763114-26-7Relevant articles and documents
Novel preparation method of olaparib
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Paragraph 0020; 0024, (2021/08/11)
The invention relates to a novel preparation method of olaparib. The novel preparation method comprises the following preparation steps: 1, reacting 4-methylphthalazin-1(2H)-one with NBS and AIBN in a reaction solvent; 2, carrying out a coupling reaction on 4-(bromomethyl)phthalazin-1(2H)-one and (4-fluoro-3-(methoxycarbonyl)phenyl)boric acid in a reaction solvent under the action of a catalyst and an alkali; 3, hydrolyzing methyl 2-fluoro-5-((4-oxo-3, 4-phthalazin-1-yl)methyl)benzoate in a reaction solvent under the action of alkali; and 4, reacting the 2-fluoro-5-((4-oxo-3, 4-dihydrophthalazin-1-yl)methyl)benzoic acid with cyclopropyl (piperazine-1-yl)methyl ketone hydrochloride in a reaction solvent under the action of a condensing agent and alkali to obtain a crude olaparib product, and recrystallizing to obtain the high-purity olaparib. According to the process of the novel preparation method, the total yield can be effectively improved, impurities caused by cyano hydrolysis can be obviously reduced, and the purity and quality of the prepared olaparib are improved.
Design, synthesis and activity evaluation of new phthalazinone parp inhibitors
Cai, Jin,Chen, Xixi,Huang, Mingqi,Ji, Min,Li, Xiaojing,Ren, Jinghui,Tang, Tu,Wang, Yuhong,Yang, Jia,Yang, Zhenyong
, p. 620 - 629 (2021/07/09)
Poly(ADP-ribose)polymerase (PARP) is a significant therapeutic target for the treatment of numerous human diseases. Olaparib has been approved as a PARP inhibitor. In this paper, a series of new compounds were designed and synthesized with Olaparib as the lead compound. In order to evaluate the inhibitory activities against PARP1 of the synthesized compounds, in vitro PARP1 inhibition assay and intracellular PARylation assay were conducted. The results showed that the inhibitory activities of the derivatives were related to the type of substituent and the length of alkyl chain connecting the aromatic ring. 3-(4,5-Dimethyl- 2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT)-based assay also proved that these compounds demonstrating strong inhibition to PARP1 also have high anti-proliferative activities against BRCA2-deficient cell line (Capan-1). Analysis of the entire results suggest that compound 23 with desirable inhibitory efficiency may hold promise for further in vivo exploration of PARP inhibition.
Preparation method of 2-fluoro-5-[(4-oxo-3H-2,3-diazanaphthalene)methyl]benzoic acid
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Paragraph 0005; 0012, (2021/04/10)
The invention discloses a preparation method of 2-fluoro-5-[(4-oxo-3H-2,3-diazanaphthalene)methyl]benzoic acid, wherein the method comprises the steps: S1, preparation of (3-oxo-1,3-dihydroisobenzofuran-1-yl)dimethyl phosphate; S2, preparation of 2-fluoro-5-(3-oxo-3H-isobenzofuran-1-yl methylene)bromobenzene; S3, preparation of 2-fluoro-5-(3-oxo-3H-isobenzofuran-1-yl methylene)methyl benzoate; and S4, preparation of 2-fluoro-5-[(4-oxo-3H-2,3-diazanaphthalene)methyl]benzoic acid. The preparation method has the advantages of simple operation, mild reaction conditions, easy purification of the intermediates, increase of the total yield compared with the prior art, and reduction of the industrial cost.
Olaparib intermediate and preparation method of olaparib
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Paragraph 0015; 0028; 0031-0032; 0035; 0038-0039; 0042; 0045, (2021/03/18)
The invention discloses an olaparib intermediate and a preparation method of olaparib, and the method comprises the following steps: suspending a compound II in a solvent, adding alkali, heating to areaction temperature, and reacting to obtain a compound III; mixing the compound III with a solvent, adding hydrazine hydrate and alkali, heating to a reaction temperature, and keeping the temperatureto react to a reaction end point to obtain a compound IV; and mixing and stirring the compound IV, a catalyst and a solvent, heating to a reaction temperature, adding thionyl chloride, carrying out aheat preservation reaction to the reaction end point, cooling, sequentially adding an alkali and cyclopropanoyl piperazine, carrying out a heat preservation reaction until the reaction is complete, and reacting to obtain olaparib according to a reaction formula shown in the specification. The method provided by the invention has the advantages of cheap and easily available raw materials, simple operation, mild reaction conditions, high purity and high yield of the obtained target product, no highly toxic substances, simple post-treatment and less three wastes, and meets the green and environment-friendly production requirements.
Novel synthesis method of olaparib bulk drug
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, (2021/06/22)
The invention introduces a novel synthesis method of an antitumor drug, namely olaparib. According to the invention, a dimer impurity is effectively removed by an acid-base pouring method in virtue of the different chemical properties that the dimer impurity cannot form salt and a previous intermediate of olaparib can form salt, and the HPLC purity of the obtained finished product can reach 99.9%. According to a route in the invention, the yield of the olaparib finished product is effectively improved, the total yield of six steps reaches 42.4%, and the route has important significance on industrial production of olaparib.
Preparation method of olaparib key intermediate
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, (2021/03/31)
The invention provides a preparation method of an olaparib key intermediates 4-(3-bromo-4-fluorobenzyl)phthalazin-1(2H)-one (a compound shown as a formula IV) and 2-fluoro-5-[(4-oxo-3,4-dihydro-1-phthalazinyl)methyl]benzoic acid (a compound shown as a formula V). Specifically, (3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonic acid dimethyl ester is used as a raw material to be subjected to a Wittig-Horner reaction with 3-bromo-4-fluorobenzaldehyde to obtain a formula III, the formula III and hydrazine hydrate are subjected to cyclization to obtain a formula IV, and the formula IV is subjected toa reaction with n-butyllithium and carbon dioxide to obtain an olaparib intermediate V. The method is economical and environment-friendly, and the yield is greatly improved.
Synthetic method of olaparib
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, (2020/03/06)
The invention discloses a synthesis method of olaparib, which comprises the following steps: carrying out reaction on dimethyl phosphite and o-carboxybenzaldehyde to generate (3-oxo-1, 3-dihydroisobenzofuran-1-yl) dimethyl phosphate; enabling (3-oxo-1, 3-dihydroisobenzofuran-1-yl) dimethyl phosphate to react with 2-fluoro-5-formylbenzoic acid to generate 2-fluoro-5-[(4-oxo-3, 4-dihydro naphthyridine-1-yl) methyl] benzoic acid; reacting 2-fluoro-5-[(4-oxo-3, 4-dihydro naphthyridine-1-yl) methyl] benzoic acid with oxalyl chloride to generate 2-fluoro-5-[(4-oxo-3, 4-dihydro naphthyridine-1-yl) methyl] benzoyl chloride; reacting 2-fluoro-5-[(4-oxo-3, 4-dihydro naphthyridine-1-yl) methyl] benzoyl chloride to react with piperazine cyclopropyl ketone, so as to generate olaparib. The invention provides a new olaparib synthesis route, the raw materials are easy to obtain, the operation post-treatment is simple, the reaction conditions of each step are mild, and the total yield reaches 93%.
ANTI-CANCER NUCLEAR HORMONE RECEPTOR-TARGETING COMPOUNDS
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Page/Page column 136, (2020/11/30)
The disclosure relates to anti-cancer compounds derived from nuclear steroid receptor binders, to products containing the same, as well as to methods of their use and preparation.
Identification of probe-quality degraders for Poly(ADP-ribose) polymerase-1 (PARP-1)
Chang, Xinyue,Huang, Wenhai,Liang, Meihao,Ma, Zhen,Shen, Zhengrong,Wang, Zunyuan,Zeng, Shenxin,Zhang, Chixiao,Zhang, Zhimin
, p. 1606 - 1615 (2020/08/19)
Poly(ADP-ribose) polymerase-1 (PARP-1), a critical DNA repair enzyme in the base excision repair pathway, has been pursued as an attractive cancer therapeutic target. Intervention with PARP-1 has been proved to be more sensitive to cancer cells carrying BRCA1/2 mutations. Several PARP-1 inhibitors have been available on market for the treatment of breast, ovarian and prostatic cancer. Promisingly, the newly developed proteolysis targeting chimaeras (PROTACs) may provide a more potential strategy based on the degradation of PARP-1. Here we report the design, synthesis, and evaluation of a proteolysis targeting chimaera (PROTAC) based on the combination of PARP-1 inhibitor olaparib and the CRBN (cereblon) ligand lenalidomide. In SW620 cells, our probe-quality degrader compound 2 effectively induced PARP-1 degradation which results in anti-proliferation, cells apoptosis, cell cycle arresting, and cancer cells migratory inhibition. Thus, our findings qualify a new chemical probe for PARP-1 knockdown.
Synthesis, Cytotoxicity, and Mechanistic Investigation of Platinum(IV) Anticancer Complexes Conjugated with Poly(ADP-ribose) Polymerase Inhibitors
Xu, Zoufeng,Li, Cai,Zhou, Qiyuan,Deng, Zhiqin,Tong, Zixuan,Tse, Man-Kit,Zhu, Guangyu
, p. 16279 - 16291 (2019/11/28)
Many clinical trials using combinations of platinum drugs and PARP-1 inhibitors (PARPi) have been carried out, with the hope that such combinations will lead to enhanced therapeutic outcomes against tumors. Herein, we obtained seven potential PARPi with structural diversity and then conjugated them with cisplatin-based platinum(IV) complexes. Both the synthesized PARPi ligands and PARPi-Pt conjugates [PARPi-Pt(IV)] show inhibitory effects against PARP-1's catalytic activity. The PARPi-Pt(IV) conjugates are cytotoxic in a panel of human cancer cell lines, and the leading ones display the ability to overcome cisplatin resistance. A mechanistic investigation reveals that the representative PARPi-Pt(IV) conjugates efficiently enter cells, bind to genomic DNA, disturb cell cycle distribution, and induce apoptotic cell death in both cisplatin-sensitive and-resistant cells. Our study provides a strategy to improve the cytotoxicity of platinum(IV)-based anticancer complexes and overcome cisplatin resistance by using a small-molecule anticancer complex that simultaneously damages DNA and inhibits PARP.
