CN106220646B - A kind of method of enzymatic clarification cefalexin mother liquor recycled - Google Patents
A kind of method of enzymatic clarification cefalexin mother liquor recycled Download PDFInfo
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- CN106220646B CN106220646B CN201610617650.XA CN201610617650A CN106220646B CN 106220646 B CN106220646 B CN 106220646B CN 201610617650 A CN201610617650 A CN 201610617650A CN 106220646 B CN106220646 B CN 106220646B
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- cefalexin
- mother liquor
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- enzymatic clarification
- desorption
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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
- C07D501/22—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with radicals containing only hydrogen and carbon atoms, attached in position 3
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- Cephalosporin Compounds (AREA)
Abstract
The invention discloses a kind of methods of enzymatic clarification cefalexin mother liquor recycled, and include the following steps：1）Under certain temperature, with acid solution adjusting cefalexin mother liquor to pH value to 2.0 ~ 3.0；2）Above-mentioned mother liquor is adsorbed, is washed, desorption operation, obtains the solution after desorption；3）Solution after obtained desorption is crystallized with ammonium hydroxide, is filtered, washed, is dried cefalexin finished product；4）By step 3）In filtrate decompression distillation；5）By the disposing mother liquor after the above-mentioned ethyl alcohol distilled and distillation, the dissolving of preparation and preceding 7 ADCA of synthesis for next strippant.Preparation method this method of the present invention is easy to operate, of low cost, energy conservation and environmental protection；Meanwhile using cefalexin made from the method for the present invention compared to the yield higher for not recycling cefalexin made from mother liquor.
Description
Technical field
The present invention relates to a kind of methods of cefalexin mother liquor recycled, and belong in cefalexin mother liquor production industry
The recycling field of resource.
Background technology
Production by Enzymes cefalexin is simple for process, easy to operate, is existing most economical method.The synthesis road of this method
Line is as follows：7-ADCA forms cefalexin by enzymatic synthesis and phthalic anhydride propylhomoserin methyl esters salt, and product head is obtained using ammonium hydroxide tune crystalline substance
Cefalexin.
Reaction finishes, and after extracting cefalexin, also is not extracted by out containing a large amount of cefalexin in mother liquor, now conventional
The method used is that a certain amount of betanaphthol is added in mother liquor, so that it is formed double salt with cefalexin, complex salt crystal is filtered
Out, it dissolves again, cefalexin therein is extracted with dichloromethane, by turning crystalline substance, be nested into the crystal solution of main technique
It is recycled.The method introduces naphthols and dichloromethane toxicant, and in complex salt crystal and two step mother liquors of extraction
Still remaining a certain amount of cefalexin can not recycle, and cause pollution and waste.Up to now, nobody is to cefalexin mother
Liquid carries out the substantive experiment of resin recycling.Currently, lacking a kind of effective recycling cephalo easy to operate, of low cost, environmentally friendly
The method of ammonia benzyl mother liquor.
Invention content
The technical problem to be solved in the invention is how efficient circulation utilizes cefalexin mother liquor, provides a kind of operation letter
It is single, of low cost, the method for environmentally friendly effective recycling cefalexin mother liquor.
In order to solve the above technical problems, the technical solution adopted in the present invention is：
A kind of method of enzymatic clarification cefalexin mother liquor recycled, includes the following steps：
Step 1), at a certain temperature, with the pH value of acid regulator adjusting cefalexin mother liquor between 2.0~3.0,
Obtain acidified mother liquor；
Step 2), temperature be 20~25 DEG C at, by above-mentioned steps 1) in acidified mother liquor cross macropore resin absorbing column, into
Row absorption, washing, desorption operation obtain the solution of desorption, and adsorption flow rate is 1.0~1.5BV/h, and washing speed is 1.0
~1.5BV/h, parsing flow velocity are 0.5~1.5BV/h, and the parsing agent that desorption uses is the ethanol water of pH=1.0, ethyl alcohol
The quality proportioning of ethyl alcohol and water is 1 in aqueous solution:4~1:6, the pH of aqueous solution is adjusted using sulfuric acid；
The desorption solution of step 2) is crystallized with the ammonium hydroxide of mass fraction 10~20%, is obtained by filtration by step 3)
Filter residue and filtrate；
Step 4) is washed filter residue, is dried, and the finished product of cefalexin is obtained；
Step 5) is evaporated under reduced pressure filtrate, and vacuum distillation temperature is 48~52 DEG C, the solvent that will be distilled respectively
With the disposing mother liquor after distillation, for the preparation of strippant next time and/or for dissolving 7-ADCA.
Technical solution of the present invention further improvement lies in that：Temperature is 20~25 DEG C in the step 1), acid regulator
For the sulfuric acid of mass fraction 20~30%.
Technical solution of the present invention further improvement lies in that：Resin column is macroporous resin adsorption column in the step 2), is inhaled
Enclosure temperature is 20~25 DEG C.
Technical solution of the present invention further improvement lies in that：Adsorption flow rate is 1.0~1.5BV/h, water in the step 2)
It is 1.0~1.5BV/h to wash speed, and parsing flow velocity is 0.5~1.5BV/h.
Technical solution of the present invention further improvement lies in that：In the step 2) in desorption operation the parsing agent that uses for
The ethanol water of pH=1.0.
Technical solution of the present invention further improvement lies in that：The quality proportioning of ethyl alcohol and water is 1 in the ethanol water:
4~1:6, the pH of aqueous solution is adjusted using sulfuric acid.
Technical solution of the present invention further improvement lies in that：Alkaline conditioner in the step 3) be mass fraction 10~
20% ammonium hydroxide.
Technical solution of the present invention further improvement lies in that：Vacuum distillation temperature in the step 5) is 35~55 DEG C.
By adopting the above-described technical solution, the technological progress that the present invention obtains is：
The present invention relates to a kind of methods of enzymatic clarification cefalexin mother liquor recycled, by the mother liquor after reaction
It adsorbed, washed, the solution that desorption operates, this solution is further crystallized to, is filtered, washed, dried and to obtain cephalo ammonia
The finished product of benzyl；Meanwhile it being evaporated under reduced pressure filtered filtrate, by the disposing mother liquor after the ethyl alcohol distilled and distillation, use is next
The dissolving of the preceding 7-ADCA of preparation and synthesis of strippant in step.
This method is easy to operate, of low cost, energy conservation and environmental protection；Meanwhile using cefalexin phase made from the method for the present invention
Compared with the yield higher for not recycling cefalexin made from mother liquor.
Mother liquor pH value is adjusted with acid solution first in the present invention, avoids the cefalexin in adsorption process
The precipitation of crystal, meanwhile, it ensure that the yield that crystal is precipitated in the follow-up process.
Present invention employs resin isolation technics, and specific to the present invention using a kind of macroporous absorbent resin, it is one
Class has organic matter the high molecular polymer of concentration, centrifugation with the characteristics of adsorbing.It is porous due to macroporous absorbent resin
Property structure keep it different to molecular size substance have screening effect, it is selective from mother liquor by the suction-operated of physics
Ground adsorbs organic substance, to achieve the purpose that separating-purifying.Its stable in physicochemical property is right insoluble in acid, alkali and organic solvent
Organic matter is selectively good, and is not influenced by existing for inorganic salts and strong ion, low molecular compound, in water and organic solvent
Middle adsorbable solvent and expand, to realize sized molecules separation purpose.Meanwhile considering in entire technical process
To the influence of the polarity, the concentration of solvent, pressure and adsorption flow rate factor of solvent, the item of adsorption and desorption is strictly controlled
Part is further ensured that in mother liquor that cefalexin can be adsorbed on macroporous absorbent resin.
Present invention employs the modes of vacuum distillation to come out ethanol distillation in filtrate, and distillation at a lower temperature is produced
Product avoid the decomposition reaction that the high temperature of product generates；Meanwhile the reaction does not need high-temperature heating equipment, saves the energy, instead
The container answered does not need high temperature resistant yet, also reduces the cost of production.
Specific implementation mode
The present invention is described in further details with reference to embodiment：
The method of a kind of enzymatic clarification cefalexin mother liquor of the present invention recycled, includes the following steps：
A kind of method of enzymatic clarification cefalexin mother liquor recycled, includes the following steps：
Step 1), at 20~25 DEG C, the pH value that cefalexin mother liquor is adjusted with the sulfuric acid of mass fraction 20-30% exists
Between 2.0~3.0, acidified mother liquor is obtained；
Step 2), temperature be 20~25 DEG C at, by above-mentioned steps 1) in acidified mother liquor cross macropore resin absorbing column, into
Row absorption, washing, desorption operation obtain the solution of desorption, and adsorption flow rate is 1.0~1.5BV/h, and washing speed is 1.0
~1.5BV/h, parsing flow velocity are 0.5~1.5BV/h, and the parsing agent that desorption uses is the ethanol water of pH=1.0, ethyl alcohol
The quality proportioning of ethyl alcohol and water is 1 in aqueous solution:4~1:6, the pH of aqueous solution is adjusted using sulfuric acid；
The desorption solution of step 2) is crystallized with the ammonium hydroxide of mass fraction 10~20%, is obtained by filtration by step 3)
Filter residue and filtrate；
Step 4) is washed filter residue, is dried, and the finished product of cefalexin is obtained；
Step 5) is evaporated under reduced pressure filtrate, and vacuum distillation temperature is 48~52 DEG C, the solvent that will be distilled respectively
With the disposing mother liquor after distillation, for the preparation of strippant next time and/or for dissolving 7-ADCA.With reference to embodiment pair
The present invention is described in further details：
Cefalexin mother liquor employed in following embodiments is institute after the upper normal production cefalexin Crystallization Separation of production
The mother liquor of generation.Wherein cefalexin content 15mg/ml or so, 7-DACA content 0.3mg/ml, phenylglycine content 0.1mg/
ml。
Embodiment 1,
2.6L cefalexin mother liquors are taken, with 25% sulfuric acid tune pH to 2.52, temperature controls 21 DEG C.Then pass through resin to inhale
Attached, adsorption flow rate 1.5BV/h, resin column loading amount is 500mL, eutectoid content 2600mL, about 39g cefalexins.With the water washing of 1BV
After resin column, parsed with the speed of 1BV/h with the molten aqueous solution of 20% ethyl alcohol of pH=1.0, temperature controls 21 DEG C, collects
0.75BV terminates.By the desorbed solution 0.75BV (total 375mL) of collection with 15% ammonium hydroxide tune pH to going out crystalline substance, growing the grain 30 minutes.After
The ammonium hydroxide of continuous dropwise addition 15% stops being added dropwise, temperature is down to 9.5 DEG C, growing the grain 30 minutes to pH=4.50.Vacuum filtration, in temperature
It is 2 hours dry at 40 DEG C, obtain cefalexin 38.0g, the cefalexin rate of recovery 97.4%, (remarks：1BV refers to 1 times of resin column
Volume) through high performance liquid chromatography detection, cefalexin purity 99.8%.
The secondary mother liquid of crystallization, under the conditions of 48 DEG C, hydrous ethanol 105mL, gas chromatographic detection content are recycled in vacuum distillation
69.0%, ethanol recovery 96.6%, secondary mother liquid volume is 245mL, ethyl alcohol residual 0.01%, cefalexin after recycling ethyl alcohol
Remain 2.2mg/ml.
Embodiment 2,
2.6L cefalexin mother liquors are taken, with 25% sulfuric acid tune pH to 2.60, temperature is controlled at 21 DEG C.Then pass through resin
Absorption, adsorption flow rate 1.5BV/h, resin column loading amount are 500mL, eutectoid content 2600mL, about 39g cefalexins.With the washing of 1BV
After washing resin column, parsed with the speed of 1BV/h with the molten aqueous solution of 20% ethyl alcohol of pH=1.0, temperature controls 20 DEG C.It collects
0.75BV terminates.By the desorbed solution 0.75BV (total 375mL) of collection with 15% ammonium hydroxide tune pH to going out crystalline substance, growing the grain 30 minutes.After
The ammonium hydroxide of continuous dropwise addition 15% stops being added dropwise, temperature is down to 8.5 DEG C, growing the grain 30 minutes to pH=4.50.Vacuum filtration, in temperature
It is 2 hours dry at 40 DEG C, obtain cefalexin 37.8g, the cefalexin rate of recovery 96.9%, (1BV refers to 1 times of resin column volume)
Through high performance liquid chromatography detection, cefalexin purity 99.8%.
The secondary mother liquid of crystallization, under the conditions of 50 DEG C, hydrous ethanol 100mL, gas chromatographic detection content are recycled in vacuum distillation
68.8%, ethanol recovery 91.7%, secondary mother liquid volume is 248mL, ethyl alcohol residual 0.02%, cefalexin after recycling ethyl alcohol
Remain 2.2mg/ml.
Embodiment 3,
2.6L cefalexin mother liquors are taken, with 25% sulfuric acid tune pH to 2.55, temperature is controlled at 22 DEG C.Then pass through resin
Absorption, adsorption flow rate 1.5BV/h, resin column loading amount are 500mL, eutectoid content 2600mL, about 39g cefalexins.With the washing of 1BV
After washing resin column, parsed with the speed of 1BV/h with the molten aqueous solution of 20% ethyl alcohol of pH=1.0, temperature is controlled at 21 DEG C, is collected
0.75BV terminates.By the desorbed solution 0.75BV (total 375mL) of collection with 15% ammonium hydroxide tune pH to going out crystalline substance, growing the grain 30 minutes.After
The ammonium hydroxide of continuous dropwise addition 15% stops being added dropwise, temperature is down to 9.0 DEG C, growing the grain 30 minutes to pH=4.50.Vacuum filtration, in temperature
It is 2 hours dry at 40 DEG C, obtain cefalexin 38.0g, the cefalexin rate of recovery 97.4%, (remarks：1BV refers to 1 times of resin column
Volume) through high performance liquid chromatography detection, cefalexin purity is 99.8%.
The secondary mother liquid of crystallization, under the conditions of 51 DEG C, hydrous ethanol 110mL, gas chromatographic detection content are recycled in vacuum distillation
64.1%, ethanol recovery 94.0%, secondary mother liquid volume is 245mL, ethyl alcohol residual 0.01%, cefalexin after recycling ethyl alcohol
Remain 2.2mg/ml.
Embodiment 4,
2.6L cefalexin mother liquors are taken, with 25% sulfuric acid tune pH to 2.42.Temperature is controlled at 22 DEG C.Then pass through resin
Absorption, adsorption flow rate 1.5BV/h, resin column loading amount are 500mL, eutectoid content 2600mL, about 39g cefalexins.With the washing of 1BV
After washing resin column, parsed with the speed of 1BV/h with the molten aqueous solution of 20% ethyl alcohol of pH=1.0, temperature is controlled at 23 DEG C, is collected
0.75BV terminates.By the desorbed solution 0.75BV (total 375mL) of collection with 15% ammonium hydroxide tune pH to going out crystalline substance, growing the grain 30 minutes.After
The ammonium hydroxide of continuous dropwise addition 15% stops being added dropwise, temperature is down to 9.5 DEG C, growing the grain 30 minutes to pH=4.50.Vacuum filtration, in temperature
It is 2 hours dry at 40 DEG C, obtain cefalexin 38.2g, the cefalexin rate of recovery 97.9%, (remarks：1BV refers to 1 times of resin column
Volume) through high performance liquid chromatography detection, cefalexin purity is 99.6%.
The secondary mother liquid of crystallization, under the conditions of 52 DEG C, hydrous ethanol 97mL, gas chromatographic detection content are recycled in vacuum distillation
69.3%, ethanol recovery 89.6%, secondary mother liquid volume is 245mL, ethyl alcohol residual 0.01%, cefalexin after recycling ethyl alcohol
Remain 2.3mg/ml.
It, can will be after the above-mentioned ethyl alcohol distilled and distillation after the method for the present invention recycling cefalexin mother liquor finishes
Disposing mother liquor, the dissolving for 7-ADCA before the preparation and synthesis of next strippant.The production that this method will be used to recycle mother liquor
Product are compared with the product for not recycling mother liquor, and the results are shown in Table 1, although the quality in product does not obviously change
Become, still, after mother liquid recycling is used, the weight yield of product improves 3 to 5 percentage points.
Table 1
Claims (6)
1. a kind of method of enzymatic clarification cefalexin mother liquor recycled, includes the following steps：
Step 1）, in the case where temperature is 20 ~ 25 DEG C, with the pH value of acid regulator adjusting cefalexin mother liquor between 2.0 ~ 3.0,
Obtain acidified mother liquor；
Step 2）, by above-mentioned steps 1）In acidified mother liquor cross resin column, adsorbed, washed, desorption operation, desorbed
Attached solution；
The parsing agent used in desorption operation is the ethanol water of pH=1.0；The quality of ethyl alcohol and water is matched in ethanol water
Than being 1:4~1:6；
Step 3）, by step 2）Desorption solution crystallized with alkaline conditioner, filter residue and filtrate is obtained by filtration；
Step 4）, filter residue is washed, is dried, the finished product of cefalexin is obtained；
Step 5）, filtrate is evaporated under reduced pressure, respectively by the disposing mother liquor after the solvent distilled and distillation, for next
The preparation of secondary strippant and/or for dissolving 7-ADCA；
Vacuum distillation temperature is 35 ~ 55 DEG C.
2. the method for a kind of enzymatic clarification cefalexin mother liquor according to claim 1 recycled, it is characterised in that：
The step 1）Middle acid regulator is the sulfuric acid of mass fraction 20 ~ 30%.
3. the method for a kind of enzymatic clarification cefalexin mother liquor according to claim 1 recycled, it is characterised in that：
The step 2）Middle resin column is macroporous resin adsorption column, and adsorption temp is 20 ~ 25 DEG C.
4. the method for a kind of enzymatic clarification cefalexin mother liquor according to claim 3 recycled, it is characterised in that：
The step 2）Middle adsorption flow rate is 1.0 ~ 1.5 BV/h, and washing speed is 1.0 ~ 1.5 BV/h, parsing flow velocity for 0.5 ~
1.5BV/h。
5. the method for a kind of enzymatic clarification cefalexin mother liquor according to claim 1 recycled, it is characterised in that：
The pH of aqueous solution is adjusted using sulfuric acid.
6. according to a kind of method of enzymatic clarification cefalexin mother liquor recycled of claim 1 ~ 5 any one of them,
It is characterized in that：The step 3）In alkaline conditioner be mass fraction 10 ~ 20% ammonium hydroxide.
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| CN108084209B (en) * | 2018-02-09 | 2020-06-02 | 国药集团威奇达药业有限公司 | method for recovering β -lactam antibiotics from β -lactam antibiotic mother liquor synthesized by enzyme method |
| CN108084210A (en) * | 2018-02-09 | 2018-05-29 | 国药集团威奇达药业有限公司 | The method that cefalexin is recycled from enzymatic clarification cefalexin mother liquor |
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| NL1007077C2 (en) * | 1997-09-19 | 1999-03-22 | Dsm Nv | Method for the recovery of a ß-lactam antibiotic. |
| NL1007076C2 (en) * | 1997-09-19 | 1999-03-22 | Dsm Nv | Method for the recovery of a ß-lactam antibiotic. |
| CN102060861B (en) * | 2010-11-04 | 2012-12-12 | 浙江工业大学 | Desalination concentration method for cephalo mother liquor |
| CN104058537B (en) * | 2014-04-30 | 2015-08-05 | 浙江工业大学 | A kind of method processing Cephalexin Monohydrate Micro/Compacted enzymatic clarification mother liquor waste water |
| CN105349608B (en) * | 2015-12-16 | 2019-01-25 | 厦门市天泉鑫膜科技股份有限公司 | The recoverying and utilizing method of phenylglycine in a kind of cefalexin crystalline mother solution |
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Effective date of registration: 20190213 Address after: 050000 No. 388 Heping East Road, Shijiazhuang City, Hebei Province Patentee after: Huabei Pharmaceutical Co., Ltd. Address before: 052165 No. 98 Hainan Road, Shijiazhuang Economic and Technological Development Zone, Hebei Province Patentee before: NCPC Hebei Huamin Pharma Co., Ltd. |