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Synthesis method of parecoxib sodium impurity

A technology of parecoxib sodium and its synthesis method, which is applied in the field of chemical pharmacy, can solve problems affecting product quality, etc., and achieve the effects of improving accurate positioning and qualitative, easy-to-obtain raw materials, and simple operation

Inactive Publication Date: 2015-09-30
CHENGDU CLIMB PHARMA TECH
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Problems solved by technology

[0004] Impurity D 4-[5-methyl-3-(3-phenylsulfonic acid)-1,2-oxazol-4-yl]benzenesulfonic acid is hydrolyzed due to double sulfonation during the synthesis of parecoxib sodium The impurity produced may remain in the final product of Parecoxib Sodium, affecting the quality of the product. Its structural formula is as shown in (I). After retrieval, there is no bibliographical report about the synthesis of this impurity. Therefore, a Parecoxib Sodium is provided. The synthetic method of Buna impurity D has important practical significance for the preparation of impurity standard

Method used

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  • Synthesis method of parecoxib sodium impurity
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  • Synthesis method of parecoxib sodium impurity

Examples

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Embodiment 1

[0022] Example 1: Synthetic method of parecoxib sodium impurity D 4-[5-methyl-3-(3-phenylsulfonic acid)-1,2-oxazol-4-yl]benzenesulfonic acid

[0023] Add 3g of 5-methyl-3,4-diphenylisoxazole, 6g of dichloromethane, and 42g of chlorosulfonic acid into the reaction flask, reflux at 40°C for 14h, add the reaction solution dropwise to 50g of water, 12g of dichloro Extract with methane, concentrate to dryness, add 12g ethyl acetate to crystallize for 1.5h, filter to get 4-[5-methyl-3-(3-phenylsulfonyl chloride)-1,2-oxazol-4-yl]benzenesulfonate Acid chloride 4.1g, yield 74.4%.

[0024] Add 3 g of the above 4-[5-methyl-3-(3-phenylsulfonyl chloride)-1,2-oxazol-4-yl]benzenesulfonyl chloride to the reaction flask, add 10 g of water, 10 g of acetonitrile, Reflux at 85°C for 12h, depressurize to -0.09MPa and concentrate to obtain 2.6g of white solid , That is, 4-[5-methyl-3-(3-phenylsulfonic acid)-1,2-oxazol-4-yl]benzenesulfonic acid with a yield of 94.8%.

[0025] Parecoxib sodium imp...

Embodiment 2

[0028] Example 2: Synthetic method of parecoxib sodium impurity D 4-[5-methyl-3-(3-phenylsulfonic acid)-1,2-oxazol-4-yl]benzenesulfonic acid

[0029] Add 3g of 5-methyl-3,4-diphenylisoxazole, 18g of dichloromethane, and 60g of chlorosulfonic acid into the reaction flask, reflux at 50°C for 18 hours, add the reaction solution dropwise to 50g of water, 12g of dichloromethane Extract with methane, concentrate to dryness, add 12g ethyl acetate to crystallize for 2.5h, filter to get 4-[5-methyl-3-(3-phenylsulfonyl chloride)-1,2-oxazol-4-yl]benzenesulfonate Acid chloride 4.3g, yield 78.0%.

[0030] Add 4g of the above 4-[5-methyl-3-(3-phenylsulfonyl chloride)-1,2-oxazol-4-yl]benzenesulfonyl chloride to the reaction flask, add 20g of water and 20g of acetonitrile, Reflux at 95°C for 20 hours, depressurize to -0.08MPa and concentrate to obtain 3.5g of white solid, which is 4-[5-methyl-3-(3-phenylsulfonic acid)-1,2-oxazol-4-yl] Benzenesulfonic acid, yield 95.7%, purity 99.3%.

Embodiment 3

[0031] Embodiment 3: The synthetic method of parecoxib sodium impurity D 4-[5-methyl-3-(3-phenylsulfonic acid)-1,2-oxazol-4-yl]benzenesulfonic acid

[0032] Add 5g of 5-methyl-3,4-diphenylisoxazole, 20g of dichloromethane, and 85g of chlorosulfonic acid into the reaction flask, reflux at 43°C for 15 hours, add the reaction solution dropwise to 80g of water, 20g of dichloro Extract with methane, concentrate to dryness, add 20g ethyl acetate to crystallize for 1.8h, filter to get 4-[5-methyl-3-(3-phenylsulfonyl chloride)-1,2-oxazol-4-yl]benzenesulfonate Acid chloride 7.4g, yield 80.5%.

[0033] Add 5g of the above 4-[5-methyl-3-(3-phenylsulfonyl chloride)-1,2-oxazol-4-yl]benzenesulfonyl chloride to the reaction flask, add 15g of water and 15g of acetonitrile, Reflux at 88°C for 15 hours, reduce the pressure to -0.07MPa and concentrate to obtain 4.4g of white solid, which is 4-[5-methyl-3-(3-phenylsulfonic acid)-1,2-oxazol-4-yl] Benzenesulfonic acid, yield 96.2%, purity 99.5%. ...

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Abstract

The invention discloses a synthesis method of a parecoxib sodium impurity 4-[5-methyl-3-(3-phenylsulfonic acid)-1,2-oxazole-4-yl] benzenesulfonic acid, belonging to the technical field of chemical pharmacy. The synthesis method comprises the following step of performing sulfonation reaction and hydrolysis reaction on starting raw materials including 5-methyl-3,4-diphenyl isoxazole, dichloromethane and chlorosulfonic acid to produce the parecoxib sodium impurity. The synthesized high-purity parecoxib sodium impurity can be used as an impurity standard sample in the detection analysis of a finished product of parecoxib sodium, so that accurate positioning and qualifying effects of the detection analysis of the finished product of parecoxib sodium for the impurity can be improved, which is beneficial to enhancing the control over the impurity and further improving the quality of the finished product of parecoxib sodium. The synthesis method disclosed by the invention has the advantages that the raw materials are cheap and easily available, the operation is simple, the product yield is 95%+ / -5%, and HPLC purity is 99% or above.

Description

technical field [0001] The invention belongs to the technical field of chemical pharmacy, in particular to parecoxib sodium impurity D 4-[5-methyl-3-(3-phenylsulfonic acid)-1,2-oxazol-4-yl]benzenesulfonic acid synthetic method. Background technique [0002] The inflammatory response after noxious stimuli such as surgery and trauma can lead to the release of inflammatory mediators and pain-causing substances. In addition to directly causing pain, they can also cause blood vessels to dilate, tissue edema, increase the sensitivity of effector receptors, and reduce the pain threshold. This results in peripheral hyperalgesia. Selective COX-2 inhibitors can effectively inhibit the expression of peripheral COX-2 and reduce the synthesis of peripheral prostaglandins, thereby exerting analgesic and anti-inflammatory effects. At the same time, they can inhibit the expression of central COX-2, inhibit the synthesis of central prostaglandins and inhibit pain hypersensitivity Give full...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D261/08
CPCC07D261/08
Inventor 蒋明勇刘芍利叶丁林蓉莹
Owner CHENGDU CLIMB PHARMA TECH
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