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Synthetic method of celecoxib intermediate p-Sulfonamidophenylhydrazine hydrochloride

A technology of hydrazinobenzenesulfonamide and celecoxib, which is applied in the field of preparation of small molecular compounds, can solve problems such as high energy consumption, lack of access, excess nitrous acid, etc., to reduce safety risks, avoid difficult control, and facilitate personnel operation Effect

Active Publication Date: 2020-03-10
HUNAN FANGSHENG PHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It is also not feasible to add the acid solution of sulfamate to the sodium nitrite solution, because this trans-addition will cause excess nitrous acid in the system, causing the diazonium salt to decompose
Therefore, the traditional reaction mode results in a lower yield of the product
In order to reduce the occurrence of side reactions as much as possible, the existing technology reduces the temperature of the reaction system as much as possible, which will lead to high energy consumption; then try to control the adding speed of sodium nitrite, but the speed control can not completely eliminate the side reactions
[0006] Above, since 2015, although many domestic patent applications have been published, it is said that intermediates with ideal purity can be obtained, but the inventor has tried and failed to obtain the disclosed results

Method used

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  • Synthetic method of celecoxib intermediate p-Sulfonamidophenylhydrazine hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038]Add 61.3g of purified water into a 500ml reaction flask, stir and add 71.3g of 32% concentrated hydrochloric acid and 22.7g of sulfonamide. Prepare a solution of 45.0g purified water and 9.38g sodium nitrite in a 1000ml reaction bottle, and add the two kinds into the conical container at the same time. The reaction temperature is controlled at 5-15°C, and stay in it for 40-60 seconds before being discharged from the bottom. , Transfer to another reaction vial, which is stored at 0-10°C. After the diazotization reaction, 10 g of 20% sodium sulfite aqueous solution was added to the system at a temperature of 0-10° C. and stirred for 0.5-1 h. Slowly heat up to 80-90°C, add 87.1g of 32% concentrated hydrochloric acid, keep warm for 0.5-1h, cool down to 60°C, add 9.08g of Fe powder, 9.08g of activated carbon, continue to heat up to 80-90°C, stir for 0.5-1h, Filtrate while it is hot, concentrate the filtrate to 50% of the weight of the original filtrate, cool to 15-25°C to cr...

Embodiment 2

[0040] Add 61.3g of purified water into a 500ml reaction flask, stir and add 71.3g of 32% concentrated hydrochloric acid and 22.7g of sulfonamide. Prepare a solution of 45.0g of purified water and 9.38g of sodium nitrite in a 1000ml reaction bottle, stir and cool down to 0-10°C, slowly add the sulfasulfonamide solution to the sodium nitrite solution, control the system temperature at 0-10°C, and continue stirring 0.5 ~ 1h, the diazonium salt solution was obtained. Add 17 g of 20% sodium sulfite aqueous solution to the system, control the temperature of the system at 0-10° C., and stir for 0.5-1 h. Slowly heat up to 80-90°C, add 87.1g of 32% concentrated hydrochloric acid, keep warm for 0.5-1h, cool down to 60°C, add 9.08g of Fe powder, 9.08g of activated carbon, continue to heat up to 80-90°C, stir for 0.5-1h, Filtrate while it is hot, concentrate the filtrate to 50% of the weight of the original filtrate, cool to 15-25°C to crystallize for 0.5-1h, centrifuge and dry to obtai...

Embodiment 3 and 4

[0042] Repeat the operation of Example 2, the difference is that Example 3 only adds iron powder, and Example 4 only adds gac. The filtrate was concentrated to 50% and then analyzed, and the sulfonamides could be detected from the intermediate (p-hydrazinobenzenesulfonamide hydrochloride). The results are shown in Table 1.

[0043] Embodiment 2 to 4 gained intermediate purity table

[0044]

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Abstract

The invention provides a synthetic method of celecoxib intermediate p-Sulfonamidophenylhydrazine hydrochloride. The synthetic method comprises the following steps: 1) preparing a hydrochloric acid aqueous solution of sulfanilamide and an aqueous solution of sodium nitrite; 2) carrying out a diazotization reaction on the sulfonamide aqueous solution and the sodium nitrite aqueous solution, whereinthe reaction time does not exceed 1 minute; 3) transferring the obtained reaction solution into a sodium sulfite aqueous solution, and reducing excessive nitrous acid at the reduction temperature of 5-10 DEG C, (4) acidifying the reduced reaction solution, and removing impurities by using Fe powder and activated carbon, and (5) crystallizing the solution subjected to impurity removal. The synthetic method can improve the yield and purity of the intermediate through various improvements.

Description

technical field [0001] The invention relates to the field of organic synthesis, in particular to a preparation method of small molecule compounds. Background technique [0002] Blankenbuehler M, Parkin S et al. described in the literature the method for preparing the intermediate of celecoxib phenylhydrazine hydrochloride: using p-chlorobenzenesulfonamide and hydrazine hydrate through a nucleophilic substitution reaction. The reaction time of this method is longer (24h), the yield is lower (55%), and the reaction conditions are harsh, and the more toxic hydrazine hydrate is used. [0003] Wang Xinrong, Huang Haiting, Sun Zhenfang, etc. described the method of preparing celecoxib phenylhydrazine hydrochloride intermediate in the literature: p-chlorophenylbenzenesulfonamide and hydrochloric acid were reacted at 0 °C, and sodium nitrite solution was added dropwise to control the reaction. Store the prepared diazonium salt at a temperature of 0-3°C; cool the sodium sulfite solu...

Claims

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Application Information

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IPC IPC(8): C07C303/40C07C311/39
CPCC07C303/40C07C311/39
Inventor 张庆华陈波徐汨
Owner HUNAN FANGSHENG PHARMACEUTICAL CO LTD