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Olaparib intermediate and preparation method of olaparib

An intermediate and solvent technology, applied in the field of intermediates and preparation, can solve the problems of unfavorable industrial production, expensive raw materials, difficult post-processing, etc., and achieve the effects of less three wastes, simple post-processing, and simple operation.

Pending Publication Date: 2021-03-16
南京方生和医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method adopts pyrocatechol borane as raw material in the boration reaction, and the raw material price is expensive; in the coupling reaction, a palladium catalyst is used, which is not only expensive, but also difficult in post-treatment, which is unfavorable for industrial production

Method used

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  • Olaparib intermediate and preparation method of olaparib
  • Olaparib intermediate and preparation method of olaparib
  • Olaparib intermediate and preparation method of olaparib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] (1) Preparation of compound III

[0030] Add 50g of compound II and 500g of water into a 1L four-neck flask, stir, heat up to 25-30°C, quickly add aqueous sodium hydroxide solution (9g sodium hydroxide + 250g water), keep warm for 15min, the system gradually dissolves, TLC monitors the compound I reacted completely. Adjust the pH to 1-2 with 6M hydrochloric acid, let stand to separate the liquids; wash the organic phase twice with 1L saturated brine, and dry with anhydrous sodium sulfate; concentrate under reduced pressure until solvent-free. Add 45g of tetrahydrofuran and 250g of water, at this time the system precipitates an oily substance; cool down to 20-25°C, the oily substance becomes viscous, add a mixed solvent of ethyl acetate (50mL) and petroleum ether (100mL) dropwise; after stirring for 1h A large amount of solid was precipitated; filtered with suction, the filter cake was rinsed with water, and the filter cake was dried under reduced pressure at 50-60°C un...

Embodiment 2

[0036] (1) Preparation of compound III

[0037] Add 50g of compound II and 500g of DMF into a 1L four-neck flask, stir, raise the temperature to 20-25°C, quickly add 9g of potassium hydroxide, keep it warm for 15min, the system gradually dissolves, and TLC monitors that the reaction of compound I is complete. The pH was adjusted to 1-2 with 6M hydrochloric acid, and the liquids were separated; the organic phase was washed twice with 1 L saturated brine, and dried with anhydrous sodium sulfate; concentrated under reduced pressure until solvent-free. Add 45g of tetrahydrofuran and 250g of water, and the system precipitates an oily substance at this time; continue to add a mixed solvent of ethyl acetate (50mL) and petroleum ether (100mL); after stirring for 1h, a large amount of solids are precipitated; Dry the material under reduced pressure at -60°C to constant weight to obtain 48.5 g of solid with a purity of 98.6%.

[0038] (2) Preparation of Compound IV

[0039] Add 20g of...

Embodiment 3

[0043] (1) Preparation of compound III

[0044] Add 50g of compound II and 500g of acetonitrile into a 1L four-neck flask, stir, raise the temperature to 25-30°C, add 18g of pyridine, and keep it warm for 15 minutes. The system gradually dissolves, and the reaction of compound I is monitored by TLC. The pH was adjusted to 1-2 with 6M hydrochloric acid, and the liquids were separated; the organic phase was washed twice with 1 L saturated brine, and dried with anhydrous sodium sulfate; concentrated under reduced pressure until solvent-free. Add 45g of acetonitrile and 250g of water, at this time the system precipitates an oily substance; cool down to 20-25°C, the oily substance becomes viscous, add dropwise a mixed solvent of ethyl acetate (50mL) and petroleum ether (100mL); after stirring for 1h A large amount of solid was precipitated; filtered with suction, the filter cake was rinsed with water, and the filter cake was dried under reduced pressure to constant weight to obtain...

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Abstract

The invention discloses an olaparib intermediate and a preparation method of olaparib, and the method comprises the following steps: suspending a compound II in a solvent, adding alkali, heating to areaction temperature, and reacting to obtain a compound III; mixing the compound III with a solvent, adding hydrazine hydrate and alkali, heating to a reaction temperature, and keeping the temperatureto react to a reaction end point to obtain a compound IV; and mixing and stirring the compound IV, a catalyst and a solvent, heating to a reaction temperature, adding thionyl chloride, carrying out aheat preservation reaction to the reaction end point, cooling, sequentially adding an alkali and cyclopropanoyl piperazine, carrying out a heat preservation reaction until the reaction is complete, and reacting to obtain olaparib according to a reaction formula shown in the specification. The method provided by the invention has the advantages of cheap and easily available raw materials, simple operation, mild reaction conditions, high purity and high yield of the obtained target product, no highly toxic substances, simple post-treatment and less three wastes, and meets the green and environment-friendly production requirements.

Description

technical field [0001] The present invention relates to an intermediate and a preparation method, in particular to an olaparib intermediate and a preparation method of olaparib. Background technique [0002] Olaparib is an inhibitor of poly(ADP-ribose) polymerase (PARP), a DNA repair enzyme that plays a key role in the DNA repair pathway, PARPi can be lethal by synthesis effect to produce antitumor activity. [0003] Olapari was approved for marketing in Europe and the United States on December 16, 2014 and December 19, 2014, respectively. It is the first PARPi to be marketed in the world. The approved indications are complete or partial responses to platinum-based chemotherapy Recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer; deleterious or suspected deleterious BRCA mutation (gBRCAm)-associated advanced ovarian cancer that has been treated with three or more chemotherapy regimens; treatment deleterious or suspected deleterious BRCA-mutated (gBRC...

Claims

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Application Information

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IPC IPC(8): C07D307/88C07D237/32
CPCC07D307/88C07D237/32
Inventor 周步高张明雨惠舰宁武松徐光辉
Owner 南京方生和医药科技有限公司
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