Preparation method of parecoxib meta-isomer impurity

A parecoxib and isomerization technology, applied in the field of medicinal chemical synthesis, can solve the problems of uncontrollable safety factors, cumbersome steps, high cost, etc., and achieve good industrial application prospects, stable process, and reduce by-products. Effect

CN110642801APending Publication Date: 2020-01-03深圳市祥根生物科技有限公司
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Patent Information

Authority / Receiving Office
CN · China
Patent Type
Applications(China)
Current Assignee / Owner
Publication Date
2020-01-03

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Abstract

The invention relates to the technical field of chemical synthesis of medicines, and concretely relates to a preparation method of a parecoxib meta-isomer impurity. The method comprises the followingsteps: 5-methyl-3-phenylisoxazole-4-carboxylic acid and 3-bromobenzenesulfonamide which are used as raw materials undergo a coupling reaction under the action of silver carbonate and a Pd catalyst togenerate N-[3-(5-methyl-3-phenyl-4-isoxazolyl)phenyl]sulfonamide, and then the N-[3-(5-methyl-3-phenyl-4-isoxazolyl)phenyl]sulfonamide and propionyl chloride undergo an acylation reaction to generateN-[[3-(5-methyl-3-phenyl-4-isoxazolyl)phenyl]sulfonyl]propanamide. Compared with the prior art, the preparation method of the invention has the advantages of cheap and easily available raw materials,simple synthesis steps, mild reaction conditions, easiness in control, reduction of the generation of byproducts, great improvement of the product yield, reduction of the cost, stable technological process, good reproducibility, and suitableness for large-scale production.
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Description

technical field

[0001] The invention relates to the technical field of pharmaceutical chemical synthesis, in particular to a method for preparing parecoxib meta-isomeric impurities. Background technique

[0002] Parecoxib (parecoxib), the chemical name is N-[[4-(5-methyl-3-phenyl-4-isoxazolyl)phenyl]sulfonyl]propionamide, the chemical structure is as (I) shown. The drug is the first specific cyclooxygenase-2 (COX-2) inhibitor developed by Pharmacia that can be administered intravenously and intramuscularly, and was launched in the UK in 2002.

[0003]

[0004] At present, parecoxib sold on the market generally adopts sulfonation during the synthesis process, which inevitably produces meta-isomers, which may remain in the final product of parecoxib, thereby affecting product quality. Its structural formula is as follows (II) shown.

[0005]

[0006] For example, patent CN104557756A discloses a method for synthesizing meta-isomeric impurities of parecoxib. The method ...

Examples

Embodiment 1

[0038] The preparation method of the parecoxib meta-isomeric impurity N-[[3-(5-methyl-3-phenyl-4-isoxazolyl)phenyl]sulfonyl]propionamide in this embodiment is as follows:

[0039] Step S1, the preparation of N-[3-(5-methyl-3-phenyl-4-isoxazolyl)phenyl]sulfonamide:

[0040] Add 5-methyl-3-phenylisoxazole-4-carboxylic acid (2.03g, 10mmol, 1.0eq), 3-bromobenzenesulfonamide (2.36g, 10mmol, 1.0eq), silver carbonate to a 100mL three-necked flask (6.89g, 25mmol, 2.5eq), triphenylphosphine (1.57g, 6mmol, 0.6eq), bis(acetylacetonate)palladium(II) (609mg, 2mmol, 0.2eq) and anhydrous N-methylpyrrolidone ( 16mL), then replaced with nitrogen for 3 times, heated to 160°C for 24 hours, cooled to room temperature, added water (30mL) and ethyl acetate (50mL), stirred for 10 minutes, filtered with diatomaceous earth, separated, and the water phase Then extract 2 times with ethyl acetate (30mL), combine the organic phases, wash with saturated brine and water successively, then dry with anhydrou...

Embodiment 2

[0059] The preparation method of the parecoxib meta-isomeric impurity N-[[3-(5-methyl-3-phenyl-4-isoxazolyl)phenyl]sulfonyl]propanamide of the present embodiment is mainly the same as The same as in Example 1, the difference is that the method is as follows:

[0060] Step S1, the preparation of N-[3-(5-methyl-3-phenyl-4-isoxazolyl)phenyl]sulfonamide:

[0061] Add 5-methyl-3-phenylisoxazole-4-carboxylic acid (2.03g, 10mmol, 1.0eq), 3-bromobenzenesulfonamide (2.36g, 10mmol, 1.0eq), silver carbonate to a 100mL three-necked flask (5.52g, 20mmol, 2.0eq), triphenylphosphine (1.31g, 5mmol, 0.5eq), palladium chloride (89mg, 0.5mmol, 0.05eq) and anhydrous N,N-dimethylpropenyl urea ( 10mL), then replaced with nitrogen for 3 times, heated to 130°C for 24 hours, cooled to room temperature, added water (30mL) and ethyl acetate (50mL), stirred for 10 minutes, filtered with diatomaceous earth, separated, and the aqueous phase Then extract 2 times with ethyl acetate (30mL), combine the orga...

Embodiment 3

[0066] The preparation method of the parecoxib meta-isomeric impurity N-[[3-(5-methyl-3-phenyl-4-isoxazolyl)phenyl]sulfonyl]propanamide of the present embodiment is mainly the same as The same as in Example 1, the difference is that the method is as follows:

[0067] Step S1, the preparation of N-[3-(5-methyl-3-phenyl-4-isoxazolyl)phenyl]sulfonamide:

[0068] Add 5-methyl-3-phenylisoxazole-4-carboxylic acid (2.03g, 10mmol, 1.0eq), 3-bromobenzenesulfonamide (2.36g, 10mmol, 1.0eq), silver carbonate to a 100mL three-necked flask (11.03g, 40mmol, 4.0eq), triphenylphosphine (2.10g, 8mmol, 0.8eq), palladium trifluoroacetate (665mg, 2mmol, 0.2eq) and anhydrous N,N-dimethylacetamide (20mL ), then replaced with nitrogen for 3 times, raised the temperature to 160°C for 24 hours, cooled to room temperature, added water (30mL) and ethyl acetate (50mL), stirred for 10 minutes, filtered with diatomaceous earth, separated, and the water phase was re- Extracted twice with ethyl acetate (30m...