Olaparib refining method

A refining method and temperature control technology, which is applied in the field of medicine, can solve the problems of cumbersome steps, low yield, and many side reactions, and achieve the effects of high product yield, simple synthetic route, and cheap raw materials

Inactive Publication Date: 2018-09-28
SHANDONG YUXIN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The preparation method of the prior art has cumbersome steps and many side reactions, and is not suitable for industrial production; or the yield is low, raw materials are wasted, and production costs are increased
In addition, in some cases, due to improper control of the production process, the purity of the drug did not meet the requirements
The prior art does not disclose a special purification method for this, so it is necessary to further purify such unqualified products or crude products to improve the yield and purity of the product

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] (1) Synthesis of crude olaparib

[0031] a. Under the protection of nitrogen, add 3.6 g of sodium hydride and suspend in 203 mL of N,N-dimethylformamide in the reaction flask, stir at room temperature for 1 h, add 13.4 g of phthalide (II) and 3-bromo-4-fluorobenzene Formaldehyde (Ⅲ) 20.3g, continue to stir at room temperature for 2.5h to terminate the reaction. The reaction solution was dried under reduced pressure, and the residue was dissolved in 150 ml of ethyl acetate, washed with deionized water, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure to obtain 29.70 g of white crystals. The yield was 93%. HPLC The purity is 99.92%.

[0032] b. Add 29.70g of compound IV, 0.93 mol of sodium ethoxide, and 200ml of ethanol to the reaction flask, reflux and stir for 1 hour, add 10% hydrochloric acid to adjust the pH to 3, and then add 6.06ml of 80% (mass fraction) hydrazine monohydrate , The reaction was stirred for 3 hou...

Embodiment 2

[0037] (1) Synthesis of crude olaparib

[0038] a. Under the protection of nitrogen, add 3.6 g of sodium hydride and suspend in 366 mL of N,N-dimethylformamide in the reaction flask, stir at room temperature for 1 hour, add 13.4 g of phthalide (II) and 3-bromo-4-fluorobenzene Formaldehyde (Ⅲ) 18.3g, continue to stir at room temperature for 2.5h to terminate the reaction. The reaction solution was dried under reduced pressure, the residue was dissolved in 150ml of ethyl acetate, washed with deionized water, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure to obtain 28.76g of white crystals. The yield was 90%. HPLC The purity is 99.85%.

[0039] b. Add 28.76 g of compound IV, 0.09 mol of sodium ethoxide, and 200 ml of ethanol to the reaction flask, stir at reflux for 1 hour, add 10% hydrochloric acid to adjust the pH to 1, and then add 5.87 ml of 80% (mass fraction) hydrazine monohydrate , The reaction was stirred for 3 hour...

Embodiment 3

[0044] (1) Synthesis of crude olaparib

[0045] a. Under the protection of nitrogen, add 3.6g of sodium hydride and suspend in 406mL of N,N-dimethylformamide in the reaction flask, stir at room temperature for 1h, add 13.4g of phthalide (II) and 3-bromo-4-fluorobenzene Formaldehyde (Ⅲ) 20.3g, continue to stir at room temperature for 2.5h to terminate the reaction. The reaction solution was dried under reduced pressure, the residue was dissolved in 150ml of ethyl acetate, washed with deionized water, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure to obtain 30.02g of white crystals. The yield was 94%. HPLC The purity is 99.92%.

[0046] b. Add 30.02g of compound IV, 0.094mol of sodium ethoxide, and 200ml of ethanol to the reaction flask, reflux and stir the reaction for 1h, add 10% hydrochloric acid to adjust the pH to 1, and then add 6.12ml of 80% (mass fraction) hydrazine monohydrate (0.094mol, molecular weight: 50.06), ...

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Abstract

The invention discloses an olaparib refining method, which comprises: (1) dissolving an olaparib crude product in a mixed solvent of ethyl acetate and acetone, and controlling the temperature at 45-50DEG C until olaparib is completely dissolved; (2) adding active carbon, decolorizing, filtering, cooling the filtrate to a temperature of -10-0 DEG C, crystallizing, and growing the crystal; and (3)filtering, washing the filtered solid by using acetone, and carrying out vacuum drying to obtain the refined olaparib. With the refining method of the present invention, the purity of the obtained olaparib can reach more than 99.9%, the total impurity and the single impurity are respectively controlled within 0.1% and 0.05%, the quality of the product is remarkably improved, the refining process is easy to operate, and the refining method is suitable for industrial production.

Description

Technical field [0001] The invention belongs to the technical field of medicine, and specifically relates to a method for refining the anti-tumor drug olaparib. Background technique [0002] Olapani was first developed by the British biotechnology company KuDOS (Kudos) Pharmaceuticals Co., Ltd., and is an oral polyadenylic acid diphosphate ribose transferase (PARP) inhibitor. It mainly blocks the repair of DNA damage, causes the accumulation of DNA damage, and ultimately kills tumor cells; in addition, it can increase the sensitivity of cells to other endogenous and exogenous DNA damage factors; inhibit angiogenesis; enhance the immunity of normal cells, thereby Resist the invasion of cancer cells. [0003] The therapeutic effect of olaparib on ovarian cancer has been highly recognized. EMEA and FDA have successively granted orphan drug certification for olaparib to treat ovarian cancer. [0004] The chemical name of olaparib is 4-[3-(4-cyclopropanecarbonyl-piperazine-1-carbonyl)-...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D237/32
CPCC07D237/32
Inventor 刘振腾徐淑周韩云龙柴倩
Owner SHANDONG YUXIN PHARMA CO LTD
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