CN102816803A - Method for recycling active ingredients in amoxicillin mother liquor synthesized by enzymatic method - Google Patents
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Abstract
The invention discloses a method for recycling active ingredients in the amoxicillin mother liquor synthesized by an enzymatic method. The method includes synthesizing the amoxicillin mother liquor by the enzymatic method; separating the amoxicillin mother liquor through a macro-porous resin column, eluting the separated amoxicillin mother liquor by deionized water, and collecting an eluant rich in D-4-Hydroxyphenylglycine and an eluant rich in 6-amino penicillanic acid (APA) respectively; filtering the eluant rich in D-4-Hydroxyphenylglycine with Daltonian ultrafiltration membranes with a cutoff molecular weight of 150 to 200; performing nanofiltration concentration on the Daltonian ultrafiltration membranes for the filtered liquor with the cutoff molecular weight of 150 to 200, and standing, crystallizing and filtering the concentrated liquor to obtain solids, and drying the solids to obtain the D-4-Hydroxyphenylglycine. According to the method, the technological design is reasonable, the operation is convenient, the recycling effect is good, and energy is saved and the environment is protected.
Description
Technical field
The present invention relates to the organism mother liquor and recycle technology, specifically a kind of method that adopts macroporous resin to recycle the synthetic amoxycilline Trihydrate bp of enzyme process mother liquor.
Background technology
Amoxycilline Trihydrate bp (Amoxicillin) has another name called the silent XiLin of An Moxilin or peace, is a kind of the most frequently used PCs wide spectrum β-Nei Xiananleikangshengsu.The method of synthetic amoxycilline Trihydrate bp has two kinds usually: a kind of is chemical synthesis, and another kind of is the enzyme catalysis synthesis method.The enzyme catalysis synthesis method is called for short enzyme process, is under immobilized penicillin acylated enzyme catalysis, is formed at the aqueous phase stirring reaction by parent nucleus 6-amino-penicillanic acid (hereinafter to be referred as 6-APA) and D-p-hydroxyphenylglycine methyl ester.It is compared with chemical synthesis, can avoid the use of various organic solvents and reagent-, and reaction conditions gentle (room temperature and neutrality) so its energy consumption is low, easy to operate, environmental friendliness, therefore is the compound method of preferential employing at present.
The synthetic amoxycilline Trihydrate bp of existing enzyme process technology often will add excessive D-p-hydroxyphenylglycine methyl ester when feeding intake, improve the transformation efficiency of 6-APA with this.In addition, it owing to receive the influence of acylase, has quite a few can be hydrolyzed to inactive D-D-pHPG in reaction process in the D-p-hydroxyphenylglycine methyl ester.Except that containing a small amount of amoxycilline Trihydrate bp, also contain the D-D-pHPG that many unreacted 6-APA, D-p-hydroxyphenylglycine methyl ester and hydrolysis produce in the mother liquor of therefore being discharged behind its synthetic amoxycilline Trihydrate bp.Especially when the activity of the enzyme of selecting for use was high more, the residual volume of D-D-pHPG was also big more.So how the mentioned component in the effective recycling mother liquor becomes the important topic that current amoxycilline Trihydrate bp enzyme process synthesis technique faces.
One Chinese patent application CN102392060 discloses a kind of method of utilizing nanofiltration to reclaim effective ingredient in the mother liquor of the synthetic amoxycilline Trihydrate bp of enzyme process, and this method steps is following: pH value to 9.0 ~ 9.5 of mother liquor are regulated in (1); (2) utilize Semacylase to the processing that is hydrolyzed of above-mentioned mother liquor; (3) mother liquor after the concentrated hydrolysis of nanofiltration; (4) utilize 6-APA and D-D-pHPG in the isoelectric point crystallizing method Separation and Recovery mother liquor.Though the document has provided a kind of way that solves the recycling of effective constituent in the mother liquor of the synthetic amoxycilline Trihydrate bp of enzyme process, still there are many places not fully up to expectations in it.In the example hydrolysising mother liquid, it not only contains the 6-APA of unstable chemcial property, also contains D-D-pHPG and a large amount of impurity simultaneously; Therefore directly adopt nf membrane to concentrate; Not only power consumption is big, and the solution ingredient after concentrating is complicated, adopts the iso-electric point mode to separate 6-APA and D-p-hydroxyphenylglycine methyl ester more thus; Its efficient is low, and product purity is poor.
Summary of the invention
The purpose of this invention is to provide that a kind of technological design is reasonable, easy and simple to handle, recovering effect is good, the recoverying and utilizing method of the synthetic amoxycilline Trihydrate bp of the enzyme process of energy-conserving and environment-protective mother liquor effective constituent.
For realizing the object of the invention, the technical scheme that the present invention adopted is:
The recoverying and utilizing method of effective constituent in the mother liquor of the synthetic amoxycilline Trihydrate bp of a kind of enzyme process, its following steps:
(a) with alkaline solution enzyme process is synthesized amoxycilline Trihydrate bp mother liquor pH regulator to 7.5～8.5, add Semacylase and be hydrolyzed, obtain hydrolyzed solution;
Alkaline solution in this step can be selected strong aqua or sodium hydroxide solution.The consumption of Semacylase can calculate according to hydrolysis reaction, counts the 1-2.5% of mother liquor usually with weightmeasurement ratio.After hydrolysis, amoxycilline Trihydrate bp remaining in the mother liquor is hydrolyzed to 6-APA and D-D-pHPG, and remaining substrate in the former building-up reactions (D-p-hydroxyphenylglycine methyl ester) also is hydrolyzed to the D-D-pHPG.
(b) with said hydrolyzed liquid with salt acid for adjusting pH value to 6.0～7.0, through the macroporous resin column separating treatment, the deionized water wash-out is collected the elutriant be rich in the D-D-pHPG and the elutriant that is rich in 6-APA respectively; The elutriant that is rich in 6-APA returned to the technology of the synthetic amoxycilline Trihydrate bp of enzyme process apply mechanically as raw material;
Hydrochloric acid in this step can adopt volume(tric)fraction than the hydrochloric acid that is 15～34%, and it is the pH value of regulator solution quickly and easily.When the pH of hydrolyzed solution value was 6.0～7.0, the D-D-pHPG was electroneutral, Van der Waals force between the skeleton structure of its molecule and macroporous resin and hydrogen bond action power all a little less than, receive a little less than the macroporous resin absorption effect, eluted earlier than 6-APA.On the contrary, be 6.0～7.0 o'clock at pH value, the 6-APA molecule has certain electric charge, and Van der Waals force between the skeleton structure of its molecule and macroporous resin and hydrogen bond action power are stronger, and it is stronger to receive the macroporous resin absorption effect, and the back is eluted.
(c) with the above-mentioned elutriant that is rich in the D-D-pHPG with acid for adjusting pH to 9.5～10.0, adopt molecular weight cut-off 1500～2000 daltonian ultrafiltration membrance filters, obtain-filtrate A.
(d) above-mentioned filtrating A being used molecular weight cut-off is that 150 ~ 200 daltonian nf membrane are carried out nanofiltration and concentrated, and obtains liquid concentrator.
(e) with acid the pH value of liquid concentrator is adjusted to 5.0～6.0, leaves standstill, crystallization, filtration, the gained solid drying obtains the D-D-pHPG.
The D-D-pHPG according to the ordinary method esterification after, the D-p-hydroxyphenylglycine methyl ester of generation can return to the technology of the synthetic amoxycilline Trihydrate bp of enzyme process and apply mechanically as raw material.
The inventive method is through at first separating hydrolysising mother liquid through the macroporous resin column wash-out; Thus mother liquor effectively is separated into elutriant that is rich in the D-D-pHPG and the elutriant that is rich in 6-APA, the elutriant that directly will be rich in 6-APA then returns to the technology of the synthetic amoxycilline Trihydrate bp of enzyme process to be applied mechanically as raw material.The untoward reaction of effectively having avoided 6-APA in subsequent technique, to be produced thus.After this; The elutriant that will be rich in the D-D-pHPG again carries out membrane filtration; Further the place has removed the impurity in the D-D-pHPG elutriant thus, thereby greatly reduces the pressure of follow-up nf membrane nf membrane both sides when concentrating, and has improved concentrated speed; Shorten man-hour (about 50%); Reduced equipment loss, reduced cost of equipment maintenance (can reduce m of e frequency 3-4 doubly), also technical guarantee is provided simultaneously for isoelectric point crystallizing purifying D-D-pHPG than directly adopting nanofiltration to concentrate.
The inventive method can make the disposable D-D-pHPG high purity of separating out up to 95-98%, and it has effectively overcome because the unfavorable defective of D-D-pHPG crystalline quality that D-D-pHPG and 6-APA coexistence are caused.
The optimum condition of the inventive method is:
Above-mentioned macroporous resin column separating treatment, preferred separating treatment condition are 15～20 ℃ of last appearance temperature, flow velocity 1～2BV/h; During the deionized water wash-out, 25～30 ℃ of eluting temperatures, flow velocity 2-4BV/h.
It is the punching resin of polarity or non-polar material, specific surface area 500-1300m2g-1 that macroporous resin column according to the invention can be selected aperture 5-30nm, skeleton structure for use.All macroporous resin column that meets this condition all can be used as preferred macroporous resin column in the inventive method.
Preferred any one macroporous resin column among XAD-4, XAD1600N, NKA II, the SP850 ﹑ H103 also in the inventive method.
The said hydrolysis of a step, preferred reaction conditions is that temperature is controlled at 25～30 ℃, the reaction times is 1～4 hour.
The said preferred processing condition of crystallization that leave standstill of e step are that temperature is 0～10 ℃, and the time is 2～3 h.Crystallization rate is very fast under this condition, and crystallization is complete, and products obtained therefrom purity is high.
In the said liquid concentrator of d step, the concentration of D-D-pHPG is preferably 60～70mg/mL, and when under this concentration, carrying out subsequent disposal, crystallization rate is fast, unit consumption of energy is low, and products obtained therefrom yield and purity are all higher.
The said elutriant that is rich in 6-APA, the concentration of its 6-APA is preferably 6～8mg/mL, the elutriant under this concentration; 6-APA concentration is higher, impurity is less; It is synthetic directly to be used for the enzyme process of amoxycilline Trihydrate bp as raw material, can reduce the charging capacity of 6-APA, saves production cost.
In a word, the selection of above-mentioned optimum condition can further improve recovering effect of the present invention.
The inventive method, it is simple also to have technological operation simultaneously, lower for equipment requirements, unit consumption of energy is low, the characteristics of effect stability.
Description of drawings
Fig. 1 is a process flow sheet of the present invention.
Fig. 2 is H103 macroporous resin absorption concentration profile figure in the embodiment of the invention 1; The concentration profile of
expression absorption D-D-pHPG among the figure, the concentration profile of
expression absorption 6-APA.
Embodiment
Further specify content of the present invention with specific embodiment below, but and mean never in any form and limit the invention.
The synthetic amoxycilline Trihydrate bp of the enzyme process that uses among following embodiment mother liquor is the mother liquor in the technology of the synthetic amoxycilline Trihydrate bp of conventional enzyme process.
Embodiment 1
(a) get the synthetic amoxycilline Trihydrate bp mother liquor 2000L (wherein, remaining amoxycilline Trihydrate bp content is 3 mg/mL, and D-D-pHPG content is 15 mg/mL, and D-p-hydroxyphenylglycine methyl ester content is 5 mg/mL) of enzyme process.Regulate pH to 7.5 with sodium hydroxide solution; Add the 50kg Semacylase; 25 ℃ of controlled temperature, reaction 2h makes the amoxycilline Trihydrate bp hydrolysis in the mother liquor generate D-D-pHPG and 6-amino-penicillanic acid; The D-p-hydroxyphenylglycine methyl ester is hydrolyzed into the D-D-pHPG, obtains hydrolyzed solution.Detect each component concentration in the hydrolyzed solution with performance liquid chromatography, D-D-pHPG content is 18mg/mL, and the content of 6-APA is 2mg/mL.
(b) use volume(tric)fraction and regulate hydrolyzed solution pH to 6.0-7.0, through H103 macroporous resin (Chemical Plant of Nankai Univ.'s productions) hydrolyzed solution is carried out separating treatment then, last kind of 15 ℃～20 ℃ of temperature, last kind flow velocity 1～2BV ∕ h than the hydrochloric acid that is 15%.The footpath post of resin column compares 1:10.Adopt the deionized water wash-out, elution flow rate 2～4BV ∕ h.Figure is as shown in Figure 2 through test macroporous resin absorption concentration profile.
Calculate the effluent volume that is rich in the D-D-pHPG according to the concentration profile of the concentration profile of D-D-pHPG shown in Figure 2 and 6-APA and be about former 1.3 times of going up appearance hydrolyzed solution volume, the yield of D-D-pHPG is 98%; The volume that is rich in the 6-APA elutriant is former 1.2 times of going up appearance hydrolyzed solution volume, and the yield of 6-APA is 63%.
The elutriant 2600L that the collection leading portion is rich in the D-D-pHPG is in the A container for storing liquid, and wherein, D-D-pHPG concentration is 13mg ∕ mL.The elutriant 2400L that the collection back segment is rich in 6-APA is in the B container for storing liquid, and wherein, 6-APA concentration is 7mg ∕ mL.As shown in Figure 1 the returning to the technology of the synthetic amoxycilline Trihydrate bp of enzyme process of elutriant of being rich in 6-APA applied mechanically as raw material.
(c) ultrafiltration removal of impurities: utilize strong aqua will be rich in the elutriant pH regulator to 10.0 of D-D-pHPG; Adopt molecular weight cut-off 2000 daltonian ultrafiltration membrance filters; Remove residual insoluble solid particle, pigment and other macromole impurity in the elutriant, obtain ultrafiltrated.
(d) nanofiltration concentrates: adopting molecular weight cut-off is that 150 daltonian nf membrane are carried out nanofiltration to ultrafiltrated and concentrated, and the concentration that obtains the D-D-pHPG is the liquid concentrator of 70mg/mL.
(e) isoelectric point crystallizing: utilize volume(tric)fraction than being 15～34% hydrochloric acid soln the pH value of liquid concentrator is adjusted to 5.0, under 0 ~ 5 ℃, leave standstill 3h, crystallization is filtered, and filtrate is dry, obtains the D-D-pHPG.
The recovery of D-D-pHPG reaches more than 97% in the present embodiment, and can be used as raw material after its esterification fully, to be used for the enzyme process of amoxycilline Trihydrate bp synthetic.
Embodiment 2
Fig. 1 is seen in technical process, and operation steps is following:
Behind the synthetic amoxycilline Trihydrate bp of enzyme process, extract the amoxycilline Trihydrate bp, then mother liquor reclaimed:
(a) mother liquor hydrolysis: utilize strong aqua with synthetic amoxycilline Trihydrate bp mother liquor (2000L) pH regulator to 7.5 of enzyme process, add Semacylase (50kg), react 1h down, remove by filter acylase, obtain hydrolyzed solution at 30 ℃; Under this pH value and the temperature condition, through the 1h reaction, amoxycilline Trihydrate bp remaining in the mother liquor fully is hydrolyzed to 6-APA and D-D-pHPG, and the remaining substrate D-of building-up reactions p-hydroxyphenylglycine methyl ester also is hydrolyzed to the D-D-pHPG.
(b) resin isolation: utilize volume(tric)fraction than being the pH value to 7.0 that 34% hydrochloric acid is regulated hydrolyzed solution, adopt XAD-4 macroporous resin column (productions of U.S. Rohn & hass company) to separate, 15 ℃ of last kind of temperature, flow velocity 2BV ∕ h.Use the deionized water wash-out, 25 ℃ of eluting temperatures, flow velocity 4 BV ∕ h.Resin Static Adsorption data (in massfraction) D-D-pHPG is that 8. 1%, 6-APA are 28. 7%.The concentration of D-D-pHPG, 6-APA in the high effective liquid chromatography for measuring elutriant; Collect elutriant that is rich in the D-D-pHPG and the elutriant that is rich in 6-APA respectively; The concentration of 6-APA is 6mg/mL in the elutriant of the said 6-APA of being rich in; The 6-APA recovery reaches 62%, and the enzyme process that is used for the amoxycilline Trihydrate bp as raw material is synthetic.
(c) ultrafiltration removal of impurities: utilize strong aqua will be rich in the elutriant pH regulator to 10.0 of D-D-pHPG, adopt molecular weight cut-off 1500 daltonian ultrafiltration membrance filters, obtain ultrafiltrated.
(d) nanofiltration concentrates: adopting molecular weight cut-off is that 200 daltonian nf membrane are carried out nanofiltration to ultrafiltrated and concentrated, and obtains liquid concentrator, and the concentration of D-D-pHPG is 70mg/mL in the control liquid concentrator.
(e) isoelectric point crystallizing: utilize volume(tric)fraction than being 34% hydrochloric acid the pH value of liquid concentrator is adjusted to 5.0, under 0 ~ 5 ℃, leave standstill the 2h crystallization, filter, the gained solid drying obtains the D-D-pHPG, and the recovery reaches 95%.
Embodiment 3
(a) mother liquor hydrolysis: utilize mass ratio be 10% sodium hydroxide solution with the synthetic amoxycilline Trihydrate bp of enzyme process mother liquor pH regulator to 8.0, add Semacylase, at 25 ℃ of reaction 2 h down, remove by filter acylase, obtain hydrolyzed solution; Under this pH value and the temperature condition, through the 2h reaction, amoxycilline Trihydrate bp remaining in the mother liquor fully is hydrolyzed to 6-APA and D-D-pHPG, and the remaining substrate D-of building-up reactions p-hydroxyphenylglycine methyl ester also is hydrolyzed to the D-D-pHPG.
(b) resin isolation: utilizing volume(tric)fraction is the pH value to 6.5 that 15～34% hydrochloric acid is regulated hydrolyzed solution, and the XAD1600N macroporous resin column that adopts U.S. Rohn & hass company to produce is separated, 18 ℃ of last kind of temperature, and flow velocity 1.5BV ∕ h,
Use the deionized water wash-out, 30 ℃ of eluting temperatures, flow velocity 3 BV ∕ h.Resin Static Adsorption data (in massfraction) D-D-pHPG is that 10. 9%, 6-APA are 30.2%.Adopt the concentration of D-D-pHPG, 6-APA in the high effective liquid chromatography for measuring elutriant; Collect elutriant that is rich in the D-D-pHPG and the elutriant that is rich in 6-APA respectively; The concentration of 6-APA is 8mg/mL in the elutriant of the said 6-APA of being rich in; The 6-APA recovery reaches 63%, and the enzyme process that is used for the amoxycilline Trihydrate bp as raw material is synthetic.
(c) ultrafiltration removal of impurities: utilize sodium hydroxide will be rich in the elutriant pH regulator to 9.5 of D-D-pHPG, adopt molecular weight cut-off 1500 daltonian ultrafiltration membrance filters, obtain ultrafiltrated; Carry out uf processing under these conditions, can effectively remove insoluble solid particle residual in the elutriant, pigment and other macromole impurity.
(d) nanofiltration concentrates: adopting molecular weight cut-off is that 180 daltonian nf membrane are carried out nanofiltration to ultrafiltrated and concentrated, and obtains liquid concentrator, and the concentration of D-D-pHPG is 65mg/mL in the control liquid concentrator.
(e) isoelectric point crystallizing: utilize volume(tric)fraction than being 20% hydrochloric acid the pH value of liquid concentrator is adjusted to 5.5, under 5 ~ 10 ℃, leave standstill the 2h crystallization, filter, the gained solid drying obtains the D-D-pHPG.
The recovery of present embodiment D-D-pHPG reaches 96%.
Embodiment 4
(a) mother liquor hydrolysis: utilize strong aqua with the synthetic amoxycilline Trihydrate bp of enzyme process mother liquor pH regulator to 8.5, add Semacylase, react 4 h down, remove by filter acylase, obtain hydrolyzed solution at 28 ℃; Under this pH value and the temperature condition, through the 4h reaction, amoxycilline Trihydrate bp remaining in the mother liquor fully is hydrolyzed to 6-APA and D-D-pHPG, and the remaining substrate D-of building-up reactions p-hydroxyphenylglycine methyl ester also is hydrolyzed to the D-D-pHPG.
(b) resin isolation: utilizing volume(tric)fraction is the pH value to 6.0 that 15～34% hydrochloric acid is regulated hydrolyzed solution, and the NKA II macroporous resin column that adopts Nankai University to produce is separated, 20 ℃ of last kind of temperature; Flow velocity 1BV ∕ h; Use the deionized water wash-out, 25 ℃ of eluting temperatures, flow velocity 2 BV ∕ h.Resin Static Adsorption data (in massfraction) D-D-pHPG is that 11. 7%, 6-APA are 50.2%.Adopt the concentration of D-D-pHPG, 6-APA in the high effective liquid chromatography for measuring elutriant; Collect elutriant that is rich in the D-D-pHPG and the elutriant that is rich in 6-APA respectively; The concentration of 6-APA is 7mg/mL in the elutriant of the said 6-APA of being rich in; The 6-APA recovery reaches 62%, and the enzyme process that is used for the amoxycilline Trihydrate bp as raw material is synthetic.
(c) ultrafiltration removal of impurities: utilize strong aqua will be rich in the elutriant pH regulator to 9.5 of D-D-pHPG, adopt molecular weight cut-off 1800 daltonian ultrafiltration membrance filters, obtain ultrafiltrated; Carry out uf processing under these conditions, can effectively remove insoluble solid particle residual in the elutriant, pigment and other macromole impurity.
(d) nanofiltration concentrates: adopting molecular weight cut-off is that 150 daltonian nf membrane are carried out nanofiltration to ultrafiltrated and concentrated, and obtains liquid concentrator, and the concentration of D-D-pHPG is 60mg/mL in the control liquid concentrator.
(e) isoelectric point crystallizing: to utilize volume(tric)fraction be 18% hydrochloric acid is adjusted to 6.0 with the pH value of liquid concentrator, under 5 ~ 10 ℃, leaves standstill 3 h crystallizations, filters, and the gained solid drying obtains the D-D-pHPG, and the recovery reaches 96%.
Embodiment 5
(a) (wherein, remaining amoxycilline Trihydrate bp content is 3 mg/mL, and D-D-pHPG content is 15 mg/mL, and D-p-hydroxyphenylglycine methyl ester content is 5 mg/mL to get the synthetic amoxycilline Trihydrate bp mother liquor 1500L of enzyme process.Regulate pH to 7.5 with sodium hydroxide solution; Add the 50kg Semacylase; 25 ℃ of controlled temperature, reaction 2h makes the amoxycilline Trihydrate bp hydrolysis in the mother liquor generate D-D-pHPG and 6-amino-penicillanic acid; The D-p-hydroxyphenylglycine methyl ester is hydrolyzed into the D-D-pHPG, obtains hydrolyzed solution.Detect each component concentration in the hydrolyzed solution with performance liquid chromatography, D-D-pHPG content is 18mg/mL, and the content of 6-APA is 2mg/mL.
(b) use volume(tric)fraction and regulate hydrolyzed solution PH to 6.0-7.0, the D101C macroporous resin (its aperture 10nm ± 1, the specific surface area 500-550m that produce through Xi'an Lan Xiao company then than the hydrochloric acid that is 15
2G
-) hydrolyzed solution is carried out separating treatment, last appearance flow velocity 1.0BV ∕ h adopts the deionized water wash-out, elution flow rate 2.5BV ∕ h, resin Static Adsorption data (in massfraction) D-D-pHPG is 8.4%, 6-APA is 25.9%.
The elutriant 2100L that the collection leading portion is rich in the D-D-pHPG is in the A container for storing liquid, and wherein, D-D-pHPG concentration is 12mg ∕ mL.The elutriant 1950L that the collection back segment is rich in 6-APA is in the B container for storing liquid, and wherein, 6-APA concentration is 7mg ∕ mL.As shown in Figure 1 the returning to the technology of the synthetic amoxycilline Trihydrate bp of enzyme process of elutriant of being rich in 6-APA applied mechanically as raw material.
(c) ultrafiltration removal of impurities: utilize strong aqua will be rich in the elutriant pH regulator to 10.0 of D-D-pHPG; Adopt molecular weight cut-off 2000 daltonian ultrafiltration membrance filters; Remove residual insoluble solid particle, pigment and other macromole impurity in the elutriant, obtain ultrafiltrated.
(d) nanofiltration concentrates: adopting molecular weight cut-off is that 150 daltonian nf membrane are carried out nanofiltration to ultrafiltrated and concentrated, and the concentration that obtains the D-D-pHPG is the liquid concentrator of 70mg/mL.
(e) isoelectric point crystallizing: utilize volume(tric)fraction than being 15～34% hydrochloric acid soln the pH value of liquid concentrator is adjusted to 5.0, under 0 ~ 5 ℃, leave standstill 3h, crystallization is filtered, and filtrate is dry, obtains the D-D-pHPG.
The recovery of D-D-pHPG reaches 95% in the present embodiment, and can be used as raw material after its esterification fully, to be used for the enzyme process of amoxycilline Trihydrate bp synthetic.
Claims (8)
1. an enzyme process synthesizes the recoverying and utilizing method of effective constituent in the mother liquor of amoxycilline Trihydrate bp, it is characterized in that following steps:
(a) with alkaline solution enzyme process is synthesized amoxycilline Trihydrate bp mother liquor pH regulator to 7.5～8.5, add Semacylase and be hydrolyzed, obtain hydrolyzed solution;
(b) with said hydrolyzed liquid with salt acid for adjusting pH value to 6.0～7.0, through the macroporous resin column separating treatment, the deionized water wash-out is collected the elutriant be rich in the D-D-pHPG and the elutriant that is rich in 6-APA respectively; The elutriant that is rich in 6-APA returned to the technology of the synthetic amoxycilline Trihydrate bp of enzyme process apply mechanically as raw material;
(c) with the above-mentioned elutriant that is rich in the D-D-pHPG with acid for adjusting pH to 9.5～10.0, adopt molecular weight cut-off 1500～2000 daltonian membrane filtrations, obtain the A that filtrates;
(d) above-mentioned filtrating A being used molecular weight cut-off is that 150～200 daltonian nf membrane are carried out nanofiltration and concentrated, and obtains liquid concentrator;
(e) with acid the pH value of liquid concentrator is adjusted to 5.0～6.0, leaves standstill, crystallization, filtration, the gained solid drying obtains the D-D-pHPG.
2. according to the recoverying and utilizing method of effective constituent in the mother liquor of the synthetic amoxycilline Trihydrate bp of the said enzyme process of claim 1, it is characterized in that said macroporous resin column separating treatment, appearance temperature is 15～20 ℃ on it, flow velocity 1～2BV/h; During the deionized water wash-out, 25～30 ℃ of eluting temperatures, flow velocity 2～4BV/h.
3. synthesize the recoverying and utilizing method of effective constituent in the mother liquor of amoxycilline Trihydrate bp according to claim 1 or 2 said enzyme process; It is characterized in that described said macroporous resin column aperture 5～30nm; Skeleton structure is polarity or non-polar material, specific surface area 500～1300m2g-1.
4. according to the recoverying and utilizing method of effective constituent in claim 1 or the synthetic amoxycilline Trihydrate bp of the 2 said enzyme process mother liquor, it is characterized in that the said hydrolysis of a step, its reaction conditions is that temperature is controlled at 25～30 ℃, and the reaction times is 1～4 hour.
5. according to the recoverying and utilizing method of effective constituent in the mother liquor of the synthetic amoxycilline Trihydrate bp of the said enzyme process of claim 1, it is characterized in that in the said liquid concentrator of d step, the concentration of D-D-pHPG is 60～70mg/mL.
6. according to the recoverying and utilizing method of effective constituent in claim 1 or the synthetic amoxycilline Trihydrate bp of the 2 said enzyme process mother liquor, it is characterized in that the said crystalline temperature that leaves standstill of e step is 0～10 ℃, the time is 2～3 h.
7. according to the recoverying and utilizing method of effective constituent in claim 1 or the synthetic amoxycilline Trihydrate bp of the 2 said enzyme process mother liquor, it is characterized in that the elutriant of the said 6-APA of being rich in, the concentration of its 6-APA is 6～8mg/mL.
8. according to the recoverying and utilizing method of effective constituent in claim 1 or the synthetic amoxycilline Trihydrate bp of the 2 said enzyme process mother liquor, it is characterized in that described macroporous resin is among any one among XAD-4, XAD1600N, NKA II, the SP850 ﹑ H103.
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| CN103045474A (en) * | 2013-01-07 | 2013-04-17 | 厦门市天泉鑫膜科技股份有限公司 | Recovery equipment and technology for hydroxy phenylglycine in amoxicillin synthetic mother solution |
| CN103553952A (en) * | 2013-10-11 | 2014-02-05 | 孟兰尊 | Method for recovering alpha-amino-p-hydroxyphenylacetic acid in solution |
| 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 |
| CN104628587A (en) * | 2015-02-12 | 2015-05-20 | 山东鲁抗立科药业有限公司 | Method for recovering D-p-hydroxyphenylglycine in amoxicillin production waste liquid |
| CN105085294A (en) * | 2015-09-16 | 2015-11-25 | 山东鲁抗立科药业有限公司 | Method for recovering D-p-hydroxyphenylglycine (D-HPG) from cefprozil production waste liquid in enzyme synthesis 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 |
| CN105349608A (en) * | 2015-12-16 | 2016-02-24 | 厦门市天泉鑫膜科技股份有限公司 | Method for recycling phenylglycine in cefalexin crystallization mother liquid |
| CN105567777A (en) * | 2016-03-07 | 2016-05-11 | 内蒙古常盛制药有限公司 | Method for recycling amoxicillin mother solution |
| CN105838771A (en) * | 2015-01-16 | 2016-08-10 | 上海凯鑫分离技术股份有限公司 | Recovery process of amoxicillin crystal mother solution |
| CN106399446A (en) * | 2016-11-04 | 2017-02-15 | 内蒙古常盛制药有限公司 | Method for preparing amoxicillin from degreased liquid |
| CN107698607A (en) * | 2017-08-25 | 2018-02-16 | 国药集团威奇达药业有限公司 | The comprehensive recovering process of active ingredient in the crystalline mother solution of enzymatic clarification ampicillin |
| CN110257457A (en) * | 2019-06-17 | 2019-09-20 | 齐鲁天和惠世制药有限公司 | A kind of method that enzymatic isolation method recycles kanamycin A from amikacin treatment fluid |
| 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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| CN103045474A (en) * | 2013-01-07 | 2013-04-17 | 厦门市天泉鑫膜科技股份有限公司 | Recovery equipment and technology for hydroxy phenylglycine in amoxicillin synthetic mother solution |
| CN103553952A (en) * | 2013-10-11 | 2014-02-05 | 孟兰尊 | Method for recovering alpha-amino-p-hydroxyphenylacetic acid in solution |
| CN103553952B (en) * | 2013-10-11 | 2016-03-30 | 河北润邦化工有限公司 | The recovery method of alpha-amino group-p-hydroxyphenylaceticacid in a kind of solution |
| 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 |
| CN104357528B (en) * | 2014-10-29 | 2018-04-27 | 国药集团威奇达药业有限公司 | The method of active ingredient in synthetical recovery enzymatic amoxicillin mother liquor |
| CN105838771A (en) * | 2015-01-16 | 2016-08-10 | 上海凯鑫分离技术股份有限公司 | Recovery process of amoxicillin crystal mother solution |
| CN105838771B (en) * | 2015-01-16 | 2019-09-27 | 上海凯鑫分离技术股份有限公司 | Amoxicillin crystalline mother solution recovery process |
| CN104628587A (en) * | 2015-02-12 | 2015-05-20 | 山东鲁抗立科药业有限公司 | Method for recovering D-p-hydroxyphenylglycine in amoxicillin production waste liquid |
| CN104628587B (en) * | 2015-02-12 | 2016-06-22 | 艾美科健（中国）生物医药有限公司 | A kind of amoxicillin of reclaiming produces the method for D-pHPG in waste liquid |
| CN105085294A (en) * | 2015-09-16 | 2015-11-25 | 山东鲁抗立科药业有限公司 | Method for recovering D-p-hydroxyphenylglycine (D-HPG) from cefprozil production waste liquid in enzyme synthesis 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 |
| 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 |
| CN105349608A (en) * | 2015-12-16 | 2016-02-24 | 厦门市天泉鑫膜科技股份有限公司 | Method for recycling phenylglycine in cefalexin crystallization mother liquid |
| CN105567777A (en) * | 2016-03-07 | 2016-05-11 | 内蒙古常盛制药有限公司 | Method for recycling amoxicillin mother solution |
| CN106399446A (en) * | 2016-11-04 | 2017-02-15 | 内蒙古常盛制药有限公司 | Method for preparing amoxicillin from degreased liquid |
| CN107698607A (en) * | 2017-08-25 | 2018-02-16 | 国药集团威奇达药业有限公司 | The comprehensive recovering process of active ingredient in the crystalline mother solution of enzymatic clarification ampicillin |
| CN107698607B (en) * | 2017-08-25 | 2019-09-06 | 国药集团威奇达药业有限公司 | The comprehensive recovering process of effective component in the crystalline mother solution of enzymatic clarification ampicillin |
| CN110257457A (en) * | 2019-06-17 | 2019-09-20 | 齐鲁天和惠世制药有限公司 | A kind of method that enzymatic isolation method recycles kanamycin A from amikacin treatment fluid |
| CN110257457B (en) * | 2019-06-17 | 2022-09-30 | 山东安信制药有限公司 | Method for recovering kanamycin A from amikacin treatment liquid by enzymolysis method |
| 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 |
| CN111393315B (en) * | 2020-02-20 | 2023-04-07 | 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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