CN109943482B - Method for preparing ethyl r-4-chloro-3-hydroxybutyrate by coupling extraction of enzyme membrane reactor - Google Patents
Method for preparing ethyl r-4-chloro-3-hydroxybutyrate by coupling extraction of enzyme membrane reactor Download PDFInfo
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Abstract
The invention relates to a method for preparing ethyl r-4-chloro-3-hydroxybutyrate by coupling extraction of an enzyme membrane reactor, which comprises the enzyme membrane reactor, an organic solvent charging barrel and a substrate charging barrel, wherein filter membranes are distributed in the enzyme membrane reactor, a feed liquid outlet is connected to one side of the upper end of the enzyme membrane reactor, an organic solvent outlet is arranged on one side of the enzyme membrane reactor, a feed liquid inlet is connected to one side of the lower end of the enzyme membrane reactor, and an organic solution inlet is arranged on the other side of the enzyme membrane reactor. The method has simple process, reduces emulsification in the reaction and extraction processes, improves the yield, reduces the loss of organic solvent, does not need to extract for multiple times, has simple and convenient operation, is beneficial to large-scale industrial production, can continuously collect products, removes the inhibition of the products on enzyme or the poison on cells, improves the molar conversion rate, and is more beneficial to industrial production.
Description
Technical Field
The invention relates to the technical field of enzyme engineering, in particular to a method for preparing ethyl r-4-chloro-3-hydroxybutyrate by coupling extraction of an enzyme membrane reactor.
Background
The ethyl R-4-chloro-3-hydroxybutyrate is an important intermediate for synthesizing L-carnitine and chiral compounds such as large lactim A and (R) -gamma-amino-beta-hydroxybutyrate (GABOB), and the market demand is very large.
The preparation of the ethyl r-4-chloro-3-hydroxybutyrate mainly adopts a biological method, the currently widely used method is to prepare r-carbonyl reductase and a coenzyme regeneration system by adopting a microbiological method, then the r-4-chloro-3-hydroxybutyrate is synthesized by biologically catalyzing ethyl 4-chloroacetoacetate by utilizing the two enzymes, and because the ethyl r-4-chloro-3-hydroxybutyrate is insoluble in water and has higher toxicity to cells/enzymes, a water/organic solvent two-phase system reaction is generally adopted, so that the product can keep low concentration in a water phase to reduce the toxic action to the cells.
The existence of enzyme or cells can emulsify an organic solvent and water into a uniform phase, which causes difficulty in subsequent extraction process and reduces yield, and at present, no literature or patent reports exist how to eliminate emulsification, and only patent document CN104651292A discloses a method for removing a substrate COBE and a product s-4-chloro-3-hydroxy ethyl butyrate inhibition in situ by using macroporous adsorption resin, but the method needs a large amount of eluent and resin regeneration, generates a large amount of waste water and solid waste, and has complex operation and higher cost.
Disclosure of Invention
The invention aims to provide a method for preparing ethyl r-4-chloro-3-hydroxybutyrate by coupling extraction of an enzyme membrane reactor, which aims to solve the problems that an organic solvent and water are emulsified into a uniform phase due to the existence of enzyme or cells, the difficulty is caused in the subsequent extraction process, and the yield is reduced. At present, no literature or patent reports how to eliminate the emulsification phenomenon exist, and only patent document CN104651292A discloses a method for removing a substrate COBE and a product s-4-chloro-3-hydroxy ethyl butyrate inhibition in situ by using macroporous adsorption resin, but the method needs a large amount of eluent and resin regeneration, generates a large amount of waste water and solid waste, and has the problems of complex operation and higher cost.
In order to achieve the purpose, the invention provides the following technical scheme: a method for preparing ethyl (3-hydroxy-4-chloro-butyrate) by coupling extraction of an enzyme membrane reactor comprises the enzyme membrane reactor, an organic solvent charging barrel and a substrate charging barrel, wherein filter membranes are distributed in the enzyme membrane reactor, a feed liquid outlet is connected to one side of the upper end of the enzyme membrane reactor, an organic solvent outlet is arranged on one side of the enzyme membrane reactor, a feed liquid inlet is connected to one side of the lower end of the enzyme membrane reactor, an organic solution inlet is arranged on the other side of the enzyme membrane reactor, the organic solution inlet and the organic solvent outlet are respectively communicated with the organic solvent charging barrel through pipelines, a pressure pump is distributed on the pipeline connecting the organic solvent charging barrel and the organic solution inlet, a stirring paddle penetrates through the middle part of the inner side of the organic solvent charging barrel, the feed liquid outlet and the feed liquid inlet are respectively communicated with the substrate charging barrel through pipelines, and a heat-preserving jacket is attached to the outer wall of the substrate charging barrel, the inner side of the filter membrane is distributed with membrane holes, wherein.
Preferably, the filter membrane may be a ceramic membrane, a mixed fiber ester microporous filter membrane, a cellulose nitrate filter membrane, a polyvinylidene fluoride filter membrane, a cellulose acetate filter membrane, a regenerated cellulose filter membrane, a polyamide filter membrane, a polytetrafluoroethylene filter membrane, a polyvinyl chloride filter membrane, or a modified composite membrane of the above materials.
Preferably, the filters of claim 1 and 2 have a retention accuracy of from 1kD to 100 kD.
Preferably, the s-carbonyl reductase and the glucose dehydrogenase used in the step can be one or more of enzyme powder, enzyme liquid and genetically engineered bacteria.
Preferably, the fixative used in the step can be glutaraldehyde, epichlorohydrin, hexamethylene diamine, maleic acid, bisazo benzene.
Preferably, the organic solvent in the step (a) may be one or two of ethyl acetate, butyl acetate, toluene, xylene, octanol, chloroform, isopropanol, n-hexane, cyclohexane, n-butanol, isobutanol, and dibutyl phthalate.
The gas chromatograph used by the invention is an FULI9790 gas chromatograph, and the chemical purity detection conditions are as follows: a detector: FID detector, chromatography column: SE-54 capillary chromatography column (30 m 0.32mm 0.5 μm), 2.0 μ L sample size, 250 ℃ vaporization chamber temperature, 260 ℃ detector temperature, temperature programmed: keeping the temperature at 130 ℃ for 5min, heating the temperature to 5 ℃ per minute, keeping the temperature for 10min when the temperature is raised to 240 ℃, and detecting the optical purity under the conditions that: a detector: FID detector, chromatography column: GC/CP-Chirasil-DexCB, the sample volume is 10 mu L, the vaporization chamber temperature is 280 ℃, the detector temperature is 280 ℃, and a temperature programming mode is adopted: keeping the temperature at 110 ℃ for 2min, heating the temperature to 2 ℃ per minute, and keeping the temperature for 2min when the temperature is increased to 160 ℃.
Compared with the prior art, the invention has the beneficial effects that:
(1) the ethyl gamma-4-chloro-3-hydroxybutyrate is prepared by coupling extraction of the enzyme membrane reactor, the product can be continuously collected, the inhibition of the product on enzyme or the poison on cells can be relieved, the molar conversion rate can be improved, and the industrial production is more facilitated.
(2) The method has the advantages of reducing emulsification in the reaction and extraction processes, improving the yield, reducing the loss of organic solvent, avoiding extraction for many times, along with simple and convenient operation and contribution to large-scale industrial production.
Drawings
FIG. 1 is a schematic diagram of an enzyme membrane reactor apparatus for preparing ethyl r-4-chloro-3-hydroxybutyrate by coupled extraction of the enzyme membrane reactor according to the present invention;
FIG. 2 is a schematic diagram of the cross-sectional structure of a filter membrane of the method for preparing ethyl r-4-chloro-3-hydroxybutyrate by coupled extraction with an enzyme membrane reactor according to the present invention;
in the figure: 1. an enzyme membrane reactor; 2. filtering the membrane; 3. a feed liquid outlet; 4. an organic solvent outlet; 5. a feed liquid inlet; 6. a pressure pump; 7. an organic solvent cartridge; 8. a stirring paddle; 9. a substrate cartridge; 10. a heat-preserving jacket; 11. a membrane pore; 12. and (4) an organic solution inlet.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Referring to fig. 1-2, the present invention provides a technical solution: a method for preparing ethyl (3-hydroxy-4-chloro-butyrate) by coupling extraction of an enzyme membrane reactor comprises an enzyme membrane reactor 1, a filter membrane 2, a feed liquid outlet 3, an organic solvent outlet 4, a feed liquid inlet 5, a pressure pump 6, an organic solvent charging barrel 7, a stirring paddle 8, a substrate charging barrel 9, a heat-preservation jacket 10, a membrane hole 11 and an organic solution inlet 12, wherein the filter membrane 2 is distributed in the enzyme membrane reactor 1, the feed liquid outlet 3 is connected to one side of the upper end of the enzyme membrane reactor 1, the organic solvent outlet 4 is arranged on one side of the enzyme membrane reactor 1, the feed liquid inlet 5 is connected to one side of the lower end of the enzyme membrane reactor 1, the organic solution inlet 12 is arranged on the other side of the enzyme membrane reactor 1, the organic solution inlet 12 and the organic solvent outlet 4 are respectively communicated with the organic solvent charging barrel 7 through pipelines, and the pressure pump 6 is distributed on the pipeline connecting the organic solvent charging barrel 7 with the organic solution inlet 12, the middle part of the inner side of the organic solvent charging barrel 7 is penetrated with a stirring paddle 8, the feed liquid outlet 3 and the feed liquid inlet 5 are respectively communicated with a substrate charging barrel 9 through pipelines, the outer wall of the substrate charging barrel 9 is adhered with a heat-insulating jacket 10, the inner side of the filter membrane 2 is distributed with membrane holes 11, wherein,
the method comprises the following steps:
1) the stationary liquid is led into an enzyme membrane reactor 1 through a pressure pump 6 and circulated for 30min-3h at 20 ℃.
2) Dissolving r-carbonyl reductase and glucose dehydrogenase in phosphate buffer solution with pH7.0 to make both enzymes have activity of 5-50 ku/L, introducing into enzyme membrane reactor 1 via pressure pump 6, and circulating at 10-20 deg.C for 1-3 h.
3) Introducing a mixed solution containing 5-30% of ethyl 4-chloroacetoacetate, 50-300g/L of glucose and 0-70% of an organic solvent into the enzyme membrane reactor 1 through a pressure pump 6, and circulating. The temperature is controlled at 20-40 deg.C, and pH is controlled at 5.0-8.0. The enzyme reaction time is 3-24 h.
4) And 3-24h after the enzyme catalysis reaction starts, introducing the same organic solvent as in the reaction into the other side of the filter membrane 2, and circulating. The temperature is controlled to be 20-40 ℃, and the pressure difference between the filter membranes 2 is controlled to be 0.02-0.5 Mpa. And when the enzyme membrane reactor 1 does not contain the product, the whole process is finished.
A method for preparing ethyl r-4-chloro-3-hydroxybutyrate by coupling extraction of an enzyme membrane reactor comprises the following steps:
(1) introducing glutaraldehyde into the enzyme membrane reactor 1 through a pressure pump 6, and circulating at 20 deg.C for 30 min;
(2) dissolving r-carbonyl reductase and glucose dehydrogenase in phosphate buffer solution with pH7.0 to ensure that the enzyme activities of the two are both 50ku/L, then guiding the two into an enzyme membrane reactor 1 through a pressure pump 6, and circulating the two at 20 ℃ for 2h, wherein the used membrane is a PVDF hollow fiber membrane, and the interception precision is 1 kD;
(3) leading a mixed solution containing 15 percent of 4-chloroacetoacetic acid ethyl ester, 150g/L glucose and 30 percent of ethyl acetate into an enzyme membrane reactor 1 through a pressure pump 6, circulating, controlling the temperature to be 30 ℃, controlling the pH to be 7.0 and controlling the enzyme reaction time to be 24 hours;
(4) and after the enzymatic reaction starts for 24 hours, introducing ethyl acetate into the other side of the membrane, circulating, controlling the temperature to be 30 ℃, controlling the pressure difference between the membranes to be 0.5Mpa, extracting for 8 hours, detecting the purity and the content of the product after the extraction is finished, and calculating the yield, wherein the chemical purity of the final product is 99.5%, the optical purity is 99.9%, and the yield is 99.5%.
Although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that various changes in the embodiments and/or modifications of the invention can be made, and equivalents and modifications of some features of the invention can be made without departing from the spirit and scope of the invention.
Claims (5)
1. A method for preparing ethyl r-4-chloro-3-hydroxybutyrate by coupled extraction of an enzyme membrane reactor comprises the enzyme membrane reactor (1), an organic solvent charging barrel (7) and a substrate charging barrel (9), and is characterized in that: the device is characterized in that a filter membrane (2) is distributed in the enzyme membrane reactor (1), a feed liquid outlet (3) is connected to one side of the upper end of the enzyme membrane reactor (1), an organic solvent outlet (4) is arranged on one side of the enzyme membrane reactor (1), a feed liquid inlet (5) is connected to one side of the lower end of the enzyme membrane reactor (1), an organic solution inlet (12) is mounted on the other side of the enzyme membrane reactor (1), the organic solution inlet (12) and the organic solvent outlet (4) are respectively communicated with an organic solvent charging barrel (7) through pipelines, a pressure pump (6) is distributed on the pipeline connecting the organic solvent charging barrel (7) and the organic solution inlet (12), a stirring paddle (8) penetrates through the middle part of the inner side of the organic solvent charging barrel (7), the feed liquid outlet (3) and the feed liquid inlet (5) are respectively communicated with a substrate charging barrel (9) through pipelines, and the outer wall of the substrate charging barrel (9) is adhered with a heat-insulating jacket (10), the inner side of the filter membrane (2) is distributed with membrane holes (11),
wherein the method comprises the steps of:
1) introducing the stationary liquid into an enzyme membrane reactor (1) through a pressure pump (6), and circulating for 30min-3h at 20 ℃; the fixing solution used is glutaraldehyde;
2) dissolving r-carbonyl reductase and glucose dehydrogenase in phosphate buffer solution with pH7.0 to make enzyme activity of both 5-50 ku/L, introducing into enzyme membrane reactor (1) by pressure pump (6), and circulating at 10-20 deg.C for 1-3 h;
3) introducing a mixed solution containing 5-30% of ethyl 4-chloroacetoacetate, 50-300g/L of glucose and 30% of an organic solvent into the enzyme membrane reactor (1) through a pressure pump (6) and circulating; controlling the temperature at 20-40 deg.C and pH at 5.0-8.0; the enzyme reaction time is 3-24 h;
4) after the enzyme catalysis reaction starts for 3-24h, introducing the organic solvent which is the same as that in the reaction into the other side of the filter membrane (2), and circulating; the temperature is controlled to be 20-40 ℃, and the pressure difference between the filter membranes (2) is controlled to be 0.02-0.5 Mpa; the extraction time is 8h, and the whole process is finished.
2. The method of claim 1 for preparing ethyl r-4-chloro-3-hydroxybutyrate using coupled extraction with an enzymatic membrane reactor, wherein: the filter membrane (2) is made of a ceramic membrane, a mixed fiber ester microporous filter membrane, a cellulose nitrate filter membrane, a polyvinylidene fluoride filter membrane, a cellulose acetate filter membrane, a regenerated cellulose filter membrane, a polyamide filter membrane, a polytetrafluoroethylene filter membrane, a polyvinyl chloride filter membrane and a modified composite membrane of the above materials.
3. The method of claim 1 for preparing ethyl r-4-chloro-3-hydroxybutyrate using coupled extraction with an enzymatic membrane reactor, wherein: the interception precision of the filter membrane (2) is 1kD-100 kD.
4. The method of claim 1 for preparing ethyl r-4-chloro-3-hydroxybutyrate using coupled extraction with an enzymatic membrane reactor, wherein: the r-carbonyl reductase and the glucose dehydrogenase used in the step (2) are one or more of enzyme powder, enzyme liquid and genetically engineered bacteria.
5. The method of claim 1 for preparing ethyl r-4-chloro-3-hydroxybutyrate using coupled extraction with an enzymatic membrane reactor, wherein: the organic solvent in the step (3) is one or two of ethyl acetate, butyl acetate, toluene, xylene, octanol, chloroform, isopropanol, n-hexane, cyclohexane, n-butanol, isobutanol and dibutyl phthalate.
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