283173-50-2

Usage

Uses

1. Used in Pharmaceutical Industry:
8-FLUOR-2-4-[(METHYLAMINO)METHYL]FENYL-1,3,4,5-TETRAHYDRO-6HAZEPINO[5,4,3-CD]INDOOL-6-ON is used as a pharmaceutical compound for its potential therapeutic effects. 8-FLUOR-2-4-[(METHYLAMINO)METHYL]FENYL-1,3,4,5-TETRAHYDRO-6HAZEPINO[5,4,3-CD]INDOOL-6-ON's unique structure may allow it to interact with specific biological targets, making it a candidate for the development of new drugs.
2. Used in Chemical Research:
8-FLUOR-2-4-[(METHYLAMINO)METHYL]FENYL-1,3,4,5-TETRAHYDRO-6HAZEPINO[5,4,3-CD]INDOOL-6-ON is used as a research tool in chemical screening to identify drugs that enhance or mitigate cellular responses to various stimuli. Its unique chemical properties make it a valuable compound for studying the mechanisms of cellular responses and developing targeted therapies.
3. Used in Material Science:
8-FLUOR-2-4-[(METHYLAMINO)METHYL]FENYL-1,3,4,5-TETRAHYDRO-6HAZEPINO[5,4,3-CD]INDOOL-6-ON may also find applications in material science due to its potential to form novel materials with specific properties. 8-FLUOR-2-4-[(METHYLAMINO)METHYL]FENYL-1,3,4,5-TETRAHYDRO-6HAZEPINO[5,4,3-CD]INDOOL-6-ON's structure could be exploited to create new materials with applications in various industries, such as electronics, coatings, or adhesives.

Mechanism of action

Rucaparib inhibits "the contraction of isolated vascular smooth muscle, including that from the tumours of cancer patients. It also reduces the migration of some cancer and normal cells in culture." As a PARP inhibitor, rucaparib is expected to be more effective in the 9% of pancreatic cancers with a BRCA mutation (BRCA1 or BRCA2).

Synthesis

Synthesis of rucaparib camsylate begins from commercially available phthalimide acetal 151. Unveiling of the aldehyde via treatment with aqueous HCl and precipitation from toluene provided aldehyde 152 in 62% yield. To avoid polymerization, 152 was immediately subjected to 6-fluoro-1Hindole- 4-carboxylic acid methyl ester (153) under reductive conditions in the presence of acid to give rise to tryptamine derivative 154. After considerable research, optimal conditions for this transformation (triethylsilane in DCM/TFA) were found that were successful on up to 15.7 kg scale, enabling clean separation of the aldehyde reduction byproduct following crystallization. Conversion of the phthalimide within 154 to the corresponding amine using aqueous methylamine at room temperature was accompanied by an intramolecular cyclization reaction to secure the intermediate lactam as a solid in 89% isolated yield. This was followed by a high-yielding bromination reaction (83%) at the indole C-2 position employing pyridinium tribromide, providing access to indoloazepinone 155. After screening various catalysts for the coupling of bromide 155 and commercial boronic acid 156, Pd(dppf)Cl2· DCM was found to reliably deliver the desired coupling product with reasonable rates of reaction. Thus, after development of an extensively optimized reaction protocol, Suzuki coupling of 155 and 4-formylphenylboronic acid (156) with Pd(dppf)Cl2·DCM and Na2CO3 in DMA at 90 °C generated the desired 2-arylated indole 157 in high yield (92%) after trituration and reslurry with methanol. Conversion of aldehyde 157 to amine 158 necessitated a two-pot procedure designed to limit the formation of dimerization and aldehyde reduction products that generally arise under conventional onepot reductive amination conditions and have traditionally been problematic on scale. Toward this end, subjection of aldehyde 157 to a methylamine solution in EtOH/MeOH/THF and wash of the resulting reaction solids with methanol led to efficient isolation of pure imine intermediate, which could be immediately reduced with NaBH4 in THF/MeOH, providing hydrochloride salt 158 upon acidic workup in 76% over two steps. The two remaining steps for conversion to the drug involve a salt-swap, first breaking the HCl salt with NaOH in MeOH, then treatment with (S)-camphorsulfonic acid/IPA/ H2O at 70 °C. Filtration and washing of the cake with water generated rucaparib camsylate (XVII) in 95% yield.

Synthetic route

C19H16FN3O → Rucaparib (283173-50-2)

Conditions	Yield
Stage #1: C19H16FN3O With sodium tetrahydroborate In ethanol for 1h; Stage #2: With sodium hydroxide In water at 10℃; for 2h;	90.83%
With palladium 10% on activated carbon; hydrogen for 12h; Reagent/catalyst;	84%
Multi-step reaction with 2 steps 1.1: sodium tetrahydroborate / methanol; tetrahydrofuran / 3 h / 0 - 20 °C / Large scale 1.2: 1 h / Large scale 1.3: 18 h / Large scale 2.1: sodium hydroxide / methanol; water; tetrahydrofuran / 18 h / 20 °C / Large scale View Scheme
Multi-step reaction with 2 steps 1.1: sodium tetrahydroborate; methanol / tetrahydrofuran / 2 h / 0 - 20 °C 1.2: 2 h 2.1: sodium hydroxide / water; methanol / 12 h / 0 - 5 °C View Scheme

[4-(8-fluoro-6-oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-2-yl)-benzyl]-methyl-carbamic acid methyl ester (880160-69-0) → Rucaparib (283173-50-2)

Conditions	Yield
With hydrogen bromide; acetic acid at 20℃; for 12h;	89.7%
Stage #1: [4-(8-fluoro-6-oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-2-yl)-benzyl]-methyl-carbamic acid methyl ester With hydrogen bromide; acetic acid at 20℃; for 46h; Stage #2: With sodium hydroxide In water at 0 - 35℃; pH=10;	88%

tert-butyl (4-(6-(tert-butyl)-8-fluoro-2-(4-methoxybenzyl)-1-oxo-2,3,4,6-tetrahydro-1H-azepino[5,4,3-cd]indol-5-yl)benzyl)(methyl)carbamate → Rucaparib (283173-50-2)

Conditions	Yield
With trifluoroacetic acid at 100℃; for 24h; Sealed tube;	88%

C35H40FN3O4 → Rucaparib (283173-50-2)

Conditions	Yield
With diphenylether; trifluoroacetic acid at 100℃; for 24h;	88%

C27H24FN3O3 → Rucaparib (283173-50-2)

Conditions	Yield
With palladium on activated charcoal; hydrogen In ethanol; ethyl acetate at 20℃; for 2h;	87.4%

4-(8-fluoro-6-oxo-3,4,5,6-tetrahydro-1H-aza-[5,4,3-cd]indol-2-yl)benzyl(methyl)benzyl amine → Rucaparib (283173-50-2)

Conditions	Yield
With palladium on activated charcoal; hydrogen In tetrahydrofuran; ethanol at 20℃; for 2h;	86.8%

8-fluoro-2-((4-methylaminomethyl)phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one hydrochloride (773059-19-1) → Rucaparib (283173-50-2)

Conditions	Yield
With sodium hydroxide In tetrahydrofuran; methanol; water at 20℃; for 18h; Large scale;	84%

4-(8-fluoro-6-oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd] indol-2-yl)-benzaldehyde (283173-84-2) + methylamine (74-89-5) → Rucaparib (283173-50-2)

Conditions	Yield
Stage #1: 4-(8-fluoro-6-oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd] indol-2-yl)-benzaldehyde; methylamine In methanol at 20℃; for 2h; Stage #2: With sodium tetrahydroborate In tetrahydrofuran; methanol at 0 - 20℃;	66%

4-(8-fluoro-6-oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd] indol-2-yl)-benzaldehyde (283173-84-2) + 2-phenyl-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-6-one (283172-68-9) → Rucaparib (283173-50-2)

Conditions	Yield
With methylamine

4-(8-fluoro-6-oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd] indol-2-yl)-benzaldehyde (283173-84-2) → Rucaparib (283173-50-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: hydrogenchloride; sodium cyanoborohydride / methanol; water; tetrahydrofuran; ethanol / Large scale 2: sodium hydroxide / methanol; water; tetrahydrofuran / 18 h / 20 °C / Large scale View Scheme
Multi-step reaction with 3 steps 1.1: methanol; tetrahydrofuran; ethanol / 2 h / Large scale 2.1: sodium tetrahydroborate / methanol; tetrahydrofuran / 3 h / 0 - 20 °C / Large scale 2.2: 1 h / Large scale 2.3: 18 h / Large scale 3.1: sodium hydroxide / methanol; water; tetrahydrofuran / 18 h / 20 °C / Large scale View Scheme
Multi-step reaction with 3 steps 1.1: methanol; tetrahydrofuran / 2 h / 0 - 20 °C 2.1: sodium tetrahydroborate; methanol / tetrahydrofuran / 2 h / 0 - 20 °C 2.2: 2 h 3.1: sodium hydroxide / water; methanol / 12 h / 0 - 5 °C View Scheme
Multi-step reaction with 2 steps 1.1: toluene-4-sulfonic acid / ethanol / 2 h / 10 °C 2.1: sodium tetrahydroborate / ethanol / 1 h 2.2: 2 h / 10 °C View Scheme

3-(2-(phthalimido)ethyl)-6-fluoro-1H-indole-4-carboxylic acid methyl ester (1408282-25-6) → Rucaparib (283173-50-2)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: methylamine / water / 17 h / 20 °C / Large scale 2.1: pyridinium hydrobromide perbromide / tetrahydrofuran; dichloromethane / 1 h / 0 - 5 °C / Large scale 3.1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / N,N-dimethyl acetamide / 2 h / 20 - 95 °C / Large scale 3.2: 9 h / 20 °C / Large scale 4.1: hydrogenchloride; sodium cyanoborohydride / methanol; water; tetrahydrofuran; ethanol / Large scale 5.1: sodium hydroxide / methanol; water; tetrahydrofuran / 18 h / 20 °C / Large scale View Scheme
Multi-step reaction with 6 steps 1.1: methylamine / water / 17 h / 20 °C / Large scale 2.1: pyridinium hydrobromide perbromide / tetrahydrofuran; dichloromethane / 1 h / 0 - 5 °C / Large scale 3.1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / N,N-dimethyl acetamide / 2 h / 20 - 95 °C / Large scale 3.2: 9 h / 20 °C / Large scale 4.1: methanol; tetrahydrofuran; ethanol / 2 h / Large scale 5.1: sodium tetrahydroborate / methanol; tetrahydrofuran / 3 h / 0 - 20 °C / Large scale 5.2: 1 h / Large scale 5.3: 18 h / Large scale 6.1: sodium hydroxide / methanol; water; tetrahydrofuran / 18 h / 20 °C / Large scale View Scheme
Multi-step reaction with 5 steps 1.1: methylamine / water / 24 h / 0 - 20 °C 2.1: pyridinium hydrobromide perbromide; sodium carbonate / dichloromethane; tetrahydrofuran / 1 h / 10 - 20 °C 3.1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / N,N-dimethyl acetamide / 1 h / 20 - 95 °C / Inert atmosphere 3.2: 2 h / 20 - 98 °C / Inert atmosphere 4.1: tetrahydrofuran; methanol; ethanol / 12 h / 25 - 33 °C 5.1: palladium 10% on activated carbon; hydrogen / 12 h View Scheme

6-fluoro-3,10-diazatricyclo[6.4.1.04,13]trideca-1,4(13),5,7-tetraen-9-one (1408282-26-7) → Rucaparib (283173-50-2)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: pyridinium hydrobromide perbromide / tetrahydrofuran; dichloromethane / 1 h / 0 - 5 °C / Large scale 2.1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / N,N-dimethyl acetamide / 2 h / 20 - 95 °C / Large scale 2.2: 9 h / 20 °C / Large scale 3.1: hydrogenchloride; sodium cyanoborohydride / methanol; water; tetrahydrofuran; ethanol / Large scale 4.1: sodium hydroxide / methanol; water; tetrahydrofuran / 18 h / 20 °C / Large scale View Scheme
Multi-step reaction with 5 steps 1.1: pyridinium hydrobromide perbromide / tetrahydrofuran; dichloromethane / 1 h / 0 - 5 °C / Large scale 2.1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / N,N-dimethyl acetamide / 2 h / 20 - 95 °C / Large scale 2.2: 9 h / 20 °C / Large scale 3.1: methanol; tetrahydrofuran; ethanol / 2 h / Large scale 4.1: sodium tetrahydroborate / methanol; tetrahydrofuran / 3 h / 0 - 20 °C / Large scale 4.2: 1 h / Large scale 4.3: 18 h / Large scale 5.1: sodium hydroxide / methanol; water; tetrahydrofuran / 18 h / 20 °C / Large scale View Scheme
Multi-step reaction with 3 steps 1.1: Pyr·HBr3 / tetrahydrofuran; dichloromethane / 2 h / 0 - 20 °C 2.1: tetrakis(triphenylphosphine) palladium(0); sodium carbonate / 1,4-dioxane / 12 h / 90 °C 3.1: methanol / 2 h / 20 °C 3.2: 0 - 20 °C View Scheme

2-bromo-8-fluoro-1,3,4,5-tetrahydro-6H-pyrrolo[4,3,2-ef][2]benzazepin-6-one (283173-80-8) → Rucaparib (283173-50-2)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / N,N-dimethyl acetamide / 2 h / 20 - 95 °C / Large scale 1.2: 9 h / 20 °C / Large scale 2.1: hydrogenchloride; sodium cyanoborohydride / methanol; water; tetrahydrofuran; ethanol / Large scale 3.1: sodium hydroxide / methanol; water; tetrahydrofuran / 18 h / 20 °C / Large scale View Scheme
Multi-step reaction with 4 steps 1.1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / N,N-dimethyl acetamide / 2 h / 20 - 95 °C / Large scale 1.2: 9 h / 20 °C / Large scale 2.1: methanol; tetrahydrofuran; ethanol / 2 h / Large scale 3.1: sodium tetrahydroborate / methanol; tetrahydrofuran / 3 h / 0 - 20 °C / Large scale 3.2: 1 h / Large scale 3.3: 18 h / Large scale 4.1: sodium hydroxide / methanol; water; tetrahydrofuran / 18 h / 20 °C / Large scale View Scheme
Multi-step reaction with 2 steps 1.1: tetrakis(triphenylphosphine) palladium(0); sodium carbonate / 1,4-dioxane / 12 h / 90 °C 2.1: methanol / 2 h / 20 °C 2.2: 0 - 20 °C View Scheme

C16H17ClFNO2 → Rucaparib (283173-50-2)

Conditions

Yield

Multi-step reaction with 7 steps 1.1: aluminum (III) chloride; chloroacetyl chloride / 2 h / 20 °C 2.1: hydroxylamine hydrochloride; sodium acetate / tetrahydrofuran; methanol; water / 2 h / 50 °C 3.1: thionyl chloride / 1,4-dioxane / 6 h / 70 °C 4.1: 1,8-diazabicyclo[5.4.0]undec-7-ene; water / tetrahydrofuran / 24 h / 20 °C 5.1: Pyr·HBr3 / tetrahydrofuran; dichloromethane / 2 h / 0 - 20 °C 6.1: tetrakis(triphenylphosphine) palladium(0); sodium carbonate / 1,4-dioxane / 12 h / 90 °C 7.1: methanol / 2 h / 20 °C 7.2: 0 - 20 °C View Scheme

C16H16FNO2 → Rucaparib (283173-50-2)

Conditions

Yield

Multi-step reaction with 6 steps 1.1: hydroxylamine hydrochloride; sodium acetate / tetrahydrofuran; methanol; water / 2 h / 50 °C 2.1: thionyl chloride / 1,4-dioxane / 6 h / 70 °C 3.1: 1,8-diazabicyclo[5.4.0]undec-7-ene; water / tetrahydrofuran / 24 h / 20 °C 4.1: Pyr·HBr3 / tetrahydrofuran; dichloromethane / 2 h / 0 - 20 °C 5.1: tetrakis(triphenylphosphine) palladium(0); sodium carbonate / 1,4-dioxane / 12 h / 90 °C 6.1: methanol / 2 h / 20 °C 6.2: 0 - 20 °C View Scheme

6-fluoro-1H-indole (399-51-9) → Rucaparib (283173-50-2)

Conditions

Yield

Multi-step reaction with 10 steps 1.1: acetic anhydride; acetic acid / 48 h / 50 °C 2.1: n-butyllithium / tetrahydrofuran / 0.5 h / -78 °C 2.2: 1 h 3.1: thionyl chloride / 1,2-dichloro-ethane / 1 h / 20 °C 4.1: aluminum (III) chloride; chloroacetyl chloride / 2 h / 20 °C 5.1: hydroxylamine hydrochloride; sodium acetate / tetrahydrofuran; methanol; water / 2 h / 50 °C 6.1: thionyl chloride / 1,4-dioxane / 6 h / 70 °C 7.1: 1,8-diazabicyclo[5.4.0]undec-7-ene; water / tetrahydrofuran / 24 h / 20 °C 8.1: Pyr·HBr3 / tetrahydrofuran; dichloromethane / 2 h / 0 - 20 °C 9.1: tetrakis(triphenylphosphine) palladium(0); sodium carbonate / 1,4-dioxane / 12 h / 90 °C 10.1: methanol / 2 h / 20 °C 10.2: 0 - 20 °C View Scheme

C16H17FN2O2 → Rucaparib (283173-50-2)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: thionyl chloride / 1,4-dioxane / 6 h / 70 °C 2.1: 1,8-diazabicyclo[5.4.0]undec-7-ene; water / tetrahydrofuran / 24 h / 20 °C 3.1: Pyr·HBr3 / tetrahydrofuran; dichloromethane / 2 h / 0 - 20 °C 4.1: tetrakis(triphenylphosphine) palladium(0); sodium carbonate / 1,4-dioxane / 12 h / 90 °C 5.1: methanol / 2 h / 20 °C 5.2: 0 - 20 °C View Scheme

C16H17FN2O2 → Rucaparib (283173-50-2)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: 1,8-diazabicyclo[5.4.0]undec-7-ene; water / tetrahydrofuran / 24 h / 20 °C 2.1: Pyr·HBr3 / tetrahydrofuran; dichloromethane / 2 h / 0 - 20 °C 3.1: tetrakis(triphenylphosphine) palladium(0); sodium carbonate / 1,4-dioxane / 12 h / 90 °C 4.1: methanol / 2 h / 20 °C 4.2: 0 - 20 °C View Scheme

6-Fluoroindole-3-propionic acid (141071-78-5) → Rucaparib (283173-50-2)

Conditions

Yield

Multi-step reaction with 9 steps 1.1: n-butyllithium / tetrahydrofuran / 0.5 h / -78 °C 1.2: 1 h 2.1: thionyl chloride / 1,2-dichloro-ethane / 1 h / 20 °C 3.1: aluminum (III) chloride; chloroacetyl chloride / 2 h / 20 °C 4.1: hydroxylamine hydrochloride; sodium acetate / tetrahydrofuran; methanol; water / 2 h / 50 °C 5.1: thionyl chloride / 1,4-dioxane / 6 h / 70 °C 6.1: 1,8-diazabicyclo[5.4.0]undec-7-ene; water / tetrahydrofuran / 24 h / 20 °C 7.1: Pyr·HBr3 / tetrahydrofuran; dichloromethane / 2 h / 0 - 20 °C 8.1: tetrakis(triphenylphosphine) palladium(0); sodium carbonate / 1,4-dioxane / 12 h / 90 °C 9.1: methanol / 2 h / 20 °C 9.2: 0 - 20 °C View Scheme

C16H18FNO3 → Rucaparib (283173-50-2)

Conditions

Yield

Multi-step reaction with 8 steps 1.1: thionyl chloride / 1,2-dichloro-ethane / 1 h / 20 °C 2.1: aluminum (III) chloride; chloroacetyl chloride / 2 h / 20 °C 3.1: hydroxylamine hydrochloride; sodium acetate / tetrahydrofuran; methanol; water / 2 h / 50 °C 4.1: thionyl chloride / 1,4-dioxane / 6 h / 70 °C 5.1: 1,8-diazabicyclo[5.4.0]undec-7-ene; water / tetrahydrofuran / 24 h / 20 °C 6.1: Pyr·HBr3 / tetrahydrofuran; dichloromethane / 2 h / 0 - 20 °C 7.1: tetrakis(triphenylphosphine) palladium(0); sodium carbonate / 1,4-dioxane / 12 h / 90 °C 8.1: methanol / 2 h / 20 °C 8.2: 0 - 20 °C View Scheme

4-formylphenylboronic acid, (87199-17-5) → Rucaparib (283173-50-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: ethanol / 0 - 20 °C 2: hydrogen / ethanol / 5 h / 40 °C / 3750.38 Torr / Autoclave 3: bis(acetato)bis(triphenylphosphine)palladium(0); sodium carbonate / methanol; water / 4 h / 60 °C / Inert atmosphere View Scheme

8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one phosphate → Rucaparib (283173-50-2)

Conditions	Yield
With sodium hydroxide In water; acetone at 30℃; for 1.5h;

C8H10BNO2 → Rucaparib (283173-50-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: hydrogen / ethanol / 5 h / 40 °C / 3750.38 Torr / Autoclave 2: bis(acetato)bis(triphenylphosphine)palladium(0); sodium carbonate / methanol; water / 4 h / 60 °C / Inert atmosphere View Scheme

2-bromo-8-fluoro-1,3,4,5-tetrahydro-6H-pyrrolo[4,3,2-ef][2]benzazepin-6-one (283173-80-8) + (4-((methylamino)methyl)phenyl)boronic acid (518336-26-0) → Rucaparib (283173-50-2)

Conditions	Yield
With bis(acetato)bis(triphenylphosphine)palladium(0); sodium carbonate In methanol; water at 60℃; for 4h; Reagent/catalyst; Inert atmosphere;	6.82 g

ADDQNPWRAYLDLLFPTDTLLLDLLWC{[(2R)-1-({[(4-{6-fluoro-9-oxo-3,10-diazatricyclo[6.4.1.04,13]trideca-1,4,6,8(13)-tetraen-2-yl}phenyl)methyl](methyl)carbamoyl}oxy)propan-2-yl]sulfanyl}G → Rucaparib (283173-50-2)

Conditions	Yield
With GLUTATHIONE In aq. buffer at 37℃;

2-(4-(4-((methylamino)methyl)phenyl)but-3-yn-1-yl)isoindoline-1,3-dione → Rucaparib (283173-50-2)

Conditions

Yield

Multi-step reaction with 5 steps 1: triethylamine / dichloromethane / 18.22 h / 0 - 20 °C 2: trifluoroacetic acid; trifluorormethanesulfonic acid / water / 18 h / 20 °C 3: boron trifluoride diethyl etherate; acetic acid / 18 h / 90 °C / Inert atmosphere 4: hydrazine / ethanol; tetrahydrofuran / 9 h / 110 °C 5: 5%-palladium/activated carbon; hydrogen; hydrogenchloride / water; methanol / 18 h / 20 °C View Scheme

N-(4-(4-(1,3-dioxoisoindolin-2-yl)but-1-yn-1-yl)benzyl)-2,2,2-trifluoro-N-methylacetamide → Rucaparib (283173-50-2)

Conditions	Yield
Multi-step reaction with 4 steps 1: trifluoroacetic acid; trifluorormethanesulfonic acid / water / 18 h / 20 °C 2: boron trifluoride diethyl etherate; acetic acid / 18 h / 90 °C / Inert atmosphere 3: hydrazine / ethanol; tetrahydrofuran / 9 h / 110 °C 4: 5%-palladium/activated carbon; hydrogen; hydrogenchloride / water; methanol / 18 h / 20 °C View Scheme

N-(4-(4-(1,3-dioxoisoindolin-2-yl)butanoyl)benzyl)-2,2,2-trifluoro-N-methylacetamide → Rucaparib (283173-50-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: boron trifluoride diethyl etherate; acetic acid / 18 h / 90 °C / Inert atmosphere 2: hydrazine / ethanol; tetrahydrofuran / 9 h / 110 °C 3: 5%-palladium/activated carbon; hydrogen; hydrogenchloride / water; methanol / 18 h / 20 °C View Scheme

9-bromo-8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-pyrrolo[4,3,2-ef][2]benzazepin-6-one → Rucaparib (283173-50-2)

Conditions	Yield
With hydrogenchloride; 5%-palladium/activated carbon; hydrogen In methanol; water at 20℃; for 18h;	734 mg

N-methyl-4-bromobenzylamine (699-03-6) → Rucaparib (283173-50-2)

Conditions

Yield

Multi-step reaction with 6 steps 1.1: copper(l) iodide; caesium carbonate / 1,4-dioxane / 1.25 h / Inert atmosphere 1.2: 19 h / 80 °C / Inert atmosphere 2.1: triethylamine / dichloromethane / 18.22 h / 0 - 20 °C 3.1: trifluoroacetic acid; trifluorormethanesulfonic acid / water / 18 h / 20 °C 4.1: boron trifluoride diethyl etherate; acetic acid / 18 h / 90 °C / Inert atmosphere 5.1: hydrazine / ethanol; tetrahydrofuran / 9 h / 110 °C 6.1: 5%-palladium/activated carbon; hydrogen; hydrogenchloride / water; methanol / 18 h / 20 °C View Scheme

Rucaparib (283173-50-2) + methanesulfonic acid (75-75-2) → 8-fluoro-2-(4-methylaminomethylphenyl)-1,3,4,5-tetrahydroazepino[5,4,3-cd]indol-6-one mesylate (773059-20-4)

Conditions	Yield
In methanol	97%
In tetrahydrofuran; acetone at 50℃; Solvent;

Rucaparib (283173-50-2) + maleic acid (110-16-7) → 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one maleate salt

Conditions	Yield
In isopropyl alcohol Product distribution / selectivity;	97%

Rucaparib (283173-50-2) + [(1S)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl]methanesulfonic acid (76-26-6, 3144-16-9, 5872-08-2, 35963-20-3) → 8-fluoro-2-((4-methylaminomethyl)phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one (S)-camphorsulfonate

Conditions	Yield
In water; isopropyl alcohol at 70℃; for 1h;	95%
In methanol; water at 0 - 40℃; for 29h; Reflux;	81%

Rucaparib (283173-50-2) + 17-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12,15-pentaoxaheptadecanal → C44H51FN6O10

Conditions	Yield
With sodium tris(acetoxy)borohydride In dichloromethane at 0 - 23℃; for 2h;	90%

Rucaparib (283173-50-2) + (1S)-10-camphorsulfonic acid (3144-16-9) → 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one ((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl)methanesulfonic acid salt

Conditions	Yield
In methanol at 60 - 65℃; for 0.5h;	89.86%
In tetrahydrofuran; water for 0.833333h; Product distribution / selectivity; Reflux;
for 2.5h;
In 1,4-dioxane; water at 30℃; for 12h; Time;

Rucaparib (283173-50-2) + di-tert-butyl dicarbonate (24424-99-5) → C24H26FN3O3

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In dichloromethane at 23℃; for 0.5h;	89%

Rucaparib (283173-50-2) + 5-hexynal (29329-03-1) → C25H26FN3O

Conditions	Yield
With sodium tris(acetoxy)borohydride In dichloromethane at 23℃; for 1h; Inert atmosphere;	74%

Rucaparib (283173-50-2) + methyl 4-formylbutanoate (6026-86-4) → C24H26FN3O3

Conditions	Yield
Stage #1: Rucaparib; methyl 4-formylbutanoate With sodium tris(acetoxy)borohydride In dichloromethane at 23℃; for 1h; Inert atmosphere; Stage #2: With water; lithium hydroxide In tetrahydrofuran at 23℃; for 2h;	54%

Rucaparib (283173-50-2) + Trimethylboroxine (823-96-1) → C20H20FN3O

Conditions	Yield
With pentamethylcyclopentadienyl(benzene)cobalt(III) hexafluorophosphate; potassium carbonate; silver carbonate In 2-methyltetrahydrofuran at 100℃; for 16h; Inert atmosphere; Sealed tube;	39%

methanol (67-56-1) + Rucaparib (283173-50-2) → phosphate salt of 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one

Conditions	Yield
Stage #1: methanol; Rucaparib for 0.166667h; Stage #2: With phosphoric acid In methanol at 20℃; for 0.5h;

Rucaparib (283173-50-2) + camphor-10-sulfonic acid (76-26-6, 3144-16-9, 5872-08-2, 35963-20-3) → 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one ((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl)methanesulfonic acid salt + 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one ((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl)methanesulfonic acid salt

Conditions	Yield
In water; isopropyl alcohol at 70℃; for 0.166667h; Product distribution / selectivity;

Rucaparib (283173-50-2) + camphor-10-sulfonic acid (76-26-6, 3144-16-9, 5872-08-2, 35963-20-3) → CO-338

Conditions	Yield
In water; isopropyl alcohol at 70℃; for 0.166667h;

Rucaparib (283173-50-2) + (R)-10-camphorsulfonic acid (35963-20-3) → 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one ((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl)methanesulfonic acid salt

Conditions	Yield
In water; isopropyl alcohol at 70℃; for 0.166667h;
In ethanol at 75 - 85℃; for 3h; Solvent; Temperature;	0.25 g

Rucaparib (283173-50-2) + C27H38ClN6O4Pt(1+)*NO3(1-) → C46H54ClFN9O4Pt(1+)*NO3(1-)

Conditions	Yield
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 16h;

Rucaparib (283173-50-2) + C31H40ClN6O4Pt(1+)*NO3(1-) → C50H56ClFN9O4Pt(1+)*NO3(1-)

Conditions	Yield
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 16h;

Upstream product

• 87199-17-5 4-formylphenylboronic acid, 
• 459868-92-9 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one phosphate 
• 283173-80-8 2-bromo-8-fluoro-1,3,4,5-tetrahydro-6H-pyrrolo[4,3,2-ef][2]benzazepin-6-one 
• 518336-26-0 (4-((methylamino)methyl)phenyl)boronic acid 
• 1342359-36-7 eethyl 2-methyl-3-nitro-5-fluorobenzoate 
• 697739-03-0 5-fluoro-2-methyl-3-nitrobenzoic acid methyl ester 
• 14396-90-8 N-(3-butynyl)phthalimide 
• 699-03-6 N-methyl-4-bromobenzylamine 

Downstream Products

• 773059-20-4 8-fluoro-2-(4-methylaminomethylphenyl)-1,3,4,5-tetrahydroazepino[5,4,3-cd]indol-6-one mesylate 

Relevant academic research and scientific papers

Copper-Mediated Radiosynthesis of [18F]Rucaparib

The poly(ADP-ribose) polymerase (PARP) inhibitor rucaparib is used in the clinic to treat BRCA-mutated cancers. Herein, we report two strategies to access the 18F-isotopologue of rucaparib by applying a copper-mediated nucleophilic 18F-fluorodeboronation. The most successful approach features an aldehydic boronic ester precursor that is subjected to reductive amination post-18F-labeling and affords [18F]rucaparib with an activity yield of 11% ± 3% (n = 3) and a molar activity (Am) up to 30 GBq/μmol. Preliminary in vitro studies are presented.

Late-Stage C-H Arylation of Azepinoindole via Pd/Cu Catalysis: A Step Efficient and Convergent Synthesis of Rucaparib

The C-H arylation of indoles holds the promise to shorten synthetic routes in the production of pharmaceuticals. However, latestage C-H activation reactions often rely on the presence of protecting groups or stoichiometric metal additives. The regiospecific C-H arylation of a highly functionalized azepino[5,3,4-cd]indole scaffold lacking directing groups via Pd(II) and Cu(II) co-catalysis is reported. The direct C-H coupling was demonstrated in the convergent synthesis of rucaparib, an FDA approved anticancer drug.

Synthesis method of rucaparib camsylate

The invention relates to a synthesis method of rucaparib camsylate. The method comprises the following steps: 1) carrying out a reaction on a compound M-1 and pyridinium tribromide by using tetrahydrofuran and/or dichloromethane as a solvent to obtain a compound M-2; 2) carrying out a reaction on the compound M-2 and p-formyl phenylboronic acid under the catalytic action of 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride by using N,N-dimethylacetamide as a solvent to obtain a compound M-3, wherein the reaction temperature is higher than or equal to 90 DEG C; 3) carrying out a reaction on the compound M-3 and methylamine under the catalytic action of p-toluenesulfonic acid by using methanol and/or ethanol as a solvent, adding sodium borohydride, and reducing to obtain a compound M-4; 4) carrying out a reaction on the compound M-4 and an alkali by taking water as a solvent to obtain a compound M-5; and 5) carrying out a reaction on the compound M-5 and camphorsulfonic acid by taking methanol and/or ethanol as a solvent to obtain the rucaparib camsylate. According to the invention, the compounds M-1, M-3 and M-4 react at room temperature, the conditions are mild and controllable, the reaction period is short, the synthesis efficiency can be effectively improved, the production cost is reduced, and the purity of the obtained product reaches 99.95-99.98%.

CRYSTALLINE OF CAMPHORSULFONIC ACID SALT OF RUCAPARIB AND METHOD OF PREPARING OF TRICYCLIC COMPOUNDS, RUCAPARIB AND CRYSTALLINE OF CAMPHORSULFONIC ACID SALT OF RUCAPARIB

A method of preparing a tricyclic compound of formula (I), comprising the step of converting a compound of formula (II) into a compound of formula (III); and hydrogenating the compound of formula (III) in the presence of hydrogenation catalyst and hydrogen to form the tricyclic compound of formula (I); wherein R1 is H or a C1-3 alkyl group; and R2 is H, a halogen element or a C1-3 alkyl group.

Preparation method of 3, 4-bridged ring indole compound and synthetic method of Rucaparib

The invention relates to a preparation method of a 3, 4-bridged ring indole compound. The method comprises the following steps of: adding an o-alkyne iodobenzene derivative (1), diazacycloacetone (2),a palladium salt, a ligand, an inorganic base and an organic solvent into a reaction tube, replacing the system with inert gas, carrying out heating reaction, and then performing separating and purifying to obtain the 3, 4-bridged ring indole compound (3). The invention further provides a preparation method of a Rucaparib drug molecule capable of being used for treating ovarian cancer. The methodis efficient and simple, the traditional method of synthesizing a target product by using functionalized indole is avoided, and the method has high atomic economic effect, is greener and more environmentally friendly, the synthetic method has the characteristics of cheap and easily available raw materials, mild reaction conditions, simple operation, stable product quality, high purity and the like, and has great application value in the synthesis of physiologically active natural products and drug molecules containing 3, 4-bridged ring indole skeleton.

Synthesis of 3,4-Fused Tricyclic Indoles through Cascade Carbopalladation and C-H Amination: Development and Total Synthesis of Rucaparib

3,4-Fused tricyclic indole scaffolds are ubiquitous in bioactive natural products and pharmaceuticals. A new protocol for the synthesis of 3,4-fused tricyclic indoles has been developed through cascade carbopalladation and C-H amination with N,N-di-tert-butyldiaziridinone. The protocol allows access to a range of 3,4-fused tricyclic indoles, including those containing various linkers and fused with medium-sized rings. Rucaparib can be synthesized via this reaction, providing an advantageous synthetic method for the FDA-approved cancer medicine.

Simple and convenient production method of rucaparib

The invention relates to a simple and convenient production method of rucaparib. The method comprises the steps of conducting condensation on 5-fluoro-2-methyl-3-nitrobenzoate and 4-(N-methyl-N-PG-aminomethyl)benzoate under the action of an alkaline, subjecting an obtained condensation product and ethylene oxide to a hydroxyethylation reaction, carrying out sulfonyl chloride protection and catalytic hydrogenation indole cyclization to produce 2-(4-methylaminomethyl)phenyl-3-(2-sulphonate)ethyl-6-fluoro-1H-indole-4-formate, and then subjecting the 2-(4-methylaminomethyl)phenyl-3-(2-sulphonate)ethyl-6-fluoro-1H-indole-4-formate and ammonia to an SN2 substitution reaction and an amidation reaction to produce the rucaparib through a one-pot method. The raw materials of the method are cheap andeasy to obtain, and the method is short in technology process, simple and convenient to operate, little in wastewater quantity and environmentally friendly, and benefits industrial production of rucaparib.

PROCESS FOR THE PREPARATION OF RUCAPARIB AND NOVEL SYNTHESIS INTERMEDIATES

The present invention relates to a process for the preparation of rucaparib; the invention also refers to novel intermediates of synthesis as well as their use in the preparation of i.a. rucaparib.

COMPOUNDS, COMPOSITIONS, AND METHODS FOR TREATMENT OF DISEASES INVOLVING ACIDIC OR HYPOXIC DISEASED TISSUES

Compounds for treatment of diseases having acidic or hypoxic diseased tissues and pharmaceutical compositions comprising the compounds, as well as methods for making and using the compounds and compositions.

POLYMORPHS OF RUCAPARIB CAMSYLATE AND METHODS OF MAKING SAME

Novel polymorphs of rucaparib camsylate include Form alpha having XRPD peaks at diffraction angles (2θ) of 6.14±0.2, 12.41±0.2, 15.34±0.2, 15.95±0.2, 16.36±0.2, 16.51±0.2 and 19.67±0.2, Form beta having XRPD peaks at diffraction angles (2θ) of 6.86±0.2, 9.58±0.2, 12.75±0.2, 14.56±0.2, 15.05±0.2, 20.76±0.2 and 22.45±0.2, and Form gamma having XRPD peaks at diffraction angles (2θ) of 9.5±0.2, 12.73±0.2, 14.77±0.2, 15.16±0.2, 20.62±0.2, 22.33±0.2, 22.63±0.2 and 27.29±0.2. Methods are disclosed for the preparation of such polymorphic forms and pharmaceutical compositions containing such polymorphic forms. A method is disclosed for preparing a highly pure Form B of rucaparib camsylate. Pharmaceutical compositions containing highly pure Form B prepared by the method are disclosed.