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Method for preparing parecoxib

A technology of parecoxib and dioxo, which is applied in the direction of organic chemistry, can solve the problems of unstable storage, high equipment requirements, and very high safety requirements, and achieve high product yield and purity, easy post-treatment operation, Effects requiring low reaction conditions

Active Publication Date: 2015-11-25
KPC PHARM INC
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AI Technical Summary

Problems solved by technology

[0009] The main disadvantages of this route are: the conversion rate of the enamine intermediate generated in the first step is not high, the conventional storage is unstable, and it needs to be purified by vacuum distillation, which requires high equipment for industrial production; the second step of acetylation Reaction requires the use of more expensive 2,6-lutidine as an acid-binding agent, which increases the production cost of the entire process route
[0013] The main disadvantage of this route is: the highly active butyllithium reagent is used in the middle, and the safety requirements of this reagent are very high when it is used in industrial scale-up, and it is easy to cause hidden dangers of safety accidents
[0016] The main disadvantage of this route is: in the second step of acetylation reaction, the conversion rate of using pyridine as the base-catalyzed raw material reaction is low, and the material obtained after the reaction treatment is mixed with a large amount of unreacted raw material, which needs to be separated by column chromatography Product, during industrial scale-up production, increases the difficulty of purification and production cost of reaction intermediates in this step
When the third step reacts with hydroxylamine hydrochloride, it is easy to be mixed with by-products that remove acetyl groups, which also increases the difficulty and cost of intermediate purification in this step

Method used

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  • Method for preparing parecoxib
  • Method for preparing parecoxib
  • Method for preparing parecoxib

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Experimental program
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preparation example Construction

[0050] F, the preparation of parecoxib:

[0051] The N-(4-(5-hydroxyl-5-methyl-3-phenyl-4,5-dihydroisoxazol-4-yl)phenylsulfonyl)propionamide prepared in step E was prepared in -5 Add it into an acidic solvent with a solid-to-liquid volume ratio of 1:2~1:3 in an ice bath at ~5°C, and keep stirring at a temperature of 0~30°C for 4~12 hours to obtain the target parecoxib.

[0052] The organic solvent described in step A is one of benzene, toluene, tetrahydrofuran, ethyl acetate, dichloromethane, chloroform or acetonitrile.

[0053] The Lewis acid catalyst described in step A is one of aluminum trichloride, titanium tetrachloride, boron trifluoride, ferric chloride, zinc chloride, niobium pentoxide, trisulphonate, p-toluenesulfonic acid species, the amount added is 5-20% of the molar weight of the raw material.

[0054] The sulfonating reagent described in step B is one of chlorosulfonic acid, concentrated sulfuric acid, oleum, and sulfur trioxide.

[0055] The sulfonating reag...

Embodiment 1

[0076] Preparation of 1,2-diphenylbutane-1,3-dione (III)

[0077] Weigh 4.0 g (20.4 mmol, 1e.q) of 3-oxo-2-phenylbutyryl chloride and dissolve it in 40 mL of benzene solution, add 150 mg of aluminum trichloride solid, heat to reflux for 12 hours, and wait for TLC to show that the raw material reacts After completion, stop the reaction, wash once with saturated aqueous sodium bicarbonate solution, and once with saturated brine, dry the organic phase with anhydrous sodium sulfate, and spin dry the solvent to obtain about 4.0 g of solid product, with a yield of 84%. 1 HNMR (500MHz, CDCl 3 ): δ =7.6-7.1(m,10H),5.40(s,1H),2.26(s,3H).

Embodiment 2

[0079] Preparation of 4-(1,3-dioxo-1-phenylbut-2-yl)benzene-1-sulfonyl chloride (IV)

[0080] Weigh 2.4 grams of 1,2-diphenylbutane-1,3-dione, add the above raw materials in batches to 5 ml of chlorosulfonic acid under stirring under ice bath conditions, and keep stirring at 0°C After 6 hours, after stopping the reaction, the reaction mixture was poured into 10 g of crushed ice, and a white solid precipitated out. The white solid was collected by filtration, washed with a small amount of ice water, and the dried white solid product was 3.1 g, with a yield of 91%. 1 HNMR (500MHz, CDCl 3 ): δ =7.70(dd, J =8.1Hz,2H),7.60(dd, J =8.1Hz, 2H), 7.53-7.41(m, 5H), 5.48(s, 1H), 2.26(s, 3H).

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Abstract

The invention discloses a method for preparing parecoxib. The method comprises the following steps: an initial raw material 3-oxo-2-phenylbutanoyl chloride and benzene undergo a Friedel-Crafts reaction to generate 1,2-diphenylbutane-1,3-dione, 1,2-diphenylbutane-1,3-dione is sulfonated by chlorosulfonic acid or concentrated sulfuric acid / acetyl chloride to obtain 4-(1,3-dioxo-1-phenylbutyl-2-yl)-1-sulfonyl chloride, 4-(1,3-dioxo-1-phenylbutyl-2-yl)-1-sulfonyl chloride is acted by ammonia water to generate 4-(1,3-dioxo-1-phenylbutyl-2-yl)-1-sulfonamide, and 4-(1,3-dioxo-1-phenylbutyl-2-yl)-1-sulfonamide reacts with propionic anhydride or propionyl chloride to obtain N-(4-(1,3-dioxo-1-phenylbutyl-2-yl)phenylsulfonyl)propionamide, N-(4-(1,3-dioxo-1-phenylbutyl-2-yl)phenylsulfonyl)propionamide undergoes condensation by using hydroxylamine hydrochloride to synthesize a ring, and dehydration is carried out under an acidic condition to obtain parecoxib. The parecoxib is prepared from 3-oxo-2-phenylbutanoyl chloride as the initial raw material through the Friedel-Crafts reaction, a sulfonation reaction, an amidation reaction and a condensation reaction. The method has the advantages of low cost of the initial raw material, simple process, low requirements of reaction conditions, simple post-treatment operation, high product yield and purity, and realization of large-scale production.

Description

technical field [0001] The invention belongs to the technical field of medicine preparation, and in particular relates to a method for preparing parecoxib. Background technique [0002] In recent years, non-steroidal anti-inflammatory drugs have shown a variety of medicinal activities, especially as selective inhibitors of cyclooxygenase-2 (COX-2), and parecoxib is one of the representatives. [0003] [0004] Parecoxib, clinically used is its sodium salt form Parecoxib sodium, English name: ParecoxibSodium, chemical name: N-[[4-(5-methyl-3-phenyl-4-isoxan Azolyl)phenyl]sulfonyl]propionamide sodium salt. Molecular formula: C 19 h 17 N 2 o 4 SNa. Indications: For short-term treatment of pain after surgery. Parecoxib sodium is a highly selective inhibitor. Clinical studies have shown that in the short-term treatment of postoperative pain, it can reduce the need for anesthetics and adverse reactions in patients. Studies have shown that parecoxib sodium has a preempti...

Claims

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Application Information

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IPC IPC(8): C07D261/08
CPCC07D261/08
Inventor 金毅张伟林军朱常成吴迪席亮段月娟
Owner KPC PHARM INC
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