Preparation method of Olaparib and analogue of Olaparib

The technology of an analog and a substituent is applied in the field of preparation of raw materials, and can solve the problems of expensive palladium catalyst, complicated reaction, unsuitable for industrial production, etc., and achieve the effects of promoting development, easy availability of raw materials, environmental protection and economical process.

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

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Problems solved by technology

The reaction of this method is complex, and the palladium catal...

Method used

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  • Preparation method of Olaparib and analogue of Olaparib
  • Preparation method of Olaparib and analogue of Olaparib
  • Preparation method of Olaparib and analogue of Olaparib

Examples

Experimental program
Comparison scheme
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Embodiment 1

[0043] The preparation method of olaparib comprises the following steps:

[0044] a), add 1.68g of 2-fluoro-5-formylbenzoic acid and 5mL of thionyl chloride into the round bottom flask, add a few drops of N, N-dimethylformamide, and react at room temperature until the raw materials are completely reacted, then reduce The thionyl chloride was removed under pressure to obtain 1.8 g of an oily product, 2-fluoro-5-formylbenzoyl chloride, which was directly used in the next reaction.

[0045] b), 1.65 g of 1-cyclopropanylpiperazine was dissolved in 20 mL of dichloromethane, 1.5 mL of triethylamine was added, and the 2-fluoro-5-formylbenzoyl chloride prepared in the previous step was added dropwise at 0°C in 10 mL The solution of dichloromethane, dropwise, react at room temperature until the raw materials are completely reacted, wash with 1M hydrochloric acid, saturated sodium carbonate, and saturated brine, dry the organic layer, dry over anhydrous sodium sulfate, filter, and conce...

Embodiment 2

[0049] The preparation method of olaparib comprises the following steps:

[0050] a), add 3.4g of 2-fluoro-5-formylbenzoic acid, 30mL of dichloromethane, 3mL of thionyl chloride into the round bottom flask, add dropwise a few drops of N,N-dimethylformamide, and reflux until The reaction of the raw material was complete, and the solvent was removed under reduced pressure to obtain 3.7 g of an oily substance, 2-fluoro-5-formylbenzoyl chloride, which could be directly used in the next reaction.

[0051] Dissolve 3.3 g of 1-cyclopropanoylpiperazine in 20 mL of dioxane, add 4 mL of diisopropylethylamine, and add the 2-fluoro-5-formylbenzoyl chloride prepared in the previous step dropwise at 0°C in 10 mL The solution of dioxane, dropwise, reflux reaction until the reaction of the raw materials is complete, washed with hydrochloric acid, saturated sodium carbonate, and saturated brine to wash the organic layer, dried over anhydrous sodium sulfate, filtered, and concentrated under red...

Embodiment 3

[0055] The preparation method of olaparib comprises the following steps:

[0056] a) Add 1.68g of 2-fluoro-5-formylbenzoic acid, 30mL of dichloromethane and 1g of triphosgene to a round bottom flask, add a few drops of N,N-dimethylformamide, and reflux until the raw materials react Completely, the solvent was removed under reduced pressure to obtain 1.8 g of oily product, 2-fluoro-5-formylbenzoyl chloride, which could be directly used in the next reaction.

[0057] Dissolve 1.5g of 1-cyclopropanoylpiperazine in 20mL of toluene, add 1.1mL of N-methylmorpholine, and add dropwise at room temperature the solution of 2-fluoro-5-formylbenzoyl chloride dissolved in 10mL of toluene , dropwise, reflux reaction until the raw materials are completely reacted, washed with hydrochloric acid, saturated sodium carbonate, and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain intermediate (VIa): 3-( 4-cyclopropylformyl)piperaziny...

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Abstract

The invention discloses a preparation method of Olaparib and an analogue of the Olaparib. 2-fluoro-5-formyl benzoic acid is taken as a raw material and reacts with 1-substitutent piperazine to produce 3-(4-substitutent)piperazine-1-carbonyl)-4-fluorobenzalde which reacts with (3-oxo-1,3-dihydro-isobenzofuran-1-yl)dialkyl phosphate to produce 1-(substitutent)-4-[5-(3-oxo-3H-isobenzofuran-1-yl-methylene)-2-fluorobenzoyl]piperazine, then the 1-(substitutent)-4-[5-(3-oxo-3H-isobenzofuran-1-yl-methylene)-2-fluorobenzoyl]piperazine reacts with hydrazine hydrate to produce the Olaparib (Ia,R=cyclopropyl formyl) and the analogue (Ib,R=BOC) of the Olaparib; or 3-(4-substitutent)paperazine-1-carbonyl)-4-fluorobenzalde reacts with phthalide to produce 1-(substituent)-4-[5-(2,3-dihydro-1,3-dioxo-1H-indene-2-yl)-2-fluorobenzoyl]piperazine which reacts with the hydrazine hydrate to produce the Olaparib (Ia,R=cyclopropyl formyl) and the analogue (Ib,R=BOC) of the Olaparib.

Description

technical field [0001] The invention relates to the technical field of preparation of raw materials, in particular to a preparation method of Olaparib and analogues thereof. 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. 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: [0003] [0004] Document J.Med.Chem., 2008, 51:6581-6591 reported the synthesis method of olaparib, see the following formula: [0005] [0006] This route uses o-carboxybenzaldehyde as a raw material, reacts with dimethyl phosphite and 2-fluoro-5-formylbenzonitrile successively to gener...

Claims

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Application Information

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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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