4H-pyrrolo[3,2,1-j]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione (905854-03-7) + Tivantinib (905854-02-6)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: diethyl ether / 0 °C 1.2: -78 - 20 °C 2.1: potassium tert-butylate / tetrahydrofuran / 2.5 h / 0 °C 3.1: magnesium; methanol / 0.67 h / Inert atmosphere; Reflux 4.1: CHIRALPAK® AD column / methanol; carbon dioxide / liquid CO2 View Scheme
Multi-step reaction with 4 steps 1.1: diethyl ether / 0 °C 1.2: -78 - 20 °C 2.1: potassium tert-butylate / tetrahydrofuran / 2.5 h / 0 °C 3.1: zinc; mercury dichloride; hydrogenchloride / ethanol / Reflux 4.1: CHIRALPAK® AD column / methanol; carbon dioxide / liquid CO2 View Scheme
Multi-step reaction with 5 steps 1.1: diethyl ether / 0 °C 1.2: -78 - 20 °C 2.1: potassium tert-butylate / tetrahydrofuran / 2.5 h / 0 °C 3.1: palladium 10% on activated carbon; hydrogen / methanol / 48 h / 20 °C / 760.05 Torr 4.1: potassium tert-butylate / tert-butyl alcohol / 16 h / 50 °C 5.1: CHIRALPAK® AD column / methanol; carbon dioxide / liquid CO2 View Scheme
Multi-step reaction with 5 steps 1.1: diethyl ether / 0 °C 1.2: -78 - 20 °C 2.1: potassium tert-butylate / tetrahydrofuran / 2.5 h / 0 °C 3.1: zinc; mercury dichloride; hydrogenchloride / ethanol / Reflux 4.1: potassium tert-butylate / tert-butyl alcohol / 16 h / 50 °C 5.1: CHIRALPAK® AD column / methanol; carbon dioxide / liquid CO2 View Scheme

(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)oxoacetic acid methyl ester (345264-02-0) → (+)-3(S),4(S)-3-(5,6-dihydro-4H-pyrrolo[3,2,1-j]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione (905854-03-7) + Tivantinib (905854-02-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: potassium tert-butylate / tetrahydrofuran / 2.5 h / 0 °C 2: magnesium; methanol / 0.67 h / Inert atmosphere; Reflux 3: CHIRALPAK® AD column / methanol; carbon dioxide / liquid CO2 View Scheme
Multi-step reaction with 3 steps 1: potassium tert-butylate / tetrahydrofuran / 2.5 h / 0 °C 2: zinc; mercury dichloride; hydrogenchloride / ethanol / Reflux 3: CHIRALPAK® AD column / methanol; carbon dioxide / liquid CO2 View Scheme
Multi-step reaction with 4 steps 1: potassium tert-butylate / tetrahydrofuran / 2.5 h / 0 °C 2: palladium 10% on activated carbon; hydrogen / methanol / 48 h / 20 °C / 760.05 Torr 3: potassium tert-butylate / tert-butyl alcohol / 16 h / 50 °C 4: CHIRALPAK® AD column / methanol; carbon dioxide / liquid CO2 View Scheme
Multi-step reaction with 4 steps 1: potassium tert-butylate / tetrahydrofuran / 2.5 h / 0 °C 2: zinc; mercury dichloride; hydrogenchloride / ethanol / Reflux 3: potassium tert-butylate / tert-butyl alcohol / 16 h / 50 °C 4: CHIRALPAK® AD column / methanol; carbon dioxide / liquid CO2 View Scheme

3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dion (345261-20-3) → (+)-3(S),4(S)-3-(5,6-dihydro-4H-pyrrolo[3,2,1-j]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione (905854-03-7) + Tivantinib (905854-02-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: magnesium; methanol / 0.67 h / Inert atmosphere; Reflux 2: CHIRALPAK® AD column / methanol; carbon dioxide / liquid CO2 View Scheme
Multi-step reaction with 2 steps 1: zinc; mercury dichloride; hydrogenchloride / ethanol / Reflux 2: CHIRALPAK® AD column / methanol; carbon dioxide / liquid CO2 View Scheme
Multi-step reaction with 3 steps 1: zinc; mercury dichloride; hydrogenchloride / ethanol / Reflux 2: potassium tert-butylate / tert-butyl alcohol / 16 h / 50 °C 3: CHIRALPAK® AD column / methanol; carbon dioxide / liquid CO2 View Scheme
Multi-step reaction with 3 steps 1: palladium 10% on activated carbon; hydrogen / methanol / 48 h / 20 °C / 760.05 Torr 2: potassium tert-butylate / tert-butyl alcohol / 16 h / 50 °C 3: CHIRALPAK® AD column / methanol; carbon dioxide / liquid CO2 View Scheme

Tivantinib (905854-02-6) → (3R,4R)-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-5-thioxo-pyrrolidin-2-one (1094609-99-0) + (3R,4R)-4-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-3-(1H-indol-3-yl)-5-thioxo-pyrrolidin-2-one (1094609-98-9)

Conditions	Yield
With Lawessons reagent In tetrahydrofuran for 17h; Heating / reflux;

Tivantinib (905854-02-6) → 1-[(3R,4R)-4-(1H-indol-3-yl)-pyrrolidin-3-yl]-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline (1094610-07-7)

Conditions	Yield
Stage #1: Tivantinib With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 60℃; Stage #2: With hydrogenchloride; water In tetrahydrofuran at 0℃; pH=< 2; Stage #3: With 2-chloro-1-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-ethanone; water In tetrahydrofuran pH=> 9;

Upstream product

• 345261-20-3 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dion 
• 345264-02-0 (5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)oxoacetic acid methyl ester 
• 5840-01-7 5,6-dihydro-4H-pyrrolo-[3,2,1-ij]quinoline 
• 124730-56-9 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1-carboxylic acid 
• 124730-53-6 5,6-dihydro-4H-pyrrolo [3,2,1-ij]quinoline-1-carboxylic acid ethyl ester 
• 152712-44-2 3-(3,4-dihydro-2H-quinolin-1-yl)-2-oxopropionic acid ethyl ester 
• 635-46-1 1,2,3,4-tetrahydroisoquinoline 
• 1313508-66-5 (3R,4R)-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione pseudoephedrine complex 
• 1000873-98-2 (±)-cis-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione 
• 905854-03-7 (+)-3(S),4(S)-3-(5,6-dihydro-4H-pyrrolo[3,2,1-j]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione 
• 1000873-98-2 (±)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione 

Relevant articles and documents

COMBINATIONAL COMPOSITIONS AND METHODS FOR TREATMENT OF CANCER

The present invention provides methods of treating a cell proliferative disorder, such as a cancer, by administering to a subject in need thereof a therapeutically effective amount of a pyrroloquinolinyl-pyrrole-2,5-dione compound or a pyrroloquinolinyl-pyrrolidine-2,5-dione compound in combination with a therapeutically effective amount of a second anti-proliferative agent.

Purified Pyrroloquinolinyl-Pyrrolidine-2,5-Dione Compositions And Methods For Preparing And Using Same

The present invention relates to a form 1 and form 2 polymorph of (?)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione. The present invention also relates to (?)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinol