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Preparation method for olaparib

A technology of piperazine and carbonyl, which is applied in the field of preparation of olaparib, can solve the problems of high activity of cyclopropylformyl chloride, low yield of olaparib, cumbersome purification steps, etc., and achieve good industrial application prospects, method Convenience and high chromatographic purity

Active Publication Date: 2016-10-05
SICHUAN KELUN PHARMA RES INST CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The route is carried out under the action of a base by reacting 4-(4-fluoro-3-(piperazine-1-carbonyl)benzyl)naphthalene-1(2-hydrogen)-one with cyclopropanecarbonyl chloride; After the end, extract with a large amount of dichloromethane, remove the solvent by distillation under reduced pressure, and recrystallize to obtain olaparib; due to the high activity of cyclopropylformyl chloride, side reactions easily occur, a large amount of heat is generated, and the safety of industrial production is poor, so that The yield of olaparib in this method is low, and the purification steps are loaded down with trivial details, are unfavorable for realizing industrialization

Method used

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  • Preparation method for olaparib
  • Preparation method for olaparib
  • Preparation method for olaparib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036]

[0037] At 10°C, add 2000ml of N,N-dimethylacetamide to the reaction kettle, and add 4-(4-fluoro-3-(piperazine-1-carbonyl)benzyl)phthalein-1( 2-Hydro)-ketone (40g, 0.109mol), HBTU (48g, 0.127mol), cyclopropanecarboxylic acid (12g, 0.139mol), and finally N,N-diisopropylethylamine (0.218mol, 28.17g , 38ml), after reacting at 10°C for 8 hours, add 800ml of water, slowly precipitate the solid, suction filter, wash, and dry to obtain 42g of white solid, namely olaparib; HPLC purity 99.83%, yield 88.6%.

[0038] NMR data of olaparib:

[0039] 1 H NMR(400Hz,DMSO)δ12.598(s,1H),8.26(dd J=10.0Hz,1.4Hz,1H),7.96(dJ=10.0Hz,1H),7.90(dJ=8.2Hz,1H) ,7.80-7.86(m,1H),7.42-7.46(m,1H),7.38(d J=7.7Hz,1H),7.23(d J=12.2Hz,1H),4.33(s,2H),3.41- 3.74 (m, 6H), 3.19 (s, 2H), 1.94 (d J = 22.7Hz, 1H), 0.70-0.75 (m, 4H).

[0040] 13 C NMR (100Hz, DMSO) δ171.2, 164.0, 159.3, 158.0, 154.7, 144.7, 134.8, 134.7, 133.4, 131.7, 131.6, 131.4, 129.0, 128.93, 128.88, 127.9, 126.0, 1047.3, 126.3 ,46.4...

Embodiment 2

[0042]

[0043] At 50°C, add 2000ml of N,N-dimethylacetamide into the reaction kettle, and add 4-(4-fluoro-3-(piperazine-1-carbonyl)benzyl)phthalein-1( 2-Hydro)-ketone (40g, 0.109mol), HBTU (48g, 0.127mol), cyclopropanecarboxylic acid (12g, 0.139mol), and finally N,N-diisopropylethylamine (0.218mol, 28.17g , 38ml), reacted at 50°C for 4 hours, cooled to room temperature, added 800ml of water, slowly precipitated solid, suction filtered, washed, and dried to obtain 39g of white solid, namely olaparib; HPLC purity 99.81%, yield 82.3 %.

Embodiment 3

[0045]

[0046] At 10°C, add 2000ml of N,N-dimethylformamide into the reaction kettle, and add 4-(4-fluoro-3-(piperazine-1-carbonyl)benzyl)naphthyridine-1( 2-hydrogen)-ketone (40g, 0.109mol), HOBT (17.67g, 0.131mol), cyclopropanecarboxylic acid (12g, 0.139mol) g, finally added triethylamine (19.66g, 0.194mol, 27mL), 20 Stir at ℃ for about 7 hours. After the reaction, add 800ml of water, stir, and slowly precipitate solids, suction filter, wash, and dry to obtain 43.2 g of white solids, namely olaparib; HPLC purity 99.92%, yield 91.2% .

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Abstract

The invention discloses a preparation method for olaparib. The preparation method comprises the following steps: subjecting 4-(4-fluoro-3-(piperazine-1-carbonyl)benzyl)phthalazin-1(2H)-one, a condensing agent, cyclopropanecarboxylic acid, alkali and a polar organic solvent to a reaction at 0 to 120 DEG C for 2 to 8 h; adding water; allowing a solid to be precipitated; and carrying out pumping filtration, washing and drying so as to obtain olaparib. According to the invention, cyclopropanecarboxylic acid is used as a raw material; reaction conditions are mild; operational safety is good; organic solvents like dichloromethane is not needed for aftertreatment; separation and purification steps are simple; the yield of olaparib is high, as high as 92% or above; raw materials are easily available; the method is simple; side reactions are few; the chromatographic purity of olaparib is high; industrial scale-up production can be easily implemented; and the method has good industrial application prospects.

Description

technical field [0001] The invention relates to a preparation method of olaparib. Background technique [0002] Olaparib (trade name Lynparza), CAS: 763113-22-0, is a poly ADP-ribose polymerase (PARP) inhibitor, which can prevent enzymes involved in cell repair and is suitable for certain gene mutations Patients, it has a good market prospect in the treatment of cancer, and its indications include ovarian cancer, breast cancer, gastric cancer, non-small cell lung cancer, colon cancer, etc. World patent WO2014008592 reports a PARP inhibitor, such as: olaparib and its pharmaceutically acceptable salts [0003] Currently, the reported synthetic routes of olaparib mainly include: [0004] (1) The synthetic route disclosed in Chinese patent CN 101528714 A is: [0005] [0006] The route is via the reaction of 5-[(3,4-dihydro-4-oxo-1-phthalazinyl)methyl]-2-fluorobenzoic acid with an excess of cyclopropamoylpiperazine under the action of a condensing agent ; After the reacti...

Claims

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Application Information

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IPC IPC(8): C07D237/32
Inventor 李宏名伍伟庹世川王利春王晶翼
Owner SICHUAN KELUN PHARMA RES INST CO LTD
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