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A kind of preparation method of olaparib

A compound and catalyst technology, applied in the field of preparation of olaparib, can solve the problems of difficult process control, many by-products, and low yield, and achieve the effects of mild and easy-to-control reaction conditions, increased yield, and high purity

Active Publication Date: 2018-01-12
SHANDONG LUOXIN PHARMA GRP HENGXIN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0016] Summarizing the above route, there are following defects in the process of preparing olaparib: the route is long, the yield is low, the process is not easy to control, and there are many by-products

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1-1

[0037] Embodiment 1-1: Synthesis of compound 3

[0038] Magnesium (2.4 g, 0.1 mol), triethylamine (59 g, 1 mol) and compound 2 (359.7 g, 3 mol) were added to 5 L of tetrahydrofuran. Compound 1 (247 g, 1 mol) was added, heated to 60° C., and stirred for 2 h. After the reaction was completed, tetrahydrofuran was distilled off under reduced pressure. Then use 0.1M hydrochloric acid solution to acidify the solution to pH 1, extract with ether, combine the organic phase, and wash the organic phase with anhydrous MgSO 4 After drying, suction filtration and vacuum drying, compound 3 (197 g, 0.93 mol) was obtained with a yield of 93% and a purity of 99.5% by HPLC.

Embodiment 1-2

[0039] Embodiment 1-2: the synthesis of compound 3

[0040]Magnesium (4.8 g, 0.2 mol), triethylamine (82.6 g, 1.4 mol) and compound 2 (155.9 g, 1.3 mol) were added to 5 L of acetonitrile. Add compound 1 (247g, 1mol), heat to 65°C, and stir for 2h. After the reaction is complete, tetrahydrofuran is distilled off under reduced pressure. Then use 0.1M hydrochloric acid solution to acidify the solution to pH 1, extract with ether, combine the organic phase, and wash the organic phase with anhydrous MgSO 4 After drying, suction filtration and vacuum drying, compound 3 (201 g, 0.95 mol) was obtained with a yield of 95% and a purity of 99.8% by HPLC.

Embodiment 1-3

[0041] Embodiment 1-3: the synthesis of compound 3

[0042] Magnesium (7.2 g, 0.3 mol), triethylamine (118 g, 2 mol) and compound 2 (120 g, 1 mol) were added to 5 L of tetrahydrofuran. Compound 1 (247 g, 1 mol) was added, heated to 70°C, and stirred for 2 h. After the reaction was completed, tetrahydrofuran was distilled off under reduced pressure. Then use 0.1M hydrochloric acid solution to acidify the solution to pH 1, extract with ether, combine the organic phase, and wash the organic phase with anhydrous MgSO 4 After drying, suction filtration and vacuum drying, compound 3 (195 g, 0.92 mol) was obtained with a yield of 92% and a purity of 99.5% by HPLC.

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Abstract

The invention discloses a preparing method for Olaparib. 5-bromomethyl-2-fluorobenzaote serves as a raw material and is subjected to a boric acid reaction with catecholborane, and a compound 3 is obtained; the compound 3 is subjected to a Suzuki coupling reaction, and a compound 5 is obtained; the compound 5 is subjected to a hydrolysis reaction, and a compound 6 is obtained; the compound 6 reacts with a compound 7 under the action of a CDI catalyst, and Olaparib is obtained. According to the preparing method, the raw material is easy to obtain, the course is short, operation and posttreatment are simple, the reaction conditions in all the steps are mild, the reaction yields of all the steps reach 90% or above, the total yield is increased to 82.3% from 49% achieved in the prior art, and the preparing method is environmentally friendly and suitable for industrial production.

Description

technical field [0001] The invention relates to the technical field of medicine and chemical industry, in particular to a preparation method of olaparib. 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]- The structural formula of 2-fluorobenzoyl]piperazine is: [0003] [0004] The literature J.Med.Chem., 2008, 51:6581-6591 reported the synthesis of olaparib and its analogues, the intermediate 2-fluoro-5-[(4-oxo-3,4-dihydrophenol Azin-1-yl)methyl]benzoic acid (IV) takes o-carboxybenzaldehyde as a raw material, first reacts with dimethyl phosphite to obtain the produc...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D237/32
CPCC07D237/32
Inventor 李华王春艳刘树欣
Owner SHANDONG LUOXIN PHARMA GRP HENGXIN PHARMA CO LTD
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