- Copper-Mediated Radiosynthesis of [18F]Rucaparib
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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.
- Chen, Zijun,Destro, Gianluca,Guibbal, Florian,Chan, Chung Ying,Cornelissen, Bart,Gouverneur, Véronique
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p. 7290 - 7294
(2021/09/14)
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- Late-Stage C-H Arylation of Azepinoindole via Pd/Cu Catalysis: A Step Efficient and Convergent Synthesis of Rucaparib
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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.
- Beckers, Igor,De Vos, Dirk,O'Rourke, Galahad
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- Synthesis method of rucaparib camsylate
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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%.
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- CRYSTALLINE OF CAMPHORSULFONIC ACID SALT OF RUCAPARIB AND METHOD OF PREPARING OF TRICYCLIC COMPOUNDS, RUCAPARIB AND CRYSTALLINE OF CAMPHORSULFONIC ACID SALT OF RUCAPARIB
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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.
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- Preparation method of 3, 4-bridged ring indole compound and synthetic method of Rucaparib
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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.
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Paragraph 0045; 0050
(2020/09/20)
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- Synthesis of 3,4-Fused Tricyclic Indoles through Cascade Carbopalladation and C-H Amination: Development and Total Synthesis of Rucaparib
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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.
- Cheng, Cang,Zuo, Xiang,Tu, Dongdong,Wan, Bin,Zhang, Yanghui
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supporting information
p. 4985 - 4989
(2020/07/04)
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- POLYMORPHS OF RUCAPARIB CAMSYLATE AND METHODS OF MAKING SAME
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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.
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- Simple and convenient production method of rucaparib
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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.
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- NOVEL CRYSTALLINE FORMS OF RUCAPARIB (S)-CAMSYLATE SALT AND RUCAPARIB FREE BASE
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The present invention provides, crystalline Form M1, Form M2 and Form M3 of Rucaparib (S)-camsylate salt. It also provides crystalline Form M1, Form M2, Form M3, Form M4 and Form M5 of Rucaparib and processes for the preparation of the same.
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Page/Page column 15
(2019/11/12)
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- Preparation method ofdrug Rucaparib for treating ovarian cancer
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The invention discloses a preparation method of drug Rucaparib for treating an ovarian cancer. The method comprises the following steps that step 1, a compound A and a compound B with a PG protectinggroup are acylated in an organic solvent a under the action of an acid binding agent, and a compound of a formula I is prepared; step 2, an enamine bond of the compound of the formula I is hydrolyzedin an aqueous organic solvent b under the action of acid c to obtain a compound of a formula II; step 3, after the reduction of a nitro group to an amino group of the compound of formula II under theaction of a reducing agent, cyclodehydration is conducted to obtain a compound of a formula III; step 4, the compound of the formula III and N-(2-acetaldehyde) phthalimide are condensed under the action of acid d to obtain a compound of a formula IV; step 5, the compound of the formula IV is cyclized to obtain a compound of a formula V while removing the phthaloyl protecting group; step 6, the PGprotecting group of the compound of the formula V is removed to obtain the Rucaparib. The method reduces the cost of producing the drug Rucaparib for treating the ovarian cancer.
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- PROCESS FOR THE PREPARATION OF RUCAPARIB AND NOVEL SYNTHESIS INTERMEDIATES
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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.
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- COMPOUNDS, COMPOSITIONS, AND METHODS FOR TREATMENT OF DISEASES INVOLVING ACIDIC OR HYPOXIC DISEASED TISSUES
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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.
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Page/Page column 136; 137
(2019/07/20)
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- Poly(ADP-ribose) Polymerase in Neurodegeneration: Radiosynthesis and Radioligand Binding in ARC-SWE tg Mice
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We report the synthesis, radiosynthesis, and characterization of a radioligand for poly(ADP-ribose) polymerase (PARP). PARP is of central importance in cell homeostasis, neuroplasticity, and neurodegeneration in the brain. A radiolabeled PARP inhibitor was developed and used for autoradiographic quantification of PARP protein concentration in wild-type and transgenic rodent brains ex vivo in high resolution. The binding of [3H]rucaparib was found to be confined to PARP-expressing domains, for example, cerebellar cortex or hippocampal regions in both models. Saturation binding experiments confirmed selective and reversible binding to a single site (Kd = 1.1 ± 0.2 nM).
- Alluri, Santosh R.,Riss, Patrick J.
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p. 1259 - 1263
(2018/06/26)
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- SOLID STATE FORMS OF RUCAPARIB AND OF RUCAPARIB SALTS
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Disclosed are solid state forms of Rucaparib and of Rucaparib salts, and pharmaceutical compositions thereof.
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- Multkilogram scale-up of a reductive alkylation route to a novel PARP inhibitor
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Novel PARP inhibitor 1 is a promising new candidate for treatment of breast and ovarian cancer. A modified synthetic route to 1 has been developed and demonstrated on 7 kg scale. In order to scale up the synthesis to multikilogram scale, several synthetic challenges needed to be overcome. The key issues included significant thermal hazards present in a Leimgruber-Batcho indole synthesis, a low-yielding side-chain installation, a nonrobust Suzuki coupling and hydrogen cyanide generation during a reductive amination. In addition to these issues, changing from intravenous to oral delivery required a new salt form and therefore a new crystallization procedure. This contribution describes development work to solve these issues and scaling up of the new process in the pilot plant.
- Gillmore, Adam T.,Badland, Matthew,Crook, Clare L.,Castro, Nieves M.,Critcher, Douglas J.,Fussell, Steven J.,Jones, Katherine J.,Jones, Matthew C.,Kougoulos, Eleftherios,Mathew, Jinu S.,McMillan, Lynne,Pearce, John E.,Rawlinson, Fiona L.,Sherlock, Alexandra E.,Walton, Robert
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p. 1897 - 1904
(2013/03/13)
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- Method of preparing poly(ADP-ribose) polymerases inhibitors
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This invention relates to a new and convergent route to small molecule inhibitors of poly(ADP-ribose) polymerase, such as 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one, via a key Sonogashira coupling reaction and a CuI-promoted indole formation.
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Page/Page column 6; 11
(2010/10/20)
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- Tricyclic inhibitors of poly(ADP-ribose) polymerases
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Compounds of the formula below are poly(ADP-ribosyl)transferase (PARP) inhibitors, and are useful as therapuetics in treatment of cancers and the amelioration of the effects of stroke, head trauma, and nuerodegenerative disease. STR1As cancer therapuetics, the compounds of the invention may be used, e.g., in combination with cytotoxic agents and/or radiation.
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