Preparing method for parecoxib sodium

A technology of parecoxib sodium and its compound, which is applied in the field of preparation of parecoxib sodium, can solve the problems of low yield, long oxazole ring process route, unsuitability for industrial production, etc., achieve high selectivity and shorten synthesis The process route is conducive to the effect of enlarging production

Active Publication Date: 2016-03-23
SHANDONG LUOXIN PARMACEUTICAL GROUP STOCK CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The above two processes for synthesizing the oxazole ring are long and the yield is low, so they are not suitable for industrialized production

Method used

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  • Preparing method for parecoxib sodium
  • Preparing method for parecoxib sodium
  • Preparing method for parecoxib sodium

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Embodiment 1: the synthesis of compound III

[0048] First add 12.11g (100mmol) of benzaldoxime (Compound I) into 200ml of dichloromethane, then add 16.02g (120mmol) of N-chlorosuccinimide (NCS), keep the temperature for 5 hours, then add 1- Add 6.97g (60mmol) of phenyl-1-propyne (compound II), add 12.12g (120mmol) of triethylamine, react at room temperature, monitor the reaction by thin layer chromatography, stop the reaction after the reaction is complete. The reaction solution was washed successively with dilute hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and recrystallized from a mixture of petroleum ether and ethyl acetate to obtain 12.74 g (54.2 mmol) of compound III with a yield of 90.3 %, purity 99.5% (HPLC method).

Embodiment 2

[0049] Embodiment 2: the synthesis of compound III

[0050] First, add 24.23g (200mmol) of benzaldoxime (compound I) into 500ml of dichloromethane, add 40.06g (300mmol) of N-chlorosuccinimide (NCS), maintain the temperature for 3 hours, then add 1- Phenyl-1-propyne (Compound II) 11.62g (100mmol) was added with 30.31g (300mmol) of triethylamine, the temperature was controlled at 60°C, and the reaction was monitored by TLC. After the reaction was complete, the reaction was stopped. The reaction solution was washed successively with dilute hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and recrystallized from a mixture of petroleum ether and ethyl acetate to obtain 21.75 g (92.5 mmol) of compound III with a yield of 92.5 %, purity 99.2% (HPLC method).

Embodiment 3

[0051] Embodiment 3: the synthesis of compound III

[0052] First, add 12.11g (100mmol) of benzaldoxime (compound I) into 300ml of methyl chloride, then add 13.35g (100mmol) of N-chlorosuccinimide (NCS), keep the temperature for 2 hours, then add 1-benzene Diethylamine 10.10 g (100 mmol) was added to 11.62 g (100 mmol) of 1-propyne (compound II), and the temperature was controlled at 80° C. to react, and the reaction was monitored by thin-layer chromatography. After the reaction was complete, the reaction was stopped. The reaction solution was washed successively with dilute hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and recrystallized from a mixture of petroleum ether and ethyl acetate to obtain 21.58 g (91.8 mmol) of compound III, with a yield of 91.8 %, purity 99.1% (HPLC method).

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Abstract

The invention belongs to the field of medicine chemical industry and particularly relates to a preparing method for parecoxib sodium. According to the method, benzaldoxime (compound I) and 1-phenyl-1-propyne (compound II) are subjected to an addition reaction under existence of a catalyst and an acid-binding agent to construct an isoxazole ring to obtain a parecoxib sodium intermediate (compound III); the compound III is subjected to a sulfonation and sulfonylation reaction to obtain a compound IV, and the compound IV and propionic anhydride react to form salt to obtain parecoxib sodium (compound V). According to the method, the dipole ring addition reaction is creatively adopted for preparing the compound III, common safe and low-toxicity reagents chlorosulfuric chlorosulfonic acid and ammonia water with relative stable nature are used to be subjected to the sulfonylation reaction, and the method has the advantages that the reaction condition is mild, operation is reasonable, selectivity is high, and product quality is high; raw and auxiliary materials in the reaction are low in price, and the production cost is reduced.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a preparation method of parecoxib sodium. Background technique [0002] Parecoxib Sodium for Injection is the world's first specific cyclooxygenase-2 (COX-2) inhibitor that can be administered intravenously and intramuscularly, developed by Pharmacia in 2002. It was approved to go on the market in Europe in April, and it was imported and launched in China in 2008, under the trade name "Tunai" and the specifications are 40mg and 20mg. As the world's first COX-2 inhibitor for injection, parecoxib has good analgesic efficacy, and has the unique advantages of inhibiting hypersensitivity and eradicating pain. It fits the new analgesic model, promotes new analgesic concepts, and meets clinical needs It is expected to become the basic postoperative drug, so that more patients can enjoy painless surgery, thus providing a better choice for postoperative analgesia...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D261/08
CPCC07D261/08
Inventor 孙松夏见伟刘纯海
Owner SHANDONG LUOXIN PARMACEUTICAL GROUP STOCK CO LTD
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