Preparation method of 4-carboxy-3-hydroxy-5-mercapto-isothiazole salt

A technology of isothiazole salt and hydroxyl, which is applied in the field of preparation of pharmaceutical intermediates, can solve the problems of increased production cycle and cost, poor product quality, and fewer manufacturers, and achieve significant economic benefits, good product quality, and reduced production cycle. Effect

Active Publication Date: 2011-12-14
CANGZHOU SENARY CHEM SCI TEC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] 4-carboxy-3-hydroxy-5-mercapto-isothiazole salt is a special side chain for the production of cefotetan, and there are few domestic manufacturers with cumbersome processes and poor product quality
[0009] The above-mentioned patent is referred to in the bibliographical material Cefotetan Side Chain (Fine and Specialty Chemicals 2003-24, P25-26), and a three-step synthesis of 4-carboxy-3-hydroxyl-5-mercapto from initial raw materials malononitrile and carbon disulfide is introduced. -The method of isothiazolium salt, the intermediate of each step needs to be refined and purified, which increases the production cycle and cost

Method used

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  • Preparation method of 4-carboxy-3-hydroxy-5-mercapto-isothiazole salt

Examples

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Embodiment 1

[0026] (1), the synthesis of dicyano-U-vinyl mercaptide: add mass concentration 95% ethanol 500kg, 52kg industrial sodium hydroxide in 1000L glass-lined reactor, stir and dissolve clarification, cool to 0 ℃-10 with salt water °C, slowly add 40 kg of malononitrile, and stir for 30 minutes to obtain a light green transparent liquid. Control the temperature at 10-15°C, add 46 kg of carbon disulfide dropwise, and a large amount of light yellow solid precipitates. The temperature was raised to 20° C., and the reaction was carried out for 2 hours to obtain a yellow-white viscous substance, which was filtered and dried to obtain a light yellow solid. Dissolve the above-mentioned light yellow solid in 120kg of purified water, add 600kg of ethanol dropwise to the water after dissolving, and after the addition, lower the temperature to 0-5°C and grow the crystal for 2 hours. Filtrate, wash with absolute ethanol, and spin dry to obtain a light yellow solid, which is vacuum-dried to obta...

Embodiment 2

[0029] (1), the synthesis of dicyano-U-vinyl mercaptide: with embodiment 1.

[0030] (2), the synthesis of 4-carboxy-3-hydroxyl-5-mercapto-isothiazolium salt: add water 300kg in 1000L enamel reaction kettle, dicyano-U-vinyl mercaptide 92kg (dry), after stirring and dissolving , add 82 kg of hydrogen peroxide with a mass concentration of 30% dropwise. After adding, heat up to 20° C., stir for 1 hour, add 110 kg of sodium hydroxide, stir for 1 hour, transfer to a 500L stainless steel belt reflux reactor, and steam to reflux. For hydrolysis reaction, the reflux temperature is 115°C, reflux for 4 hours. After the reaction is completed, transfer the material to a 500L enamel kettle to cool down, add 300kg of water, control the temperature at 5-10°C, and add isooctanoic acid dropwise to adjust the pH value to 7.8-8.2. Cool down to about 0°C, grow crystals for 2 hours, filter, spin dry, wash with acetone-water slurry (volume ratio of acetone-water: water:acetone=1:1), spin dry, vacuu...

Embodiment 3

[0032] (1), the synthesis of dicyano-U-vinyl mercaptide: add mass concentration 95% ethanol 500kg, 73kg industrial potassium hydroxide in 1000L glass-lined reactor, stir and dissolve clarification, cool to 0 ℃-10 with salt water °C, slowly add 40 kg of malononitrile, and stir for 30 minutes to obtain a light green transparent liquid. Control the temperature at 10-15°C, add 46 kg of carbon disulfide dropwise, and a large amount of light yellow solid precipitates. The temperature was raised to 20° C., and the reaction was carried out for 2 hours to obtain a yellow-white viscous substance, which was filtered and dried to obtain a light yellow solid. Dissolve the above-mentioned light yellow solid in 120kg of purified water, add 600kg of ethanol dropwise to the water after dissolving, and after the addition, lower the temperature to 0-5°C and grow the crystal for 2 hours. Filtrate, wash with absolute ethanol, and spin dry to obtain a light yellow solid, which is vacuum-dried to o...

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Abstract

The invention discloses a preparation method of 4-carboxy-3-hydroxyl-5-mercapto-isothiazolium salt. The steps of the method are: (1) Synthesis of dicyano-U-vinyl mercaptide: from malononitrile Reaction with carbon disulfide in the presence of ethanol and alkali to obtain dicyano-U-vinyl mercaptide, (2) Synthesis of 4-carboxy-3-hydroxyl-5-mercapto-isothiazolium salt: dicyano-U-ethylene The base thiolate is cyclized under the oxidation of hydrogen peroxide, and then reflux reaction under the action of alkali, and then the pH value is adjusted with acid to precipitate 4-carboxy-3-hydroxy-5-mercapto-isothiazole salt. The method changes the original three-step synthesis into two-step synthesis, reduces the production period, improves the yield, reduces the production cost, and is more suitable for industrial production.

Description

technical field [0001] The invention relates to a preparation method of a pharmaceutical intermediate, in particular to a preparation method of a cefotetan side chain compound 4-carboxy-3-hydroxyl-5-mercapto-isothiazolium salt. Background technique [0002] Cefotetan is the second-generation cephalosporin antibiotic jointly developed by Japan Yamanouchi Company and AstraZeneca Company. It is widely used in clinical practice. It has the following chemical structure: [0003] [0004] The disodium salt of cefotetan acid is used clinically, which mainly has a strong antibacterial effect on a variety of Gram-negative aerobic and anaerobic bacteria, and has a weaker effect on Gram-positive bacteria. It also has a strong antibacterial effect on strains producing β-lactamase. This product has a higher and longer-lasting blood concentration after injection. This product is mainly used for the treatment of superficial secondary infections such as sepsis, burns, and surgical incis...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D275/03
Inventor 牛志刚白松明李志刚于树岭
Owner CANGZHOU SENARY CHEM SCI TEC
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