Preparation methods of niraparib and intermediate of niraparib as well as intermediate compound

A technology for compounds and intermediates, which is applied to the preparation of niraparib and its intermediates and the field of intermediate compounds, can solve the problems of high production cost, cumbersome enzyme catalysis operations, expensive purchase price of enzymes, etc., and achieves low cost and high productivity. The effect of high rate and easy availability of raw materials

Active Publication Date: 2018-02-06
钟桂发
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0012] This route uses enzymes to catalyze the synthesis of key chiral intermediates. The purchase price o...

Method used

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  • Preparation methods of niraparib and intermediate of niraparib as well as intermediate compound
  • Preparation methods of niraparib and intermediate of niraparib as well as intermediate compound
  • Preparation methods of niraparib and intermediate of niraparib as well as intermediate compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Synthesis of Example 1 Compound 1 (1a, 1b, 1c)

[0048]

[0049] Synthesis of 1a: In a 1000mL eggplant-shaped bottle replaced with nitrogen, 86g (0.4mol) of p-bromophenylacetic acid, 35.4g (0.2mol) of (S)-4-benzyl-2-oxazolidinone, and 112ml of triethylamine ( 0.8mol) and 350mL toluene, stirred and heated to 80°C, dissolved 49.5ml (0.4mol) of pivaloyl chloride in 300ml toluene, slowly dropped into the reaction solution, after the addition was completed, heated to 110°C, reacted for 14h, TLC showed the reaction completely, cooled to room temperature, filtered, the filter cake was washed twice with ethyl acetate, and the organic phases were combined. The organic phase was washed with water, washed with dilute hydrochloric acid (2M), washed with 5% sodium bicarbonate, dried over anhydrous sodium sulfate, and mixed. Filtration, concentration under reduced pressure, separation by silica gel column chromatography to obtain 62.1 g of white solid (1a), yield 83%, purity 98%,...

Embodiment 2

[0052] Synthesis of Example 2 Compound 2 (2a, 2b, 2c, 2d, 2e)

[0053]

[0054] Synthesis of 2a

[0055] Method 1: In a 2L three-neck bottle replaced with nitrogen, add 14.3ml (0.128mol) of titanium tetrachloride and 450mL of dichloromethane, cool to 0 degrees, slowly add 12ml (0.04mol) of tetraisopropyl titanate dropwise, and drop After stirring at 0°C for 15 minutes, 31 ml of diisopropylethylamine (0.176) was added dropwise. After dripping, stir for 30 minutes. 60 g (0.16 mol) of compound (1a) was dissolved in 400 ml of dichloromethane and added dropwise to the above reaction solution, and stirred for 2 h after the drop was completed. Then 43ml (0.48mol) of methyl acrylate was added dropwise, and stirred at 0°C for 3 days. After the reaction was complete, 1 L of saturated ammonium chloride solution and 150 g of diatomaceous earth were added, filtered, and the filter cake was washed twice with dichloromethane. The dichloromethane layer was washed with 1M dilute hydroch...

Embodiment 3

[0061] The synthesis of embodiment 3 compound 3

[0062]

[0063]Sodium borohydride reduction method: In a 1L eggplant-shaped bottle, add 50g (0.108mmol) or (2b) of compound (2a), 250ml methanol and 250ml tetrahydrofuran, cool to 0 degrees, add sodium borohydride 16.8g (0.434mmol ). React at 0°C for 3h, slowly rise to room temperature, and stir overnight. TLC showed that the reaction was complete, cooled to 0°C, quenched by adding 2M dilute hydrochloric acid, removed methanol and tetrahydrofuran under reduced pressure, extracted with ethyl acetate (3×300mL), combined organic layers, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, silica gel Column chromatography separation gave white solid (3) 22.6g, yield 81%, purity 98.3%, 1H NMR (500MHz, Chloroform-d) δ7.50-7.36 (m, 2H), 7.16-7.05 (m, 2H) , 3.79-3.64(m, 2H), 3.58(t, J=6.4Hz, 2H), 2.76(ddt, J=11.4, 9.5, 5.7Hz, 1H), 1.83(dddd, J=13.4, 10.1, 6.2, 5.2Hz, 1H), 1.76-1.68(m, 2H), 1.59(dtd,...

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PUM

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Abstract

The invention discloses a preparation method of an intermediate of niraparib. The intermediate is as shown in the following formula. The preparation method comprises the following steps of using (S)-oxazolidone and p-bromophenylacetic acid as initial raw materials, and carrying out amide condensation, Michael addition, the reduction of ester and amide, the synthesis of sulfonyl ester, ammonification ring formation and a reaction of salt formation with an organic acid, so as to obtain the intermediate. The invention also discloses a preparation method of the niraparib and an intermediate compound of the niraparib. The preparation methods provided by the invention are low in cost and are suitable for industrialized production; raw materials are easily obtained and the yield is higher. The formula structure is shown in the description.

Description

technical field [0001] The present invention specifically relates to a preparation method of niraparib and its intermediates and intermediate compounds. Background technique [0002] PARP is a class of ribozymes widely present in eukaryotic cells that catalyze poly-ADP-ribosylation, and contains at least 17 subtypes, among which PARP-1 is the most studied. PARP-1 is mainly involved in DNA damage repair. After its sensory damage is activated, it quickly consumes a large amount of nicotinamide adenine dinucleotide in the cell to perform ADP-ribosylation of itself and other target proteins, thereby repairing the damage. PARP inhibitors inhibit the DNA damage repair of tumor cells and promote the apoptosis of tumor cells, and are mainly used to treat hereditary cancers such as breast cancer, ovarian cancer, prostate cancer, and pancreatic cancer that share the same "rogue gene". [0003] Niraparib (Niraparib) is a new oral PARP-1 inhibitor developed by Merck (taken over by Tesa...

Claims

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Application Information

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IPC IPC(8): C07D401/10C07D263/22C07D211/18
CPCC07D211/18C07D263/22C07D401/10Y02P20/55
Inventor 钟桂发
Owner 钟桂发
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