CN116589437A - Continuous crystallization method of D-pantolactone - Google Patents
Continuous crystallization method of D-pantolactone Download PDFInfo
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- CN116589437A CN116589437A CN202310365629.5A CN202310365629A CN116589437A CN 116589437 A CN116589437 A CN 116589437A CN 202310365629 A CN202310365629 A CN 202310365629A CN 116589437 A CN116589437 A CN 116589437A
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- pantolactone
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- 238000002425 crystallisation Methods 0.000 title claims abstract description 166
- SERHXTVXHNVDKA-BYPYZUCNSA-N (R)-pantolactone Chemical compound CC1(C)COC(=O)[C@@H]1O SERHXTVXHNVDKA-BYPYZUCNSA-N 0.000 title claims abstract description 113
- 230000008025 crystallization Effects 0.000 claims abstract description 147
- 239000013078 crystal Substances 0.000 claims abstract description 99
- 239000012535 impurity Substances 0.000 claims abstract description 54
- 238000004519 manufacturing process Methods 0.000 claims abstract description 4
- 238000000034 method Methods 0.000 claims description 53
- 239000012452 mother liquor Substances 0.000 claims description 49
- 239000007788 liquid Substances 0.000 claims description 44
- 239000002245 particle Substances 0.000 claims description 31
- 238000000926 separation method Methods 0.000 claims description 30
- 238000003756 stirring Methods 0.000 claims description 27
- 239000002002 slurry Substances 0.000 claims description 24
- 239000007787 solid Substances 0.000 claims description 22
- 238000005406 washing Methods 0.000 claims description 22
- 238000002360 preparation method Methods 0.000 claims description 18
- 229920006395 saturated elastomer Polymers 0.000 claims description 11
- 238000002791 soaking Methods 0.000 claims description 10
- 239000000243 solution Substances 0.000 claims description 10
- 238000007599 discharging Methods 0.000 claims description 7
- OTOIIPJYVQJATP-BYPYZUCNSA-N (R)-pantoic acid Chemical compound OCC(C)(C)[C@@H](O)C(O)=O OTOIIPJYVQJATP-BYPYZUCNSA-N 0.000 claims description 6
- SERHXTVXHNVDKA-SCSAIBSYSA-N (3s)-3-hydroxy-4,4-dimethyloxolan-2-one Chemical compound CC1(C)COC(=O)[C@H]1O SERHXTVXHNVDKA-SCSAIBSYSA-N 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 238000011144 upstream manufacturing Methods 0.000 claims description 3
- 238000005119 centrifugation Methods 0.000 claims description 2
- 239000006185 dispersion Substances 0.000 claims description 2
- 239000012450 pharmaceutical intermediate Substances 0.000 claims description 2
- 238000005516 engineering process Methods 0.000 abstract description 5
- 238000001914 filtration Methods 0.000 abstract description 3
- 238000005265 energy consumption Methods 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 58
- 230000000052 comparative effect Effects 0.000 description 18
- 238000010899 nucleation Methods 0.000 description 15
- 230000006911 nucleation Effects 0.000 description 15
- 230000003287 optical effect Effects 0.000 description 9
- 239000000203 mixture Substances 0.000 description 8
- 229940115458 pantolactone Drugs 0.000 description 8
- 238000001816 cooling Methods 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
- 230000008020 evaporation Effects 0.000 description 6
- SERHXTVXHNVDKA-UHFFFAOYSA-N pantolactone Chemical compound CC1(C)COC(=O)C1O SERHXTVXHNVDKA-UHFFFAOYSA-N 0.000 description 6
- 230000000630 rising effect Effects 0.000 description 6
- 238000010998 test method Methods 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 3
- 238000001878 scanning electron micrograph Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 description 2
- GHOKWGTUZJEAQD-UHFFFAOYSA-N Chick antidermatitis factor Natural products OCC(C)(C)C(O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- -1 D-pantoic acid lactone Chemical class 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- FAPWYRCQGJNNSJ-UBKPKTQASA-L calcium D-pantothenic acid Chemical compound [Ca+2].OCC(C)(C)[C@@H](O)C(=O)NCCC([O-])=O.OCC(C)(C)[C@@H](O)C(=O)NCCC([O-])=O FAPWYRCQGJNNSJ-UBKPKTQASA-L 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 238000001000 micrograph Methods 0.000 description 2
- SIEVQTNTRMBCHO-UHFFFAOYSA-N pantolactone Natural products CC1(C)OC(=O)CC1O SIEVQTNTRMBCHO-UHFFFAOYSA-N 0.000 description 2
- 239000011703 D-panthenol Substances 0.000 description 1
- 235000004866 D-panthenol Nutrition 0.000 description 1
- SNPLKNRPJHDVJA-ZETCQYMHSA-N D-panthenol Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCCO SNPLKNRPJHDVJA-ZETCQYMHSA-N 0.000 description 1
- 229930003571 Vitamin B5 Natural products 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000010923 batch production Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 229960002079 calcium pantothenate Drugs 0.000 description 1
- QGJOPFRUJISHPQ-NJFSPNSNSA-N carbon disulfide-14c Chemical compound S=[14C]=S QGJOPFRUJISHPQ-NJFSPNSNSA-N 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229960003949 dexpanthenol Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000011713 pantothenic acid Substances 0.000 description 1
- 235000019161 pantothenic acid Nutrition 0.000 description 1
- 229940055726 pantothenic acid Drugs 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 238000013094 purity test Methods 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000011675 vitamin B5 Substances 0.000 description 1
- 235000009492 vitamin B5 Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/32—Oxygen atoms
- C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/10—Process efficiency
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The application provides a continuous crystallization method of D-pantolactone, which adopts a three-stage continuous crystallization kettle in the continuous crystallization method, and the purity of the obtained crystal product is improved, the granularity is increased, the filtering performance is improved, and the fluidity of the obtained product is ensured, so that the impurity content of the product is reduced. The application creatively combines the prior D-pantolactone intermittent reaction crystallization technology with the continuous crystallization equipment technology, reforms the D-pantolactone continuous reaction crystallization technology, improves the crystallization efficiency and the production capacity of the D-pantolactone, improves the product performance and reduces the energy consumption.
Description
Technical Field
The application belongs to the technical field of crystallization processes, and relates to a continuous crystallization method of D-pantolactone.
Background
D-PANTOLACTONE (D- (-) -PANTOLACTONE), also known as dihydro-3-hydroxy-4, 4-dimethyl-2 (3H) furanone, CAS number 599-04-2. D-pantolactone is a very important pharmaceutical intermediate, mainly used for synthesizing vitamin B5 drugs, D-panthenol and D-calcium pantothenate, which are the main products of pantothenic acid in the liver. D-pantolactone is a hygroscopic crystal (benzene/petroleum ether, or sublimated), which is readily soluble in water, ethanol, diethyl ether, chloroform, carbon disulfide, benzene.
Crystallization is one of the most effective methods for producing pure solids, and when crystallization, solutes in solution are separated due to their solubility and impurity solubility, and the crystallization process directly affects the crystal form and purity of the product. The conventional crystallization process of D-pantolactone is similar to the conventional crystallization process, and can be basically divided into three processes of nucleation, crystal growth and crystal growth. The crystallization process flow adopted at present is that mother liquor from the tower bottom of an upstream rectifying tower enters a first-stage crystallization kettle, the temperature is reduced and kept for 24 hours, and crude D-pantolactone is discharged. Transferring the residual crystal slurry into a secondary crystallization kettle; recrystallizing in a secondary crystallization kettle, cooling to-10deg.C by ethylene glycol, maintaining for 24 hr, washing the product in water and active carbon for one time, and centrifuging to obtain refined D-pantolactone; and then washing the mixture for the second time in water and active carbon, and centrifuging the mixture to obtain the di-refined D-pantolactone.
At present, the crystallization process of D-pantolactone mainly comprises cooling crystallization, and the following problems mainly exist in the actual operation process: (1) cooling rate: the cooling rate is fast and then slow, so that burst nucleation is serious in the crystallization process, and the granularity of the final product is small; (2) The crystallization temperature is that the crystallization final temperature is-10 ℃, so that impurities are mixed in the product, and the purity is unqualified; (3) The crystallization time is 60-80h, and the time is long.
Based on the state of the art, the inventor believes that based on the existing industrial crystallization production equipment, developing a reasonable and scientific continuous crystallization technology suitable for D-pantolactone is urgent, and seeking a continuous crystallization technology for D-pantolactone with low impurity content, large granularity, low energy consumption, high efficiency, stable product quality, simple flow and low production cost.
Disclosure of Invention
In order to solve the defects of the prior art, the application aims to provide a continuous crystallization method of D-pantolactone, which realizes continuous crystallization, improves the purity of crystal products, increases the granularity, improves the filtering performance and reduces the crystallization process time. The washing mode in the process of reducing and optimizing crystallization reduces the solvent residue of the left ester product, ensures the fluidity of the finally obtained D-pantolactone product, and reduces the impurity carried by the product.
In order to solve the technical problems, the application adopts the following technical scheme:
in order to achieve the aim of the application, the application adopts the following technical scheme:
it is an object of the present application to provide a continuous crystallization method of D-pantolactone, comprising the steps of:
(1) Under the stirring action, D-pantolactone mother liquor with the concentration of 80-85wt% is introduced into a first-stage crystallization kettle, the temperature is kept at 60-75 ℃ for 20-40min, then the temperature is reduced to 45-60 ℃, crystal slurry is discharged from the first-stage crystallization kettle and enters a second-stage crystallization kettle, wherein in the process of temperature rise and fall, the liquid level change is kept within 10% of the balance liquid level;
(2) Controlling the temperature of the second-stage crystallization kettle to be 30-45 ℃, adding D-pantolactone seed crystals under the stirring condition, enabling the seed crystals to be uniformly dispersed in the second-stage crystallization kettle, and discharging the crystal slurry from the second-stage crystallization kettle and entering the third-stage crystallization kettle when the crystal slurry volume reaches more than 80% of the second-stage crystallization kettle;
(3) Controlling the temperature of the third-order crystallization kettle to be 5-20 ℃, and under the stirring condition, enabling D-pantolactone crystals to stably grow, discharging crystal slurry from the third-order crystallization kettle, and entering a solid-liquid separation system, wherein in the stable crystal growth process, the liquid level change is maintained within 10% of the balance liquid level;
(4) In the solid-liquid separation system, the separated solid is discharged from the solid-liquid separation system, and the mother liquor is recycled.
Preferably, the D-pantolactone mother liquor of step (1) is a D-pantolactone upstream mother liquor;
preferably, the D-pantolactone mother liquor in the step (1) has a pantolactone impurity content of 0.5-1wt%, a maximum single impurity (the mass fraction of the single impurity in the mother liquor is the largest impurity) content of 2-3wt%, and a total impurity (all impurities in the mother liquor) content of 8-9wt%.
Preferably, the stirring rate of step (1) is from 100 to 350rpm;
preferably, the addition volume of the D-pantolactone mother liquor in the step (1) is 50-70% of the volume of the first-stage crystallization kettle.
Preferably, the seed crystal in the step (2) has a particle size of 0.45-0.65mm;
preferably, the seed crystal in the step (2) is added in an amount of 2-5g based on 90-110g of D-pantolactone mother liquor.
Preferably, the time of uniform dispersion in the step (2) is 4-7h;
preferably, the stirring rate in step (2) is from 100 to 350rpm.
Preferably, the stirring rate of step (3) is 50-200rpm;
preferably, the time for stable growth of the crystals in step (3) is 6 to 10 hours.
Preferably, the mother liquor in the step (4) is evaporated and separated, and then enters a first-stage crystallization kettle for circulation, and is subjected to a multistage continuous crystallization process together with the continuously-supplemented D-pantolactone mother liquor;
preferably, the solid-liquid separation in the step (4) is performed by centrifugation;
preferably, the step (4) further comprises sequentially cleaning and drying the solid obtained after the solid-liquid separation.
Preferably, the preparation method further comprises post-treatment of the solid obtained by solid-liquid separation;
preferably, the post-treatment comprises: adding saturated D-pantolactone saturated water-soluble solution into the solid obtained after solid-liquid separation for soaking and washing;
preferably, the saturated aqueous solution of the saturated D-pantolactone is added in an amount of 45 to 60g based on 60g of the dry solid obtained after the solid-liquid separation.
The second object of the present application is to provide a method for continuous crystallization to obtain D-pantolactone as described in one of the objects.
Preferably, in the D-pantoic acid lactone, the pantoic acid content is less than or equal to 0.2%, the maximum single impurity is less than or equal to 0.1%, the total impurity is less than or equal to 0.5%, the L-pantoic acid lactone is less than or equal to 1.0%, and the product purity is more than 99%.
Preferably, the D-pantolactone has an average particle diameter of 0.7 to 0.9mm.
The application also aims to provide the application of the D-pantolactone in preparing a drug intermediate.
Compared with the prior art, the application has the following beneficial effects:
the method provided by the application provides a process for continuously and stably producing D-pantolactone crystals with high purity, low impurity content, large granularity and easiness in filtration.
The method of the application confirms the cooling rate, the crystallization end temperature, the crystal seed adding temperature, the grain diameter and the weight in the cooling crystallization, improves the purity of the product, ensures that the content of the pantoic acid in the D-pantolactone related substances is less than or equal to 0.2%, the maximum single impurity is less than or equal to 0.1%, the total impurity is less than or equal to 0.5%, the L-pantolactone is less than or equal to 1.0%, and the purity of the product is more than 99%.
The method of the application defines a post-treatment method of the crystal product, so that the yield of the D-pantolactone after washing is more than 90 percent.
Drawings
FIG. 1 is a scanning electron microscope image of a D-pantolactone crystal product using a conventional batch crystallization process, scale 1000 μm;
FIG. 2 is a scanning electron micrograph of a D-pantolactone crystal product obtained by continuous crystallization in example 1, on a scale of 1000. Mu.m.
Detailed Description
It should be noted that the following detailed description is exemplary and is intended to provide further explanation of the application. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The technical scheme of the application is further described by the following specific embodiments. It should be apparent to those skilled in the art that the examples are merely provided to aid in understanding the present application and should not be construed as limiting the application in any way.
Example 1
The embodiment provides a continuous crystallization method of D-pantolactone, which comprises the following steps:
(1) Under the action of stirring speed of 100rpm, D-pantolactone mother liquor with concentration of 80wt% and volume of 50% of the volume of the first-stage crystallization kettle is introduced into the first-stage crystallization kettle, the temperature is kept at 60 ℃ for 30min, then the temperature is reduced to 45 ℃, crystal slurry is discharged from the first-stage crystallization kettle and enters the second-stage crystallization kettle, wherein the liquid level change is kept within 10% of the balance liquid level in the process of rising and falling;
(2) The temperature of the second-stage crystallization kettle is controlled to be 30 ℃, under the condition of the stirring speed of 100rpm, D-pantolactone seed crystals with the particle size of 0.45-0.65 mmD-pantolactone (the adding amount of the seed crystals is 2g based on the adding amount of the D-pantolactone mother liquor of 100 g) are added, so that the seed crystals are uniformly dispersed for 4 hours in the second-stage crystallization kettle, the volume of crystal slurry reaches more than 80 percent of the volume of the second-stage crystallization kettle, and the crystal slurry is discharged from the second-stage crystallization kettle and enters the third-stage crystallization kettle;
(3) Controlling the temperature of the third-order crystallization kettle to be 5 ℃, and stably growing D-pantolactone crystals for 6 hours under the condition of 50rpm of stirring rate, discharging crystal slurry from the third-order crystallization kettle, and entering a solid-liquid separation system, wherein the liquid level change is maintained within 10% of the balance liquid level in the stable crystal growth process;
(4) In the centrifugal system, the separated solid is discharged from the centrifugal system, and saturated D-pantolactone mother liquor is added for soaking and washing (the addition amount of the saturated D-pantolactone saturated water-soluble solution is 50g calculated as 60g of dried solid obtained after centrifugal separation), and the mixture enters a first-stage crystallization kettle for circulation after evaporation and separation, and is subjected to multistage continuous crystallization together with the continuously-supplemented D-pantolactone mother liquor.
The product obtained in example 1 was tested as follows:
(1) Particle size test (test equipment: malvern laser particle sizer Mastersizer 3000): FIG. 2 is a scanning electron microscope image of the product obtained in this example, and the average particle size of the product obtained in FIG. 2 is 0.97mm;
(2) Optical rotation test (test equipment: digital automatic polarimeter SGW-2): the optical rotation of the obtained product is 2.4697;
(3) Purity test (HPLC): it can be seen that the maximum single impurity of the product is 0.03%, and the total impurity is 0.04%.
In the preparation method, the whole process takes 13.5 hours, and the problem of burst nucleation does not occur in the preparation process.
Example 2
The embodiment provides a continuous crystallization method of D-pantolactone, which comprises the following steps:
(1) Under the action of stirring speed of 250rpm, D-pantolactone mother liquor with concentration of 82wt% and volume of 60% of the volume of the first-stage crystallization kettle is introduced into the first-stage crystallization kettle, the temperature is kept at 70 ℃ for 30min, then the temperature is reduced to 55 ℃, crystal slurry is discharged from the first-stage crystallization kettle and enters the second-stage crystallization kettle, wherein the liquid level change is kept within 10% of the balance liquid level in the process of rising and falling;
(2) The temperature of the second-stage crystallization kettle is controlled to be 40 ℃, under the condition of the stirring speed of 250rpm, D-pantolactone seed crystals with the particle size of 0.45-0.65 mmD-pantolactone (the adding amount of the seed crystals is 3g based on the adding amount of the D-pantolactone mother liquor of 100 g) are added, so that the seed crystals are uniformly dispersed for 5 hours in the second-stage crystallization kettle, the volume of crystal slurry reaches more than 80 percent of the volume of the second-stage crystallization kettle, and the crystal slurry is discharged from the second-stage crystallization kettle and enters the third-stage crystallization kettle;
(3) Controlling the temperature of the third-order crystallization kettle to be 15 ℃, and stably growing D-pantolactone crystals for 8 hours under the condition of stirring speed of 150rpm, discharging crystal slurry from the third-order crystallization kettle, and entering a solid-liquid separation system, wherein the liquid level change is maintained within 10% of the balance liquid level in the stable crystal growth process;
(4) In the centrifugal system, the separated solid is discharged from the centrifugal system, and saturated D-pantolactone mother liquor is added for soaking and washing (the addition amount of the saturated D-pantolactone saturated water-soluble solution is 50g calculated as 60g of dried solid obtained after centrifugal separation), and the mixture enters a first-stage crystallization kettle for circulation after evaporation and separation, and is subjected to multistage continuous crystallization together with the continuously-supplemented D-pantolactone mother liquor.
The product obtained in this example was tested by the same test method as in example 1, and it was found that the average particle diameter of the obtained product was 0.97mm, the optical rotation of the product was-2.3874, the maximum single impurity of the product was 0.04%, and the total impurities were 0.08%.
In the preparation method, the whole process takes 16.5 hours, and the problem of burst nucleation does not occur in the preparation process.
Example 3
The embodiment provides a continuous crystallization method of D-pantolactone, which comprises the following steps:
(1) Under the action of stirring speed of 350rpm, D-pantolactone mother liquor with concentration of 85wt% and volume of 70% of the volume of the first-stage crystallization kettle is introduced into the first-stage crystallization kettle, the temperature is kept at 75 ℃ for 30min, then the temperature is reduced to 60 ℃, crystal slurry is discharged from the first-stage crystallization kettle and enters the second-stage crystallization kettle, wherein the liquid level change is kept within 10% of the balance liquid level in the process of rising and falling;
(2) The temperature of the second-stage crystallization kettle is controlled to be 45 ℃, under the condition of the stirring speed of 350rpm, D-pantolactone seed crystals with the particle size of 0.45-0.65 mmD-pantolactone (the adding amount of the seed crystals is 5g based on the adding amount of the D-pantolactone mother liquor of 100 g) are added, so that the seed crystals are uniformly dispersed for 7h in the second-stage crystallization kettle, the volume of crystal slurry reaches more than 80 percent of the volume of the second-stage crystallization kettle, and the crystal slurry is discharged from the second-stage crystallization kettle and enters the third-stage crystallization kettle;
(3) Controlling the temperature of the third-order crystallization kettle to be 20 ℃, and stably growing D-pantolactone crystals for 10 hours under the condition of the stirring speed of 200rpm, discharging crystal slurry from the third-order crystallization kettle, and entering a solid-liquid separation system, wherein the liquid level change is maintained within 10% of the balance liquid level in the stable crystal growth process;
(4) In the centrifugal system, the separated solid is discharged from the centrifugal system, and saturated D-pantolactone mother liquor is added for soaking and washing (the addition amount of the saturated D-pantolactone saturated water-soluble solution is 50g calculated as 60g of dried solid obtained after centrifugal separation), and the mixture enters a first-stage crystallization kettle for circulation after evaporation and separation, and is subjected to multistage continuous crystallization together with the continuously-supplemented D-pantolactone mother liquor.
The product obtained in this example was tested by the same test method as in example 1, and it was found that the average particle diameter of the obtained product was 0.95mm, the optical rotation of the product was-2.5928, the maximum single impurity of the product was 0.03%, and the total impurities were 0.05%.
In the preparation method, the whole process takes 20.5 hours, and the problem of burst nucleation does not occur in the preparation process.
Comparative example 1
Adopts one-step cooling crystallization, a conventional batch process, and no seed crystal is added.
D-pantolactone mother liquor with the concentration of 85wt% is introduced into the first-stage crystallization kettle, and the temperature is 70-90 ℃. The crystallization kettle is filled with low-temperature brine, cooled to 20 ℃ in 12h, kept for 24h, then transferred to a second crystallization kettle, recrystallized in ethylene glycol, cooled to-10 ℃ in 12h, kept for 24h, and then washed twice in active carbon to obtain the final product. The whole process time is 72 hours, and the time is longer. The mother liquor burst is seriously nucleated, impurities are occluded in the crystal, the granularity of the final crystal product is smaller, the impurity content is high, the pantoic acid content is more than 0.2%, the maximum single impurity is more than 0.1%, the total impurities are more than 0.5%, and the L-pantolactone is more than 1.0%, so that the purity of the product is less than 95%.
The particle size, optical rotation and impurities of the D-pantolactone products in example 1 and comparative example 1 are shown in the following table.
TABLE 1 comparison of pantolactone crystallization process
Fig. 1 is a scanning electron micrograph of a D-pantolactone crystal product of comparative example 1 using a conventional batch crystallization process, and fig. 2 is a scanning electron micrograph of a D-pantolactone crystal product of example 1 using a continuous crystallization process, and it is known from a comparison of fig. 1 and fig. 2 that the average particle size of the D-pantolactone crystal produced using a conventional batch crystallization process is reduced by 30%, and a burst nucleation phenomenon occurs, and magazines are occluded in the crystal, and the total impurities are increased to 0.17%.
Comparative example 2
The two-step crystallization method is adopted, a first-order crystallization kettle and a second-order crystallization kettle are provided, a third-order crystallization kettle is not provided, and a second-order continuous crystallization process is simulated.
(1) Under the action of stirring speed of 250rpm, D-pantolactone mother liquor with concentration of 85wt% and volume of 60% of the volume of the first-stage crystallization kettle is introduced into the first-stage crystallization kettle, the temperature is kept at 70 ℃ for 30min, then the temperature is reduced to 55 ℃, crystal slurry is discharged from the first-stage crystallization kettle and enters the second-stage crystallization kettle, wherein the liquid level change is kept within 10% of the balance liquid level in the process of rising and falling;
(2) The temperature of the second-stage crystallization kettle is controlled to be 40 ℃, and D-pantolactone seed crystals with the particle size of 0.45-0.65 mmD-pantolactone seed crystals (the seed crystal addition amount is 3g based on 100g of the D-pantolactone mother liquor) are added under the condition that the stirring speed is 250rpm, so that the D-pantolactone crystals stably grow for 8 hours.
(4) In the centrifugal system, the separated solid is discharged from the centrifugal system, and saturated D-pantolactone mother liquor is added for soaking and washing (the addition amount of the saturated D-pantolactone saturated water-soluble solution is 50g calculated as 60g of dried solid obtained after centrifugal separation), and the mixture enters a first-stage crystallization kettle for circulation after evaporation and separation, and is subjected to multistage continuous crystallization together with the continuously-supplemented D-pantolactone mother liquor.
The product obtained in this comparative example was tested by the same test method as in example 1, and it was found that the average particle diameter of the obtained product was 0.67mm, the optical rotation of the product was-2.4775, the maximum single impurity of the product was 0.04%, and the total impurities were 0.09%.
In the preparation method, the whole process takes 11.5 hours, and the problem of burst nucleation occurs in the preparation process.
As is clear from the comparison between comparative example 2 and example 1, the time for stable growth of the crystal in the crystallization kettle without the third stage is reduced, and the supersaturation degree after adding the seed crystal is not used for crystal growth, and the burst nucleation phenomenon occurs, the average particle diameter is reduced to 0.67mm, and the total impurities are raised to 0.09%.
Comparative example 3
The two-step crystallization method is adopted, a first-order crystallization kettle and a third-order crystallization kettle are provided, a second-order crystallization kettle is not provided, and a second-order continuous crystallization process is simulated.
(1) Under the action of stirring speed of 250rpm, D-pantolactone mother liquor with concentration of 85wt% and volume of 60% of the volume of the first-stage crystallization kettle is introduced into the first-stage crystallization kettle, the temperature is kept at 70 ℃ for 30min, then the temperature is reduced to 55 ℃, crystal slurry is discharged from the first-stage crystallization kettle and enters the second-stage crystallization kettle, wherein the liquid level change is kept within 10% of the balance liquid level in the process of rising and falling;
(2) The temperature of the second-stage crystallization kettle is controlled to be 15 ℃, and D-pantolactone seed crystals with the particle size of 0.45-0.65 mmD-pantolactone seed crystals (the seed crystal addition amount is 3g based on 100g of the D-pantolactone mother liquor) are added under the condition that the stirring speed is 250rpm, so that the D-pantolactone crystals stably grow for 8 hours.
(4) In the centrifugal system, the separated solid is discharged from the centrifugal system, and saturated D-pantolactone mother liquor is added for soaking and washing (the addition amount of the saturated D-pantolactone saturated water-soluble solution is 50g calculated as 60g of dried solid obtained after centrifugal separation), and the mixture enters a first-stage crystallization kettle for circulation after evaporation and separation, and is subjected to multistage continuous crystallization together with the continuously-supplemented D-pantolactone mother liquor.
The product obtained in this comparative example was tested by the same test method as in example 1, and it was found that the average particle diameter of the obtained product was 0.58mm, the optical rotation of the product was-2.4793, the maximum single impurity of the product was 0.07, and the total impurities were 0.12%.
In the preparation method, the whole process takes 11.5 hours, and the problem of burst nucleation occurs in the preparation process.
As is clear from a comparison between comparative example 3 and example 1, the crystallization kettle of the second stage was not used, the seed crystal addition temperature was too low, and an explosive nucleation phenomenon had occurred before the seed crystal addition, resulting in occlusion of impurities in the inside of the product, the average particle diameter of the product was 0.58mm, and the total impurities increased to 0.12%.
Comparative example 4
The two-step crystallization method is adopted, a second-order crystallization kettle and a third-order crystallization kettle are provided, a first-order crystallization kettle is not provided, and a second-order continuous crystallization process is simulated.
(1) Under the action of stirring speed of 250rpm, D-pantolactone mother liquor with concentration of 85wt% and volume of 60% of the volume of the first-stage crystallization kettle is introduced into the first-stage crystallization kettle, the temperature is kept at 70 ℃ for 30min, then the temperature is reduced to 40 ℃, crystal slurry is discharged from the first-stage crystallization kettle and enters the second-stage crystallization kettle, wherein the liquid level change is kept within 10% of the balance liquid level in the process of rising and falling;
(2) The temperature of the second-stage crystallization kettle is controlled to be 15 ℃, and D-pantolactone seed crystals with the particle size of 0.45-0.65 mmD-pantolactone seed crystals (the seed crystal addition amount is 3g based on 100g of the D-pantolactone mother liquor) are added under the condition that the stirring speed is 250rpm, so that the D-pantolactone crystals stably grow for 8 hours.
(4) In the centrifugal system, the separated solid is discharged from the centrifugal system, and saturated D-pantolactone mother liquor is added for soaking and washing (the addition amount of the saturated D-pantolactone saturated water-soluble solution is 50g calculated as 60g of dried solid obtained after centrifugal separation), and the mixture enters a first-stage crystallization kettle for circulation after evaporation and separation, and is subjected to multistage continuous crystallization together with the continuously-supplemented D-pantolactone mother liquor.
The result shows that the crystallization kettle at the first stage is not needed in the crystallization process, the temperature is reduced too fast, the burst nucleation phenomenon is serious, a large number of fine crystals appear, the D-pantolactone crystals with the particle size of more than 90mm account for 3.28% of the total crystals, and the average particle size is 0.56mm.
The product obtained in this comparative example was tested by the same test method as in example 1, and it was found that the average particle diameter of the obtained product was 0.56mm, the optical rotation of the product was-2.4674, the maximum single impurity of the product was 0.04%, and the total impurities were 0.13%.
In the preparation method, the whole process takes 11.5 hours, and the problem of burst nucleation occurs in the preparation process.
As is clear from the comparison between comparative example 4 and example 1, the crystallization kettle without the first stage had too fast a temperature drop and severe burst nucleation, and a large number of fine crystals were present, with an average particle size of 0.56mm and a total impurity of 0.10%.
Comparative example 5
The difference from example 1 was only that D-pantolactone seed crystals of less than 0.45mm obtained by recrystallization were added, and the other preparation methods were the same as in example 1.
The products obtained in this comparative example were tested by the same test method as in example 1, and it was found that the average particle diameter of the obtained products was in the range of 0.50 to 0.70mm, the optical rotation of the products was-2.4778, the maximum single impurity of the products was 0.04%, and the total impurities were 0.10%.
In the preparation method, the whole process takes 13.5 hours, and the problem of burst nucleation occurs in the preparation process.
As is clear from a comparison of comparative example 5 and example 1, when D-pantolactone seed crystals of less than 0.45mm obtained by recrystallization are added, a large amount of small particle size nuclei are generated by burst nucleation of mother liquor, and finally small products with particle sizes of 0.50-0.70mm are obtained, and impurities are easily occluded in the crystals to cause maximum single impurity of 0.04% and total impurity of 0.10%.
Comparative example 6
The difference from example 2 is only that the crystalline product is rinsed with pure water by adding activated carbon, and the rest of the preparation method is the same as example 2.
The washing yields of the D-pantolactone products in example 2 and comparative example 6 are shown in the following Table for the maximum single impurity.
Actual yield = (mass of crystals obtained in practice/g)/(mass of crystals in solution/g) ×100%
Washing yield = (product mass after washing/g)/(wet product mass/g) ×100%
As is clear from the comparison between example 2 and comparative example 6, the saturated aqueous solution is used for soaking and washing the D-pantolactone crystals, compared with the pure water washing, the consumption of the washing solvent is reduced by 30%, the solubility of the D-pantolactone in water is very high, the product with large particle size can be dissolved into small particle size by using the water washing, the particle size is reduced by thirty percent, the crystals are not dissolved in the washing solvent, and the occurrence of recrystallization phenomenon is avoided. In addition, the residual active carbon in the product becomes new impurities, and the total impurities are increased. The actual yield is improved to 58.53% after the saturated solution is adopted for soaking and washing, the washing yield is improved to 90%, no pantoic acid impurity exists, the maximum single impurity is 0.03%, the total impurity is 0.09%, and the content of L-inverse acid lactone is 0.36%.
The applicant declares that the above is only a specific embodiment of the present application, but the scope of the present application is not limited thereto, and it should be apparent to those skilled in the art that any changes or substitutions that are easily conceivable within the technical scope of the present application disclosed by the present application fall within the scope of the present application and the disclosure.
Claims (10)
1. A continuous crystallization method of D-pantolactone, characterized in that the continuous crystallization method comprises the steps of:
(1) Under the stirring action, D-pantolactone mother liquor with the concentration of 80-85wt% is introduced into a first-stage crystallization kettle, the temperature is kept at 60-75 ℃ for 20-40min, then the temperature is reduced to 45-60 ℃, crystal slurry is discharged from the first-stage crystallization kettle and enters a second-stage crystallization kettle, wherein in the process of temperature rise and fall, the liquid level change is kept within 10% of the balance liquid level;
(2) Controlling the temperature of the second-stage crystallization kettle to be 30-45 ℃, adding D-pantolactone seed crystals under the stirring condition, enabling the seed crystals to be uniformly dispersed in the second-stage crystallization kettle, and discharging the crystal slurry from the second-stage crystallization kettle and entering the third-stage crystallization kettle when the crystal slurry volume reaches more than 80% of the second-stage crystallization kettle;
(3) Controlling the temperature of the third-order crystallization kettle to be 5-20 ℃, and under the stirring condition, enabling D-pantolactone crystals to stably grow, discharging crystal slurry from the third-order crystallization kettle, and entering a solid-liquid separation system, wherein in the stable crystal growth process, the liquid level change is maintained within 10% of the balance liquid level;
(4) In the solid-liquid separation system, the separated solid is discharged from the solid-liquid separation system, and the mother liquor is recycled.
2. The continuous crystallization process according to claim 1, wherein the D-pantolactone mother liquor of step (1) is a D-pantolactone upstream mother liquor;
preferably, the D-pantolactone mother liquor in the step (1) contains 0.5-1wt% of pantoic acid impurities, 2-3wt% of the maximum single impurities and 8-9wt% of total impurities;
preferably, the stirring rate of step (1) is from 100 to 350rpm;
preferably, the addition volume of the D-pantolactone mother liquor in the step (1) is 50-70% of the volume of the first-stage crystallization kettle.
3. The continuous crystallization method according to claim 1, wherein the seed crystal of step (2) has a particle diameter of 0.45 to 0.65mm;
preferably, the seed crystal in the step (2) is added in an amount of 2-5g based on 90-110g of D-pantolactone mother liquor.
4. The continuous crystallization process according to claim 1, wherein the time of the uniform dispersion in step (2) is 4 to 7 hours;
preferably, the stirring rate in step (2) is from 100 to 350rpm.
5. The continuous crystallization process according to claim 1, wherein the stirring rate of step (3) is 50-200rpm;
preferably, the time for stable growth of the crystals in step (3) is 6 to 10 hours.
6. The continuous crystallization method according to claim 1, wherein the mother liquor obtained in the step (4) is evaporated and separated, and then enters a first-stage crystallization kettle for circulation, and the mother liquor and the continuously-supplemented D-pantolactone mother liquor are subjected to a multistage continuous crystallization process together;
preferably, the solid-liquid separation in the step (4) is performed by centrifugation.
7. The continuous crystallization method according to claim 6, wherein the production method further comprises post-treatment of a solid obtained by solid-liquid separation;
preferably, the post-treatment comprises: adding saturated D-pantolactone saturated water-soluble solution into the solid obtained after solid-liquid separation for soaking and washing;
preferably, the saturated aqueous solution of the saturated D-pantolactone is added in an amount of 45 to 60g based on 60g of the dry solid obtained after the solid-liquid separation.
8. The D-pantolactone is obtained by crystallization by the continuous crystallization method as claimed in any one of claims 1 to 7.
9. The D-pantolactone of claim 8, wherein the D-pantolactone has a pantoic acid content of 0.2% or less, a maximum single impurity of 0.1% or less, a total impurity of 0.5% or less, L-pantolactone of 1.0% or less, and a product purity of 99% or more;
preferably, the D-pantolactone has an average particle diameter of 0.7 to 0.9mm.
10. Use of D-pantolactone as claimed in claim 8 in the preparation of a pharmaceutical intermediate.
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Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102229584A (en) * | 2011-04-19 | 2011-11-02 | 吴江 | Method for preparing D-(-)- or L-(+)-pantoic acid lactone by splitting pantoic acid lactone |
| US20180111911A1 (en) * | 2015-06-19 | 2018-04-26 | Basf Se | Preparation of pantolactone |
| CN108129345A (en) * | 2018-01-10 | 2018-06-08 | 精晶药业股份有限公司 | A kind of preparation method of D-VB5 calcium |
| CN110734415A (en) * | 2019-11-28 | 2020-01-31 | 安徽泰格生物科技有限公司 | Aqueous solution crystallization method of D-pantoic acid lactone |
| CN110862362A (en) * | 2019-11-28 | 2020-03-06 | 安徽泰格生物科技有限公司 | Refining method of D-pantoic acid lactone |
| CN112047851A (en) * | 2020-08-20 | 2020-12-08 | 山东新和成精化科技有限公司 | Preparation method of D-panthenol |
| CN112209819A (en) * | 2020-09-27 | 2021-01-12 | 安徽泰格生物科技有限公司 | Preparation method of D-pantoic acid calcium |
| CN112679453A (en) * | 2020-12-16 | 2021-04-20 | 蚌埠丰原医药科技发展有限公司 | Preparation method of D-pantoic acid lactone |
-
2023
- 2023-04-07 CN CN202310365629.5A patent/CN116589437A/en active Pending
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102229584A (en) * | 2011-04-19 | 2011-11-02 | 吴江 | Method for preparing D-(-)- or L-(+)-pantoic acid lactone by splitting pantoic acid lactone |
| US20180111911A1 (en) * | 2015-06-19 | 2018-04-26 | Basf Se | Preparation of pantolactone |
| CN108129345A (en) * | 2018-01-10 | 2018-06-08 | 精晶药业股份有限公司 | A kind of preparation method of D-VB5 calcium |
| CN110734415A (en) * | 2019-11-28 | 2020-01-31 | 安徽泰格生物科技有限公司 | Aqueous solution crystallization method of D-pantoic acid lactone |
| CN110862362A (en) * | 2019-11-28 | 2020-03-06 | 安徽泰格生物科技有限公司 | Refining method of D-pantoic acid lactone |
| CN112047851A (en) * | 2020-08-20 | 2020-12-08 | 山东新和成精化科技有限公司 | Preparation method of D-panthenol |
| CN112209819A (en) * | 2020-09-27 | 2021-01-12 | 安徽泰格生物科技有限公司 | Preparation method of D-pantoic acid calcium |
| CN112679453A (en) * | 2020-12-16 | 2021-04-20 | 蚌埠丰原医药科技发展有限公司 | Preparation method of D-pantoic acid lactone |
Non-Patent Citations (1)
| Title |
|---|
| 郑贝贝;孙勤;: "D-泛解酸内酯结晶系统过饱和度测量方法的选择", 化工时刊, no. 05, 26 May 2013 (2013-05-26), pages 11 - 14 * |
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