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Olaparib compound refining method

A refining method, the technology of olaparib, applied in the direction of organic chemistry, etc., can solve the problem of no scavenging effect of double-substituted products, and achieve the effect of fast reaction rate, high yield, and reduction of product impurity content

Inactive Publication Date: 2017-10-20
SHANDONG YUXIN PHARMA CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] Although the above-mentioned refining method has a good scavenging effect on most of the impurities in olaparib, it has almost no scavenging effect on the special impurity of the double-substituted product, so it is necessary to develop a new refining method to obtain high-purity olaparib. Rapani

Method used

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  • Olaparib compound refining method
  • Olaparib compound refining method

Examples

Experimental program
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Effect test

Embodiment 1

[0042] Dissolve bromobenzene (0.05mol) and potassium tert-butoxide (0.06mol) in 100mL of toluene, heat up to 90°C, react for 3h, add 20mL of toluene dissolved in compound 6 (0.06mol) dropwise, and continue at 110°C Stir for 24h, cool to room temperature, wash with water (3*50mL), wash the organic layer with anhydrous Na 2 SO 4 Dry, concentrate under reduced pressure to remove toluene, and the residue is analyzed by column chromatography (CH 2 Cl 2 as eluent) to obtain compound 5 (11.25 g) with a yield of 94.17%.

Embodiment 2

[0044] Add 0.06mol methyl o-fluorobenzoate, 0.022mol DIC, and 6.6mmol DMAP into 100mL of dichloromethane, stir to dissolve, continue to stir at room temperature for 30min, gradually raise the temperature to 45-50°C, and then add 1- Cyclopropamoylpiperazine (0.08mol), continue to stir and react for 9-10h. After the reaction was completed, the temperature was lowered to 0°C and stirred for 45 minutes, filtered, the filtrate was washed with water (3*50mL), dried over anhydrous sodium sulfate, dichloromethane was distilled off under reduced pressure to obtain a solid, namely compound 2 (15.27g), the yield was 92.57%.

Embodiment 3

[0046] Preparation of ionic liquids

[0047] Install a stirrer on the reaction kettle, add 0.1mol [Emim]Cl under nitrogen protection, and slowly add 0.26mol AlCl in batches 3 , stirred at about 40°C for 3 hours to ensure that the reaction was complete, and a colorless and transparent [Emim]Cl-AlCl was obtained 3 ionic liquid.

[0048] Preparation of crude olaparib

[0049] Compound 5 (0.03mol) and [Emim]Cl-AlCl 3 (0.03mol) ionic liquid was mixed in the bottle, stirred, and the temperature was raised to 50-55°C, and compound 2 (0.02mol) was slowly added dropwise within 30 minutes, and the stirring was stopped after 3-4 hours of reaction. Cool down to room temperature, the product and the ionic liquid are separated automatically, the product layer is poured into chloroform for extraction, the organic phase is retained, washed with toluene, suction filtered, and dried under reduced pressure to obtain olaparib (compound 1) 8.15g, the yield 93.79%.

[0050] Part 2: Refining me...

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Abstract

The invention relates to an olaparib compound refining method. The method includes synthesis of a crude olaparib product and refining of olaparib. Refining includes steps: 1) adding ethyl acetate petroleum ether mixed liquid and the crude olaparib product into a reaction bottle, slowly heating to 50-55 DEG C, performing heat-preservation stirring for 20min, heating to 70-75 DEG C, stirring, and dissolving the crude product to obtain crude product solution; adding activated carbon into the crude product solution, decolorizing, filtering and collecting filtrate; 2) slowly cooling the filtrate to 20-25 DEG C, keeping the temperature and stirring; 3) cooling the filtrate to 0 DEG C or below, controlling a stirring speed at 15r / min, adding seed crystal, controlling the temperature and the stirring speed to grow the crystal for 1.5h, filtering, flushing a filter cake with a small quantity of ethyl acetate petroleum ether mixed liquid, and drying to obtain a refined olaparib product. The refining method has advantages of simple conditions, reduction of olaparib disubstituted substances, high product purity and the like.

Description

technical field [0001] The invention relates to a method for refining known medicines, in particular to a method for refining olaparib compounds, and belongs to the technical field of medicine purification. Background technique [0002] Olaparib (Olaparib), the chemical name is 1-(cyclopropylformyl)-4-[5-[(3,4-dihydro-4-oxo-1-phthalazinyl)methyl]-2 -Fluorobenzoyl]piperazine, developed by AstraZeneca, is a polyadenosine diphosphate-ribose polymerase [poly(ADP-ribose) polymerase] (PARP) inhibitor. The drug was approved by the U.S. Food and Drug Administration (FDA) on December 19, 2014 (trade name: Lynparza), for the maintenance treatment of adult patients with platinum-sensitive recurrent BRCA-mutated ovarian cancer, becoming the first drug for BRCA PARP inhibitors in mutant platinum-sensitive recurrent ovarian cancer. Its chemical structural formula is as follows: [0003] [0004] In the preparation process of olaparib, all can produce the double substitution product ...

Claims

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Application Information

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IPC IPC(8): C07D237/32
CPCC07D237/32
Inventor 刘振腾孙逸威李震徐桂超冷香香黄春艳
Owner SHANDONG YUXIN PHARMA CO LTD
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