CN101831482A - Application of nanofiltration membrane in splitting D,L-amino acid by using acyltransferase or D-amino acylase - Google Patents
Application of nanofiltration membrane in splitting D,L-amino acid by using acyltransferase or D-amino acylase Download PDFInfo
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- 239000012528 membrane Substances 0.000 title claims abstract description 67
- 238000001728 nano-filtration Methods 0.000 title claims abstract description 60
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- 150000008575 L-amino acids Chemical class 0.000 title claims abstract description 11
- 101710097070 D-aminoacylase Proteins 0.000 title abstract description 4
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- -1 N-acetylamino Chemical group 0.000 claims abstract description 27
- 239000002253 acid Substances 0.000 claims abstract description 24
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- 238000000108 ultra-filtration Methods 0.000 claims abstract description 12
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- 238000000746 purification Methods 0.000 claims description 7
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- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
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- 238000000926 separation method Methods 0.000 claims description 6
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- XUYPXLNMDZIRQH-ZCFIWIBFSA-N N-acetyl-D-methionine Chemical compound CSCC[C@H](C(O)=O)NC(C)=O XUYPXLNMDZIRQH-ZCFIWIBFSA-N 0.000 description 2
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Abstract
The invention discloses application of a nanofiltration membrane in splitting D,L-amino acid by using acyltransferase or D-amino acylase. The application of the nanofiltration membrane is that: by ultra-filtration, enzyme and other high molecular substances are separated from splitting solution obtained by splitting N-acetyl-D,L-amino acid with the acyltransferase or D-amino acylase and then chiral amino acid is separated from N-acetylamino acid by the filtration of the nanofiltration membrane.
Description
Technical field: the present invention relates to D, the amino acid whose fractionation of L-, particularly nanofiltration membrane is at D, the application in the amino acid whose fractionation of L-.
Background technology: utilize acyltransferase (Acylase; claim L-Aminoacylase again) or D-L-Aminoacylase (D-aminoacylase) fractionation D; L-amino acid is a kind of common method for preparing chiral amino acid; the amino acid that this method commonly used splits has the methionine(Met) (immobilization of L-Aminoacylase and to D; the optical resolution of L-methionine(Met); Han Jihong etc.; ion-exchange and absorption; 1993 the 9th the 2nd phases of volume; 107-113); (enzyme process splits DL-theanine and separation and purification thereof to theanine; Guo Liyun etc.; tea science; 2006 the 26th the 1st phases of volume; 31-36); (enzyme process of DL-phenylalanine splits research to phenylalanine; He Shiguo etc.; chemical reaction engineering and technology; in March, 2004; 64-69); tryptophane (acetylase kinetic resolution N-acetyltryptophan; synthetic chemistry; the 9th the 1st phase of volume of calendar year 2001; 48-50); (the cunninghamella echinulata L-Aminoacylase splits the research of DL-L-Ala to L-Ala; amino acid and Biological resources; 2002 the 27th the 2nd phases of volume; 38-41) etc., the method that amino acid whose fractionation in above-mentioned is separated different products in the L-Aminoacylase cracking is mainly utilizes isoelectric point precipitation or ion exchange method, and these two kinds of methods all have the cost height; the consumption chemical reagent is many, heavy-polluted shortcoming.
Nanofiltration membrane (Nanofiltration) is the pressure drive membrane between reverse osmosis membrane and ultra-filtration membrane, cutoff value 200-1000 dalton.Whether charged according to nanofiltration membrane, can be divided into charged nanofiltration membrane and non-charged nanofiltration membrane.Charged nanofiltration membrane integral body or surface have electric charge, these groups that have electric charge can produce the Donnan effect by electrostatic interaction, thereby realize that the different valence state ionic separates, according to electrically charged different in kind, charged nanofiltration membrane can be divided into positively charged nanofiltration membranes (having the cation activity group), bear nanofiltration membrane (having the cation activity group) and charge embedded film, wherein the application of bear nanofiltration membrane is comparatively extensive, and common nanofiltration membrane mainly contains crosslinked aromatic polyamides, crosslinked polyamide, crosslinked poly-piperazine amide, crosslinked poly-piperazine amide, SPSF, polymeric amide, various material such as aromatic polyamides.
Summary of the invention:
Conscientiously research by the contriver; surprised discovery; at acyltransferase selectivity or D-L-Aminoacylase with N-acetyl-D; after L-amino acid is hydrolyzed into chiral amino acid and N-acetylamino acid; by nanofiltration membrane chiral amino acid, N-acetylamino acid are separated, can effectively improve separation efficiency, improve the purity of chiral amino acid; simplify technology, reduce cost.
The invention provides nanofiltration membrane is utilizing acyltransferase or D-L-Aminoacylase to split D, the application in the L-amino acid.
Being applied as through acyltransferase or D-L-Aminoacylase of described nanofiltration membrane to N-acetyl-D; L-amino acid carries out fractionation liquid after the cracking behind ultra-filtration and separation enzyme and other macromolecular substance, adopts nanofiltration membrane to filter again chiral amino acid is separated with the N-acetylamino acid.
Described chiral amino acid is a kind of in methionine(Met), theanine, phenylalanine, tryptophane, the L-Ala.Preferred L-methionine(Met).
The preferred bear nanofiltration membrane of described nanofiltration membrane.
The material of described bear nanofiltration membrane is selected from crosslinked aromatic polyamides, crosslinked polyamide, crosslinked poly-piperazine amide, crosslinked poly-piperazine amide, SPSF, polymeric amide, aromatic polyamides.The anion active group of bear nanofiltration membrane is selected from sulfonic group (SO
3H) or, carboxyl (COOH), preferred sulfonated polysulfone membrane.
The preferred 500-1000 dalton of the cutoff value of described bear nanofiltration membrane, preferred especially 800-1000 dalton
The preferred cutoff value of described bear nanofiltration membrane is 1000 daltonian SPSF nanofiltration membrane.
Working pressure was 0.25-1.2Mpa when described nanofiltration membrane was filtered.
Described acyltransferase or D-L-Aminoacylase split D, and the amino acid whose step of L-is as follows:
1) preparation of N-acetylamino acid;
2) acyltransferase or D-L-Aminoacylase cracking N-acetylamino acid, described enzymatic lysis reaction product carry out ultrafiltration to separate enzyme;
3) with step 2) product that obtains stream adopts nanofiltration membrane to filter, and obtain trapped fluid and see through liquid; The chiral amino acid that is split enters through liquid, and the N-acetylamino acid that is not split is stayed in the trapped fluid;
4) liquid that sees through that step 3) is obtained carries out crystallization and separates the chiral amino acid that makes thus;
5) trapped fluid of ion-exchange purification step 3) gained;
The crystalline mother solution of 6) acetylize step 4) gained, and be circulated to step 2) carries out enzymolysis in;
7) the N-acetylamino acid of racemize step 5) purifying, and this racemic product is circulated to step 2).
In the following description; how for example with the L-methionine(Met); other outer L-amino acid of L-methionine(Met) also can take similar method to split; obtain L-amino acid; except the enzyme that adopts and enzymatic hydrolysis condition are different; amino acid whose preparation method of D-and the amino acid whose preparation method of L-are similar; described D-L-Aminoacylase and enzymatic lysis condition also are (Yan Feng etc. well known in the prior art; D-amino acid acylase splits D; the L-phenylalanine prepares the D-phenylalanine; amino acid and Biological resources, 2008 the 30th the 1st phases of volume, 36-38)
1) preparation of N-acetylamino acid
Amino acid whose acetylize is known to those skilled in the art.Many documents relate to from total free aminoacids by Schotten-Baumann or Einhorn-method obtain the acid of N-acetylamino (Organikum, VEB Deutscher Verlag derWissenschaften, 16.Auflage, Berlin 1986, S.407).For example, the methionine(Met) (US6114163 that can be acetylation; WO97/21667).Preferred adopt solid form or with the form supply D of the alkaline solution of 30-50%, the L-methionine(Met) adopts D, L-Sodium L-methioninate salts solution.In addition, also can use and contain D, (L)-, (D), L-or D, the mother liquor of L-methionine(Met).By to D, add diacetyl oxide or Acetyl Chloride 98Min. in the aqueous solution of L-methionine(Met), and alkali (for example sodium hydroxide/potassium) carries out acetylize under 20-40 ℃.Split for ensuing enzyme, can directly use the N-ethanoyl-D that comes from the acetylize step, the alkaline salt solution of L-methionine(Met).In this case, do not need to separate N-ethanoyl-D, the L-methionine(Met).
2) acyltransferase or D-L-Aminoacylase cracking N-acetylamino acid
With the L-methionine(Met) is example, and reaction formula is as follows:
This step it is known to the person skilled in the art that according to the US6114163 disclosed method carries out.By N-ethanoyl-D with about 0.4-2.0mol/L, the alkaline aqueous solution of L-methionine(Met), the preferred sodium salt of pH value between 6.0 and 7.5 contacts with acyltransferase and carries out.At this, N-ethanoyl-L-methionine(Met) is optionally split into acetate and L-methionine(Met) by enzyme, and N-ethanoyl-D-methionine(Met) is unaffected.Before preferred enzyme splits, the pH value is adjusted to the process racemize N-ethanoyl-D that comes from step 7) of 7.0-7.5, L-methionine salt solution circulated is to the mixture for the treatment of enzymatic lysis, and described mixture can be through gac and filtration treatment.Then suspension is filtered on pressure filter, and clear filtrate is collected in the jar.Can add the zinc chloride of trace or cobalt chloride catalyzer as the enzyme resolution reaction.To N-ethanoyl-D, the concentration of L-methionine(Met) basic salt is about 0.5-1.0mol/L to water with described solution dilution, preferred 0.6-0.9mol/L, and be supplied to the reactor that is used for the enzymatic lysis reaction.Described reactor can comprise the ultra filtration unit with film, and described film has 5000-20000 dalton, the preferred daltonian cutoff value of 7500-12000 (cut-off).With described N-ethanoyl-D, L-methionine salt solution infeeds in the so-called enzyme mebrane reactor (Enzyme Membrane Reactor) (EP1170277 and the document of quoting thereof) with pump, and is mixed into and wherein contains acyltransferase, and is preferred
In the concentrated stream of acyltransferase or its Equivalent (concentrate stream) (meaning that part of mixture that wherein has enzyme).Also can behind enzyme selectivity ground cracking N-ethanoyl-L-methionine(Met), filter by strainer again.Described enzyme selectivity ground cracking N-ethanoyl-L-methionine(Met) an alkali metal salt, particular certain cancers is to form L-methionine(Met) and alkali metal acetate.Having molecular weight is that about 80000 daltonian acyltransferases can not see through ultra-filtration membrane, therefore stays to concentrate in the stream.Every other littler compound can see through described film and enter in the product stream.It is to carry out under the 7.0-7.5 with pH value scope that this enzymatic reaction advantageously is 20-40 ℃ in temperature.
3) with step 2) product that obtains stream adopts nanofiltration membrane to filter, and obtain trapped fluid and see through liquid; The chiral amino acid that is split enters through liquid, and the N-acetylamino acid that is not split is stayed in the trapped fluid.
The preferred bear nanofiltration membrane of described nanofiltration membrane.
The material of described bear nanofiltration membrane is selected from crosslinked aromatic polyamides, crosslinked polyamide, crosslinked poly-piperazine amide, crosslinked poly-piperazine amide, SPSF, polymeric amide, aromatic polyamides, and the anion active group of described bear nanofiltration membrane is selected from sulfonic group (SO
3H) or, carboxyl is (COOH).Preferred sulfonated polysulfone membrane.
The preferred 500-1000 dalton of the cutoff value of described bear nanofiltration membrane, preferred especially 800-1000 dalton.
The preferred cutoff value of described bear nanofiltration membrane is 1000 daltonian SPSF nanofiltration membrane.
Working pressure was 0.25-1.2Mpa when described nanofiltration membrane was filtered.Trapped fluid is 1 with the volume ratio that sees through liquid: 4-1: 1, preferred 1: 1.5-1: 1.By with step 2) the product stream that obtains adopts the daltonian bear nanofiltration membrane of cutoff value 500-1000 to filter, obtain trapped fluid and see through liquid, see through liquid and be material by nanofiltration membrane, it mainly is the L-methionine(Met), and trapped fluid is mainly to be N-acetyl-L-methionine(Met) by the material of nanofiltration membrane.In filtration procedure, preferred pressurization is filtered.
4) liquid that sees through that step 3) is obtained carries out crystallization and separates the chiral amino acid that makes thus;
With the L-methionine(Met) is example, and the liquid that sees through that step 3) is obtained is pumped into evaporation unit and carries out crystallization under reduced pressure, and described evaporation unit can be common thin-film evaporator or falling-film evaporator etc., and similar technology can be with reference to US6114163.Preferably, being lower than and concentrating under the racemic temperature of generation, especially be lower than 90 ℃.Can be by the described liquid that sees through of the filtration purifying of gac and pressure filter with the removal of impurity of between preferred 70-90 ℃, decolouring.In order to obtain chiral amino acid, can carry out filtration by microfilter, described strainer has the cutoff value of at least 0.2 μ m; Also can obtain by the filter paper of routine or the method for filter cloth.Be used for that the preferred film of this purpose is soughed by polyethers or polypropylene or other material well known by persons skilled in the art are made.The L-methionine(Met) can be by crystallization (US6114163) during cooling.Subsequently, it can filter by centrifugal, through cleaning and drying.Preferably, cleaning solution is made of methanol aqueous solution (methanol content 65-90 weight %).Cleaning solution can be recovered and can reclaim methyl alcohol by distillation.Most preferably, the crystal that obtains is suspended in the methanol solution to remove last impurity and to guarantee the quality of microorganism.Preferably be lower than the step that suspends under 40 ℃ the temperature.The crystal that suspends filters by centrifugal again, and cleans with above-mentioned methanol solution.Can be by distilling recycle methanol cleaning solution again.L-methionine content as product can reach more than 98%.
5) trapped fluid of ion-exchange purification step 3) gained
The trapped fluid of step 3) gained comprises unreacted N-acetylamino acid and a small amount of chiral amino acid that does not see through nanofiltration membrane.In order not waste the latter (very expensive), must be further purified this material.Preferably carry out this purifying by ion-exchange techniques.In order to obtain the by product of purifying, to carry out ion exchange treatment be that well known by persons skilled in the art (EP 276392 to becoming to be grouped into similar mixing solutions with trapped fluid; WO 97/21667).With the L-methionine(Met) is example, and by described trapped fluid is stood Zeo-karb, it is mutually static that unprotected L-methionine(Met) and alkalimetal ion then are adsorbed to, and remaining product such as N-ethanoyl-D, (L)-and methionine(Met) and acetate be by wash-out.In a preferred mode, described solution is heated to 45-80 ℃ and be pumped on the post that is filled with resin cation (R.C.).Ion is adsorbed for L-methionine(Met) and basic metal (preferred sodium), and N-ethanoyl-D, (L) acidic moiety of methionine(Met) and acetate is by this post.Advantageously, this process can by three independently ion exchange column carry out.In first post, from the mother liquor of crystal separation such as above-mentioned processing to separate the L-methionine(Met) and to the solution demineralization.Subsequently, on resin anion(R.A) and resin cation (R.C.), successfully handle N-ethanoyl-D, (L)-methionine(Met) and acetate part.Resin anion(R.A) is intended to remove all negatively charged ion from mixture, typical, especially can damage the muriate of stainless steel equipment in the racemize step 7).Resin cation (R.C.) is used for removing the alkalimetal ion and the L that can cause incomplete racemic last trace in the step 7), (D) methionine(Met).According to method known to those skilled in the art, ion exchange resin can be loaded with H again
+Or OH
-The part that contains the L-methionine(Met) still is present in first cation seperation column, and the general knowledge by those skilled in the art is by wash-out, collection.The L-methionine(Met) that ion-exchange purification obtains randomly can preferably add and carry out crystallization in the step 4) by for example by Crystallization Separation.
The crystalline mother solution of 6) acetylize step 4) gained, and it is added step 2) carries out enzymolysis in;
The mother liquor of crystallisation process step 4), based on ecological reason, it needs to be acetylation sometimes, racemize and add step 2 again) in carry out enzymolysis.With the L-methionine(Met) is example, and the mother liquor of crystallisation process step 4) comprises a spot of D-methionine(Met), also might have minor N-ethanoyl-D, (L)-and methionine(Met).In order to improve yield, the D-methionine(Met) needs to be acetylation and to be incorporated into again into described process sometimes.If there is minor N-ethanoyl-D, (L)-methionine(Met), can directly it be added step 2) carry out enzymolysis, also can carry out adding step 2 after the racemize) carry out enzymolysis.At a spot of D-methionine(Met), the pH value of mother liquor need be adjusted to 8.0-12.0, and add the Acetyl Chloride 98Min. or the diacetyl oxide (the Schotten-Baumann-method of having stated) of respective amount to this mixture.After finishing, concentrate the mixture of gained, and it be circulated to step 2) in carry out enzymolysis.Randomly, the described acetylize crystalline mother solution of racemization mixture is circulated to step 2 with it again) in carry out enzymolysis.
Randomly, the described acetylize crystalline mother solution of racemization mixture is circulated to step 2 with it again) in carry out enzymolysis.
7) the N-acetylamino acid of racemize step 5) purifying, and this racemic product is circulated to step 2)
With the L-methionine(Met) is example, and reaction formula is as follows:
In order to improve the yield of chiral amino acid, isolating N-acetylamino acid must be circulated in the flow process.Yet,, must carry out N-acetylamino acid racemize in order to finish this purpose.Racemize N-acetylamino acid is known (research of acetyl-D-methionine(Met) racemization technology, Zhang Qingyu etc., (chemical industry and engineering, in March, 2004, the 21st the 2nd phase of volume, 91-95 for a person skilled in the art; WO 97/21650; EP 175840; US6 114163).Preferably with ion exchange process concentrate separately and the part of demineralization is carried out N-ethanoyl-D, (L)-racemize of methionine(Met).More preferably, by adding the resulting N-ethanoyl-D of a spot of diacetyl oxide racemize, (L)-melts of methionine(Met) to be to form N-ethanoyl-D, L-methionine(Met).This mixture is heated to about 120-150 ℃, and quenching in the solution of the basic metal that dilutes (preferred sodium) oxyhydroxide subsequently.
Perhaps, be example with the L-methionine(Met), of the present invention another preferred embodiment in, L-methionine solution purifying and demineralization of step 5) preparation is added to the crystallization solution of step 4).Before crystallization, preferably before activated carbon treatment, the solution that the optional L-methionine solution that is concentrated of step 5) is injected towards step 4) is favourable.Another preferred variant of the present invention relates to as follows, before enzymatic lysis, zine ion and/or cobalt ion is added to mixture.This method has increased the enzymatic lysis ability significantly.Advantageously, utilize every liter of reaction mixture 10
-3-10
-5The zine ion of M.In this case, the amount of the cobalt ion of use can be a per unit enzyme 10
-3-10
-5Cobalt ion.In order further to minimize waste streams, preferably in the process of purifying L-methionine crystal, collect the washed with methanol solution that uses and distill the methyl alcohol that can utilize again from reaction process.Remaining heavy phase comprises a large amount of L-methionine(Met) and N-ethanoyl-D, L-methionine(Met).This heavy phase can randomly be circulated in the acetylation of step 6).The result is that this material is by in the preparation process of the extremely total L-methionine(Met) of recombine.From the method for foregoing description as can be seen, the preparation method of L-methionine(Met) provided by the invention since its high-quality product that produces minimum refuse amount and obtain high productive rate can operate technically highly diversifiedly.The combination of method steps makes and obtains the higher total recovery of L-methionine(Met), and this obviously is better than prior art, and helps to obtain above-mentioned favourable result.
Term, D, (L)-, (D), L-or D, L-are meant the mixture of the enantiomer with the different D-that measure and L-isomer.At D, (L)-mixture in, the D-enantiomer mainly exists with respect to the L-form.Equally, at (D), in the L-mixture, L-for the ratio of D-isomer greater than 1.D, L-mixture are racemize or almost racemic mixture.
Unlike the prior art, the application of nanofiltration membrane provided by the invention in the amino acid preparation, after the product behind the enzymolysis being advanced macromolecular substance such as ultrafiltration elimination enzyme, adopt nanofiltration membrane further to filter again, chiral amino acid and N-acetylamino acid are separated, with in the prior art enzymolysis after product is compared through the technology that reclaims by ion-exchange step again after the ultrafiltration, preparation method provided by the invention has improved the rate of recovery and the quality of chiral amino acid, reduced subsequent step 6 simultaneously) in used amount of resin and corresponding wash-out when carrying out ion-exchange, the chemical reagent amount that regenerating resin is used, therefore also reduce production cost, reduced the discharging of pollutent.Obtain racemic N-acetylamino acid to step 2 by the recycled step 7)) enzymolysis step in; can improve the yield of chiral amino acid; with the L-methionine(Met) is example; meet that " yield of the pharmaceutical grade L-methionine(Met) of 2005 editions requirements of Chinese pharmacopoeia can reach (with respect to N-ethanoyl-D, the molar percentage yield of L-methionine(Met)) more than 95%.
Embodiment:
Described embodiment is only for being the preparation method's of example implementation example with the L-methionine(Met), can not be interpreted as restriction to embodiment of the present invention, preparation method provided by the invention can implement in any favourable mode in conjunction with any common practise basis.Present embodiment can reach (with respect to N-acetyl-D, the molar percentage yield of L methionine(Met)) more than 95% at the yield of the L-methionine(Met) that meets 2005 editions requirements of Chinese Pharmacopoeia after the circular flow.
1) acetylize D, the racemic mixture of L-methionine(Met)
According to the disclosed method acetylize of US6114163 D, the L-methionine(Met) obtains N-ethanoyl-D, the L-methionine(Met).
2) this acetylize mixture of enzymatic lysis
According to the disclosed method of US6114163, with N-acetyl-D, the L-methionine(Met) is mixed with the pH value and is 7.0-7.5, and concentration is the sodium-salt aqueous solution of 0.6mol/L.According to zinc ion concentration is 10
-3The ratio of mo/L adds zinc chloride to N-acetyl-D in the L-Sodium L-methioninate salt brine solution.The employing commodity are by name
Acyltransferase, enzyme activity is 30000U/g, service temperature is 37 ℃, final transformation efficiency is 85%, is that the reaction solution of 10000 daltonian ultra-filtration membranes after to final conversion carries out ultrafiltration and remove with the macromolecular cpds such as enzyme during product is flowed with cutoff value.
3) with step 2) product that obtains stream adopts the bear nanofiltration membrane to filter, and obtain trapped fluid and see through liquid;
Adopting molecular weight cut-off is that the product stream that 1000 SPSF nanofiltration membrane (NTR7450, Nitto Denko is Japan) to step 2) obtains filters, obtain trapped fluid and see through liquid, working pressure is 0.8Mpa, and service temperature is 35 ℃, and described trapped fluid is 1: 1 with the volume ratio that sees through liquid.
4) liquid that sees through that step 3) is obtained carries out crystallization and separates the L-methionine(Met) that makes thus
According to US6114163, step 3) and the resin cation (R.C.) elutriant that sees through liquid and step 5) that obtains are used activated carbon decolorizing under 70 ℃ of conditions, under reduced pressure, be pumped into thin-film evaporator after the destainer press filtration and carry out condensing crystal, Tc is lower than 90 ℃.Centrifuging is carried out in the gained crystallization, and cleans the L-methionine(Met) crystallization of gained under normal temperature with 90% methanol solution, and centrifuging again recycles after the Methanol Recovery distillation, obtains L-methionine(Met) crystallization drying under reduced pressure, 110 ℃ of drying temperatures.The L-methionine content that obtains is 98.7%.
5) ion-exchange purification step 3) gained sees through liquid
The step 3) gained seen through liquid according to EP276392; The disclosed method of WO97/21667 is carried out ion-exchange purification: will be heated to back 70 ℃ through liquid and handle by cationic resin column 1, the liquid that sees through that to handle is then handled through resin anion(R.A) post and cationic resin column 2 respectively again, wash-out cationic resin column 1 and 2, join in the elutriant in the preceding solution of step 4) activated carbon decolorizing and carry out crystallization together, preparation L-methionine(Met).Wash-out resin anion(R.A) post, elutriant are that step 7) is standby.
The crystalline mother solution of 6) acetylize step 4) gained;
The crystalline mother solution that step 4) is obtained carries out acetylize, with sodium hydroxide the pH value of mother liquor is transferred to 10, adopts among the US6114163 disclosed method to carry out acetylize with diacetyl oxide.(in March, 2004, the 21st the 2nd phase of volume, 91-95) disclosed method is carried out for the research of acetyl-D-methionine(Met) racemization technology, chemical industry and engineering according to Zhang Qingyu etc. with the product after the acidylate.Product after the acetylize can add step 2) in carry out enzymolysis, also can carry out racemization and handle, and be circulated to step 2) in carry out enzymolysis.Ratio decision in this crystalline mother solution that mainly obtains according to step 4) between D-methionine(Met) and the L-methionine(Met); after the D-methionine(Met) is more for a long time with regard to acetylize, need to carry out racemization and handle, when the L-methionine(Met) can be circulated to step 2 after the acetylize more for a long time) in carry out enzymolysis.
7) the N-ethanoyl-D of racemize step 6) purifying, (L)-methionine(Met), circulation enters step 2).
With the elutriant in the step 5) resin anion(R.A) post (the N-ethanoyl-D that contains purifying, (L)-methionine(Met)) according to WO 97/21650; EP 175840; (the 21st the 2nd phase of volume, 91-95) disclosed method adopted diacetyl oxide to carry out racemize and obtained almost racemic N-ethanoyl-D, the L-methionine(Met) chemical industry and engineering, March in 2004 for US6 114163 and Zhang Qingyu etc.Regulate N-ethanoyl-D with sodium hydroxide solution and water, the concentration of L-methionine(Met) is 0.6-0.9mol, and pH is 7.0-8.0, is 10 according to zinc ion concentration
-3Mo/L adds zinc chloride, adds step 2) carry out enzyme digestion reaction.
Claims (10)
1. nanofiltration membrane is utilizing acyltransferase or D-L-Aminoacylase to split D, the application in the L-amino acid.
2. according to claim 1; it is characterized in that being applied as through acyltransferase or D-L-Aminoacylase of nanofiltration membrane to N-acetyl-D; L-amino acid carries out fractionation liquid after the cracking behind ultra-filtration and separation enzyme and other macromolecular substance, adopts nanofiltration membrane to filter again chiral amino acid is separated with the N-acetylamino acid.
3. as claimed in claim 1 or 2, it is characterized in that described chiral amino acid is a kind of in methionine(Met), theanine, phenylalanine, tryptophane, the L-Ala.
4. as described in arbitrary in the claim 1 to 3, it is characterized in that the preferred bear nanofiltration membrane of described nanofiltration membrane.
5. as described in the claim 4, the material that it is characterized in that described bear nanofiltration membrane is selected from crosslinked aromatic polyamides, crosslinked polyamide, crosslinked poly-piperazine amide, crosslinked poly-piperazine amide, SPSF, polymeric amide, aromatic polyamides, the anion active group of bear nanofiltration membrane be selected from sulfonic group (SO3H) or, carboxyl is (COOH).
6. as described in the claim 5, the cutoff value that it is characterized in that described bear nanofiltration membrane is 500-1000 dalton.
7. as described in the claim 6, it is characterized in that the preferred SPSF nanofiltration membrane of described bear nanofiltration membrane.
8. as described in the claim 7, it is characterized in that the preferred cutoff value of described bear nanofiltration membrane is 1000 daltonian SPSF nanofiltration membrane.
As claim 1-8 arbitrary as described in, it is characterized in that described acyltransferase or D-L-Aminoacylase split D, the amino acid whose step of L-is as follows:
1) preparation of N-acetylamino acid;
2) acyltransferase or D-L-Aminoacylase cracking N-acetylamino acid, described enzymatic lysis reaction product carry out ultrafiltration to separate enzyme;
3) with step 2) product that obtains stream adopts nanofiltration membrane to filter, and obtain trapped fluid and see through liquid; The chiral amino acid that is split enters through liquid, and the N-acetylamino acid that is not split is stayed in the trapped fluid;
4) liquid that sees through that step 3) is obtained carries out crystallization and separates the chiral amino acid that makes thus;
5) trapped fluid of ion-exchange purification step 3) gained;
The crystalline mother solution of 6) acetylize step 4) gained, and be circulated to step 2) carries out enzymolysis in;
7) the N-acetylamino acid of racemize step 5) purifying, and this racemic product is circulated to step 2).
10. preparation method as claimed in claim 9 is characterized in that trapped fluid is 1 with the volume ratio that sees through liquid in the described step 3): 4-1: 1.
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| CN104263795A (en) * | 2014-08-22 | 2015-01-07 | 四川同晟生物科技有限公司 | Method for preparing chiral alpha-naphthenic glycine |
| CN109136298A (en) * | 2018-08-10 | 2019-01-04 | 浙江正硕生物科技有限公司 | A kind of preparation method of D- amino acid |
| CN113956154A (en) * | 2021-11-15 | 2022-01-21 | 长沙贝塔医药科技有限公司 | D-lactic acid-14C, preparation method and application |
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| CN1279176C (en) * | 2002-12-02 | 2006-10-11 | 新疆威仕达生物工程股份有限公司 | Process for producing L-methionine, aminoacylase strain and aminoacylase |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1279176C (en) * | 2002-12-02 | 2006-10-11 | 新疆威仕达生物工程股份有限公司 | Process for producing L-methionine, aminoacylase strain and aminoacylase |
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| 《化工进展》 20081231 张国俊等 亲和膜手性拆分技术及手性拆分固膜 797-802 1-15 第27卷, 第6期 2 * |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104263795A (en) * | 2014-08-22 | 2015-01-07 | 四川同晟生物科技有限公司 | Method for preparing chiral alpha-naphthenic glycine |
| CN109136298A (en) * | 2018-08-10 | 2019-01-04 | 浙江正硕生物科技有限公司 | A kind of preparation method of D- amino acid |
| CN113956154A (en) * | 2021-11-15 | 2022-01-21 | 长沙贝塔医药科技有限公司 | D-lactic acid-14C, preparation method and application |
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