CN103755726A - Cefalonium refinement purification method - Google Patents

Cefalonium refinement purification method Download PDF

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Publication number
CN103755726A
CN103755726A CN201310677079.7A CN201310677079A CN103755726A CN 103755726 A CN103755726 A CN 103755726A CN 201310677079 A CN201310677079 A CN 201310677079A CN 103755726 A CN103755726 A CN 103755726A
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Prior art keywords
cephalonium
purifying
washing
acid
filtrate
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姚志扬
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FUJIAN FUKANG PHARMACEUTICAL Co Ltd
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FUJIAN FUKANG PHARMACEUTICAL Co Ltd
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Priority to CN201310677079.7A priority Critical patent/CN103755726A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
    • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
    • C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
    • C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
    • C07D501/38—Methylene radicals, substituted by nitrogen atoms; Lactams thereof with the 2-carboxyl group; Methylene radicals substituted by nitrogen-containing hetero rings attached by the ring nitrogen atom; Quaternary compounds thereof
    • C07D501/46—Methylene radicals, substituted by nitrogen atoms; Lactams thereof with the 2-carboxyl group; Methylene radicals substituted by nitrogen-containing hetero rings attached by the ring nitrogen atom; Quaternary compounds thereof with the 7-amino radical acylated by carboxylic acids containing hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/02—Preparation
    • C07D501/12—Separation; Purification

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Cephalosporin Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention discloses a cefalonium refinement purification method, wherein a cefalonium crude product is dissolved in a prepared diluted acid solution, active carbon decolorization is performed, the pH value and the temperature are adjusted, recrystallization is performed to precipitate the crystal, and the crystal is washed and dried to prepare the cefalonium pure product. The cefalonium refinement purification method has characteristics of simple operation step, high product purity, low raw material prices and low production cost.

Description

A kind of process for refining and purifying of Cephalonium
Technical field
The present invention relates to the process for refining and purifying of medicine, relate in particular to a kind of process for refining and purifying of Cephalonium.
Background technology
Cephalonium, molecular weight is to be for 458.51, No. CAS 5575-21-3, molecular formula is C 20H 18n 4o 5s 2, Chinese another name is (6R, 7R)-3-[(4-formamido--1-pyridine) and methyl]-8-oxo-7-[(2-thiophene-2-base acetyl) amino]-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid inner salt.Be mainly used in the mazoitis control of withered milk phase of milk cow.This medicine belongs to long-acting, broad-spectrum microbiotic, can effectively treat and prevent the withered each bacterial infection of milk phase of milk cow.The structural formula of this medicine is as follows:
Figure BDA0000435938530000011
Summary of the invention
The process for refining and purifying that the object of the present invention is to provide a kind of Cephalonium, the method has simple to operate, the feature that yield is high.
For achieving the above object, the present invention adopts following technical scheme:
A process for refining and purifying for Cephalonium, it comprises the following steps:
1) preparation of solvent, it is 33%～67% dilute acid soln that purified water and acid are mixed with to concentration, and be cooled to 0 ℃～40 ℃ standby;
2) by the Cephalonium dissolving crude product of 4～6wt% in the dilute acid soln described in step 1), be stirred to completely and dissolve, dissolve the activated carbon decolorizing 20～30 minutes that adds 0.13%～2wt% in backward solution, remove by filter gac, retain filtrate, the Cephalonium of purifying on the lower gac of washing with 4%～20wt%, merges the filtrate of washing water and filtration;
3) in filtrate, slowly drip inorganic alkali lye, extremely muddy rear growing the grain 20～30 minutes; Continue to drip inorganic alkali lye to filtrate pH4～5, be cooled to 0～10 ℃, at this temperature, stirred crystallization 1h～3h, removes by filter mother liquor, obtains Cephalonium xln;
4) the Cephalonium xln of described step 3) is first purified to moisture three times washing with 8～60wt%, then divide three washings with 2%～20wt% acetone, the crystal after washing is passed through to vacuum-drying and obtain product.
In described step 1), organic acid or mineral acid are Glacial acetic acid, sulfuric acid, the one in hydrochloric acid.
Described step 2) in washing during filter residue, point three washings.
In described step 3), inorganic alkali lye is NaOH solution.
The process for refining and purifying of a kind of Cephalonium of the present invention, the main method that adopts recrystallization, by the pH value of regulation system, temperature, and under agitation make Cephalonium molecule formation crystal separate out, impurity is stayed in solution and is filtered and removes, and the crystal forming is washed with organic solvent, in order to avoid plane of crystal is with impurity, it is simple that it has operation steps, product purity is high, the feature that production cost is low.
Embodiment
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment are only not used in and limit the scope of the invention for the present invention is described.In addition should be understood that those skilled in the art can make various changes or modification to the present invention after having read the content of the present invention's instruction, these equivalent form of values fall within the application's claims limited range equally.
A process for refining and purifying for Cephalonium, it comprises the following steps:
1) preparation of solvent, it is 33%～67% dilute acid soln that purified water and acid are mixed with to concentration, and be cooled to 0 ℃～40 ℃ standby;
2) by the Cephalonium dissolving crude product of 4～6wt% in the dilute acid soln described in step 1), be stirred to completely and dissolve, dissolve the activated carbon decolorizing 20～30 minutes that adds 0.13%～2wt% in backward solution, remove by filter gac, retain filtrate, the Cephalonium of purifying on the lower gac of washing with 4%～20wt%, merges the filtrate of washing water and filtration;
3) in filtrate, slowly drip inorganic alkali lye, extremely muddy rear growing the grain 20～30 minutes; Continue to drip inorganic alkali lye to filtrate pH4～5, be cooled to 0～10 ℃, at this temperature, stirred crystallization 1h～3h, removes by filter mother liquor, obtains Cephalonium xln;
4) the Cephalonium xln of described step 3) is first purified to moisture three times washing with 8～60wt%, then divide three washings with 2%～20wt% acetone, the crystal after washing is passed through to vacuum-drying and obtain product.
In described step 1), organic acid or mineral acid are Glacial acetic acid, sulfuric acid, the one in hydrochloric acid.
Described step 2) in washing during filter residue, point three washings.
In described step 3), inorganic alkali lye is NaOH solution.
Embodiment 1
In reaction flask, add water 138ml, Glacial acetic acid 160ml is mixed with mixed solvent, under agitation adds 11.56g Cephalonium crude product in mixed solvent, continues to be stirred to present clear solution; Add gac 0.4g, decolour 20 minutes, filter, the Cephalonium solution of purifying on the lower filter residue of washing with 12ml, in filtrate, dripping concentration is that 10%NaOH solution is extremely muddy, growing the grain 30 minutes, continuing to drip concentration is 10%NaOH solution, regulates pH to 4.0; Be cooled to 0 ℃, stir 1～3h and carry out growing the grain, remove by filter filtrate, with 5.96ml acetone, divide and three times crystal is washed, vacuum-drying obtains finished product, its yield 95.8%; Its purity 98.6%.
Embodiment 2
In reaction flask, add water 158ml, Glacial acetic acid 170ml is mixed with mixed solvent, under agitation adds 19.68g Cephalonium crude product in mixed solvent, continues to be stirred to present clear solution; Add gac 6.56g, decolour 30 minutes, filter, the Cephalonium solution of purifying on the lower filter residue of washing with 6.56ml, in filtrate, dripping concentration is that 30%NaOH solution is extremely muddy, growing the grain 30 minutes, continues to drip 30%NaOH solution, regulates pH to 5.0; Be cooled to 10 ℃, stir 1～3h and carry out growing the grain, remove by filter filtrate, with 65.6ml acetone, divide and three times crystal is washed, vacuum-drying obtains finished product.Its yield 94.5%; Its purity 99.2%.
Embodiment 3
In reaction flask, add water 120ml, Glacial acetic acid 130ml is mixed with mixed solvent, under agitation adds 13g Cephalonium crude product in mixed solvent, continues to be stirred to present clear solution; Add gac 2.5g, decolour 25 minutes, filter, the Cephalonium solution of purifying on the lower filter residue of washing with 25ml, drips 20%NaOH solution to muddy in filtrate, and growing the grain 20 minutes, continues to drip 20%NaOH solution, regulates pH to 4.5; Be cooled to 5 ℃, stir 1～3h and carry out growing the grain, remove by filter filtrate, with 25ml acetone, divide and three times crystal is washed, vacuum-drying obtains finished product, its yield 96.2%; Its purity 98.3%.
Embodiment 4
In reaction flask, add water 200ml, Glacial acetic acid 190ml is mixed with mixed solvent, under agitation adds 18.7g Cephalonium crude product in mixed solvent, continues to be stirred to present clear solution; Add gac 5.85g, decolour 30 minutes, filter, the Cephalonium solution of purifying on the lower filter residue of washing with 58.5ml, drips 15%NaOH solution to muddy in filtrate, and growing the grain 30 minutes, continues to drip 15%NaOH solution, regulates pH to 4.9; Be cooled to 5 ℃, stir 1～3h and carry out growing the grain, remove by filter filtrate, with 10 parts of acetone, divide and three times crystal is washed, vacuum-drying obtains finished product, its yield 94.2%; Its purity 99.3%.

Claims (4)

1. a process for refining and purifying for Cephalonium, is characterized in that: it comprises the following steps:
1) preparation of solvent, it is 33% ~ 67% dilute acid soln that purified water and acid are mixed with to concentration, and be cooled to 0 ℃～40 ℃ standby;
2) by the Cephalonium dissolving crude product of 4 ~ 6wt% in the dilute acid soln described in step 1), be stirred to completely and dissolve, dissolve the activated carbon decolorizing 20～30 minutes that adds 0.13% ~ 2wt% in backward solution, remove by filter gac, retain filtrate, the Cephalonium of purifying on the lower gac of washing with 4% ~ 20wt%, merges the filtrate of washing water and filtration;
3) in filtrate, slowly drip inorganic alkali lye, extremely muddy rear growing the grain 20～30 minutes; Continue to drip inorganic alkali lye to filtrate pH 4～5, be cooled to 0 ~ 10 ℃, at this temperature, stirred crystallization 1h～3h, removes by filter mother liquor, obtains Cephalonium xln;
4) the Cephalonium xln of described step 3) is first purified to moisture three times washing with 8 ~ 60wt%, then use 2% ~ 20wt% acetone to divide three washings, the crystal after washing is passed through to vacuum-drying and obtain product.
2. the process for refining and purifying of a kind of Cephalonium according to claim 1, is characterized in that: in described step 1), organic acid or mineral acid are Glacial acetic acid, sulfuric acid, the one in hydrochloric acid.
3. the process for refining and purifying of a kind of Cephalonium according to claim 1, is characterized in that: described step 2) in washing during filter residue, point three washings.
4. the process for refining and purifying of a kind of Cephalonium according to claim 1, is characterized in that: in described step 3), inorganic alkali lye is NaOH solution.
CN201310677079.7A 2013-12-12 2013-12-12 Cefalonium refinement purification method Pending CN103755726A (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107417704A (en) * 2017-05-31 2017-12-01 齐鲁晟华制药有限公司 A kind of process for purification of cefapirin sodium
CN110330510A (en) * 2019-08-19 2019-10-15 齐鲁动物保健品有限公司 A kind of preparation method of cefalonium dihydrate crystal form
CN116514840A (en) * 2023-06-30 2023-08-01 齐鲁晟华制药有限公司 Preparation method of delta-3 cefalotin isomer compound

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1067644A (en) * 1964-07-31 1967-05-03 Lilly Co Eli Antibiotic cephalosporin compounds and process for preparing same
US3449338A (en) * 1968-11-04 1969-06-10 Lilly Co Eli Cephalosporin ca derivatives
CN101891755A (en) * 2010-07-27 2010-11-24 海南永田药物研究院有限公司 Cefsulodin sodium compound and novel preparation method thereof
CN103242346A (en) * 2013-05-21 2013-08-14 重庆替安科技有限公司 Cefalonium preparation method

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1067644A (en) * 1964-07-31 1967-05-03 Lilly Co Eli Antibiotic cephalosporin compounds and process for preparing same
US3449338A (en) * 1968-11-04 1969-06-10 Lilly Co Eli Cephalosporin ca derivatives
CN101891755A (en) * 2010-07-27 2010-11-24 海南永田药物研究院有限公司 Cefsulodin sodium compound and novel preparation method thereof
CN103242346A (en) * 2013-05-21 2013-08-14 重庆替安科技有限公司 Cefalonium preparation method

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107417704A (en) * 2017-05-31 2017-12-01 齐鲁晟华制药有限公司 A kind of process for purification of cefapirin sodium
CN107417704B (en) * 2017-05-31 2020-05-12 齐鲁晟华制药有限公司 Method for refining cefapirin sodium
CN110330510A (en) * 2019-08-19 2019-10-15 齐鲁动物保健品有限公司 A kind of preparation method of cefalonium dihydrate crystal form
CN116514840A (en) * 2023-06-30 2023-08-01 齐鲁晟华制药有限公司 Preparation method of delta-3 cefalotin isomer compound

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Application publication date: 20140430