CN107698607A - The comprehensive recovering process of active ingredient in the crystalline mother solution of enzymatic clarification ampicillin - Google Patents

The comprehensive recovering process of active ingredient in the crystalline mother solution of enzymatic clarification ampicillin Download PDF

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CN107698607A
CN107698607A CN201710743701.8A CN201710743701A CN107698607A CN 107698607 A CN107698607 A CN 107698607A CN 201710743701 A CN201710743701 A CN 201710743701A CN 107698607 A CN107698607 A CN 107698607A
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ampicillin
concentration
apa
resin
solution
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CN107698607B (en
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袁智灏
安雪飞
李树有
刁夏
刘君臣
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WEIQIDA PHARMACEUTICAL Co Ltd OF CHINA NATIONAL PHARMACEUTICAL INDUSTRY Corp Ltd
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WEIQIDA PHARMACEUTICAL Co Ltd OF CHINA NATIONAL PHARMACEUTICAL INDUSTRY Corp Ltd
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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
    • 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
    • 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

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Separation Using Semi-Permeable Membranes (AREA)

Abstract

The invention belongs to pharmaceutical technology field, it is related to the comprehensive recovering process of active ingredient in the crystalline mother solution of enzymatic clarification ampicillin.The present invention realizes the separation of D phenylglycines and ampicillin, 6 APA and D Phenylglycine methyl esters using the separate mode of macroporous absorbent resin, D phenylglycines are not by resin adsorption, into absorption extraction raffinate, for the absorption extraction raffinate after electrodialysis, reverse osmosis concentration, crystallization, recovery obtains the D phenylglycines of high-quality；And ampicillin on resin, 6 APA and D Phenylglycine methyl esters are adsorbed after parsing, concentrated by nanofiltration, obtained nanofiltration concentrate can directly serve as the reaction bottom water and then recovery during the enzymatic clarification of ampicillin.Active ingredient D phenylglycines, ampicillin, 6 APA, D Phenylglycine methyl esters in synthetical recovery of the present invention enzyme process ampicillin crystalline mother solution, create economic benefit, while reduce the discharge of high-concentration waste water, realize environment-protecting clean green production.

Description

The comprehensive recovering process of active ingredient in the crystalline mother solution of enzymatic clarification ampicillin
Technical field
The invention belongs to pharmaceutical technology field, the synthesis for being related to active ingredient in the crystalline mother solution of enzymatic clarification ampicillin is returned Receiving method.
Background technology
Ampicillin, entitled (2S, 5R, 6R) -3,3- dimethyl -6- [(R) -2- amino -2- phenylacetylaminos] -7- of chemistry Oxo -4- thia -1- azabicyclos [3.2.0] heptane -2- formic acid, its free acid contain three molecular crystalline water, and it is a kind of conventional Penicillins wide spectrum beta-lactam antibiotic.
Ampicillin bactericidal action, penetration cell wall it is very capable, be current widely used oral penicillin One of.The preparation method of ampicillin has two kinds of chemical synthesis and enzyme process, and chemical method is because its reactions steps is complicated, synthesis condition Harshness, and whole course of reaction needs to use a variety of organic chemistry raw materials, produces the substantial amounts of three wastes, pollution is more serious, and sharp With enzymatic clarification ampicillin, the use of organic solvent can be avoided, reaction condition is gentle, and energy consumption is low, easy to operate, and 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 lifted, therefore enzyme process turns into the main path of production ampicillin.
In the technique of enzymatic clarification ampicillin, typically using D-PG methyl ester hydrochloride as acyl side-chain donor, Generation ampicillin is condensed with 6-amino-penicillanic acid (6-APA) in the case where synthesis is acted on immobilization penicillin acylated enzyme catalysis. Because synthesis is stronger with the hydrolysing activity of immobilized penicillin acylated enzyme itself, thus raw material D-PG methyl ester hydrochloride and There is a different degrees of hydrolysis product ampicillin, with the presence of substantial amounts of D-PG in crystalline mother solution, in addition in mother liquor still There are the ampicillin that can not be largely obtained by crystallizing 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 into Point, turn into the important subject that current ampicillin enzymatic clarification technique faces.
Chinese patent literature CN102851332A discloses the recovery of D-PG in a kind of mother liquor of enzyme process ampicillin The ampicillin largely remained in mother liquor is hydrolyzed to D-PG and 6- by method, this method first by way of enzymatic lysis APA, then using steps such as ultrafiltration, nanofiltration, activated carbon decolorizing, decrease temperature crystallines, reclaim the D-PG in mother liquor.Using upper The method of stating can reclaim D-PG from mother liquor, although the method for employing enzymatic lysis makes ampicillin, D-PG Methyl esters hydrolyzes, but ampicillin and D-PG methyl esters is still remained in mother liquor, and in mother liquor 6-APA then by a large amount of waves Take.Therefore, in the prior art, remained to more efficiently and environmentally friendly in the mother liquor of synthetical recovery ampicillin effective , needs be present in composition, the value for farthest excavating residual mother liquor.
The content of the invention
Therefore, it is an object of the invention to provide a kind of technological design is reasonable, easy to operate, recovering effect is good and product matter The method for measuring active ingredient in excellent synthetical recovery enzyme process ampicillin crystalline mother solution, that is, reclaim the sweet ammonia of D- benzene in mother liquor Acid, D-PG methyl esters, ampicillin and 6-APA.
In order to realize the object of the invention, the technical solution adopted in the present invention is：Using the separation side of macroporous absorbent resin Formula realizes the separation of D-PG and other three kinds of materials, and D-PG, should into absorption extraction raffinate not by resin adsorption Extraction raffinate is adsorbed after electrodialysis plant removes most of salts substances, after reverse osmosis concentration, crystallization, recovery obtains high-quality D-PG；And ampicillin, 6-APA and D-PG methyl esters on resin are adsorbed after parsing, by nanofiltration Concentration, obtained nanofiltration concentrate can directly serve as the reaction bottom water and then recovery set during the enzymatic clarification of ampicillin With.
According to the present invention, the method for active ingredient in synthetical recovery enzyme process ampicillin crystalline mother solution provided by the invention, Comprise 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 being separated 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 adsorbing extraction raffinate；
Then, solved using parsing agent to adsorbing ampicillin, 6-APA and D-PG methyl esters on resin Analysis, obtains desorbed solution, and the reaction bottom water that the desorbed solution directly serves as during the enzymatic clarification of ampicillin after nanofiltration concentrates enters And recovery；
(2) D-PG is prepared using electrodialysis, counter-infiltration, crystallization
The absorption extraction raffinate for being obtained above-mentioned steps (1) using electrodialysis plant carries out desalination, obtains removing saline solution；
Then it will be adjusted using alkali except saline solution pH to 8.8~9.5, and use molecular cut off as the anti-of 100~200 dalton This except saline solution concentrates, is obtained D-PG concentrate by permeable membrane；
Under the conditions of 30 DEG C~45 DEG C, the pH value of D-PG concentrate adjusted with acid sweet to 4.5~5.5, D- benzene Propylhomoserin crystallization gradually separates out, and is cooled to 0 DEG C~10 DEG C, growing the grain, filters, dries, obtain D-PG.
Compared with prior art, the advantage of the invention is that：
D-PG in the crystalline mother solution of enzyme process ampicillin is successfully realized using the separate mode of macroporous absorbent resin With ampicillin, 6-APA, D-PG methyl esters separation, and substantial amounts of pigment and impurity are also attracted on resin, are reached Into the purpose for removal of impurities of decolourizing.
Then, using suitable parsing agent to adsorbing ampicillin on resin, 6-APA, D-PG methyl esters enter Row parsing, desorbed solution can serve as the reaction bottom water during the enzymatic clarification of ampicillin after nanofiltration concentrates, in ammonia benzyl west 6-APA and D-PG methyl esters are consumed in woods building-up process, ampicillin is reclaimed during later crystallization, is accessed so as between 6-APA, D-PG methyl esters and ampicillin purpose into recovery mother liquor.
Using electrodialysis, counter-infiltration, crystallization treatment absorption extraction raffinate, most of salts substances can not only be removed and correlation is miscellaneous Matter, improves the solution quality of recovery D-PG, and realizes the efficient concentration of D-PG in mother liquor, significantly carries The high yield of recovery D-PG product.
Active ingredient 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 reduce the discharge of high-concentration waste water, realize environment-protecting clean Green production.
Embodiment
Below, the side of active ingredient in the synthetical recovery enzyme process ampicillin crystalline mother solution of the present invention is further illustrated Method.
In the step (1), enzyme process ampicillin crystalline mother solution is passed through after being separated 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 by resin adsorption, does not flow through resin with mother liquor and is collected as adsorbing extraction raffinate；Then, using parsing agent to adsorbing on resin Ampicillin, 6-APA and D-PG methyl esters parsed, obtain desorbed solution, the desorbed solution after nanofiltration concentrates 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 is with D-PG methyl ester hydrochloride in immobilized penicillin acid Change under enzyme catalysis, condensation generation 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.
By enzyme process ampicillin crystalline mother solution by 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 From AmberliteTMXAD-6, XAD-7, XAD-8 in XAD series.
The macroporous absorbent resin is crystallized ampicillin female by wet method dress post application in the form of circular 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 cumulative volumes per hour Resin column bed；The height of circular resin column bed is 4 or bigger with diameter ratio (i.e. ratio of height to diameter)；Macroporous absorbent resin is to ammonia benzyl west Woods, 6-APA, the adsorbance of D-PG methyl esters are related to the concentration of each material in mother liquor and the characteristic of resin, specific real Apply in example and be detected with one of above-mentioned three kinds of materials in post bed lower end exit as foundation, stop upper prop during detection.
D-PG is not adsorbed by large pore resin absorption column bed, flows through resin with mother liquor and is collected as adsorbing extraction raffinate, Without D-PG methyl esters and ampicillin, D-PG concentration it is 2.50~3.50g/L in the absorption extraction raffinate, 6-APA is dense It is 170~190ms/cm to spend for 0~0.10g/L, electrical conductivity.
Ampicillin, 6-APA, D-PG methyl esters are attracted on resin column bed, and absorption is being set using parsing agent Ampicillin, 6-APA on fat post 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 be methanol, ethanol, Isopropanol or its mixture；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 is more than 0 and less than or equal to 40%, preferably 10%~30%, and most preferably 20%；During parsing, parsing The flow control of agent is per hour is 0.5~1.0 times of resin cumulative volume, preferred 0.75 times of resin cumulative volume per hour；Parsing is opened After beginning, ampicillin in resin column outlet efflux is detected using high performance liquid chromatography, ammonia in efflux is exported when being collected into Stop collecting when benzyl XiLin concentration is less than 0.30g/L, 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, NF membrane of the molecular cut off for 150~300 dalton is used, preferably molecular cut off is 150~200 The NF membrane of dalton, typically desorbed solution is concentrated under 5~8 DEG C of cryogenic conditions, the process can remove part inorganic salts and Most of alcohols material, avoids the suppression to synthesis enzyme during subsequently applying mechanically, and ampicillin, 6-APA, D-PG Methyl esters is trapped within concentrate, and purity (high performance liquid chromatography) sum of three kinds of materials is more 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), first, the absorption extraction raffinate desalination that above-mentioned steps (1) are obtained using electrodialysis plant, 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 base material of film be Kynoar, amberplex length × width × height for 400mm × 200mm×0.2mm。
The absorption extraction raffinate that above-mentioned steps (1) are obtained is imported in the light room of electrodialysis plant, using batch cycles formula desalination Flow, in 5~10A/cm2It is 20V that electrodialysis desalination, which is handled to voltage stabilization, under the conditions of constant current density, in 20V voltage stabilizing bars It is 2~5ms/cm that electrodialysis desalination, which is handled to electrical conductivity, under part, that is, obtains desalination liquid.Extraction raffinate is adsorbed by electrodialysis desalination desalination Afterwards, the feed liquid quality except saline solution is not only increased, and the reverse osmosis concentration multiple of subsequent step has and significantly improved.
Then, will be adjusted using alkali except saline solution pH to 8.8~9.5, preferably 9.0~9.5, alkali used can be sodium hydroxide Or ammoniacal liquor.In the range of the pH, it can ensure that the solubility of D-PG is larger, so that cycles of concentration is very high.So Afterwards, reverse osmosis membrane of the molecular cut off for 100~200 dalton is used, more preferably 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 give dense The D-PG solution of contracting.
In resulting D-PG concentrate, the concentration of general D-PG is 40.00~50.00g/L, 6- APA concentration is 0~2.00g/L.
, can be with 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 With concentrated hydrochloric acid, by the pH value of the D-PG solution of concentration, slowly regulation is to 4.5~5.5, and preferably 4.8~5.2, D- is to hydroxyl Phenylglycine crystallization separate out, 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 mechanically Recovery, so as 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
Active ingredient in the crystalline mother solution of synthetical recovery ampicillin as follows：
(1) absorption and parsing of ampicillin, 6-APA and D-PG methyl esters
The enzyme process ampicillin crystalline mother solution after the Crystallization Separation of ampicillin is taken, 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 using the flow velocity of 4L per hour by large pore resin absorption column bed (resin model as 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, flow through resin with mother liquor and be collected as adsorbing extraction raffinate.As detection ampicillin, 6- in the efflux of post 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, electrical conductivity 177ms/cm, volume 24L.
After absorption terminates, mother liquor volume amounts to 24L.Then, use pH for 1.0 hydrochloric acid/methyl alcohol mixed liquor (wherein methanol accounts for the 20% of parsing agent volume) is parsed with the flow velocity of 2.0L per hour as parsing agent, stream is exported when being collected into Go out and stop collecting when ampicillin concentration in liquid is less than 0.3g/L, this portion collection to efflux amount to 12L, as parse Liquid, wherein, D-PG concentration be 0.01g/L, 6-APA concentration be 2.74g/L, D-PG methyl acetate concentrations be 1.73g/ L, ampicillin concentration is 7.51g/L；
Then, desorbed solution is concentrated at 5~8 DEG C for the NF membrane of 160 dalton using molecular cut off, obtains concentrate, its 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 result shows the liquid phase purity sum of 6-APA, D-PG methyl esters and three kinds of ampicillin material For 94.2%, the concentrate can directly serve as the reaction bottom water and then recovery during the enzymatic clarification of ampicillin.
(2) D-PG is prepared using electrodialysis, counter-infiltration, crystallization
The absorption extraction raffinate for being obtained above-mentioned steps (1) using electrodialysis plant carries out desalination, in 5A/cm2Constant current is close It is 20V, electrical conductivity 2.7ms/cm that electrodialysis desalination, which is handled to voltage stabilization, under the conditions of degree, obtains removing saline solution.
Then, it will be adjusted using 40wt% sodium hydroxide solution except saline solution pH to 9.0, use molecular cut off as 100 This except saline solution concentrates, is obtained D-PG concentrate by the reverse osmosis membrane of dalton, wherein, the concentration of D-PG is 46.24g/L, 6-APA concentration 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 15% (v/v) hydrochloric acid Glycine crystallization gradually separates out, 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
Active ingredient in the crystalline mother solution of synthetical recovery ampicillin as follows：
(1) absorption and parsing of ampicillin, 6-APA and D-PG methyl esters
The enzyme process ampicillin crystalline mother solution after the Crystallization Separation of ampicillin is taken, 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 using the flow velocity of 4L per hour by large pore resin absorption column bed (resin model as 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, flow through resin with mother liquor and be collected as adsorbing extraction raffinate.As detection ampicillin, 6- in the efflux of post 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, electrical conductivity 181ms/cm, volume 24L.
After absorption terminates, masterbatch feed volume amounts to 24L.Then, use pH for 1.0 hydrochloric acid/methyl alcohol mixed liquor (wherein methanol accounts for the 40% of parsing agent volume) is parsed with the flow velocity of 2.0L per hour as parsing agent, stream is exported when being collected into Go out and stop collecting when ampicillin concentration in liquid is less than 0.3g/L, this portion collection to efflux amount 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, desorbed solution is concentrated at 5~8 DEG C for the NF membrane of 160 dalton using molecular cut off, obtains concentrate, its 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 result shows the liquid phase purity sum of 6-APA, D-PG methyl esters and three kinds of ampicillin material For 93.7%, the concentrate can directly serve as the reaction bottom water and then recovery during the enzymatic clarification of ampicillin.
(2) D-PG is prepared using electrodialysis, counter-infiltration, crystallization
The absorption extraction raffinate for being obtained above-mentioned steps (1) using electrodialysis plant carries out desalination, in 5A/cm2Constant current is close It is 20V, electrical conductivity 3.0ms/cm that electrodialysis desalination, which is handled to voltage stabilization, under the conditions of degree, obtains removing saline solution.
Then, it will be adjusted using 40wt% sodium hydroxide solution except saline solution pH to 9.2, use molecular cut off as 100 This except saline solution concentrates, is obtained D-PG concentrate by the reverse osmosis membrane of dalton, wherein, the concentration of D-PG is 48.37g/L, 6-APA concentration 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 15% (v/v) hydrochloric acid Glycine crystallization gradually separates out, and is cooled to 5 DEG C, 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
Active ingredient in the crystalline mother solution of synthetical recovery ampicillin as follows：
(1) absorption and parsing of ampicillin, 6-APA and D-PG methyl esters
The enzyme process ampicillin crystalline mother solution after the Crystallization Separation of ampicillin is taken, 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 using the flow velocity of 4L per hour by large pore resin absorption column bed (resin model as 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, flow through resin with mother liquor and be collected as adsorbing extraction raffinate.As detection ampicillin, 6- in the efflux of post 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, electrical conductivity 175ms/cm, volume 26L.
After absorption terminates, mother liquor volume amounts to 26L.Then, use pH for 1.0 hydrochloric acid/methyl alcohol mixed liquor (wherein methanol accounts for the 20% of parsing agent volume) is parsed with the flow velocity of 2.0L per hour as parsing agent, stream is exported when being collected into Go out and stop collecting when ampicillin concentration in liquid is less than 0.3g/L, this portion collection to efflux to 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 for the NF membrane of 160 dalton using molecular cut off, 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 Chromatogram testing result shows that the liquid phase purity sum of 6-APA, D-PG methyl esters and three kinds of ampicillin material is 94.9%, The concentrate can directly serve as the reaction bottom water and then recovery during the enzymatic clarification of ampicillin.
(2) D-PG is prepared using electrodialysis, counter-infiltration, crystallization
The absorption extraction raffinate for being obtained above-mentioned steps (1) using electrodialysis plant carries out desalination, in 5A/cm2Constant current is close It is 20V, electrical conductivity 3.5ms/cm that electrodialysis desalination, which is handled to voltage stabilization, under the conditions of degree, obtains removing saline solution.
Then, it will be adjusted using 40wt% sodium hydroxide solutions except saline solution pH to 9.5, use molecular cut off as 100 This except saline solution concentrates, is obtained D-PG concentrate by the reverse osmosis membrane that you pause, wherein, the concentration of D-PG is 49.30g/L, 6-APA concentration 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 15% (v/v) hydrochloric acid Glycine crystallization gradually separates out, and is cooled to 3 DEG C, growing the grain, after being filtered, washed and dried, obtains D-PG 79.30g, D- benzene Glycine yield 88.40%, content 99.45%.

Claims (10)

1. the comprehensive recovering process of active ingredient, comprises 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 adsorbing extraction raffinate；
Then, parsed, obtained to adsorbing ampicillin, 6-APA and D-PG methyl esters on resin using parsing agent To desorbed solution, the desorbed solution directly serves as the reaction bottom water during the enzymatic clarification of ampicillin and then recovery after nanofiltration concentrates Apply mechanically；
(2) D-PG is prepared using electrodialysis, counter-infiltration, crystallization
The absorption extraction raffinate for being obtained above-mentioned steps (1) using electrodialysis plant carries out desalination, obtains removing saline solution；
Then it will be adjusted using alkali except saline solution pH to 8.8~9.5, and use counter-infiltration of the molecular cut off for 100~200 dalton This except saline solution concentrates, is obtained D-PG concentrate by film；
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 gradually separates out, and is cooled to 0 DEG C~10 DEG C, growing the grain, filters, dries, obtain D-PG.
2. the comprehensive recovering process of active ingredient in the crystalline mother solution of enzymatic clarification ampicillin as claimed in claim 1, it is special Sign is, 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 Spend for 3.20~4.20g/L, and pH value is 4.8~5.2.
3. the comprehensive recovering process of active ingredient in the crystalline mother solution of enzymatic clarification ampicillin as claimed in claim 1 or 2, its It is characterized in, in the step (1), the surface nature of the macroporous absorbent resin is intermediate-polarity macroporous adsorption resin, is specially Acrylate or 2- methacrylate based polymers, more specifically, Amberlite can be selectedTMXAD-6, XAD- in XAD series 7、XAD-8。
4. the comprehensive recovering process of active ingredient in the crystalline mother solution of enzymatic clarification ampicillin as claimed in claim 3, it is special Sign is, in the step (1), the macroporous absorbent resin passes through wet method dress post application in the form of circular resin column bed, circle The height of shape resin column bed is 4 or bigger with diameter ratio (i.e. ratio of height to diameter).
5. the comprehensive recovering process of active ingredient in the crystalline mother solution of enzymatic clarification ampicillin as claimed in claim 4, it is 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 cumulative volumes per hour Resin column bed, in the absorption extraction raffinate being collected into, D-PG concentration is 2.50~3.50g/L, 6-APA concentration is 0~ 0.10g/L, electrical conductivity are 170~190ms/cm.
6. the comprehensive recovering process of active ingredient in the crystalline mother solution of enzymatic clarification ampicillin as claimed in claim 1 or 2, its Be characterized in, in the step (1), the parsing agent is the mixed liquor of aqueous acid and alcohol, wherein, acid used for hydrochloric acid or Sulfuric acid, alcohol used are methanol, ethanol, isopropanol or its mixture；The pH of parsing agent used is 0.5~2.0；With volume basis, Based on parsing agent cumulative volume, the ratio of alcohol used is more than 0 and is less than or equal to 40%, preferably 10%~30%, and most preferably 20%.
7. the comprehensive recovering process of active ingredient in the crystalline mother solution of enzymatic clarification ampicillin as claimed in claim 6, it is special Sign is, in the step (1), during parsing, parses the flow control of agent to be per hour 0.5~1.0 times of resin cumulative volume；Solution After analysis starts, ampicillin in resin column outlet efflux is detected using high performance liquid chromatography, when being collected into outlet efflux Stop collecting when middle ampicillin concentration is less than 0.30g/L, this portion collection to efflux be desorbed solution, wherein, D- benzene Glycine concentration is 0~0.05g/L, and 6-APA concentration is 2.50~5.00g/L, D-PG methyl acetate concentrations are 1.00~ 3.00g/L, ampicillin concentration are 6.00~12.00g/L.
8. the comprehensive recovering process of active ingredient in the crystalline mother solution of enzymatic clarification ampicillin as claimed in claim 1 or 2, its It is characterized in, in the step (1), NF membrane of the molecular cut off for 150~300 dalton is used, in 5~8 DEG C of low temperature bars Desorbed solution is concentrated under part, obtains 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.
9. the comprehensive recovering process of active ingredient in the crystalline mother solution of enzymatic clarification ampicillin as claimed in claim 1 or 2, its It is characterized in, in the step (2), the absorption extraction raffinate that above-mentioned steps (1) are obtained is imported in the light room of electrodialysis plant, is used Batch cycles formula desalination flow, in 5~10A/cm2Electrodialysis desalination, which is handled to voltage stabilization, under the conditions of constant current density is 20V, it is 2~5ms/cm that electrodialysis desalination, which is handled to electrical conductivity, under the conditions of 20V voltage stabilizings, that is, obtains desalination liquid.
10. the comprehensive recovering process of active ingredient in the crystalline mother solution of enzymatic clarification ampicillin as claimed in claim 1 or 2, It is characterized in that in the step (2), will be adjusted using alkali except saline solution pH to 9.0~9.5, alkali used is sodium hydroxide or ammonia Water；Then, reverse osmosis membrane of the molecular cut off for 100~150 dalton is used, by above-mentioned except saline solution concentrates, is concentrated D-PG solution, wherein, the concentration of D-PG is 40.00~50.00g/L, and 6-APA concentration is 0~2.00g/ L。
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CN111393315A (en) * 2020-02-20 2020-07-10 国药集团威奇达药业有限公司 Method for recovering D-p-hydroxyphenylglycine in D-p-hydroxyphenylglycine crystallization mother liquor synthesized by enzyme method

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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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