Preparation method of chiral intermediate of niraparib

A chiral intermediate and intermediate technology, applied in the direction of organic chemistry, etc., can solve the problems of complicated enzyme catalysis operation, high production cost, expensive purchase price of enzyme, etc., and achieve the effects of high yield, stable properties and novel route.

Active Publication Date: 2017-11-03
钟桂发
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0011] This route uses enzymes to catalyze the synthesis of key chiral intermediates. The purchase price of enzymes is expensive, and the operation of enzyme catalysis is cumbersome, resulting in high production costs.

Method used

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  • Preparation method of chiral intermediate of niraparib
  • Preparation method of chiral intermediate of niraparib
  • Preparation method of chiral intermediate of niraparib

Examples

Experimental program
Comparison scheme
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Embodiment 1

[0043]Example 1 Synthesis of intermediate I (I-a, I-b, I-c)

[0044]

[0045] The synthesis of I-a: replace good nitrogen in 1000mL eggplant-shaped bottle, add p-bromophenylacetic acid 86g (0.4mol), (S)-4-benzyl-2-oxazolidinone 35.4g (0.2mol), triethylamine 112ml ( 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 (I-a), yield 83%, purity 98%,...

Embodiment 2

[0048] Example 2 Synthesis of Intermediate II (II-a, II-b, II-c)

[0049]

[0050] Synthesis of II-a: In a 2L three-necked flask 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 , dropwise, after stirring at 0°C for 15 minutes, 31ml of diisopropylethylamine was added dropwise, (0.176). After dripping, stir for 30 minutes. 60 g (0.16 mol) of compound (I-a) 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 15.8ml (0.24mol) of acrylonitrile was added dropwise, and the mixture was stirred and reacted at 0°C for 1 day. After the reaction was complete, 1 L of saturated ammonium chloride solution was added, filtered, and the filter cake was washed twice with dichloromethane. The dichloromethane layer was washed with 1M dilute hydrochloric acid (2×50...

Embodiment 3

[0053] The synthesis of embodiment 3 intermediate (III)

[0054]

[0055] In a 2L three-necked flask, 21.3g (0.05mol) of II-a was dissolved in 300mL of tetrahydrofuran, cooled to -10 degrees, and 12ml (0.04mol) of 1M lithium hydroxide solution (100ml) and 1.2ml of hydrogen peroxide were added dropwise in sequence. After stirring for 6 hours at -10°C. After the reaction was complete, methyl tert-butyl ether was added for extraction, the aqueous phase was adjusted to pH 2 with 1M dilute hydrochloric acid, extracted three times with ethyl acetate, the organic layers were combined, and dried over anhydrous sodium sulfate. After filtration, concentration under reduced pressure, and separation by silica gel column chromatography, 12.7 g of (III) was obtained with a yield of 95% and a purity of 97.5%.

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Abstract

The invention discloses a novel synthetic method for preparing a chiral intermediate of niraparib. The method comprises the following steps: taking 4-bromophenylacetic acid and chiral substituted oxazolone as starting materials; and carrying out amide condensation, Michael addition, hydrolysis, reduction and intramolecular cyclization to obtain the intermediate (VII). The preparation method is low in cost, raw materials are easily obtained, the yield is high, and the synthetic method is suitable for industrialized production.

Description

technical field [0001] The present invention specifically relates to a preparation method of a chiral intermediate of niraparib. 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 type of oral PARP-1 inhibitor developed by Merck (taken over by Tesaro after 2012), ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/18
CPCC07D211/18
Inventor 钟桂发
Owner 钟桂发
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