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Preparation method of non-chlorine gas of acetazolamide key intermediate 2-acetamido-5-chlorosulfonyl-1, 3, 4-thiadiazole

A technology of acetamido and acetazolamide, applied in the field of preparation of pharmaceutical intermediates

Active Publication Date: 2015-04-22
ZHONGSHUAI PHARMA SCI & TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Industrial production of acetazolamide uses compressed and liquefied liquid chlorine, which is stored in steel cylinders. The requirements for equipment and worker proficiency are very strict. Once leaked, it will cause serious consequences. Moreover, there is no obvious reaction end point in the chlorine gas oxidation process, and the reaction time is long. , the leakage of chlorine gas that cannot be absorbed cannot be completely avoided, the equipment is highly corrosive, the environment is not friendly, and it is harmful to the operator's body

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Embodiment 1: (be prior art, promptly utilize chlorine method to prepare acetamide intermediate)

[0028] First, put 2-amino-5-mercapto-1,3,4-thiadiazole (200g, 1.5mol), acetic anhydride (170mL) and glacial acetic acid (440mL) in a reaction flask, heat to reflux for 3h, after the reaction Cool to 20°C, filter, wash the filter cake with water, and dry under vacuum at 45°C to obtain 235 g of light yellow solid 2-acetylamino-5-mercapto-1,3,4-thiadiazole.

[0029] Put the above-prepared 2-amino-5-mercapto-1,3,4-thiadiazole (50.0 g) and 33% glacial acetic acid aqueous solution (290 mL) in a reaction flask, and slowly introduce chlorine gas under an ice bath, The obtained reactant was filtered until the reactant was saturated, and the filter cake was washed with water to obtain 2-acetamido-5-chlorosulfonyl-1,3,4-thiadiazole as a brown solid; the liquid phase purity was 75%.

[0030] The 2-acetylamino-5-chlorosulfonyl-1,3,4-thiadiazole prepared above was gradually added to 30...

Embodiment 2

[0032] The non-chlorine gas preparation method of the key intermediate of acetazolamide 2-acetylamino-5-chlorosulfonyl-1,3,4-thiadiazole of the present invention, the detailed steps of the preparation method are as follows:

[0033] a. First, add 100mL of hydrochloric acid with a mass percentage concentration of 35% into the reactor, and then dropwise add 180mL of hydrogen peroxide with a mass percentage concentration of 30%. ℃, after the hydrogen peroxide is added dropwise, the temperature is raised to 5-10 ℃ and the reaction is carried out for 1 hour, and the reaction liquid is obtained after the reaction;

[0034] b. Then add 10.0 g of 2-acetylamino-5-mercapto-1,3,4-thiadiazole in batches to the reaction solution obtained in step a, and the added 2-acetylamino-5-mercapto-1,3, Suspend 4-thiadiazole in the reaction system, then incubate and react at 10-15°C for 5 hours, and obtain the reactant after the reaction is completed;

[0035] c. The reactant obtained in step b is di...

Embodiment 3

[0039] The non-chlorine gas preparation method of the key intermediate of acetazolamide 2-acetylamino-5-chlorosulfonyl-1,3,4-thiadiazole of the present invention, the detailed steps of the preparation method are as follows:

[0040] a. First add 50mL of hydrochloric acid with a mass percentage concentration of 35% into the reactor bottle, and then dropwise add 235mL of hydrogen peroxide with a mass percentage concentration of 30%. During the dropping process, use an ice-salt bath to control the temperature of the reaction system at -5~ 0°C, after the hydrogen peroxide is added dropwise, raise the temperature to 5-10°C and react for 1 hour, and the reaction solution is obtained after the reaction;

[0041] b. Then add 10.0 g of 2-acetylamino-5-mercapto-1,3,4-thiadiazole in batches to the reaction solution obtained in step a, and the added 2-acetylamino-5-mercapto-1,3, 4-thiadiazole is suspended in the reaction system, and then reacted at 5-10°C for 8 hours, and the reactant is ...

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Abstract

The invention discloses a preparation method of non-chlorine gas of acetazolamide key intermediate 2-acetamido-5-chlorosulfonyl-1, 3, 4-thiadiazole. The preparation method comprises the steps of firstly adding hydrochloric acid into a reactor and then dropwise adding hydrogen peroxide to perform reaction so as to obtain a reaction solution; adding 2-acetamido-5-sulfydryl-1, 3, 4-thiadiazole into the obtained reaction solution in batch to perform reaction and obtaining a reactant after reaction is completed; directly conducting suction filtration, washing and drying on the reactant and performing drying to obtain the intermediate 2-acetamido-5-chlorosulfonyl-1, 3, 4-thiadiazole. The preparation method is more moderate in operate and more environment-friendly, and the obtained intermediate 2-acetamido-5-chlorosulfonyl-1, 3, 4-thiadiazole is good in color and luster and high in purity.

Description

technical field [0001] The invention relates to a preparation method of a pharmaceutical intermediate, belonging to the field of medicinal chemistry, in particular to a non-chlorine gas of acetazolamide key intermediate 2-acetylamino-5-chlorosulfonyl-1,3,4-thiadiazole Preparation. Background technique [0002] Acetazolamide was first synthesized in 1950 by Roblin and Clapp (Roblin, R.O.Jr&Clapp.J.W: J.Amer. Chem.Soc., 1950,72,4890), 2-amino-5-mercapto-1,3,4- Thiadiazole first reacts with acetic anhydride to obtain 2-acetylamino-5-mercapto-1,3,4-thiadiazole, and then obtains 2-acetylamino-5-chlorosulfonyl-1,3, 4-Thiadiazole, finally ammoniated with ammonia to obtain acetazolamide. In 1955, the patent of Span et al. (US222209) also disclosed the same method for preparing acetazolamide. This method has been used until now, but the biggest disadvantage of this method is the preparation of 2-acetylamino-5-chlorosulfonyl-1,3,4-thiadiazole by the chlorine gas method. Chlorine ga...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D285/135
CPCC07D285/135
Inventor 刘杰陈静牛冰
Owner ZHONGSHUAI PHARMA SCI & TECH CO LTD
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