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Preparation method of high-purity olaparib

A high-purity, monohydric alcohol technology, applied in the field of medicine, can solve the problems of unfavorable industrial production, high cost, large dosage, etc., and achieve the effects of cost saving, pollution reduction and high yield

Active Publication Date: 2016-04-20
合肥启旸生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The above routes all use the toxic coupling agent HBTU, and the consumption is large, the purification is difficult, and the cost is high, which is not conducive to industrial production

Method used

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  • Preparation method of high-purity olaparib
  • Preparation method of high-purity olaparib
  • Preparation method of high-purity olaparib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] 1. Activation

[0042] Dissolve 2-fluoro-5-[(4-oxo-3,4-dihydronaphthalene-1-yl)methyl]benzoic acid (5.1g, 17mmol) in 50ml of dichloromethane, cool to 0-10°C, carbonyldiimidazole (4.1g, 25.5mmol) was added, stirred and reacted at 20-30°C for 10 hours, and the reaction solution was concentrated to dryness to obtain an active amide intermediate.

[0043] 2. Aminolytic crystallization

[0044] Dissolve the active amide intermediate prepared in step 1 in 10ml of dichloromethane, cool down to 0-10°C, and drop into ) in 20ml of dichloromethane solution, reacted at 0-10°C for 1.5 hours, washed 3 times with 30ml of water, concentrated the organic layer to dryness, added 50ml of ethanol-water mixed solution (1:2, v / v) to the concentrate, and refluxed Dissolve, add 0.5 g of activated carbon and reflux for 15 min, filter, stir and crystallize the filtrate at 0-5°C for 10 hours, filter and dry to obtain 6.8 g of olaparib, with a yield of 92.0% and a purity of 99.87%.

Embodiment 2

[0046] 1. Activation

[0047] Dissolve 2-fluoro-5-[(4-oxo-3,4-dihydronaphthalene-1-yl)methyl]benzoic acid (5.1g, 17mmol) in 50ml of chloroform, cool to 0-10°C, carbonyldiimidazole (4.1g, 25.5mmol) was added, stirred and reacted at 20-30°C for 9 hours, and the reaction solution was concentrated to dryness to obtain an active amide intermediate.

[0048] 2. Aminolytic crystallization

[0049]The active amide intermediate prepared in step 1 was dissolved in 10ml of chloroform, cooled to 0-10°C, and added dropwise to a solution containing 1-cyclopropanoylpiperazine (2.62g, 17mmol) and pyridine (4.1ml, 51mmol). In 20ml of chloroform solution, react at 0-10°C for 2 hours, wash with 30ml of water three times, concentrate the organic layer to dryness, add 70ml of methanol-water mixed solution (1:2, v / v) to the concentrate, and reflux to dissolve, Add 0.5 g of activated carbon and reflux for 15 min, filter, stir and crystallize the filtrate at 0-5°C for 8 hours, filter and dry to obt...

Embodiment 3

[0051] 1. Activation

[0052] Dissolve 2-fluoro-5-[(4-oxo-3,4-dihydronaphthalene-1-yl)methyl]benzoic acid (5.1g, 17mmol) in 50ml tetrahydrofuran, cool to 0- At 10°C, carbonyldiimidazole (4.1 g, 25.5 mmol) was added, stirred and reacted at 20-30°C for 12 hours, and the reaction solution was concentrated to dryness to obtain an active amide intermediate.

[0053] 2. Aminolytic crystallization

[0054] Dissolve the active amide intermediate prepared in step 1 in 10ml of toluene, cool down to 0-10°C, and add dropwise (8.4ml, 51mmol) in 20ml toluene solution, reacted at 0-10°C for 1.5 hours, washed 3 times with 30ml water, concentrated the organic layer to dryness, added isopropanol-water mixed solution (2:1, v / v) 80ml, reflux to dissolve, add 0.5g of activated carbon to reflux for 15min, filter, stir and crystallize the filtrate at 0-5°C for 10 hours, filter and dry to obtain olaparib 6.5g, yield 87.8%, purity 99.89%.

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Abstract

The invention discloses a preparation method of high-purity olaparib. The preparation method comprises: subjecting 2-fluoro-5-[(4-oxo-3,4-dihydrophthalazine-1-yl)methyl] benzoic acid as a starting material to activation and aminolysis crystallization to obtain high-purity olaparib, wherein the activation refers to adding carbonyldiimidazole activating agent into a solution containing 2-fluoro-5-[(4-oxo-3,4-dihydrophthalazine-1-yl)methyl] benzoic acid to obtain active amide intermediate; with separation and purification, subjecting the active amide intermediate to direct aminolysis crystallization with 1-(cyclopropanecarbonyl)piperazine to obtain the olaparib. The purity of the olaparib prepared by the method is greater than 99.8 %, and the process is simple, high in yield, low in cost and more suitable for industrial production.

Description

1. Technical field [0001] The invention relates to a preparation method of a known medicine, in particular to a preparation method of high-purity olaparib, which belongs to the technical field of medicine. 2. Background technology [0002] Olaparib (Olaparib), the chemical name is 1-(cyclopropylformyl)-4-[5-[(3,4-dihydro-4-oxo-1-phthalazinyl)methyl]-2 -Fluorobenzoyl]piperazine, developed by KuDOS Pharmaceuticals, a wholly-owned subsidiary of AstraZeneca, is a polyadenosine diphosphate-ribose polymerase (PDA-PARP) inhibitor mainly acting on the mammary gland The oncogene (BRCA-1 or BRCA-2) promotes tumor cell apoptosis by inhibiting DNA damage repair of tumor cells, and is used for the treatment of breast cancer and ovarian cancer. In December 2014, Olaparib was approved for marketing in Europe as a monotherapy (trade name: Lynparza), for the maintenance treatment of adult patients with platinum-sensitive recurrent BRCA-mutated ovarian cancer, becoming the first treatment fo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D237/32
CPCC07D237/32
Inventor 阳应华籍业陈芳芳戴一
Owner 合肥启旸生物科技有限公司
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