CN107698607B - The comprehensive recovering process of effective component in the crystalline mother solution of enzymatic clarification ampicillin - Google Patents
The comprehensive recovering process of effective component in the crystalline mother solution of enzymatic clarification ampicillin Download PDFInfo
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- CN107698607B CN107698607B CN201710743701.8A CN201710743701A CN107698607B CN 107698607 B CN107698607 B CN 107698607B CN 201710743701 A CN201710743701 A CN 201710743701A CN 107698607 B CN107698607 B CN 107698607B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/21—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a nitrogen atom directly attached in position 6 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D499/44—Compounds with an amino radical acylated by carboxylic acids, attached in position 6
- C07D499/48—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical
- C07D499/58—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical
- C07D499/64—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical by nitrogen atoms
- C07D499/68—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical by nitrogen atoms with aromatic rings as additional substituents on the carbon chain
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/38—Separation; Purification; Stabilisation; Use of additives
- C07C227/40—Separation; Purification
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/21—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a nitrogen atom directly attached in position 6 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D499/42—Compounds with a free primary amino radical attached in position 6
Abstract
The invention belongs to pharmaceutical technology fields, are related to the comprehensive recovering process of effective component in the crystalline mother solution of enzymatic clarification ampicillin.The present invention realizes the separation of D-PG Yu ampicillin, 6-APA and D-PG methyl esters using the separate mode of macroporous absorbent resin, D-PG is not by resin adsorption, into absorption extraction raffinate, for the absorption extraction raffinate after electrodialysis, reverse osmosis concentration, crystallization, recycling obtains the D-PG of high-quality；And the ampicillin on resin, 6-APA and D-PG methyl esters are adsorbed on after parsing, it is concentrated by nanofiltration, obtained nanofiltration concentrate can directly serve as the reaction bottom water during the enzymatic clarification of ampicillin and then recovery.Effective component D-PG, ampicillin, 6-APA, D-PG methyl esters in synthetical recovery of the present invention enzyme process ampicillin crystalline mother solution, create economic benefit, while reducing the discharge of high-concentration waste water, realize environment-protecting clean green production.
Description
Technical field
The invention belongs to pharmaceutical technology field, the synthesis for being related to effective component in the crystalline mother solution of enzymatic clarification ampicillin is returned
Receiving method.
Background technique
Ampicillin, entitled (2S, 5R, 6R) -3,3- dimethyl -6- [(R) -2- amino -2- phenylacetylamino] -7- of chemistry
Oxo -4- thia -1- azabicyclo [3.2.0] heptane -2- formic acid, free acid contain three molecular crystalline water, it is a kind of common
Penicillins wide spectrum beta-lactam antibiotic.
Ampicillin bactericidal effect, penetrating cell wall it is very capable, be current widely used oral penicillin
One of.The preparation method of ampicillin has chemical synthesis and two kinds of enzyme process, and chemical method is because of its reaction step complexity, synthesis condition
Harshness, and entire reaction process needs to use a variety of organic chemistry raw materials, generates a large amount of three wastes, pollution is more serious, and sharp
With enzymatic clarification ampicillin, the use of organic solvent can avoid, reaction condition is mild, and low energy consumption, and easy to operate, whole process is green
Colour circle is protected.Meanwhile the ampicillin purity of enzymatic clarification is higher than the product of chemical method synthesis, Drug safety and stability are big
Width is promoted, therefore enzyme process becomes the main path of production ampicillin.
In the technique of enzymatic clarification ampicillin, generally using D-PG methyl ester hydrochloride as acyl side-chain donor,
It is condensed in the case where synthesis is acted on immobilization penicillin acylated enzyme catalysis with 6-amino-penicillanic acid (6-APA) and generates ampicillin.
Since synthesis is stronger with the hydrolysing activity of immobilized penicillin acylated enzyme itself, raw material D-PG methyl ester hydrochloride and
There is a different degrees of hydrolysis in product ampicillin, with the presence of a large amount of D-PG in crystalline mother solution, furthermore in mother liquor still
Having largely cannot be by crystallizing obtained ampicillin and a small amount of 6-APA for having neither part nor lot in synthetic reaction, this allows for enzyme
The economy of method synthesis ampicillin is had a greatly reduced quality.So how effectively in comprehensive reutilization mother liquor it is above-mentioned effectively at
Point, become the important subject that current ampicillin enzymatic clarification technique faces.
Chinese patent literature CN102851332A discloses the recycling of D-PG in a kind of mother liquor of enzyme process ampicillin
Remaining ampicillins a large amount of in mother liquor are hydrolyzed to D-PG and 6- first by way of enzymatic lysis by method, this method
APA recycles the D-PG in mother liquor then using ultrafiltration, nanofiltration, active carbon decoloring, decrease temperature crystalline.Using upper
The method of stating can recycle D-PG from mother liquor, although the method for using enzymatic lysis makes ampicillin, D-PG
Methyl esters hydrolysis, but still remains ampicillin and D-PG methyl esters in mother liquor, and in mother liquor 6-APA then by a large amount of waves
Take.Therefore, in the prior art, to more efficiently and environmentally friendly in the mother liquor of synthetical recovery ampicillin it is remaining effectively
, there are needs in ingredient, the value for farthest excavating residual mother liquor.
Summary of the invention
Therefore, that the purpose of the present invention is to provide a kind of technological designs is reasonable, easy to operate, recovering effect is good and product matter
The method for measuring effective component in excellent synthetical recovery enzyme process ampicillin crystalline mother solution, the i.e. sweet ammonia of D- benzene in recycling mother liquor
Acid, D-PG methyl esters, ampicillin and 6-APA.
In order to achieve the object of the present invention, the technical scheme adopted by the invention is as follows: using the separation side of macroporous absorbent resin
Formula realizes the separation of D-PG Yu other three kinds of substances, and D-PG should not into absorption extraction raffinate by resin adsorption
Extraction raffinate is adsorbed after electrodialysis plant removes most of salts substances, after reverse osmosis concentration, crystallization, recycling obtains high-quality
D-PG；And the ampicillin on resin, 6-APA and D-PG methyl esters are adsorbed on after parsing, by nanofiltration
Concentration, obtained nanofiltration concentrate can directly serve as the reaction bottom water during the enzymatic clarification of ampicillin and then recovery set
With.
According to the present invention, in the crystalline mother solution of synthetical recovery enzyme process provided by the invention ampicillin effective component method,
Include the following steps:
(1) absorption and parsing of ampicillin, 6-APA and D-PG methyl esters
Enzyme process ampicillin crystalline mother solution is female by it by macroporous absorbent resin after separating with ampicillin crystal
Ampicillin, 6-APA and D-PG methyl esters in liquid are attracted on resin, and D-PG is by resin adsorption,
Resin is flowed through with mother liquor and is collected as absorption extraction raffinate；
Then, the ampicillin, 6-APA and the D-PG methyl esters that are adsorbed on resin are solved using parsing agent
Analysis, obtains desorbed solution, the desorbed solution directly served as after nanofiltration is concentrated the reaction bottom water during the enzymatic clarification of ampicillin into
And recovery；
(2) D-PG is prepared using electrodialysis, reverse osmosis, crystallization
Desalination is carried out using the absorption extraction raffinate that electrodialysis plant obtains above-mentioned steps (1), is obtained except saline solution；
Then 8.8~9.5 will be adjusted to except saline solution pH using alkali, and use molecular cut off for the anti-of 100~200 dalton
This except saline solution is concentrated, is obtained D-PG concentrate by permeable membrane；
Under the conditions of 30 DEG C~45 DEG C, it is sweet that the pH value of D-PG concentrate is adjusted to 4.5~5.5, D- benzene with acid
Propylhomoserin crystallization is gradually precipitated, and is cooled to 0 DEG C~10 DEG C, and growing the grain filters, dry, obtains D-PG.
Compared with the prior art, the advantages of the present invention are as follows:
D-PG in the crystalline mother solution of enzyme process ampicillin is successfully realized using the separate mode of macroporous absorbent resin
With the separation of ampicillin, 6-APA, D-PG methyl esters, and a large amount of pigment and impurity are also attracted on resin, are reached
At the purpose of decoloration removal of impurities.
Then, using suitable parsing agent to be adsorbed on resin ampicillin, 6-APA, D-PG methyl esters into
Row parsing, desorbed solution can serve as the reaction bottom water during the enzymatic clarification of ampicillin after nanofiltration is concentrated, in ammonia benzyl west
6-APA and D-PG methyl esters are consumed in woods synthesis process, recycles ampicillin during later crystallization, to access
The purpose of 6-APA, D-PG methyl esters and ampicillin into recycling mother liquor.
Extraction raffinate is adsorbed using electrodialysis, reverse osmosis, crystallization treatment, most of salts substances can not only be removed and correlation is miscellaneous
Matter improves the solution quality of recycling D-PG, and realizes the efficient concentration of D-PG in mother liquor, substantially mentions
The high yield of recycling D-PG product.
Effective component D-PG, ampicillin in synthetical recovery of the present invention enzyme process ampicillin crystalline mother solution,
6-APA, D-PG methyl esters, create economic benefit, while reducing the discharge of high-concentration waste water, realize environment-protecting clean
Green production.
Specific embodiment
In the following, further illustrating the side of effective component in synthetical recovery enzyme process ampicillin crystalline mother solution of the invention
Method.
In the step (1), enzyme process ampicillin crystalline mother solution is passed through after separating with ampicillin crystal
Macroporous absorbent resin, ampicillin, 6-APA and D-PG methyl esters in mother liquor are attracted on resin, and the sweet ammonia of D- benzene
Acid flows through resin with mother liquor and is collected as absorption extraction raffinate not by resin adsorption；Then, using parsing agent to being adsorbed on resin
Ampicillin, 6-APA and D-PG methyl esters parsed, obtain desorbed solution, the desorbed solution after nanofiltration is concentrated directly
Serve as the reaction bottom water and then recovery during the enzymatic clarification of ampicillin.
In the technique of enzymatic clarification ampicillin, 6-APA and D-PG methyl ester hydrochloride are in immobilized penicillin acid
Change under enzyme catalysis, condensation generates ampicillin, the enzyme process ampicillin crystalline mother solution after the separation of ampicillin crystal
In, D-PG concentration is 2.50~3.50g/L, and 6-APA concentration is 1.30~1.60g/L, D-PG methyl acetate concentrations
For 0.50~1.00g/L, ampicillin concentration is 3.20~4.20g/L, and pH value is 4.8~5.2.
Enzyme process ampicillin crystalline mother solution is passed through into macroporous absorbent resin, ampicillin, 6-APA and D- in mother liquor
Phenylglycine methyl ester is attracted on resin, and D-PG is not by resin adsorption.Wherein, the table of the macroporous absorbent resin
Surface properties are intermediate-polarity macroporous adsorption resin, specially acrylate or 2- methacrylate based polymers, more specifically, can
Select AmberliteTMXAD-6, XAD-7, XAD-8 in XAD series.
The macroporous absorbent resin is crystallized ampicillin female wet method dress post application in the form of round resin column bed
Liquid, by large pore resin absorption column bed, is preferably passed through with certain flow velocity with the flow velocity of 1.0~3.0 times of resin total volumes per hour
Resin column bed；The height and diameter ratio (i.e. ratio of height to diameter) of round resin column bed are 4 or bigger；Macroporous absorbent resin is to ammonia benzyl west
Woods, 6-APA, the adsorbance of D-PG methyl esters are related to the characteristic of the concentration of substance each in mother liquor and resin, specific real
It applies in example and is detected with one of above-mentioned three kinds of substances in column bed lower end exit as foundation, stop upper prop when detection.
D-PG is not adsorbed by large pore resin absorption column bed, is flowed through resin with mother liquor and is collected as absorption extraction raffinate,
Without D-PG methyl esters and ampicillin in the absorption extraction raffinate, D-PG concentration is 2.50~3.50g/L, and 6-APA is dense
Degree is 0~0.10g/L, and conductivity is 170~190ms/cm.
Ampicillin, 6-APA, D-PG methyl esters are attracted on resin column bed, using parsing agent to be adsorbed on tree
Ampicillin, 6-APA on rouge column bed, D-PG methyl esters are parsed.Parsing agent used is aqueous acid and alcohol with one
The mixed liquor that fixed ratio mixes, wherein acid used can be hydrochloric acid or sulfuric acid, alcohol used can for methanol, ethyl alcohol,
Or mixtures thereof isopropanol；The pH of parsing agent used is 0.5~2.0, preferably 1.0；It is overall based on parsing agent with volume basis
Product, the ratio of alcohol used are greater than 0 and to be less than or equal to 40%, preferably 10%~30%, and most preferably 20%；When parsing, parsing
The flow control of agent be per hour be 0.5~1.0 times of resin total volume, preferred 0.75 times of resin total volume per hour；Parsing is opened
After beginning, using ampicillin in high performance liquid chromatography detection resin column outlet efflux, ammonia in efflux is exported when being collected into
Benzyl XiLin concentration be lower than 0.30g/L when stop collect, this portion collection to efflux be desorbed solution, wherein the sweet ammonia of D- benzene
Acid concentration is 0~0.05g/L, and 6-APA concentration is 2.50~5.00g/L, and D-PG methyl acetate concentrations are 1.00~3.00g/
L, ampicillin concentration are 6.00~12.00g/L.
Then, use molecular cut off for the nanofiltration membrane of 150~300 dalton, preferably molecular cut off is 150~200
Generally desorbed solution is concentrated under 5~8 DEG C of cryogenic conditions for the nanofiltration membrane of dalton, the process can remove part inorganic salts and
Most of alcohols material, avoids the inhibition during subsequent apply to synthesis enzyme, and ampicillin, 6-APA, D-PG
Methyl esters is trapped in concentrate, and the sum of purity (high performance liquid chromatography) of three kinds of substances is greater than 90%, the concentrate
The reaction bottom water during the enzymatic clarification of ampicillin can be directly served as.
Without D-PG in the nanofiltration concentrate, 6-APA concentration is 15.00~20.00g/L, D-PG
Methyl acetate concentrations are 6.00~12.00g/L, and ampicillin concentration is 35.00~50.00g/L.
In the step (2), firstly, the absorption extraction raffinate desalination obtained using electrodialysis plant to above-mentioned steps (1), electricity
Electrodialysis apparatus, for example, being provided by Shanghai Kai Xin isolation technics Co., Ltd, the membrane stack used is by 20 pairs of homogeneous-phase anion exchange films
Formed with homogeneous phase cation exchange film, the substrate of film is Kynoar, amberplex length × width × height be 400mm ×
200mm×0.2mm。
The absorption extraction raffinate that above-mentioned steps (1) are obtained imports in the light room of electrodialysis plant, using batch cycles formula desalination
Process, in 5~10A/cm2It is 20V that electrodialysis desalination, which is handled to voltage stabilization, under the conditions of constant current density, in 20V pressure stabilizing item
It is 2~5ms/cm to get to except saline solution that electrodialysis desalination, which is handled to conductivity, under part.It adsorbs extraction raffinate and desalinates desalination by electrodialysis
Afterwards, the feed liquid quality except saline solution is not only increased, and the reverse osmosis concentration multiple of subsequent step has and significantly improves.
Then, 8.8~9.5, preferably 9.0~9.5 will be adjusted to except saline solution pH using alkali, alkali used can be sodium hydroxide
Or ammonium hydroxide.Within the scope of the pH, it can guarantee that the solubility of D-PG is larger, so that cycles of concentration is very high.So
Afterwards, use molecular cut off for the reverse osmosis membrane of 100~200 dalton, more preferable molecular cut off is 100~150 dalton
Reverse osmosis membrane, most preferably molecular cut off be 100 dalton reverse osmosis membrane, will it is above-mentioned except saline solution concentration, finally obtain dense
The D-PG solution of contracting.
In obtained D-PG concentrate, the concentration of general D-PG is 40.00~50.00g/L, 6-
The concentration of APA is 0~2.00g/L.
It, can be under the conditions of 30 DEG C~45 DEG C, preferably 35 DEG C~40 DEG C in the crystallization of the step (2) D-PG
The pH value of the D-PG solution of concentration is slowly adjusted to 4.5~5.5 with concentrated hydrochloric acid, preferably 4.8~5.2, D- is to hydroxyl
Phenylglycine crystallization be precipitated, slow cooling to 0 DEG C~10 DEG C, preferably 0 DEG C~5 DEG C, by growing the grain, be filtered, washed and dried after,
Obtain the standard compliant D-PG product of quality.Crystalline mother solution therein can be recycled in above-mentioned steps (2) and apply
Recycling, to improve the yield of D-PG.
The present invention is further illustrated below by embodiment, but protection scope of the present invention is not limited to these embodiments
In.
Embodiment 1
Effective component in the crystalline mother solution of synthetical recovery ampicillin as follows:
(1) absorption and parsing of ampicillin, 6-APA and D-PG methyl esters
Take the enzyme process ampicillin crystalline mother solution after the Crystallization Separation of ampicillin, wherein D-PG concentration is
2.67g/L, 6-APA concentration are 1.44g/L, and D-PG methyl acetate concentrations are 0.89g/L, and ampicillin concentration is 4.08g/L,
PH value is 4.95.The mother liquor with the flow velocity of 4L per hour by large pore resin absorption column bed (resin model XAD-6, loading amount 2L,
Ratio of height to diameter is that 4), ampicillin, 6-APA and D-PG methyl esters are attracted on resin, and D-PG is not by resin
Absorption flows through resin with mother liquor and is collected as absorption extraction raffinate.When detection ampicillin, 6- in the efflux of column bed lower end exit
When one of APA and D-PG methyl esters, stop upper prop.In the absorption extraction raffinate being collected into, D-PG concentration is
2.62g/L, 6-APA concentration are 0.07g/L, conductivity 177ms/cm, volume 24L.
After absorption, mother liquor volume amounts to 24L.Then, use pH for 1.0 hydrochloric acid/methyl alcohol mixed liquor
(wherein methanol account for parsing agent volume 20%) as parsing agent, is parsed with the flow velocity of 2.0L per hour, when being collected into outlet stream
Stop collecting when ampicillin concentration is lower than 0.3g/L in liquid out, the efflux that this portion collection arrives amounts to 12L, as parses
Liquid, wherein D-PG concentration be 0.01g/L, 6-APA concentration be 2.74g/L, D-PG methyl acetate concentrations are 1.73g/
L, ampicillin concentration is 7.51g/L；
Then, concentrate is obtained in 5~8 DEG C of concentration desorbed solutions using the nanofiltration membrane that molecular cut off is 160 dalton,
In, 6-APA concentration is 15.89g/L, and D-PG methyl acetate concentrations are 9.34g/L, and ampicillin concentration is 42.81g/L, and
High performance liquid chromatography detection the sum of 6-APA, D-PG methyl esters and liquid phase purity of three kinds of ampicillin substance as the result is shown
It is 94.2%, which can directly serve as the reaction bottom water during the enzymatic clarification of ampicillin and then recovery.
(2) D-PG is prepared using electrodialysis, reverse osmosis, crystallization
Desalination is carried out using the absorption extraction raffinate that electrodialysis plant obtains above-mentioned steps (1), in 5A/cm2Constant current is close
It is 20V, conductivity 2.7ms/cm that electrodialysis desalination, which is handled to voltage stabilization, under the conditions of degree, is obtained except saline solution.
Then, 9.0 will be adjusted to except saline solution pH using the sodium hydroxide solution of 40wt%, and use molecular cut off for 100
This except saline solution is concentrated, is obtained D-PG concentrate by the reverse osmosis membrane of dalton, wherein the concentration of D-PG is
The concentration of 46.24g/L, 6-APA are 1.17g/L.
Under the conditions of 35 DEG C, the pH value of D-PG concentrate is adjusted to 4.8, D- benzene with the hydrochloric acid of 15% (v/v)
Glycine crystallization is gradually precipitated, and is cooled to 5 DEG C, by growing the grain, be filtered, washed and dried after, obtain D-PG 56.50g,
D-PG yield 88.17%, content 99.50%.
Embodiment 2
Effective component in the crystalline mother solution of synthetical recovery ampicillin as follows:
(1) absorption and parsing of ampicillin, 6-APA and D-PG methyl esters
Take the enzyme process ampicillin crystalline mother solution after the Crystallization Separation of ampicillin, wherein D-PG concentration is
3.11g/L, 6-APA concentration are 1.55g/L, and D-PG methyl acetate concentrations are 0.96g/L, and ampicillin concentration is 4.15g/L,
PH value is 5.05.The mother liquor with the flow velocity of 4L per hour by large pore resin absorption column bed (resin model XAD-8, loading amount 2L,
Ratio of height to diameter is that 8), ampicillin, 6-APA and D-PG methyl esters are attracted on resin, and D-PG is not by resin
Absorption flows through resin with mother liquor and is collected as absorption extraction raffinate.When detection ampicillin, 6- in the efflux of column bed lower end exit
When one of APA and D-PG methyl esters, stop upper prop.In the absorption extraction raffinate being collected into, D-PG concentration is
3.05g/L, 6-APA concentration are 0.05g/L, conductivity 181ms/cm, volume 24L.
After absorption, masterbatch feed volume amounts to 24L.Then, use pH for 1.0 hydrochloric acid/methyl alcohol mixed liquor
(wherein methanol account for parsing agent volume 40%) as parsing agent, is parsed with the flow velocity of 2.0L per hour, when being collected into outlet stream
Stopping collecting when ampicillin concentration is lower than 0.3g/L in liquid out, the efflux that this portion collection arrives amounts to 8L, as desorbed solution,
Wherein, D-PG concentration is 0.02g/L, and 6-APA concentration is 4.46g/L, and D-PG methyl acetate concentrations are 2.82g/L,
Ampicillin concentration is 11.70g/L.
Then, concentrate is obtained in 5~8 DEG C of concentration desorbed solutions using the nanofiltration membrane that molecular cut off is 160 dalton,
In, 6-APA concentration is 16.95g/L, and D-PG methyl acetate concentrations are 10.15g/L, and ampicillin concentration is 43.29g/L, and
High performance liquid chromatography detection the sum of 6-APA, D-PG methyl esters and liquid phase purity of three kinds of ampicillin substance as the result is shown
It is 93.7%, which can directly serve as the reaction bottom water during the enzymatic clarification of ampicillin and then recovery.
(2) D-PG is prepared using electrodialysis, reverse osmosis, crystallization
Desalination is carried out using the absorption extraction raffinate that electrodialysis plant obtains above-mentioned steps (1), in 5A/cm2Constant current is close
It is 20V, conductivity 3.0ms/cm that electrodialysis desalination, which is handled to voltage stabilization, under the conditions of degree, is obtained except saline solution.
Then, 9.2 will be adjusted to except saline solution pH using the sodium hydroxide solution of 40wt%, and use molecular cut off for 100
This except saline solution is concentrated, is obtained D-PG concentrate by the reverse osmosis membrane of dalton, wherein the concentration of D-PG is
The concentration of 48.37g/L, 6-APA are 0.05g/L.
Under the conditions of 35 DEG C, the pH value of D-PG concentrate is adjusted to 5.2, D- benzene with the hydrochloric acid of 15% (v/v)
Glycine crystallization is gradually precipitated, and is cooled to 5 DEG C, and growing the grain after being filtered, washed and dried, obtains D-PG 63.23g, D- benzene
Glycine yield 84.71%, content 99.20%.
Embodiment 3
Effective component in the crystalline mother solution of synthetical recovery ampicillin as follows:
(1) absorption and parsing of ampicillin, 6-APA and D-PG methyl esters
Take the enzyme process ampicillin crystalline mother solution after the Crystallization Separation of ampicillin, wherein D-PG concentration is
3.45g/L, 6-APA concentration are 1.55g/L, D-PG methyl acetate concentrations are 0.97g/L, ampicillin concentration is 3.24g/L,
PH value is 4.99.The mother liquor with the flow velocity of 4L per hour by large pore resin absorption column bed (resin model XAD-6, loading amount 2L,
Ratio of height to diameter is that 8), ampicillin, 6-APA and D-PG methyl esters are attracted on resin, and D-PG is not by resin
Absorption flows through resin with mother liquor and is collected as absorption extraction raffinate.When detection ampicillin, 6- in the efflux of column bed lower end exit
When one of APA and D-PG methyl esters, stop upper prop.In the absorption extraction raffinate being collected into, D-PG concentration is
3.40g/L, 6-APA concentration are 0.02g/L, conductivity 175ms/cm, volume 26L.
After absorption, mother liquor volume amounts to 26L.Then, use pH for 1.0 hydrochloric acid/methyl alcohol mixed liquor
(wherein methanol account for parsing agent volume 20%) as parsing agent, is parsed with the flow velocity of 2.0L per hour, when being collected into outlet stream
Out in liquid ampicillin concentration be lower than 0.3g/L when stop collect, this portion collection to efflux amount to 12L be desorbed solution,
Wherein, D-PG concentration is 0.02g/L, and 6-APA concentration is 3.36g/L, and D-PG methyl acetate concentrations are 2.04g/L,
Ampicillin concentration is 6.46g/L.
Then, desorbed solution is concentrated using the nanofiltration membrane that molecular cut off is 160 dalton, obtains concentrate, wherein 6-APA
Concentration is 18.48g/L, and D-PG methyl acetate concentrations are 11.02g/L, and ampicillin concentration is 35.53g/L, and efficient liquid phase
Chromatography testing result shows that the sum of liquid phase purity of 6-APA, D-PG methyl esters and three kinds of ampicillin substance is 94.9%,
The concentrate can directly serve as the reaction bottom water during the enzymatic clarification of ampicillin and then recovery.
(2) D-PG is prepared using electrodialysis, reverse osmosis, crystallization
Desalination is carried out using the absorption extraction raffinate that electrodialysis plant obtains above-mentioned steps (1), in 5A/cm2Constant current is close
It is 20V, conductivity 3.5ms/cm that electrodialysis desalination, which is handled to voltage stabilization, under the conditions of degree, is obtained except saline solution.
Then, 9.5 will be adjusted to except saline solution pH using 40wt% sodium hydroxide solution, and use molecular cut off for 100
You reverse osmosis membrane by this except saline solution concentration, obtain D-PG concentrate, wherein the concentration of D-PG is
The concentration of 49.30g/L, 6-APA are 0.60g/L.
Under the conditions of 40 DEG C, the pH value of D-PG concentrate is adjusted to 5.0, D- benzene with the hydrochloric acid of 15% (v/v)
Glycine crystallization is gradually precipitated, and is cooled to 3 DEG C, and growing the grain after being filtered, washed and dried, obtains D-PG 79.30g, D- benzene
Glycine yield 88.40%, content 99.45%.
Claims (9)
1. the comprehensive recovering process of effective component, includes the following steps: in a kind of crystalline mother solution of enzymatic clarification ampicillin
(1) absorption and parsing of ampicillin, 6-APA and D-PG methyl esters
Enzyme process ampicillin crystalline mother solution with ampicillin crystal after separating, by it by macroporous absorbent resin, in mother liquor
Ampicillin, 6-APA and D-PG methyl esters be attracted on resin, and D-PG is by resin adsorption, with mother
Liquid stream wears resin and is collected as absorption extraction raffinate；
Then, the ampicillin, 6-APA and the D-PG methyl esters that are adsorbed on resin are parsed using parsing agent, is obtained
To desorbed solution, which directly serves as the reaction bottom water recycling in turn during the enzymatic clarification of ampicillin after nanofiltration is concentrated
It applies；
(2) D-PG is prepared using electrodialysis, reverse osmosis, crystallization
Desalination is carried out using the absorption extraction raffinate that electrodialysis plant obtains above-mentioned steps (1), is obtained except saline solution；
Then 8.8~9.5 will be adjusted to except saline solution pH using alkali, and use molecular cut off for the reverse osmosis of 100~200 dalton
This except saline solution is concentrated, is obtained D-PG concentrate by film, wherein and the concentration of D-PG is 40.00~50.00g/L,
The concentration of 6-APA is 0~2.00g/L；
Under the conditions of 30 DEG C~45 DEG C, the pH value of D-PG concentrate is adjusted to 4.5~5.5 with acid, D-PG
Crystallization is gradually precipitated, and is cooled to 0 DEG C~10 DEG C, and growing the grain filters, dry, obtains D-PG,
Wherein, in the step (1), in the crystalline mother solution of the enzyme process ampicillin, D-PG concentration be 2.50~
3.50g/L, 6-APA concentration are 1.30~1.60g/L, and D-PG methyl acetate concentrations are 0.50~1.00g/L, and ampicillin is dense
Degree is 3.20~4.20g/L, and pH value is 4.8~5.2；
The surface nature of the macroporous absorbent resin is intermediate-polarity macroporous adsorption resin, and is acrylate or 2- methacrylic acid
Esters polymer；
It is described parsing agent be aqueous acid and alcohol mixed liquor, wherein it is used acid be hydrochloric acid or sulfuric acid, alcohol used be methanol,
Or mixtures thereof ethyl alcohol, isopropanol；The pH of parsing agent used is 0.5~2.0；With volume basis, based on parsing agent total volume, institute
It is greater than 0 and to be less than or equal to 40% with the ratio of alcohol.
2. the comprehensive recovering process of effective component in the crystalline mother solution of enzymatic clarification ampicillin as described in claim 1, special
Sign is, in the step (1), the macroporous absorbent resin is selected from AmberliteTMXAD series in XAD-6, XAD-7 and
XAD-8。
3. the comprehensive recovering process of effective component in the crystalline mother solution of enzymatic clarification ampicillin as described in claim 1, special
Sign is, in the step (1), the macroporous absorbent resin passes through wet method dress post application in the form of round resin column bed, circle
The height and diameter of shape resin column bed are 4 or bigger than being ratio of height to diameter.
4. the comprehensive recovering process of effective component in the crystalline mother solution of enzymatic clarification ampicillin as claimed in claim 3, special
Sign is, in the step (1), ampicillin crystalline mother solution is passed through with the flow velocity of 1.0~3.0 times of resin total volumes per hour
Resin column bed, in the absorption extraction raffinate being collected into, D-PG concentration be 2.50~3.50g/L, 6-APA concentration be 0~
0.10g/L, conductivity are 170~190ms/cm.
5. the comprehensive recovering process of effective component in the crystalline mother solution of enzymatic clarification ampicillin as described in claim 1, special
Sign is, in the step (1), the parsing agent is with volume basis, and based on parsing agent total volume, the ratio of alcohol used is 10%
~30%.
6. the comprehensive recovering process of effective component in the crystalline mother solution of enzymatic clarification ampicillin as described in claim 1, special
Sign is, in the step (1), when parsing, the flow control for parsing agent be per hour be 0.5~1.0 times of resin total volume；Solution
After analysis starts, using ampicillin in high performance liquid chromatography detection resin column outlet efflux, when being collected into outlet efflux
Middle ampicillin concentration be lower than 0.30g/L when stop collect, this portion collection to efflux be desorbed solution, wherein D- benzene
Glycine concentration be 0~0.05g/L, 6-APA concentration be 2.50~5.00g/L, D-PG methyl acetate concentrations be 1.00~
3.00g/L, ampicillin concentration are 6.00~12.00g/L.
7. the comprehensive recovering process of effective component in the crystalline mother solution of enzymatic clarification ampicillin as described in claim 1, special
Sign is, in the step (1), uses molecular cut off for the nanofiltration membrane of 150~300 dalton, in 5~8 DEG C of cryogenic conditions
It is lower that desorbed solution is concentrated, obtain nanofiltration concentrate；Without D-PG in the nanofiltration concentrate, 6-APA concentration is 15.00~
20.00g/L, D-PG methyl acetate concentrations are 6.00~12.00g/L, and ampicillin concentration is 35.00~50.00g/L.
8. the comprehensive recovering process of effective component in the crystalline mother solution of enzymatic clarification ampicillin as described in claim 1, special
Sign is, in the step (2), the absorption extraction raffinate that above-mentioned steps (1) are obtained is imported in the light room of electrodialysis plant, using batch
Circulating desalination process is measured, in 5~10A/cm2It is 20V that electrodialysis desalination, which is handled to voltage stabilization, under the conditions of constant current density,
It is 2~5ms/cm to get to except saline solution that electrodialysis desalination, which is handled to conductivity, under the conditions of 20V pressure stabilizing.
9. the comprehensive recovering process of effective component in the crystalline mother solution of enzymatic clarification ampicillin as described in claim 1, special
Sign is, in the step (2), 9.0~9.5 will be adjusted to except saline solution pH using alkali, alkali used is sodium hydroxide or ammonium hydroxide；So
Afterwards, use molecular cut off for the reverse osmosis membrane of 100~150 dalton, by above-mentioned except saline solution is concentrated, the D- benzene being concentrated is sweet
Propylhomoserin solution.
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| CN104357528A (en) * | 2014-10-29 | 2015-02-18 | 国药集团威奇达药业有限公司 | Method for comprehensively recovering effective ingredients in amoxicillin mother liquid prepared by enzyme process |
| CN105254520A (en) * | 2015-10-12 | 2016-01-20 | 国药集团威奇达药业有限公司 | Recovery method for D-hydroxyphenylglycine in amoxicillin crystallization mother liquor of enzymatic synthesis |
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| CN104357528A (en) * | 2014-10-29 | 2015-02-18 | 国药集团威奇达药业有限公司 | Method for comprehensively recovering effective ingredients in amoxicillin mother liquid prepared by enzyme process |
| CN105254520A (en) * | 2015-10-12 | 2016-01-20 | 国药集团威奇达药业有限公司 | Recovery method for D-hydroxyphenylglycine in amoxicillin crystallization mother liquor of enzymatic synthesis |
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