Method for crystallizing cloxacillin sodium

A cloxacillin sodium and crystallization technology, applied in the field of compound preparation, can solve the problems of uneven crystal particle size, large batch-to-batch variation, and high residual solvent, achieve uniform crystal particle size, eliminate visible foreign matter, and have good process controllability Effect

Inactive Publication Date: 2011-05-25
河北华日药业有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Since the crystallization reaction will be affected by many factors such as reaction speed, diffusion speed, diffusion speed, particle arrangement speed, reaction heat, phase change heat, etc., the existing methods have low liquid phase content, long filtration time, difficult drying, and small crystals. And incomplete, uneven crystal size, large batch-to-batch variation, low yield, unqualified visible foreign matter, high residual solvent, high production cost, etc.

Method used

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  • Method for crystallizing cloxacillin sodium

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Effect test

Embodiment 1

[0023] At room temperature, add 10g of 6-APA into 40ml of water, cool down in an ice bath, adjust the pH to 5.0-9.0 with ammonia water, and add 20ml of acetone to make solution A;

[0024] Add 11g of 3-o-chlorophenyl-5-methyl-4-isoxazole chloride into 60ml of acetone, adjust the pH of the solution to 6.0-8.0, start stirring and adjust it to 150r / min to prepare solution B.

[0025] Add 60ml of solution B into solution A, stir evenly, add a mixed solution consisting of methanol and butyl acetate with a mass ratio of 1:1; ) solution 100ml to carry out salt-forming reaction, when the generated cloxacillin sodium content reaches 10% (mg / ml), carry out vacuum distillation, vacuum pressure is-0.07~-0.09Mpa, after the crystal is separated out, carry out crystal growth 60 minutes; then perform suction filtration, wash the filter cake twice with 100 ml of acetone, and vacuum-dry at 50° C. to obtain white powder crystals (cloxacillin sodium crystals). The yield is 89.95%, the crystal gr...

Embodiment 2

[0027] At room temperature, add 10g of 6-APA into 100ml of water, cool down in an ice bath, adjust the pH to 5.0-9.0 with sodium hydroxide solution, and add 100ml of acetone to make solution A;

[0028] Add 15g of 3-o-chlorophenyl-5-methyl-4-isoxazole chloride into 100ml of acetone, and adjust the pH value of the solution to 6.0-8.0, start stirring and adjust it to 50r / min, and adjust the pH value of the solution to 6.8 -7.2, make solution B;

[0029] Add solution B into solution A, stir evenly, add a mixture of ethanol and butyl acetate with a mass ratio of 1:3; add 60 ml of butyl acetate solution of sodium isooctanoate with a mass volume ratio concentration of 30%, and perform salt formation Reaction, when the generated cloxacillin sodium content reaches 20% (mg / ml), carry out decompression distillation gradually, vacuum pressure is-0.07~-0.09Mpa, after crystal is separated out, carry out crystal growth 90 minutes; Then carry out After suction filtration, the filter cake wa...

Embodiment 3

[0031] At room temperature, add 10g of 6-APA into 75ml of water, cool down in an ice bath, adjust the pH to 5.0-9.0 with ammonia water, and add 150ml of acetone to make solution A;

[0032] Add 16g of 3-o-chlorophenyl-5-methyl-4-isoxazole chloride into 150ml of acetone, adjust the pH value of the solution to 6.0-8.0, start stirring and adjust it to 50r / min to make solution B;

[0033] Add solution B in solution A, stir evenly, add the mixed solution of isopropanol and butyl acetate that the mass ratio is 1:9; Add the sodium isooctanoate methyl isobutyl ketone (MIBK ) solution 60ml, carry out salt-forming reaction, when the generated cloxacillin sodium content reaches 20% (mg / ml), carry out decompression distillation gradually, vacuum pressure is-0.07~-0.09Mpa, after crystal is separated out, Carry out crystal growth for 120 minutes; then carry out suction filtration, wash the filter cake twice with 150ml acetone, and vacuumize and dry at 50°C to obtain white powder crystals (c...

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Abstract

The invention provides a method for crystallizing cloxacillin sodium, which comprises the following steps: weighing 6-aminopenicillanic acid and 3-chloro-O-phenyl-5-methyl-4-isoxazole acyl chloride according to a mass ratio of 1.0 / 0.5 to 2.5; adding water and acetone into the 6-aminopenicillanic acid to prepare a solution A; adding the 3-chloro-O-phenyl-5-methyl-4-isoxazole acyl chloride into the acetone to prepare a solution B; adding the solution B into the solution A to be uniformly stirred for carrying out acidylation reaction for 0.5 to 4h; adding acid for acidification after the reaction is completed, and adding mixed liquid of lower alcohol and butyl acetate for extraction; adding sodium iso-octoate organic solution for carrying out salt forming reaction, and carrying out reduced pressure distillation and crystal growing; and carrying out suction filtration, washing and drying. In the method provided by the invention, the product quality and the yield of the cloxacillin sodium can be effectively improved, the production period is shortened, and the production cost is reduced.

Description

technical field [0001] The present invention relates to the preparation method of compound, specifically the crystallization method of cloxacillin sodium. Background technique [0002] Cloxacillin Sodium is a broad-spectrum semi-synthetic penicillin, suitable for respiratory tract infection, gastrointestinal tract infection, urinary tract infection, soft tissue infection, endocarditis, meningitis, sepsis, etc. caused by sensitive bacteria. It can also be used for mixed infection caused by Streptococcus pyogenes or pneumococcus and penicillin-resistant Staphylococcus. The chemical name of cloxacillin sodium is (2S, 5R, 6R)-3,3-dimethyl-6-[5-methyl-3-(2-chlorophenyl)-4-isoxazoleformyl Amino]-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid sodium salt, molecular weight 475.87, molecular formula: C 19 h 17 ClN 3 NaO 5 S·H 2 O, the chemical structural formula is: [0003] [0004] The preparation method of cloxacillin sodium is usually 3-o-chlorophenyl-5-methy...

Claims

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Application Information

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IPC IPC(8): C07D499/76C07D499/16
Inventor 李晓宇张义恩郝小良郭秀敏金树辉安欣林韩志伟刘敏李振强刘欣焦玮孙振军
Owner 河北华日药业有限公司
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