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Preparation method of Olaparib

A technology of hydrazine monohydrate and compounds, which is applied in the field of preparation of the antineoplastic drug olaparib, can solve the problems of high raw material cost, low yield, long synthetic route, etc., and achieve product yield and purity improvement, and simple synthetic route , The effect of high total product yield

Inactive Publication Date: 2018-06-22
SHANDONG YUXIN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Disadvantages: The synthesis route of this route is long, and the last step of the reaction needs to be carried out under the conditions of O-benzotriazole-tetramethyluronium hexafluorophosphate (HBTU) and N,N-diisopropylethylamine (DIPEA). The cost of raw materials is relatively high, and the product is purified by liquid phase preparation, which is not conducive to industrial production
[0012] Although this reaction avoids the use of the expensive raw material HBTU in the last step of the document J.Med.Chem., 2008, 51:6581-6591, the reaction has the expensive raw material 2-fluoro-5-formylbenzoic acid, and the compound VIa (VIb ) and phthalide to prepare compound VIIIa low yield (about 60%), resulting in low product overall yield, still unfavorable for suitability for industrialized production

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Preparation of compound Ⅳ

[0031] Under nitrogen protection, add 2.4g of sodium hydride to the reaction flask and suspend in 150mL of dimethyl sulfoxide, stir at room temperature for 1h, add 13.4g of phthalide (II) and 20.3g of 3-bromo-4-fluorobenzaldehyde (III) , Continue stirring 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 27.81 g of white crystals with a yield of 87%. HPLC The purity is 99.82%.

Embodiment 2

[0033] Preparation of compound Ⅳ

[0034] Under the protection of nitrogen, add 3.6g of sodium hydride to the reaction flask and suspend in 150mL of N,N-dimethylformamide, stir at room temperature for 1h, add 13.4g of phthalide (II) and 3-bromo-4-fluorobenzaldehyde ( Ⅲ) 18.27g, continue stirring 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 25.87 g of white crystals. The yield was 90%, and the HPLC purity was 99.92%.

Embodiment 3

[0036] Preparation of compound Ⅳ

[0037] Under nitrogen protection, add 3.6g of sodium hydride and suspend in 150mL of tetrahydrofuran in the reaction flask, stir at room temperature for 1h, add 13.4g of phthalide (II) and 20.3g of 3-bromo-4-fluorobenzaldehyde (III), and continue stirring at room temperature 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 29.37 g of white crystals. The yield was 92%, and the HPLC purity was 99.95%.

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Abstract

The invention discloses a preparation method of Olaparib. The preparation method comprises the following steps: carrying out a reaction between phthalide (II) and 3-bromo-4-fluorobenzaldehyde (III) toobtain a compound IV, carrying out a reaction between the compound IV and hydrazine monohydrate to obtain a compound V, and carrying out a reaction between the compound V and 1-cyclopropylcarbonylpiperazine to obtain the final product of Olaparib (I). The raw materials used in the reaction are cheap and easy to obtain, and the preparation method is simple in process route, high in total yield andfew in byproducts and is applicable to industrial production.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a preparation method of the antineoplastic drug olaparib. Background technique [0002] Olaparib was first developed by the British biotechnology company KuDOS (Kudos) Pharmaceuticals Ltd. It is an oral polyadenylate diphosphate ribosyltransferase (PARP) inhibitor. It mainly blocks the repair of DNA damage, causes the accumulation of DNA damage, and finally kills tumor cells; in addition, it can also increase the sensitivity of cells to other endogenous 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 successively granted orphan drug certification for olaparib for the treatment of ovarian cancer. [0004] The chemical name of olaparib is 4-[3-(4-cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D237/32
CPCC07D237/32
Inventor 刘振腾李志滨葛福财巩腾文
Owner SHANDONG YUXIN PHARMA CO LTD
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