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Synthesis method for preparing PARP inhibitor Niraparib

A synthesis method and an inhibitor technology, which are applied in the field of synthesis of the PARP inhibitor Niraparib, can solve problems such as difficulty in realizing large-scale industrial production, restrictions on industrial safety production, and long synthesis routes, and achieve easy large-scale production and industrialization The effect of large production and short synthetic route

Inactive Publication Date: 2017-03-15
SHAANXI UNIV OF SCI & TECH
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

The synthetic route is relatively long, and Niraparib obtained by using Chiralpak AS-H normal phase chiral chromatographic column is not easy to achieve large-scale industrial production, and unstable and difficult post-processing raw materials such as sodium azide are used in the reaction, which limits industrialization Safe Production

Method used

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  • Synthesis method for preparing PARP inhibitor Niraparib
  • Synthesis method for preparing PARP inhibitor Niraparib
  • Synthesis method for preparing PARP inhibitor Niraparib

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Embodiment

[0034] Intermediate (II) The synthesis of intermediate (II) is divided into two steps, the preparation of the first step diazonium salt: 52mL (0.4mol) methyl anthranilate is mixed with 170mL 20% sulfuric acid (0.62mol), cooled to At 10°C, slowly add 42 mL of 30% sodium nitrite (0.4 mol) solution dropwise into the reaction flask. Check the excess nitrous acid with starch potassium iodide test paper to determine the end point of the reaction. The generated brown-red diazonium salt carries out the coupling reaction of the second step with tert-butyl-3-phenylpiperidine-1-carboxylate: get 100g (0.4mol) tert-butyl-3-phenylpiperidine- 1-tert-butyl formate was dissolved in 500mL of 10% sodium hydroxide solution, and was dripped into the above-mentioned diazonium salt under constant stirring, stirred for 5h, left to stand for crystallization, suction filtered, and recrystallized in ethanol to obtain 127g of the intermediate (II ), yield: 78%.

[0035] 1 H-NMR (400MHz, DMSO-d6) (pp...

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Abstract

The invention provides a novel synthesis method for preparing a PARP inhibitor Niraparib. The method comprises the steps that a starting material methyl anthranilate is subjected to diazo coupling, cyclization, amidation, BOC removal and chiral resolution, and then the Niraparib with the purity reaching 99.5% is obtained. The method is simple, convenient and easy to operate suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and relates to a synthesis method for preparing PARP inhibitor Niraparib. Background technique [0002] Niraparib is an oral poly ADP-ribose polymerase (PARP) inhibitor, which can inhibit the repair of DNA damage in cells and is suitable for cancers with BRCA1 / 2 gene mutations, such as ovarian cancer and breast cancer, developed by Tesaro, an American biotechnology company. research and development. For cancer cells with BRCA gene mutations, if PARP activity is further inhibited, these cells will generate a lot of DNA damage when they divide, leading to the death of cancer cells. The chemical name of Niraparib is 2-[4-((3S)-3-piperidinyl)phenyl]-2H-indazole-7-carboxamide, and a phase III clinical trial called NOVA has been completed. Niraparib shows very good curative effect. In the trial, the researchers recruited more than 500 patients with ovarian cancer recurrence after platinum-bas...

Claims

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Application Information

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IPC IPC(8): C07D401/10
CPCY02P20/55C07D401/10
Inventor 梁承远贾敏一田丹妮孙涵丁顺军田蕾
Owner SHAANXI UNIV OF SCI & TECH
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