Preparation method of Olaparib intermediate

An intermediate and oxo generation technology, which is applied in the field of preparation of olaparib intermediates, can solve problems such as unfavorable large-scale production control, poor reaction monitoring, etc., and achieve the effects of promoting development, easy access to raw materials, and environmentally friendly and economical processes

Inactive Publication Date: 2015-11-25
GUANGZHOU YOUMIJIAN PHARMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In this route, the cyano group is hydrolyzed to obtain two products. Although the intermediate (IV) can be obtained after the hydrazine hydrate reaction, the reaction is not easy to monitor and is not conducive to large-scale production control.

Method used

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  • Preparation method of Olaparib intermediate
  • Preparation method of Olaparib intermediate
  • Preparation method of Olaparib intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Example 1: Preparation of olaparib intermediate (IV): 2-fluoro-5-[(4-oxo-3,4-dihydrophenazin-1-yl)methyl]benzoic acid

[0033] 1.68 g of 2-fluoro-5-formylbenzoic acid and 2.5 g of dimethyl (3-oxo-1,3-dihydro-isobenzofuran-1-yl)phosphate were dissolved in 20 mL of dioxane, Add 1.4mL triethylamine dropwise at 0°C, continue the reaction until the raw materials are completely reacted, distill off the solvent under reduced pressure, add water and stir for 1 hour, filter with suction, and dry to obtain 2.0g of solid, namely intermediate (V): 2-Fluoro-5-(3-oxo-3H-isobenzofuran-1-ylmethylene)benzoic acid, yield; 70.4%. ESI-MS, m / z: 307.1 [M+Na] + , 285.1[M+H] + .

[0034] Dissolve 2.8g of intermediate V: 2-fluoro-5-(3-oxo-3H-isobenzofuran-1-ylmethylene)benzoic acid in 20mL of ethanol, add 8mL of hydrazine hydrate at room temperature, and reflux the reaction , until the raw material reaction is complete, concentrated under reduced pressure to remove the solvent, added water,...

Embodiment 2

[0035] Example 2: Preparation of olaparib intermediate (IV): 2-fluoro-5-[(4-oxo-3,4-dihydrophenazin-1-yl)methyl]benzoic acid

[0036]Dissolve 0.9g of 2-fluoro-5-formylbenzoic acid and 0.7g of phthalide in 100mL of ethyl propionate, add dropwise a solution of 1.3g of sodium methoxide in 20mL of methanol at room temperature, and keep the temperature constant with an ice-water bath during the dropwise addition. higher than 30°C. After dripping, raise the temperature and reflux, react until the raw materials are completely reacted, remove the solvent by distillation under reduced pressure, add water and stir for 1 hour, filter with suction, wash the filter cake with ethyl acetate, acidify the acetic acid solution, stir, wash with water after filtration, and dry to obtain 0.9g of solid , Intermediate (VI): 5-(2,3-dihydro-1,3-dioxo-1H-inden-2-yl)-2-fluorobenzoic acid, yield; 64.2%.

[0037] Dissolve 0.8g of intermediate (VI): 5-(2,3-dihydro-1,3-dioxo-1H-inden-2-yl)-2-fluorobenzoic ...

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Abstract

The invention relates to a preparation method of an Olaparib intermediate (IV), namely, 2-fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzoic acid. The method comprises steps as follows: 1, 2-fluoro-5-formyl benzoic acid is used as a raw material and reacts with (3-oxo-1,3-dihydro-isobenzofuran-1-yl)dialkyl phosphate to produce 2-fluoro-5-(3-oxo-3H-isobenzofuran-1-yl-methylene)benzoic acid, namely, an intermediate (V); or 2-fluoro-5-formyl benzoic acid reacts with phthalide to produce 5-(2,3-dihydro-1,3-dioxo-1H-indene-2-yl)-2-fluobenzoic acid, namely, an intermediate (VI); 2, the intermediate V or the intermediate VI reacts with hydrazine hydtaye to produce an Olaparib intermediate (IV). The preparation method is concise in process, environment-friendly, economical and suitable for the industrial key Olaparib intermediate, raw materials are easy to obtain, and purification is easy.

Description

technical field [0001] The invention relates to the technical field of compound organic synthesis route design and preparation of raw materials and intermediates, in particular to a preparation method of an olaparib intermediate. Background technique [0002] Olaparib (English name Olaparib, trade name Lynparza) is a polyadenosine diphosphate-ribose polymerase [poly(ADP-ribose) polymerase] (PARP) inhibitor developed by Astrazeneca in the United States. The drug was approved by the FDA in December 2014 for the treatment of ovarian cancer and breast cancer with BRCA gene defects. [0003] The chemical name of Olaparib is: 1-(cyclopropylformyl)-4-[5-[(3,4-dihydro-4-oxo-1-phthalazinyl)methyl]- 2-fluorobenzoyl] piperazine, its structural formula is: [0004] [0005] Comprehensive domestic and foreign public literature (J.Med.Chem., 2008, 51:6581-6591; Chinese patent CN101528714; Nanjing University of Technology's 2012 master's thesis "Study on the Synthesis of Olaparib and ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D237/32
CPCC07D237/32
Inventor 王立强邱飞岳海涛
Owner GUANGZHOU YOUMIJIAN PHARMA TECH CO LTD
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