CN104372035B - The method for synthesizing high-purity 2 ketonic acid salt - Google Patents
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Abstract
The invention discloses a kind of method for synthesizing high-purity 2 ketonic acid salt, this method is that aldehyde compound and glycine raw material are carried out into enzymic catalytic reaction under the catalytic action of L threonine aldolases and L threonine deaminase complex enzymes, generates 2 keto acid products；After the keto acid product of gained 2 is purified through chromatography, pH is adjusted to appropriate value using alkali carbonate or alkali metal hydrogencarbonate, then carries out activated carbon decolorizing, condensing crystallizing, vacuum drying successively, 2 ketonic acid salts are produced；The preparation method is simple to operate, reaction condition gentle, and pollution-free using aqueous phase system, production cost is low, and obtained 2 ketonic acid salt yield is high, purity is high.
Description
Technical field
2- ketone acids are synthesized the present invention relates to a kind of new bio method and the method for obtaining pharmaceutical grade ketonic acid salt is isolated and purified, and are belonged to
In biosynthesis field.
Background technology
2- ketonic acid salts are mainly used in biochemical reagents, in-vitro diagnosis, cosmetics adding ingredient, in addition still in important medicine
Mesosome, is mainly used in fitness and weight losing dietary supplements.ɑ-hydroxybutyric acid is widely used in by the kit of the configurations such as 2- batanone acids
The detection of dehydrogenase, and it is used as the diagnosis basis of the illnesss such as myocardial infarction, anaemia, leukaemia, hepatic sclerosis.Sodium Pyruvate is to determine
The substrate of lactic dehydrogenase, is mainly used in glutamate pyruvate transaminase vitality test in liver function test.2 pentanone acid sodium is mainly used in low
The allergy illness such as blood calcium, nettle rash, angioneurotic edema.
These compounds are primarily now chemical method synthesis, and what patent CN103073411A was announced is：Oxalic acid ester is super
Under the conditions of low-temperature anhydrous, ethyl phosphonium bromide reactive magnesium is added by solvent of tetrahydrofuran.Product is purified by rectification under vacuum again, acetic acid
Ethyl ester is extracted, and decrease temperature crystalline obtains butanone hydrochlorate in the methanol solution of substantial amounts of alkali metal hydroxide.Wherein using a large amount of
Organic solvent, its rate of recovery is low, and post-processing step process is more, and difficulty is big.Furthermore chemical method yield is low, cost is high, is not suitable for
In industrialized production.At present, although there is pertinent literature to report that biofermentation extracts pyruvic acid, main purpose in terms of bioanalysis
In terms of concentrating on gene expression and the fermentation of enzyme, extraction.What patent CN101205181A was announced is double film two-step fermentations extractions point
From Sodium Pyruvate, its zymotic fluid removes remaining thalline, protein, carbohydrate, pigment through ultrafiltration membrance filter, then after being concentrated through film plus
Enter dry sieve after the crystal powder that a large amount of 90% ethanol precipitation obtains is cleaned through methanol and get finished product.Whole process is to equipment requirement
Harsh, the yield of extraction is than relatively low, and particularly the purge process in later stage uses substantial amounts of organic solvent, and its rate of recovery is low, enterprise
Post-processing step process is more, and difficulty is big.
The content of the invention
There is yield for the existing method for being chemically synthesized ketonic acid salt low, purification is difficult, and organic solvent usage amount
Greatly, reclaim difficult, cause cost high, environmental pollution, while chemical method process step is cumbersome, being unfavorable for industrial production etc. one is
The defect of row；The purpose of the present invention is to be to provide a kind of simple to operate, reaction condition gently, and cost is low, and high yield prepares high
The method of purity 2- ketonic acid salts.
The invention provides a kind of method for synthesizing high-purity 2- ketonic acid salts, this method is in reaction solution, with the structure of formula 1
Aldehyde compound and glycine raw material under the catalytic action of L-threonine aldolase and L-threonine deaminase complex enzyme, in
PH is 6.0~8.0, and temperature is carries out enzymic catalytic reaction under conditions of 20~40 DEG C, 2- ketone acid of the generation with the structure of formula 2 is produced
Thing；After gained 2- keto acid products are purified through chromatography, pH to 4.0 is adjusted using alkali carbonate or alkali metal hydrogencarbonate
~8.0, then activated carbon decolorizing, condensing crystallizing, vacuum drying are carried out successively, produce the 2- ketonic acid salts with the structure of formula 3；Described
The total activity of L-threonine aldolase and L-threonine deaminase in L-threonine aldolase and L-threonine deaminase complex enzyme
Than for 3~4:2~3；
Wherein,
R is C1~C4Aliphatic group；
M is alkali metal ion.
The method of the high-purity 2- ketonic acid salts of synthesis of the present invention also includes following preferred scheme：
It is preferred that scheme in R be C1~C4Linear paraffin base or straight chain alkane substitute base, alkylene or substituted olefine base,
It is a kind of in alkynyl or substituted alkynyl.
It is preferred that scheme in L-threonine aldolase with respect to aldehyde compound addition for 30000U/mol~
80000U/mol；Most preferably 30000U/mol~50000U/mol.
It is preferred that scheme in L-threonine deaminase with respect to aldehyde compound addition be 20000U/mol~60000U/
mol；Most preferably 20000U/mol~40000U/mol.
It is preferred that scheme in mass percent concentration of the aldehyde compound in reaction solution be 2%~6%, aldehyde compound
Mol ratio with glycine is 1:1~1.05.
It is preferred that scheme in alkali carbonate be Na2CO3Or K2CO3。
It is preferred that scheme in alkali metal hydrogencarbonate be NaHCO3Or KHCO3。
It is preferred that scheme in activated carbon decolorizing be by purify and regulation pH after 2- keto acid products maintain temperature 20~40
In the range of DEG C, add activated carbon and carry out 0.5~1.0h of absorption.
It is preferred that scheme in activated carbon be wood activated charcoal.
It is preferred that scheme in activated carbon usage amount for purify and regulation pH after 2- keto acid product volumes 3.0~
5.0‰。
It is preferred that scheme in enzymic catalytic reaction using in reaction solution glycine residual quantity less than 0.2wt% as reaction end.
It is preferred that scheme in vacuum drying be vacuum be more than 0.09MPa, condition of the temperature in the range of 60~80 DEG C
It is lower to carry out.
It is preferred that scheme in chromatography be to be separated by ion exchange resin or polymeric adsorbent；Described ion is handed over
The sulfonic resin that resin is highly acid is changed, described polymeric adsorbent is hydrophobic polymeric adsorbent.
The L-threonine aldolase and L-threonine deaminase that the present invention is used can purchase to be had in Shanghai still section's biological medicine
Limit company or Hu'nan Fulaige Biological Technology Co. Ltd..
It is preferred that scheme in enzymic catalytic reaction carry out time be 1~3h.
The synthetic route of the 2- ketonic acid salts of the present invention is as follows：Using sodium carbonate as nertralizer, exemplified by generation 2- ketone acid sodium salts.
Beneficial effects of the present invention：The present invention is combined catalysis with L-threonine aldolase and L-threonine deaminase first
Aldehyde compound and glycine raw material carry out reaction high yield and obtain 2- Mek-Tol Unit compounds, then combine chromatography point on this basis
From with salinization, concentration Crystallization Process, obtain high-purity 2- ketone acid sodium salts.Compared to the prior art, the inventive method has
Advantage：1st, raw material sources are wide, and reaction condition is gentle (general chemical method needs subzero 70 DEG C of anhydrous condition), can give birth on a large scale
Production, the enzyme rate of recovery is high, and reusable, greatly reduces production cost.2nd, using aqueous phase system, it is to avoid chemical method is used
A large amount of solvents；And purify, in crystallization process also without using organic solvents such as alcohols, whole production process environmental protection is entered
One step reduces cost；3rd, feed stock conversion is high, and relative chemical method wants high by more than 20%；Product purity is high, is not less than 98%.
Brief description of the drawings
【Fig. 1】The chromatography figure of the 2- batanone acids made from embodiment 1.
Embodiment
Following examples are intended to further illustrate present invention, rather than limit the scope of the invention.
The reagent source being related in specific examples below：
Glycine, formaldehyde, acetaldehyde and propionic aldehyde are analytically pure commercially available common agents；Ion exchange resin (is purchased from Shanghai China
Shake Science and Technology Ltd., product type HZ-016)
Embodiment 1
Take 35.7 grams of glycine are (anhydrous) to add the acetaldehyde for adding 40%45.74mL after appropriate deionized water after dissolving
Solution, is dissolved with 3.0mol/L sodium hydroxide solutions and controls pH 7.50 or so, vacuum filtration removes insoluble matter, is settled to
600mL.L-threonine aldolase is put into by 30000U/L (to throw the total enzyme activity of enzyme, L is reaction volume to U therein) ratio and is pressed
20000U/L (to throw the total enzyme activity of enzyme, L is reaction volume to U therein) ratio input L-threonine deaminase, control reaction temperature
30 DEG C of degree, keeps pH 7.50, when liquid phase glycine remains in 0.2% in course of reaction with 3.0mol/L sodium hydroxide solution
Following terminating reaction, filters out conversion terminate liquid.Obtain containing 45.80g2- butanone acid solution 624mL, yield is 98.0%.It will turn
Change the good 200mL ion exchange columns of the directly upper regeneration of hydrochloric acid of terminate liquid, flow velocity is：6.67mL/min(2.0Bv/h).Directly
2- batanone acids are collected using deionized water as eluent, collection liquid scope is：125~815mL, volume is 690mL,
44.87g2- batanone acid, yield is 96.04%.Above-mentioned filtrate is taken to be slowly added to 28.0g Na under normal temperature condition2CO3, it is final to adjust
Save pH to 5.50 ± 0.2.Stir after half an hour, the activated carbon for adding reaction solution volume 5 ‰ is added to collection liquid stirring half an hour
Directly filter.Its filtrate is added directly into 70 DEG C of Rotary Evaporators and is concentrated under reduced pressure.When having partial crystals precipitation, directly will
Concentrate export is filtered after being cooled to 20 DEG C, and growing the grain half an hour.Filtrate volume is that 70mL contains 2- batanone acid 25.25g,
Filter cake is dried 6 hours through 70 DEG C of vacuum drying chambers, obtains 17.82g finished powders, yield is 92.2%.
Obtained 2- ketone acids liquid phase detection：
1st, mobile phase
Weigh after 5.75g ammonium dihydrogen phosphates, plus the dissolving of 950mL ultra-pure waters, adjust pH to 3.5 (to adjust and then use with 85% phosphoric acid
3N ammoniacal liquor is adjusted back), after the water system membrane filtration in 0.22 μm of aperture, 50mL methanol is added, deaerate 20min or so after mixing.
2nd, Detection wavelength：215nm
3rd, appearance time：3.8min left and right
4th, INSTRUMENT MODEL：Shimadzu -15C high performance liquid chromatographs
5th, chromatographic column：River Shen C18-spherisorb BDS 5Um 4.6*200m
6th, batanone acid chromatograms (as shown in Figure 1), related data such as table 1 below.
The batanone acid chromatograms related data of table 1
| Title | Retention time | Area | Area % | Highly | Separating degree | Tailing factor | Theoretical tray |
| Batanone acid | 3.785 | 5746487 | 99.9088 | 521005 | 4.078 | 1.034 | 2909.693 |
Comparative example 1
118g dimethyl oxalates are dissolved in 2000mL anhydrous tetrahydro furans, -78 DEG C are cooled to, 500mL is added
After 1.0mol/l ethylmagnesium bromide, stirring reaction 2h, vacuum distillation removes solvent, and residual mixture is collected through rectification under vacuum
2-Oxobutyric acid methyl esters 50g, its yield is 76%.By obtained 2-Oxobutyric acid methyl esters in 2.5L 1.0mol/l hydrochloric acid
It is heated to reflux, stirs 2h.Again with 3 extractions of 3L ethyl acetate point, organic phase is collected, and adds in organic phase anhydrous magnesium sulfate
Dry, filtering, filtrate distillation removes solvent, obtains crude product 2- batanone acid 43g, yield 74.48%.
Above-mentioned crude product batanone acid 20g is weighed, is dissolved in 50mL methanol and cools down 0 DEG C, the addition hydroxides of 70mL 10%
Sodium methanol solution, then this thermotonus 10min.Then 25 DEG C of vacuum distillations remove solvent, and remaining solid is washed with ethyl acetate,
It is filtrated to get white solid.Take solid to be placed in vacuum drying chamber air drying 2h, obtain finished product 17g.Whole process 2- batanone acids
The yield 52.13% of sodium.
Embodiment 2
Take the propionic aldehyde for adding 97%35.6mL after being dissolved after the appropriate deionized water of 37.8 grams of (anhydrous) glycine additions molten
Liquid, is dissolved with 3.0mol/L sodium hydroxide solutions and controls pH 7.50 or so, vacuum filtration removes insoluble matter, is settled to
600mL.L-threonine aldolase 30000U/L is thrown, L-threonine deaminase 20000U/L, 30 DEG C of controlling reaction temperature is used
3.0mol/L sodium hydroxides keep pH 7.50 ± 0.05, when liquid phase glycine molar yield >=99%, filter out conversion and terminate
Liquid, is obtained containing 54.73g 2 pentanone acid solution 626mL, yield 98.3%.The directly upper regeneration of hydrochloric acid of conversion terminate liquid is good
200mL ion exchange columns, flow velocity is：6.67mL/min(2.0Bv/h).Directly deionized water is used to be collected as eluent
2 pentanone is sour, and collection liquid scope is：120~815mL, volume is 695mL, and 53.37g2- oxopentanoic acids, yield is 95.85%.Take
Above-mentioned filtrate is slowly added to 28.8g Na under normal temperature condition2CO3, final regulation pH to 5.50 ± 0.2.Stir after half an hour, plus
Enter reaction solution volume 5 ‰ activated carbon be added to collection liquid stirring half an hour directly filter.Its filtrate is added directly into 70 DEG C
It is concentrated under reduced pressure in Rotary Evaporators.When having partial crystals precipitation, concentrate export is directly cooled to 20 DEG C, and growing the grain half is small
When after filtered.Filtrate volume is that 65mL contains 2 pentanone acid 27.16g, and filter cake is dried 6 hours through 70 DEG C of vacuum drying chambers,
24.6g finished powders are obtained, yield is 92.8%.
Embodiment 3
Take 34.0 grams of glycine are (anhydrous) to add after appropriate deionized water after dissolving, the acetaldehyde for adding 40%52.4mL is molten
Liquid, is dissolved with 3.0mol/L sodium hydroxide solutions and controls pH 7.50 or so, vacuum filtration removes insoluble matter, is settled to
600mL.The ratio for putting into L-threonine aldolase and 20000U/L in 40000U/L ratio puts into L-threonine deaminase, control
30 DEG C of reaction temperature processed, keeps pH 7.50, when liquid phase glycine is residual in course of reaction with 3.0mol/l sodium hydroxide solution
Less than 0.2% terminating reaction is stayed in, conversion terminate liquid is filtered out.Obtain containing 44.08g2- butanone acid solution 644mL, yield is
94.3%.Terminate liquid will be converted and directly go up the good 200mL ion exchange columns of regeneration of hydrochloric acid, flow velocity is：6.67mL/min
(2.0Bv/h).Deionized water is directly used as eluent and collects 2- batanone acids, collection liquid scope is：115-795mL, volume
For 670mL, 43.19g2- batanone acids, yield is 92.41%.Above-mentioned filtrate is taken to be slowly added to 26.8g under normal temperature condition
Na2CO3, final regulation pH to 5.50 ± 0.2.Stir after half an hour, the activated carbon for adding reaction solution volume 5 ‰ is added to collection
Liquid stirring half an hour directly filters.Its filtrate is added directly into 70 DEG C of Rotary Evaporators and is concentrated under reduced pressure.Partial crystals to be had
During precipitation, filtered after concentrate export directly is cooled into 20 DEG C, and growing the grain half an hour.Filtrate volume is that 65mL contains 2-
Batanone acid 24.14g, filter cake is dried 6 hours through 70 DEG C of vacuum drying chambers, obtains 17.23g finished powders, yield is 88.53%.
Embodiment 4
Take 34.0 grams of glycine are (anhydrous) to add after appropriate deionized water after dissolving, the acetaldehyde for adding 40%52.4mL is molten
Liquid, is dissolved with 3.0mol/L sodium hydroxide solutions and controls pH 8.00 or so, vacuum filtration removes insoluble matter, is settled to
600mL.The ratio for putting into L-threonine aldolase and 20000U/L in 30000U/L ratio puts into L-threonine deaminase, control
30 DEG C of reaction temperature processed, keeps pH 8.00, when liquid phase glycine is residual in course of reaction with 3.0mol/L sodium hydroxide solution
Less than 0.2% terminating reaction is stayed in, conversion terminate liquid is filtered out.Obtain containing 45.24g2- butanone acid solution 676mL, yield is
96.8%.Terminate liquid will be converted and directly go up the good 200mL ion exchange columns of regeneration of hydrochloric acid, flow velocity is：6.67mL/min
(2.0Bv/h).Deionized water is directly used as eluent and collects 2- batanone acids, collection liquid scope is：120-850mL, volume
For 730mL, 44.34g2- batanone acids, yield is 94.86%.Above-mentioned filtrate is taken to be slowly added to 27.4g under normal temperature condition
Na2CO3, final regulation pH to 5.50 ± 0.2.Stir after half an hour, the activated carbon for adding reaction solution volume 5 ‰ is added to collection
Liquid stirring half an hour directly filters.Its filtrate is added directly into 70 DEG C of Rotary Evaporators and is concentrated under reduced pressure.Partial crystals to be had
During precipitation, filtered after concentrate export directly is cooled into 20 DEG C, and growing the grain half an hour.Filtrate volume is that 67mL contains 2-
Batanone acid 24.77g, filter cake is dried 6 hours through 70 DEG C of vacuum drying chambers, obtains 17.70g finished powders, yield is 90.88%.
Embodiment 5
Take 34.0 grams of glycine are (anhydrous) to add after appropriate deionized water after dissolving, the acetaldehyde for adding 40%52.4mL is molten
Liquid, is dissolved with 3.0mol/L sodium hydroxide solutions and controls pH 7.50 or so, vacuum filtration removes insoluble matter, is settled to
600mL.The ratio for putting into L-threonine aldolase and 40000U/L in 60000U/L ratio puts into L-threonine deaminase, control
30 DEG C of reaction temperature processed, keeps pH 7.50, when liquid phase glycine is residual in course of reaction with 3.0mol/L sodium hydroxide solution
Less than 0.2% terminating reaction is stayed in, conversion terminate liquid is filtered out.Obtain containing 45.80g2- butanone acid solution 624mL, yield is
98.0%.Terminate liquid will be converted and directly go up the good 200mL ion exchange columns of regeneration of hydrochloric acid, flow velocity is：6.67mL/min
(2.0Bv/h).Deionized water is directly used as eluent and collects 2- batanone acids, collection liquid scope is：125-815mL, volume
For 690mL, 44.87g2- batanone acids, yield is 96.04%.Above-mentioned filtrate is taken to be slowly added to 44.15g under normal temperature condition
NaHCO3, final regulation pH to 5.50 ± 0.2.Stir after half an hour, the activated carbon for adding reaction solution volume 5 ‰ is added to collection
Liquid stirring half an hour directly filters.Its filtrate is added directly into 70 DEG C of Rotary Evaporators and is concentrated under reduced pressure.Partial crystals to be had
During precipitation, filtered after concentrate export directly is cooled into 20 DEG C, and growing the grain half an hour.Filtrate volume is that 73mL contains 2-
Batanone acid 25.02g, filter cake is dried 6 hours through 70 DEG C of vacuum drying chambers, obtains 17.74g finished powders, yield is 91.60%.
Claims (7)
1. the method for the high-purity 2- ketonic acid salts of synthesis, it is characterised in that in reaction solution, aldehyde compound with the structure of formula 1 and
Glycine raw material under the catalytic action of L-threonine aldolase and L-threonine deaminase complex enzyme, in pH be 6.0~8.0,
Temperature is carries out enzymic catalytic reaction under conditions of 20~40 DEG C, generation has the 2- keto acid products of the structure of formula 2；Gained 2- ketone acids are produced
After thing is purified through chromatography, entered using alkali carbonate or alkali metal hydrogencarbonate regulation pH to 4.0~8.0, then successively
Row activated carbon decolorizing, condensing crystallizing, vacuum drying, produce the 2- ketonic acid salts with the structure of formula 3；Described L-threonine aldolase
Total activity ratio with L-threonine aldolase in L-threonine deaminase complex enzyme and L-threonine deaminase is 3~4:2~3；
Wherein,
R is C1~C4Aliphatic group；
M is alkali metal ion；
Described activated carbon decolorizing is that the 2- keto acid products for purifying and adjusting after pH are maintained into temperature in the range of 20~40 DEG C, plus
Enter activated carbon and carry out 0.5~1.0h of absorption；Described activated carbon is wood activated charcoal；The usage amount of the activated carbon is the 2-
The 3.0 of keto acid product volume~5.0 ‰；
Described chromatography is separated by the sulfonic resin or hydrophobic polymeric adsorbent of highly acid.
2. the method as described in claim 1, it is characterised in that R is C1~C4Linear paraffin base, alkylene, one in alkynyl
Kind.
3. the method as described in claim 1, it is characterised in that L-threonine aldolase is with respect to the addition of aldehyde compound
30000U/mol~80000U/mol, L-threonine deaminase with respect to aldehyde compound addition for 20000U/mol~
60000U/mol。
4. the method as described in claim 1, it is characterised in that mass percent concentration of the aldehyde compound in reaction solution be
2%~6%, the mol ratio of aldehyde compound and glycine is 1:1~1.05.
5. the method as described in claim 1, it is characterised in that described alkali carbonate is Na2CO3Or K2CO3；Described
Alkali metal hydrogencarbonate is NaHCO3Or KHCO3。
6. the method as described in claim 1, it is characterised in that described enzymic catalytic reaction is with glycine residual quantity in reaction solution
It is reaction end less than 0.2wt%.
7. the method as described in claim 1, it is characterised in that described vacuum drying is to be more than 0.09MPa, temperature in vacuum
Degree in the range of 60~80 DEG C under conditions of carry out.
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| CN104372035A (en) | 2015-02-25 |
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