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Method for preparing intermediate thiophene sulfonamide of brinzolamide

A technology of thiophene sulfonamide and phene sulfonamide, which is applied in the field of preparation of brinzolamide intermediate thiophene sulfonamide, can solve the problems of unfavorable environmental protection, heavy odor, and high risk of butyl lithium, so as to reduce the harm to the human body and optimize the preparation The method, the effect of low production cost

Active Publication Date: 2014-09-10
山东诚汇双达药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The method needs chlorine gas flow, chlorine gas blowing, ammonia gas flow, ammonia gas blowing, etc., the steps are cumbersome, and the smell is heavy, which is not conducive to environmental protection, and it is difficult to control the reaction temperature in the oxidation step, which has the risk of flushing, inconvenient operation, and The smell is heavy, sodium tungstate with higher price is needed for oxidation, and the production cost is higher
In addition, it has been reported that butyllithium, sulfur dioxide, and hydroxylamine sulfonate can be used to place the sulfonamide group on the 2-position of the thiophene ring, but this method requires a low temperature of -70°C, and butyllithium is more dangerous, which is harmful to equipment and operation. The requirements are high, which is not conducive to mass production

Method used

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  • Method for preparing intermediate thiophene sulfonamide of brinzolamide
  • Method for preparing intermediate thiophene sulfonamide of brinzolamide

Examples

Experimental program
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Effect test

Embodiment 1

[0027] Add 210g of 3-acetyl-5-chloro-2-(benzylmercapto)thiophene and 1500g of acetonitrile into a 5L four-neck flask, stir, add 320g of glacial acetic acid and 200g of water, control the temperature between 0-15°C, and batch Add 241.6g of trichloroisocyanuric acid, and complete the addition in about 30 minutes, keep the reaction at 0-15°C, and monitor the reaction by TLC until the raw materials disappear. Water bath at 35-45°C, concentrate under reduced pressure to remove the solvent, add 1500g of 25% ethyl acetate petroleum ether solution, stir, filter, and evaporate the filtrate to dryness under reduced pressure to obtain 182.7g of light yellow oil, which is 3-acetyl-5- Chloro-2-thiophenesulfonyl chloride.

[0028] Dilute the above-mentioned sulfonyl chloride with 105g of ethyl acetate, control the temperature at 0-15°C, add it dropwise to 420g of ammonia water, stir the reaction until the sulfonyl chloride disappears, lower the temperature to about 0°C, and stir for crystal...

Embodiment 2

[0030] Add 210g of 3-acetyl-5-chloro-2-(benzylmercapto)thiophene and 1500g of ethyl acetate to a 5L four-neck flask, stir, add 320g of glacial acetic acid and 200g of water, and control the temperature between 0-15°C. Add 241.6 g of trichloroisocyanuric acid in batches, complete the addition in about 30 minutes, keep the reaction at 0-15°C, and monitor the reaction by TLC until the raw materials disappear. Water bath at 40-50°C, concentrate under reduced pressure to remove the solvent, add 1500g of 25% ethyl acetate petroleum ether solution, stir, filter, and evaporate the filtrate to dryness under reduced pressure to obtain 180.3g of light yellow oily substance, which is 3-acetyl-5- Chloro-2-thiophenesulfonyl chloride.

[0031] Dilute the above-mentioned sulfonyl chloride with 105g of ethyl acetate, control the temperature at 0-15°C, add it dropwise to an aqueous solution containing 46g of methylamine, stir the reaction until the sulfonyl chloride disappears, lower the temper...

Embodiment 3

[0033] Add 184.4g of 3-acetyl-2-(benzylmercapto)thiophene and 1500g of dichloromethane into a 5L four-neck flask, stir, add 320g of glacial acetic acid and 200g of water, control the temperature between 0-15°C, and add in batches 241.6g of trichloroisocyanuric acid was added in about 30 minutes, kept at 0-15°C for reaction, and monitored by TLC until the raw materials disappeared. Water bath at 30-35°C, concentrate under reduced pressure to remove the solvent, add 1500g of 25% ethyl acetate petroleum ether solution, stir, filter, and evaporate the filtrate to dryness under reduced pressure to obtain 160.3g of light yellow oil, which is 3-acetyl-2- Thiophenesulfonyl chloride.

[0034] Dilute the above-mentioned sulfonyl chloride with 105g of ethyl acetate, control the temperature at 0-15°C, add it dropwise to 420g of ammonia water, stir the reaction until the sulfonyl chloride disappears, lower the temperature to about 0°C, and stir for crystallization for 1h. Filter, wash wit...

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Abstract

The invention belongs to the technical field of pharmaceutical chemicals, in particular relates to a method for preparing an intermediate thiophene sulfonamide of brinzolamide and is applicable to industrial production. The method comprises the following steps: dissolving thiophene benzyl sulfide in a proper solvent, adding glacial acetic acid and water, controlling the temperature to 0-15 DEG C, adding trichloroisocyanuric acid in batches in 20-40 minutes, reacting at the constant temperature until the raw materials disappear, performing vacuum concentration in a water bath at the temperature of 30-50 DEG C to remove the solvent, adding ethyl acetate petroleum ether solution with the mass concentration of ethyl acetate being 25%, stirring, filtering, evaporating the filtrate under reduced pressure, thereby obtaining thiophenesulfonyl chloride; controlling the temperature to 0-15 DEG C, diluting thiophenesulfonyl chloride by ethyl acetate, dropwise adding a dilution into ammonium hydroxide or a water solution of amine, stirring and reacting until the raw materials disappear, filtering, washing, drying the solids, and obtaining the thiophene sulfonamide. The product obtained by using the method is high in yield, simple and convenient in operation, low in cost and mild in reaction conditions and is suitable for large-scale production.

Description

technical field [0001] The invention belongs to the technical field of medicine and chemical industry, in particular to a method for preparing brinzolamide intermediate thiophene sulfonamide, especially for preparing 3-acetyl-5-chloro-2-thiophene sulfonamide and 3-acetyl-2 -The method of thiophene sulfonamide, suitable for industrial production. Background technique [0002] Brinzolamide is a new type of local carbonic anhydrase inhibitor, which is a heterocyclic sulfonamide drug, which was approved for marketing in the United States in 1998. Brinzolamide has high selectivity and affinity, and can significantly inhibit the activity of carbonic anhydrase, effectively reducing intraocular pressure. Brinzolamide has a longer half-life and less irritation to the eyes. Its physiological pH value and suspension design make eye drops comfortable, with good tolerance and safety, and less adverse reactions (usually it can be cured without treatment. self-relief), is a very valuable...

Claims

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Application Information

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IPC IPC(8): C07D333/34
CPCC07D333/34
Inventor 王庭见谭光明李跃东葛正全
Owner 山东诚汇双达药业有限公司
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