CN117466736A - Method for extracting pleuromutilin by double solvents - Google Patents
Method for extracting pleuromutilin by double solvents Download PDFInfo
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- CN117466736A CN117466736A CN202311442010.6A CN202311442010A CN117466736A CN 117466736 A CN117466736 A CN 117466736A CN 202311442010 A CN202311442010 A CN 202311442010A CN 117466736 A CN117466736 A CN 117466736A
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- ZRZNJUXESFHSIO-UHFFFAOYSA-N Pleuromutilin Natural products CC1C(O)C(C)(C=C)CC(OC(=O)CO)C2(C)C(C)CCC31C2C(=O)CC3 ZRZNJUXESFHSIO-UHFFFAOYSA-N 0.000 title claims abstract description 34
- ZRZNJUXESFHSIO-VYTKZBNOSA-N pleuromutilin Chemical compound C([C@H]([C@]1(C)[C@@H](C[C@@](C)(C=C)[C@@H](O)[C@@H]2C)OC(=O)CO)C)C[C@]32[C@H]1C(=O)CC3 ZRZNJUXESFHSIO-VYTKZBNOSA-N 0.000 title claims abstract description 34
- 239000002904 solvent Substances 0.000 title claims abstract description 32
- 238000000034 method Methods 0.000 title claims abstract description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 249
- 238000002386 leaching Methods 0.000 claims abstract description 172
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 120
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 104
- 239000000243 solution Substances 0.000 claims abstract description 69
- 238000005406 washing Methods 0.000 claims abstract description 43
- 239000006228 supernatant Substances 0.000 claims abstract description 27
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 claims abstract description 26
- 238000001035 drying Methods 0.000 claims abstract description 21
- 238000001704 evaporation Methods 0.000 claims abstract description 21
- 238000001914 filtration Methods 0.000 claims abstract description 19
- 239000012267 brine Substances 0.000 claims abstract description 15
- 230000008020 evaporation Effects 0.000 claims abstract description 14
- 239000000706 filtrate Substances 0.000 claims abstract description 9
- 238000010438 heat treatment Methods 0.000 claims abstract description 9
- 239000007788 liquid Substances 0.000 claims abstract description 9
- 238000003825 pressing Methods 0.000 claims abstract description 9
- 238000000926 separation method Methods 0.000 claims abstract description 9
- 238000003756 stirring Methods 0.000 claims description 71
- 238000002425 crystallisation Methods 0.000 claims description 22
- 230000008025 crystallization Effects 0.000 claims description 22
- 238000002156 mixing Methods 0.000 claims description 13
- 238000007599 discharging Methods 0.000 claims description 11
- 239000013078 crystal Substances 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 8
- 238000001816 cooling Methods 0.000 claims description 6
- -1 stirring Substances 0.000 claims description 4
- 238000007738 vacuum evaporation Methods 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 3
- 239000000758 substrate Substances 0.000 claims 7
- 239000012071 phase Substances 0.000 description 18
- 238000011084 recovery Methods 0.000 description 15
- 239000000047 product Substances 0.000 description 14
- 230000001580 bacterial effect Effects 0.000 description 12
- 239000012535 impurity Substances 0.000 description 11
- 239000000498 cooling water Substances 0.000 description 10
- 239000000843 powder Substances 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- 238000000605 extraction Methods 0.000 description 8
- 239000000463 material Substances 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 238000000855 fermentation Methods 0.000 description 5
- 230000004151 fermentation Effects 0.000 description 5
- 239000011229 interlayer Substances 0.000 description 5
- 238000004806 packaging method and process Methods 0.000 description 5
- 238000005086 pumping Methods 0.000 description 5
- KUBKXMIPSJEXGM-UHFFFAOYSA-N (4-ethenyl-3-hydroxy-2,4,7,14-tetramethyl-9-oxo-6-tricyclo[5.4.3.01,8]tetradecanyl) acetate Chemical compound CC1C(O)C(C)(C=C)CC(OC(C)=O)C2(C)C(C)CCC31C2C(=O)CC3 KUBKXMIPSJEXGM-UHFFFAOYSA-N 0.000 description 4
- 239000003242 anti bacterial agent Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 238000004064 recycling Methods 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical group [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 229940088710 antibiotic agent Drugs 0.000 description 3
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 2
- 241000233866 Fungi Species 0.000 description 2
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 2
- 241000222350 Pleurotus Species 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000004945 emulsification Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000000049 pigment Substances 0.000 description 2
- 230000003068 static effect Effects 0.000 description 2
- UURAUHCOJAIIRQ-QGLSALSOSA-N tiamulin Chemical compound CCN(CC)CCSCC(=O)O[C@@H]1C[C@@](C)(C=C)[C@@H](O)[C@H](C)[C@@]23CC[C@@H](C)[C@]1(C)[C@@H]2C(=O)CC3 UURAUHCOJAIIRQ-QGLSALSOSA-N 0.000 description 2
- 229960004885 tiamulin Drugs 0.000 description 2
- LLYYNOVSVPBRGV-MVNKZKPCSA-N valnemulin Chemical compound CC(C)[C@@H](N)C(=O)NCC(C)(C)SCC(=O)O[C@@H]1C[C@@](C)(C=C)[C@@H](O)[C@H](C)[C@@]23CC[C@@H](C)[C@]1(C)[C@@H]2C(=O)CC3 LLYYNOVSVPBRGV-MVNKZKPCSA-N 0.000 description 2
- 229950008166 valnemulin Drugs 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241001052560 Thallis Species 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 230000005611 electricity Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 238000001243 protein synthesis Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 229960002771 retapamulin Drugs 0.000 description 1
- STZYTFJPGGDRJD-NHUWBDDWSA-N retapamulin Chemical compound C([C@H]([C@@]1(C)[C@@H](C[C@@](C)(C=C)[C@@H](O)[C@@H]2C)OC(=O)CS[C@@H]3C[C@H]4CC[C@H](N4C)C3)C)C[C@]32[C@H]1C(=O)CC3 STZYTFJPGGDRJD-NHUWBDDWSA-N 0.000 description 1
- 210000003705 ribosome Anatomy 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/48—Separation; Purification; Stabilisation; Use of additives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/48—Separation; Purification; Stabilisation; Use of additives
- C07C67/56—Separation; Purification; Stabilisation; Use of additives by solid-liquid treatment; by chemisorption
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/48—Separation; Purification; Stabilisation; Use of additives
- C07C67/58—Separation; Purification; Stabilisation; Use of additives by liquid-liquid treatment
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/56—Ring systems containing bridged rings
- C07C2603/58—Ring systems containing bridged rings containing three rings
- C07C2603/76—Ring systems containing bridged rings containing three rings containing at least one ring with more than six ring members
- C07C2603/80—Ring systems containing bridged rings containing three rings containing at least one ring with more than six ring members containing eight-membered rings
- C07C2603/82—Ring systems containing bridged rings containing three rings containing at least one ring with more than six ring members containing eight-membered rings having three condensed rings with in total fourteen carbon atoms and having a having a [5.4.3.0(1,8)] ring structure, e.g. pleuromutiline
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a method for extracting pleuromutilin by double solvents. A method for extracting pleuromutilin by double solvents, comprising the following steps: (1) leaching: adding methanol solution into mycelium for first leaching, and extracting supernatant; adding methanol solution for secondary leaching, and extracting supernatant; adding methanol solution for leaching for the third time, filtering and pressing after leaching, and combining the supernatant and the filtrate to obtain leaching liquor; (2) Heating the leaching solution to 48-52 ℃ under the pressure of not lower than 0.05MPa, evaporating in vacuum to recover methanol, and then washing with water to recover methanol; (3) The leaching solution subjected to water washing and evaporation in the step (3) adopts ethyl acetate for phase inversion, and then water washing and brine washing are sequentially carried out; (4) Concentrating and crystallizing the leaching solution after brine washing, and then carrying out solid-liquid separation and drying. The method for extracting pleuromutilin by using double solvents has the advantages of high yield, low loss and high purity of the proposed pleuromutilin.
Description
Technical Field
The invention belongs to the technical field of antibiotics, and particularly relates to a method for extracting pleuromutilin by double solvents.
Background
Pleuromutilin (pleuromutilin) is an antibiotic produced by deep culture of Pleurotus mutilins and plenrots passeckerianus strain of Pleurotus of higher fungus, and belongs to diterpenoid compound, wherein the main skeleton is composed of five-, six-and eight-membered rings, and the molecular formula is C 22 H 34 O 5 The relative molecule is 378.51, and the melting point is 167-168 ℃. Slightly soluble in water, and easily soluble in ethanol, acetone and diethyl ether.
Pleuromutilins are a large family of antibiotics with better antibacterial activity. It can inhibit protein synthesis by acting on bacterial ribosomal 50S subunit, leading to bacterial death, and can effectively inhibit most gram-positive bacteria and part of gram-negative bacteria. The pleuromutilin has the following purposes: can be added into animal feed as additive to effectively prevent many infectious diseases; the derivatives thereof such as tiamulin, valnemulin and the like are produced in the form of raw materials, and the tiamulin and the valnemulin are veterinary medicines on the market; is used for synthesizing the antibiotics for human use, such as Retapamulin and the like.
At present, the domestic manufacturer extracts pleuromutilin by adopting a single organic solvent such as 4-methyl-2-pentanone (MIBK), acetone, methanol, butyl acetate, ethyl acetate, ethanol and the like, but the yield and the purity of the products of the methods are not high. Wherein, although the organic solvent has strong extraction capability, other impurities are extracted, so that the purity of the product is not high, such as methanol; some of the extracted pleuromutilins contain fewer impurities, but are not very extractable and are costly, such as ethyl acetate.
In view of the above, the invention provides a pleuromutilin extraction method with high yield and high pleuromutilin purity.
Disclosure of Invention
The invention aims to provide a method for extracting pleuromutilin by double solvents, which has high yield, low loss and high purity of the proposed pleuromutilin.
In order to achieve the above purpose, the technical scheme adopted is as follows:
a method for extracting pleuromutilin by double solvents, comprising the following steps:
(1) Leaching: adding methanol solution into mycelium for first leaching, and extracting supernatant;
adding methanol solution for secondary leaching, and extracting supernatant;
adding methanol solution for leaching for the third time, filtering and pressing after leaching, and combining the supernatant and the filtrate to obtain leaching liquor;
the leaching process is to stir and leach firstly, then to stand still for leaching, and the time of stirring and leaching is the same as that of standing still leaching;
(2) Heating the leaching solution to 48-52 ℃ under the pressure of not lower than 0.05MPa, evaporating in vacuum to recover methanol, and then washing with water to recover methanol;
(3) The leaching solution subjected to water washing and evaporation in the step (3) adopts ethyl acetate for phase inversion, and then water washing and brine washing are sequentially carried out;
(4) Concentrating and crystallizing the leaching solution after brine washing, and then carrying out solid-liquid separation and drying.
Further, in the step (1), the water content in the leaching systems of the first time, the second time and the third time is 10-15wt%;
the mass-volume ratio of mycelium to methanol solution in the first, second and third leaching systemsIs 1t/12-13m 3 ；
The first, second and third stirring and leaching times are 160-200, 160-200 and 100-140min in turn, and the stirring rotation speed is 50-70 rpm.
Still further, in the step (1), the water content in the methanol solution is 7 to 8wt%.
Still further, in the step (1), the first, second and third stirring and leaching times are 180, 180 and 120min in sequence, and the stirring rotation speed is 60 revolutions/min.
Further, in the step (2), the leaching solution is heated to 50 ℃, the rotating speed is 50-70 r/min, the vacuum degree is more than 0.05MPa, and the methanol is recovered by vacuum evaporation.
Further, in the step (2), the water washing evaporation is as follows: adding 40-50deg.C water, stirring, and water washing and evaporating.
Further, in the step (3), the phase inversion of the ethyl acetate is as follows: adding ethyl acetate, uniformly mixing, standing until layering, and discharging a water phase;
the water washing is as follows: adding 40-45deg.C water, stirring, standing to delaminate, and discharging water phase;
the salt water washing is as follows: saturated brine is added and stirred uniformly, and then the mixture is stood until layering, and the water phase is discharged.
Further, in the step (4), the concentration crystallization treatment is as follows: vacuum concentrating at 40-45deg.C to recover ethyl acetate, cooling to 11-13deg.C, and crystallizing for 1.0-2.0 hr.
Still further, in the step (4), the vacuum degree is 0.06MPa, and the cooling speed is 3-5 ℃/h.
Still further, in the step (4), the temperature is reduced to 12 ℃ for crystal growth for 1.5 hours.
Compared with the prior art, the invention has the following advantages:
1. in the technical scheme of the invention, methanol is adopted for leaching, so that the leaching effect is good and the price is low; however, the methanol leaching impurity is higher, and the impurities such as pigment, 14-acetyl mutilin and the like can be removed well through ethyl acetate phase inversion leaching, so that the product quality is improved.
2. According to the technical scheme, the independent recovery of methanol and ethyl acetate is ensured through a double-solvent recovery process, and the solvent loss is reduced, so that the extraction cost is controlled.
3. In the technical scheme of the invention, the optimal leaching process is determined through experiments, and comprises leaching time, leaching temperature, solvent proportion, stirring rotation speed, stirring time, leaching times and the like, so that the product purity of pleuromutilin is more than 96%, and the product yield is more than 98.5%.
Drawings
Fig. 1 is a flowchart of example 1.
Detailed Description
In order to further illustrate a method for extracting pleuromutilin by using double solvents, which achieves the aim of the invention, the following description refers to specific implementation, structure, characteristics and efficacy of the method for extracting pleuromutilin by using double solvents according to the invention in combination with the preferred embodiments. In the following description, different "an embodiment" or "an embodiment" do not necessarily refer to the same embodiment. Furthermore, the particular features, structures, or characteristics of one or more embodiments may be combined in any suitable manner.
The following is a further detailed description of a dual solvent pleuromutilin extraction method according to the invention, in conjunction with the specific examples:
the technical scheme of the invention is as follows:
a method for extracting pleuromutilin by double solvents, comprising the following steps:
(1) Leaching: adding methanol solution into mycelium for first leaching, and extracting supernatant;
adding methanol solution for secondary leaching, and extracting supernatant;
adding methanol solution for leaching for the third time, filtering and pressing after leaching, and combining the supernatant and the filtrate to obtain leaching liquor;
the leaching process is to stir and leach firstly, then to stand still for leaching, and the time of stirring and leaching is the same as that of standing still leaching;
(2) Heating the leaching solution to 48-52 ℃ under the pressure of not lower than 0.05MPa, evaporating in vacuum to recover methanol, and then washing with water to recover methanol;
(3) The leaching solution subjected to water washing and evaporation in the step (3) adopts ethyl acetate for phase inversion, and then water washing and brine washing are sequentially carried out;
(4) Concentrating and crystallizing the leaching solution after brine washing, and then carrying out solid-liquid separation and drying.
The solvent for extracting pleuromutilin usually uses methanol, acetone, ethyl acetate, butyl acetate, methyl isobutyl ketone and the like, and different solvents have advantages and disadvantages after comparison of extraction effects. The methanol has good leaching effect and low price, but the leaching impurity is higher. According to the invention, methanol leaching and ethyl acetate phase inversion leaching are adopted, and impurities such as pigment, 14-acetyl mutilin and the like can be well removed through ethyl acetate phase inversion leaching, so that the product quality is improved.
Preferably, in the step (1), the water content in the first leaching system, the second leaching system and the third leaching system is 10-15wt%;
the mass volume ratio of mycelium to methanol solution in the first, second and third leaching systems is 1t/12-13m 3 ；
The first, second and third stirring and leaching times are 160-200, 160-200 and 100-140min in turn, and the stirring rotation speed is 50-70 rpm.
In the technical scheme, the leaching system controls the moisture to be 10-15wt%, so that the leaching time can be effectively shortened and the production efficiency can be improved during leaching.
The invention adopts the dried mycelium, can save steam and electricity consumption when drying the mycelium, and simultaneously improves the drying efficiency.
The extract has high content of effective components and the extract has best quality. Dynamic leaching is better than static leaching. Thus, the invention adopts a mode of combining dynamic leaching and static leaching, extracts pleuromutilin through dynamic leaching, and then stands to separate leaching liquor from thalli.
Further preferably, in the step (1), the water content in the methanol solution is 7-8wt%.
In the technical scheme, the mycelium is soaked by using the methanol, the methanol content of the leaching solution is controlled to be 92-93%, and the leaching is ensured to be full and the time is shortest.
Further preferably, in the step (1), the first, second and third stirring and leaching times are 180, 180 and 120min in sequence, and the stirring rotation speed is 60 revolutions/min.
Preferably, in the step (2), the leaching solution is heated to 50 ℃, the rotating speed is 50-70 r/min, the vacuum degree is more than 0.05MPa, and the methanol is recovered by vacuum evaporation.
Preferably, in the step (2), the water washing evaporation is as follows: adding 40-50deg.C water, stirring, and water washing and evaporating.
Preferably, in the step (3), the ethyl acetate phase inversion is as follows: adding ethyl acetate, uniformly mixing, standing until layering, and discharging a water phase;
the water washing is as follows: adding 40-45deg.C water, stirring, standing to delaminate, and discharging water phase;
the salt water washing is as follows: saturated brine is added and stirred uniformly, and then the mixture is stood until layering, and the water phase is discharged.
In the technical scheme, pleuromutilin is not easy to dissolve in water and is easy to dissolve in ethyl acetate. The pleuromutilin is extracted into the ethyl acetate through ethyl acetate phase inversion, but impurities remain in water, so that the purification effect is achieved. Further through water washing and brine washing, the purification purpose is achieved.
The adopted saturated brine is sodium chloride solution, and has the advantages that: (1) the saturated brine has a higher density than water, and can avoid emulsification. The solubility of organic matters in saturated saline is smaller than that in water, and yield loss can be avoided during extraction. (2) The emulsification can be broken. (3) The organic phase is washed to remove impurities of large polarity. (4) The materials and the water are better layered, and the water is convenient to drain and dewater.
Preferably, in the step (4), the concentration crystallization treatment is as follows: vacuum concentrating at 40-45deg.C to recover ethyl acetate, cooling to 11-13deg.C, and crystallizing for 1.0-2.0 hr.
Further preferably, in the step (4), the vacuum degree is 0.06MPa, and the cooling speed is 3-5 ℃/h.
Further preferably, in the step (4), the temperature is reduced to 12 ℃ for crystal growth for 1.5 hours.
Reducing solvent loss is one of the key factors controlling the extraction cost, which accounts for 80% of the total cost of extraction. How to recover the solvent to the greatest extent is the key to reduce the loss. In the technical scheme, the volatile solvent is cooled by evaporation and condensation, so that the loss is reduced. The double solvent recovery process ensures the independent recovery of the methanol and the ethyl acetate, and reduces the methanol loss from 2.0 Kg/billion to 1.8 Kg/billion. The loss of the ethyl acetate is reduced from 0.8 Kg/billion to 0.6 Kg/billion, the recovery rate of the methanol is not lower than 95 percent, and the recovery rate of the ethyl acetate is not lower than 98 percent.
Example 1.
With reference to fig. 1, the specific operation steps are as follows:
(1) Filtering the fermentation liquor containing mycelium, and flash drying to obtain powder mycelium.
(2) Leaching: adding methanol solution into mycelium for primary leaching, stirring and leaching for 160-200min at 50-70 rpm, standing and leaching for 160-200min, standing to precipitate mycelium powder, and extracting supernatant;
adding methanol solution for secondary leaching, stirring and leaching for 160-200min at 50-70 rpm, standing and leaching for 160-200min, and collecting supernatant;
adding methanol solution for leaching for the third time, stirring and leaching for 100-140min at 50-70 rpm, standing and leaching for 100-140min, filtering and pressing after leaching, and mixing the supernatant and the filtrate to obtain leaching solution. The bacterial residues after press filtration can be used as bacterial feed after drying.
Wherein the water content in the first leaching system, the second leaching system and the third leaching system is 10-15wt%. The water content in the methanol solution is 7-8wt%.
The mass volume ratio of mycelium to methanol solution in the first, second and third leaching systems is 1t/12-13m 3 。
(3) Pumping the leaching solution into a crystallization tank, starting stirring at a rotation speed of 50-70 r/min, introducing steam into the interlayer, slowly heating to 48-52 ℃, and simultaneously starting a vacuum pump to ensure that the vacuum degree of the crystallization tank is above 0.05 MPa. The methanol was evaporated to dryness and recovered using a condenser.
Adding 40-50deg.C hot water into the crystallizer, stirring, evaporating, and recovering methanol by using condenser.
The refrigerator reduces the temperature of the circulating cooling water to be lower than 10 ℃ so as to cool the volatilized solvent.
(4) Purifying:
adding ethyl acetate for phase inversion after evaporation is finished, starting stirring for 50-70 r/min, controlling the content of the dissolved materials to be 26-28wt%, stopping stirring, standing for 180min, layering, and starting a blow-down valve for water drainage.
And after the water discharge is finished, adding hot water at 40-45 ℃ into the crystallization tank, stirring uniformly, standing for 180min, and performing secondary water discharge.
And after the water discharge is finished, adding saturated brine, uniformly stirring, standing for 90min, and discharging the brine.
(5) After the water washing is finished, the temperature is raised to 40-45 ℃, the mixture is stirred for 45-55 r/min under vacuum, and the ethyl acetate is recovered by concentration. The refrigerator reduces the temperature of the circulating cooling water to be lower than 10 ℃ so as to cool the volatilized solvent.
After the concentration is finished, circulating water is started to cool, the temperature is controlled to be 3-5 ℃ per hour, the temperature is controlled to be 11-13 ℃ for crystal growth for 1.0-2.0 hours, and finally, solid-liquid separation, double-cone drying, mixing and packaging are carried out through a separator.
Comparative example 1.
The procedure of comparative example 1 was the same as in example 1, except that the methanol water contents were 4, 5, 6, 7, 8, 9, 10, 11, 12% by weight, respectively. The content of pleuromutilin in the leached fungus residues is tested, and the results are shown in table 1.
TABLE 1
As can be seen from the data in Table 1, the content of pleuromutilin in the leached residue was minimal at a water content of about 7-8% in methanol.
Example 2.
With reference to fig. 1, the specific operation steps are as follows:
(1) Filtering the fermentation liquor containing mycelium, and flash drying to obtain powder mycelium.
(2) Leaching: adding methanol solution into mycelium for primary leaching, stirring and leaching for 180min at a rotating speed of 60 r/min, standing and leaching for 180min, standing to precipitate mycelium powder, and extracting supernatant;
adding methanol solution for secondary leaching, stirring and leaching for 180min at a rotating speed of 60 r/min, standing and leaching for 180min, and extracting supernatant;
adding methanol solution for leaching for the third time, stirring and leaching for 120min at a rotation speed of 60 r/min, standing and leaching for 120min, filtering and pressing after leaching, and mixing the supernatant and the filtrate to obtain leaching liquor. The bacterial residues after press filtration can be used as bacterial feed after drying.
Wherein the water content in the first leaching system, the second leaching system and the third leaching system is 12 weight percent. The water content in the methanol solution was 7.5wt%.
The mass volume ratio of mycelium to methanol solution in the first, second and third leaching systems is 1t/12-13m 3 。
(3) Pumping the leaching solution into a crystallization tank, starting stirring at a rotating speed of 60 r/min, introducing steam into the interlayer, slowly heating to 50 ℃, and simultaneously starting a vacuum pump to ensure the vacuum degree of the crystallization tank to be 0.06MPa. The methanol was evaporated to dryness and recovered using a condenser.
Adding hot water at 45 ℃ into a crystallization tank, stirring, continuing to evaporate, and recycling methanol by using a condenser.
The refrigerator reduces the temperature of the circulating cooling water to be lower than 10 ℃ so as to cool the volatilized solvent.
(4) Purifying:
adding ethyl acetate for phase inversion after evaporation is finished, starting stirring for 60 revolutions per minute, controlling the content of the dissolved materials to 27 weight percent, stopping stirring, standing for 180 minutes, layering, and starting a blow-down valve for drainage.
After the water discharge is finished, adding hot water at 43 ℃ into the crystallization tank, stirring uniformly, standing for 180min, and performing secondary water discharge.
And after the water discharge is finished, adding saturated brine, uniformly stirring, standing for 90min, and discharging the brine.
(5) After the water washing was completed, the temperature was raised to 43℃and the mixture was stirred under vacuum for 50 rpm, followed by concentration to recover ethyl acetate. The refrigerator reduces the temperature of the circulating cooling water to be lower than 10 ℃ so as to cool the volatilized solvent.
After the concentration is finished, circulating water is started to cool, the temperature is controlled to be 4 ℃ per hour, the temperature is controlled to be 12 ℃ for crystal growth for 1.5 hours, and finally, solid-liquid separation, bipyramid drying, mixing and packaging are carried out through a separator.
The methanol recovery rate of this example was 96.2%, and the ethyl acetate recovery rate was 98.5%. The product purity of pleuromutilin is 97.2% and the product yield is 99.1%.
The content of pleuromutilin and impurities in the aqueous phase after each water wash in the purification step of the examples of the invention was determined and the results are shown in Table 2.
TABLE 2 content of pleuromutilin and impurities in aqueous phase
As can be seen from the results of the experiments of water washing and brine washing, the water washing and the saturated brine washing can remove a large amount of impurities.
Example 3.
With reference to fig. 1, the specific operation steps are as follows:
(1) Filtering the fermentation liquor containing mycelium, and flash drying to obtain powder mycelium.
(2) Leaching: adding methanol solution into mycelium for primary leaching, stirring and leaching for 160min at a rotation speed of 70 r/min, standing and leaching for 160min, standing to precipitate mycelium powder, and extracting supernatant;
adding methanol solution for secondary leaching, stirring and leaching for 160min at a rotation speed of 70 r/min, standing and leaching for 160min, and extracting supernatant;
adding methanol solution for leaching for the third time, stirring and leaching for 100min at 70 rpm, standing and leaching for 100min, filtering and pressing after leaching, and mixing the supernatant and the filtrate to obtain leaching solution. The bacterial residues after press filtration can be used as bacterial feed after drying.
Wherein the water content in the first leaching system, the second leaching system and the third leaching system is 15wt%. The water content in the methanol solution was 8wt%.
The mass volume ratio of mycelium to methanol solution in the first, second and third leaching systems is 1t/12-13m 3 。
(3) Pumping the leaching solution into a crystallization tank, starting stirring at a rotation speed of 70 r/min, introducing steam into the interlayer, slowly heating to 48 ℃, and simultaneously starting a vacuum pump to ensure the vacuum degree of the crystallization tank to be 0.06MPa. The methanol was evaporated to dryness and recovered using a condenser.
And adding 40 ℃ hot water into a crystallization tank, stirring, continuing to evaporate, and recycling the methanol by using a condenser.
The refrigerator reduces the temperature of the circulating cooling water to be lower than 10 ℃ so as to cool the volatilized solvent. (4) purification:
adding ethyl acetate for phase inversion after evaporation is finished, starting stirring for 50 revolutions per minute, controlling the content of the dissolved materials to be 26 weight percent, stopping stirring, standing for 180 minutes, layering, and starting a blow-down valve for drainage.
And after the water discharge is finished, adding hot water at 40 ℃ into the crystallization tank, stirring uniformly, standing for 180min, and performing secondary water discharge.
And after the water discharge is finished, adding saturated brine, uniformly stirring, standing for 90min, and discharging the brine.
(5) After the water washing, the temperature was raised to 40℃and the mixture was stirred under vacuum for 55 rpm, followed by concentration to recover ethyl acetate. The refrigerator reduces the temperature of the circulating cooling water to be lower than 10 ℃ so as to cool the volatilized solvent.
After the concentration is finished, circulating water is started to cool, the temperature is controlled to be 3 ℃ per hour, the temperature is controlled to be 13 ℃ for crystal growth for 2.0 hours, and finally, solid-liquid separation, bipyramid drying, mixing and packaging are carried out through a separator.
The methanol recovery rate of this example was 95.9%, and the ethyl acetate recovery rate was 98.1%. The product purity of pleuromutilin is 96.1% and the product yield is 98.6%.
Example 4.
With reference to fig. 1, the specific operation steps are as follows:
(1) Filtering the fermentation liquor containing mycelium, and flash drying to obtain powder mycelium.
(2) Leaching: adding methanol solution into mycelium for primary leaching, stirring and leaching for 200min at a rotating speed of 50 rpm, standing and leaching for 200min, standing to precipitate mycelium powder, and extracting supernatant;
adding methanol solution for secondary leaching, stirring and leaching for 200min at a rotation speed of 50 rpm, standing and leaching for 200min, and extracting supernatant;
adding methanol solution for leaching for the third time, stirring and leaching for 140min at 50 rpm, standing and leaching for 140min, filtering and pressing after leaching, and mixing the supernatant and the filtrate to obtain leaching solution. The bacterial residues after press filtration can be used as bacterial feed after drying.
Wherein the water content in the first leaching system, the second leaching system and the third leaching system is 10 weight percent. The water content in the methanol solution was 7wt%.
The mass volume ratio of mycelium to methanol solution in the first, second and third leaching systems is 1t/12-13m 3 。
(3) Pumping the leaching solution into a crystallization tank, starting stirring at a rotating speed of 50 r/min, introducing steam into the interlayer, slowly heating to 52 ℃, and simultaneously starting a vacuum pump to ensure the vacuum degree of the crystallization tank to be 0.07MPa. The methanol was evaporated to dryness and recovered using a condenser.
And adding hot water with the temperature of 50 ℃ into a crystallization tank, stirring, continuing to evaporate, and recycling the methanol by using a condenser.
The refrigerator reduces the temperature of the circulating cooling water to be lower than 10 ℃ so as to cool the volatilized solvent. The recovery rate of methanol is 96%.
(4) Purifying:
adding ethyl acetate after evaporation is completed, inverting, starting stirring for 70 revolutions per minute, controlling the content of the dissolved material to be 28 weight percent, stopping stirring, standing for 180 minutes, layering, and starting a blow-down valve to drain water.
And after the water discharge is finished, adding 45 ℃ hot water into the crystallization tank, stirring uniformly, standing for 180min, and performing secondary water discharge.
And after the water discharge is finished, adding saturated brine, uniformly stirring, standing for 90min, and discharging the brine.
(5) After the water washing, the temperature was raised to 45℃and the mixture was stirred under vacuum for 45 rpm, followed by concentration to recover ethyl acetate. The refrigerator reduces the temperature of the circulating cooling water to be lower than 10 ℃ so as to cool the volatilized solvent.
After the concentration is finished, circulating water is started to cool, the temperature is controlled to be reduced to 5 ℃ per hour, the temperature is reduced to 11 ℃ for crystal growth for 1.0h, and finally, solid-liquid separation, bipyramid drying, mixing and packaging are carried out through a separator.
The methanol recovery rate of this example was 96.4%, and the ethyl acetate recovery rate was 98.3%. The product purity of pleuromutilin is 96.8% and the product yield is 98.8%.
Example 5.
With reference to fig. 1, the specific operation steps are as follows:
(1) Filtering the fermentation liquor containing mycelium, and flash drying to obtain powder mycelium.
(2) Leaching: adding methanol solution into mycelium for primary leaching, stirring and leaching for 170min at a rotation speed of 65 r/min, standing and leaching for 170min, standing to precipitate mycelium powder, and extracting supernatant;
adding methanol solution for secondary leaching, stirring and leaching for 190min at a rotation speed of 55 r/min, standing and leaching for 190min, and extracting supernatant;
adding methanol solution for leaching for the third time, stirring and leaching for 110min at a rotation speed of 65 r/min, standing and leaching for 110min, filtering and pressing after leaching, and mixing the supernatant and the filtrate to obtain leaching liquor. The bacterial residues after press filtration can be used as bacterial feed after drying.
Wherein the water content in the first, second and third leaching systems is 14wt%. The water content in the methanol solution was 7.6wt%.
The mass volume ratio of mycelium to methanol solution in the first, second and third leaching systems is 1t/12-13m 3 。
(3) Pumping the leaching solution into a crystallization tank, starting stirring at a rotation speed of 55 r/min, introducing steam into the interlayer, slowly heating to 51 ℃, and simultaneously starting a vacuum pump to ensure that the vacuum degree of the crystallization tank is more than 0.05 MPa. The methanol was evaporated to dryness and recovered using a condenser.
And adding 48 ℃ hot water into a crystallization tank, stirring, continuing to evaporate, and recycling the methanol by using a condenser.
The refrigerator reduces the temperature of the circulating cooling water to be lower than 10 ℃ so as to cool the volatilized solvent.
(4) Purifying:
adding ethyl acetate for phase inversion after evaporation is finished, starting stirring for 60 revolutions per minute, controlling the content of the dissolved materials to 27 weight percent, stopping stirring, standing for 180 minutes, layering, and starting a blow-down valve for drainage.
After the water discharge is finished, adding hot water at 43 ℃ into the crystallization tank, stirring uniformly, standing for 180min, and performing secondary water discharge.
And after the water discharge is finished, adding saturated brine, uniformly stirring, standing for 90min, and discharging the brine.
(5) After the water washing was completed, the temperature was raised to 44℃and the mixture was stirred under vacuum for 48 rpm, followed by concentration to recover ethyl acetate. The refrigerator reduces the temperature of the circulating cooling water to be lower than 10 ℃ so as to cool the volatilized solvent.
After the concentration is finished, circulating water is started to cool, the temperature is controlled to be reduced to 5 ℃ per hour, the temperature is reduced to 112 ℃ for crystal growth for 1.5 hours, and finally, solid-liquid separation, bipyramid drying, mixing and packaging are carried out through a separator.
The methanol recovery rate of this example was 96.4%, and the ethyl acetate recovery rate was 98.9%. The product purity of pleuromutilin is 97.1% and the product yield is 98.9%.
The foregoing description is only a preferred embodiment of the present invention, and is not intended to limit the embodiment of the present invention in any way, but any simple modification, equivalent variation and modification of the above embodiment according to the technical substance of the embodiment of the present invention still fall within the scope of the technical solution of the embodiment of the present invention.
Claims (10)
1. A method for extracting pleuromutilin by double solvents, which is characterized by comprising the following steps:
(1) Leaching: adding methanol solution into mycelium for first leaching, and extracting supernatant;
adding methanol solution for secondary leaching, and extracting supernatant;
adding methanol solution for leaching for the third time, filtering and pressing after leaching, and combining the supernatant and the filtrate to obtain leaching liquor;
the leaching process is to stir and leach firstly, then to stand still for leaching, and the time of stirring and leaching is the same as that of standing still leaching;
(2) Heating the leaching solution to 48-52 ℃ under the vacuum degree of not lower than 0.05MPa, and performing water washing evaporation to recover methanol after vacuum evaporation to recover methanol;
(3) The leaching solution subjected to water washing and evaporation in the step (3) adopts ethyl acetate for phase inversion, and then water washing and brine washing are sequentially carried out;
(4) Concentrating and crystallizing the leaching solution after brine washing, and then carrying out solid-liquid separation and drying.
2. The method of claim 1, wherein the step of determining the position of the substrate comprises,
in the step (1), the water content in the leaching systems of the first time, the second time and the third time is 10-15wt%;
the mass volume ratio of mycelium to methanol solution in the first, second and third leaching systems is 1t/12-13m 3 ；
The first, second and third stirring and leaching times are 160-200, 160-200 and 100-140min in turn, and the stirring rotation speed is 50-70 rpm.
3. The method of claim 2, wherein the step of determining the position of the substrate comprises,
in the step (1), the water content in the methanol solution is 7-8wt%.
4. The method of claim 2, wherein the step of determining the position of the substrate comprises,
in the step (1), the stirring and leaching time of the first time, the second time and the third time is 180, 180 and 120 minutes in sequence, and the stirring rotating speed is 60 revolutions per minute.
5. The method of claim 1, wherein the step of determining the position of the substrate comprises,
in the step (2), the leaching solution is heated to 50 ℃, the rotating speed is 50-70 r/min, the vacuum degree is more than 0.05MPa, and the methanol is recovered by vacuum evaporation.
6. The method of claim 1, wherein the step of determining the position of the substrate comprises,
in the step (2), the water washing evaporation is as follows: adding 40-50deg.C water, stirring, and water washing and evaporating.
7. The method of claim 1, wherein the step of determining the position of the substrate comprises,
in the step (3), the phase inversion of the ethyl acetate is as follows: adding ethyl acetate, uniformly mixing, standing until layering, and discharging a water phase;
the water washing is as follows: adding 40-45deg.C water, stirring, standing to delaminate, and discharging water phase;
the salt water washing is as follows: saturated brine is added and stirred uniformly, and then the mixture is stood until layering, and the water phase is discharged.
8. The method of claim 1, wherein the step of determining the position of the substrate comprises,
in the step (4), the concentration and crystallization treatment is as follows: vacuum concentrating at 40-45deg.C to recover ethyl acetate, cooling to 11-13deg.C, and crystallizing for 1.0-2.0 hr.
9. The method of claim 8, wherein the step of determining the position of the first electrode is performed,
in the step (4), the vacuum degree is 0.06MPa, and the cooling speed is 3-5 ℃/h.
10. The method of claim 8, wherein the step of determining the position of the first electrode is performed,
in the step (4), the temperature is reduced to 12 ℃ for crystal growth for 1.5 hours.
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