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Preparation method of etoricoxib or pharmaceutically acceptable salts thereof

A kind of etoricoxib, pharmaceutical technology, applied in the field of salt preparation, can solve the problem of increasing risk

Inactive Publication Date: 2015-07-22
JINAN SANYUAN CHEM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Processes involving these hazardous chemicals increase risks in process control and result in possible risks to operators and the environment

Method used

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  • Preparation method of etoricoxib or pharmaceutically acceptable salts thereof

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Experimental program
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Effect test

Embodiment 1

[0023] Preparation of 2-hydroxy-3-p-methylthiophenyl-5-chloropyridine (compound 2)

[0024] Add 2-chloromalondialdehyde (16.0g, about 0.15mol) and p-methylthiophenylacetamide (18.1g, about 0.1mol) to ethanol (150ml), stir at room temperature for 10min, slowly add 3ml of pyridine dropwise, gradually The temperature was raised to reflux, and the reaction was stirred for 4 hours. After the reaction was completed, the solvent was evaporated, and the product was dissolved in ethyl acetate, washed with a saturated solution of sodium bicarbonate (3×50ml) and brine, dried with anhydrous sodium sulfate, and concentrated to obtain a residue Crystallization in hexane / ether gave 24.3 g of 2-hydroxy-3-p-methylthiophenyl-5-chloropyridine.

Embodiment 2a

[0026] 2-Hydroxy-3-p-methylthiophenyl-5-chloropyridine (15.1 g, about 0.06 mol) was mixed with POCl in a sealed jar 3 (150ml) were heated together at 140°C for 15 hours, after cooling to room temperature, the excess POCl was distilled off under reduced pressure 3 The residue was diluted with ethyl acetate and water, then neutralized to a pH of about 7 with saturated sodium bicarbonate solution. The organic phase was taken out, washed with brine and concentrated, and the residual solid was recrystallized in hexane / ether to obtain 13.8 g of 2,5-dichloro-3-p-methylthiophenylpyridine.

[0027]

Embodiment 2b

[0029] The POCl in embodiment 2a 3 Replaced by POBr 3 , and the rest of the reaction conditions remained unchanged to obtain 16.5 g of 2-bromo-3-p-methylthiophenyl-5-chloropyridine.

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Abstract

The invention discloses a preparation method of etoricoxib. The method comprises the following steps: 1, reacting 2-chloromalonaldehyde (compound 1) with p-methylthiophenyl acetamide (compound 2) to prepare 2-hydroxy-3-p-methylthiophenyl-5-chloropyridine (compound 3); 2, reacting the compound 3 with phosphorus oxyhalide to prepare 2-halo-3-p-methylthiophenyl-5-chloropyridine (compound 4); 3, reacting the compound 4 with hydrogen peroxide to prepare 2-halo-3-p-methylsulfonyl-5-chloropyridine (compound 5); and 4, coupling the compound 5 with 2-methyl-pyridine-5-boric acid under the catalysis of palladium to obtain etoricoxib. The preparation method has the advantages of high purity, high yield, low cost and simple operation.

Description

technical field [0001] The invention relates to a preparation method of an anti-inflammatory drug etoricoxib or a pharmaceutically acceptable salt thereof. Background technique [0002] Etoricoxib, chemically known as 5-chloro-2-(2-methyl-5-pyridyl)-3-p-methylsulfonylphenylpyridine, is a potent and selective cyclooxygenase-2 Inhibitor, which has anti-inflammatory, antipyretic and analgesic properties. Etoricoxib has been approved by regulatory authorities for clinical use as a non-steroidal anti-inflammatory drug. The drug is marketed as film-coated tablets under the trade name Arcoxia and has the following structural formula: [0003] [0004] This compound was disclosed in EP0912518B1 for the first time, and its preparation method is synthesized by palladium-catalyzed coupling of aryl / pyridyl halides with aryl / pyridyl boronic acid or stannane. The above preparation method is difficult to produce on a large scale and the material cost is expensive. [0005] EP0975596B...

Claims

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Application Information

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IPC IPC(8): C07D213/61
CPCC07D213/61
Inventor 宫庆创李国丽司志现
Owner JINAN SANYUAN CHEM CO LTD
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