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Preparation method of (S)-3-(4-bromophenyl)piperidine as Niraparib intermediate

An intermediate, bromophenyl technology, is applied in the field of preparation of the PARP inhibitor Niraparib intermediate-3-piperidine, which can solve the problems of high production cost and expensive reagents, achieve easy control of operating conditions, reduce production costs, and realize The effect of mass production

Inactive Publication Date: 2018-08-17
SOUTHEAST UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Purpose of the invention: the purpose of this invention is to provide a kind of preparation method of new Niraparib intermediate (S)-3-(4-bromophenyl) piperidine, this method overcomes the expensive reagent in the existing method, and the generation cost is high The disadvantages of this method are that the synthesis steps are greatly reduced, the reaction conditions are mild, the handling is convenient, the yield is higher, and it is easier to operate

Method used

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  • Preparation method of (S)-3-(4-bromophenyl)piperidine as Niraparib intermediate
  • Preparation method of (S)-3-(4-bromophenyl)piperidine as Niraparib intermediate
  • Preparation method of (S)-3-(4-bromophenyl)piperidine as Niraparib intermediate

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Embodiment 1 prepares compound 3

[0031]

[0032] Weigh compound 1 (1.20g, 4.9mmol) and dissolve it in 3ml of anhydrous dimethyl sulfoxide, add 211mg of sodium hydride (60%, 5.275mmol) and stir at room temperature for 3min, then weigh N-Boc-3-aminopropyl Bromine (1.05g, 4.411mmol, compound 2) was dissolved in 3ml of anhydrous dimethyl sulfoxide, and slowly added dropwise to the reaction solution. After the dropwise addition, the temperature was raised to 50°C and stirred for 35min. Add saturated ammonium chloride solution to quench the reaction, extract the aqueous phase with ethyl acetate (15ml*3, that is, 15ml each time, three times in total), combine the organic phases, wash with saturated brine (15ml*2), anhydrous sodium sulfate Drying, filtration, concentration under reduced pressure, and column chromatography (eluent: petroleum ether: ethyl acetate = 40:1) gave a white oily substance, the target compound 3 (1.69 g, yield 86%).

[0033] The target product comp...

Embodiment 2

[0037] Embodiment 2 prepares compound 4

[0038]

[0039]Weigh compound 3 (1.69g, 4.22mmol) and dissolve it in 9ml ethyl acetate, add 2ml HCl (it can also be replaced by trifluorobenzenesulfonic acid) and stir at room temperature for 30 minutes, the effect is to remove the amino protective structure, and dissolve it in 25ml after concentrating under reduced pressure. After adding potassium carbonate (0.7g, 5.064mol) to ethanol, reflux at 80°C for 20h. After the reaction, add dilute hydrochloric acid (also can be replaced by sulfuric acid) to neutralize excess alkali, then spin dry the solvent, wash with water, filter and dry to obtain a white solid which is the target compound 4 (0.75 g, yield 70%).

[0040] The target product compound 4 1 The HNMR data are as follows:

[0041] 1 H NMR (500MHz, CDCl 3 )δ:

[0042] 7.57–7.50(m,2H),7.27–7.20(m,2H),6.53(s,1H),3.65(t,J=6.7Hz,1H),3.43(dt,J=12.3,6.8Hz,1H) , 3.26 (dt, J=12.4, 6.8Hz, 1H), 2.28–2.15 (m, 1H), 1.93–1.83 (m, 1H),...

Embodiment 3

[0044] Embodiment 3 prepares compound 5

[0045]

[0046] Weigh compound 4 (0.75g, 2.96mmol) and dissolve it in 15ml THF (tetrahydrofuran), cool down to 0°C, add borane tetrahydrofuran complex (6.65ml, 1.0M in THF, 6.65mmol, CAS: 14044-65-6) Stir overnight at room temperature, then add a few drops of dilute hydrochloric acid to quench the reaction and reflux for 1.5h, evaporate the solvent under reduced pressure and spin dry, add an appropriate amount of sodium hydroxide solution, extract with dichloromethane (25ml*3), combine the organic phases, and saturated chlorination Wash with sodium (25ml*2), dry, filter, concentrate, add 25ml of water and 25ml of hydrochloric acid, reflux at 110°C for 3 hours, add an appropriate amount of sodium hydroxide to adjust the pH to 7, and extract with dichloromethane (30ml*3) , the organic phases were combined, washed with saturated sodium chloride (30ml*2) and concentrated under reduced pressure to obtain a pale yellow solid, the target c...

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PUM

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Abstract

The invention discloses a preparation method of (S)-3-(4-bromophenyl)piperidine as a Niraparib intermediate. The method comprises the following steps: carrying out nucleophilic reaction via ethyl p-bromobenzoacetate and N-boc-3-aminopropyl bromide under the action of alkali, carrying out cyclization under the alkaline condition, reducing through a reducing agent to obtain 3-(4-bromophenyl)piperidine and using a chiral resolving agent to obtain (S)-3-(4-bromophenyl)piperidine. The method is short in synthetic route, high in yield, free of hydrogen and metal catalysts and relatively low in production cost, is safe and environmentally friendly, and provides technical support for further preparation of high-purity Niraparib.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a preparation method of a PARP inhibitor Niraparib intermediate (S)-3-(4-bromophenyl)piperidine. Background technique [0002] DNA damage occurs all the time in the cell cycle. In addition to external factors such as ultraviolet radiation and chemical poisons, the stimulation of the cell's own metabolites, and errors in DNA replication will make the genome unstable and cause cancer. Therefore, cells must have a variety of DNA damage detection and repair mechanisms, so that damaged DNA can be repaired in a timely and accurate manner to maintain normal physiological functions. PARP is a poly ADP ribose polymerase that recognizes DNA damage and initiates DNA repair. For cancer cells with BRAC mutations, inhibition of PARP activity causes cancer cells to divide and generate a large amount of DNA damage, which cannot be repaired properly and leads to cell dea...

Claims

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Application Information

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IPC IPC(8): C07D211/18
CPCY02P20/55C07D211/18C07B2200/07
Inventor 蔡进王莹颖吉民宁瑶韦庆詹梦梦刘文景
Owner SOUTHEAST UNIV
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