CN117106005A - Refining method of 8DM - Google Patents
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- CN117106005A CN117106005A CN202311078844.3A CN202311078844A CN117106005A CN 117106005 A CN117106005 A CN 117106005A CN 202311078844 A CN202311078844 A CN 202311078844A CN 117106005 A CN117106005 A CN 117106005A
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- 238000000034 method Methods 0.000 title claims abstract description 38
- 238000007670 refining Methods 0.000 title claims abstract description 28
- 239000012535 impurity Substances 0.000 claims abstract description 76
- XUKUURHRXDUEBC-SXOMAYOGSA-N (3s,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-SXOMAYOGSA-N 0.000 claims abstract description 20
- 238000003756 stirring Methods 0.000 claims abstract description 18
- 238000001291 vacuum drying Methods 0.000 claims abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 12
- 238000001816 cooling Methods 0.000 claims abstract description 11
- 239000007788 liquid Substances 0.000 claims abstract description 11
- 238000000926 separation method Methods 0.000 claims abstract description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 10
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims abstract description 9
- 229910052802 copper Inorganic materials 0.000 claims abstract description 9
- 239000010949 copper Substances 0.000 claims abstract description 9
- 238000002425 crystallisation Methods 0.000 claims abstract description 9
- 230000008025 crystallization Effects 0.000 claims abstract description 9
- 238000001179 sorption measurement Methods 0.000 claims abstract description 8
- 239000012043 crude product Substances 0.000 claims description 25
- 239000000047 product Substances 0.000 claims description 25
- 239000011343 solid material Substances 0.000 claims description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 239000007864 aqueous solution Substances 0.000 claims description 12
- 239000007810 chemical reaction solvent Substances 0.000 claims description 12
- 239000003153 chemical reaction reagent Substances 0.000 claims description 10
- 239000011344 liquid material Substances 0.000 claims description 10
- 239000000463 material Substances 0.000 claims description 10
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 7
- 239000003463 adsorbent Substances 0.000 claims description 7
- 238000001035 drying Methods 0.000 claims description 5
- 238000001914 filtration Methods 0.000 claims description 5
- 238000006460 hydrolysis reaction Methods 0.000 claims description 5
- 239000012452 mother liquor Substances 0.000 claims description 5
- 239000002910 solid waste Substances 0.000 claims description 5
- 230000004580 weight loss Effects 0.000 claims description 5
- 239000010881 fly ash Substances 0.000 claims description 4
- HCWCAKKEBCNQJP-UHFFFAOYSA-N magnesium orthosilicate Chemical compound [Mg+2].[Mg+2].[O-][Si]([O-])([O-])[O-] HCWCAKKEBCNQJP-UHFFFAOYSA-N 0.000 claims description 4
- 239000000391 magnesium silicate Substances 0.000 claims description 4
- 229910052919 magnesium silicate Inorganic materials 0.000 claims description 4
- 235000019792 magnesium silicate Nutrition 0.000 claims description 4
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims 1
- 239000000243 solution Substances 0.000 claims 1
- 239000003256 environmental substance Substances 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- 239000000843 powder Substances 0.000 abstract description 2
- 230000000052 comparative effect Effects 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 6
- 238000001514 detection method Methods 0.000 description 5
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical compound [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 229910001431 copper ion Inorganic materials 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 238000005070 sampling Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229960003957 dexamethasone Drugs 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 239000004593 Epoxy Substances 0.000 description 1
- 108010009736 Protein Hydrolysates Proteins 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000010009 beating Methods 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- -1 dexamethasone epoxide Chemical class 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000006735 epoxidation reaction Methods 0.000 description 1
- 229960001469 fluticasone furoate Drugs 0.000 description 1
- XTULMSXFIHGYFS-VLSRWLAYSA-N fluticasone furoate Chemical compound O([C@]1([C@@]2(C)C[C@H](O)[C@]3(F)[C@@]4(C)C=CC(=O)C=C4[C@@H](F)C[C@H]3[C@@H]2C[C@H]1C)C(=O)SCF)C(=O)C1=CC=CO1 XTULMSXFIHGYFS-VLSRWLAYSA-N 0.000 description 1
- 229960000289 fluticasone propionate Drugs 0.000 description 1
- WMWTYOKRWGGJOA-CENSZEJFSA-N fluticasone propionate Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)SCF)(OC(=O)CC)[C@@]2(C)C[C@@H]1O WMWTYOKRWGGJOA-CENSZEJFSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- PGXWDLGWMQIXDT-UHFFFAOYSA-N methylsulfinylmethane;hydrate Chemical compound O.CS(C)=O PGXWDLGWMQIXDT-UHFFFAOYSA-N 0.000 description 1
- WHQSYGRFZMUQGQ-UHFFFAOYSA-N n,n-dimethylformamide;hydrate Chemical compound O.CN(C)C=O WHQSYGRFZMUQGQ-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000003270 steroid hormone Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
- C07J71/0005—Oxygen-containing hetero ring
- C07J71/001—Oxiranes
- C07J71/0015—Oxiranes at position 9(11)
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the field of pharmaceutical environmental chemical industry, and particularly relates to a refining method of 8DM. The specific refining method comprises the following steps: (1) stirring and dissolving; (2) removing copper by adsorption; (3) removing impurities by reaction; (4) drip water crystallization; (5) cooling and crystallizing; (6) solid-liquid separation; (7) vacuum drying. The appearance of the 8DM refined by the method is white crystalline powder, the refining yield is more than 95 percent, the purity of the 8DM is more than 99 percent, the impurity A, the impurity B and the impurity C are all less than 0.15 percent, and the other single impurity is less than 0.1 percent. The invention has the characteristics of high yield and good product quality, and the method is stable and easy to realize industrial production.
Description
Technical Field
The invention belongs to the field of pharmaceutical environmental chemical industry, and particularly relates to a refining method of 8DM.
Background
8DM is also called dexamethasone epoxide hydrolysate, the chemical name is 17 alpha-21-dihydroxyl-9 beta, 11 beta-epoxy-16 alpha-methyl pregna-1, 4-diene-3,20-dione, the English name is 17 alpha, 21-dihydroxy-9 beta, 11 beta-epoxy-16 alpha-methyl pregn-1,4-diene-3,20-dione, and the structural formula is as follows:
the 8DM is white crystal powder in appearance, is a steroid hormone drug intermediate, and can be used for synthesizing steroid drugs such as dexamethasone, fluticasone propionate, fluticasone furoate and the like.
At present, the synthesis process of 8DM in the prior art takes 8DM epoxy compound (SM 1) as a starting material, and is obtained through methylation, epoxidation and alkaline hydrolysis, and the specific synthesis route is as follows:
the 8DM crude product synthesized by the process is green in appearance, the impurity A is 0.15-0.20%, the impurity B is 0.15-0.25%, and the impurity C is 0.2-2.0%.
Impurity A is generated in the synthesis process of IM2, impurity B is introduced by SM1, both impurities are unknown impurities, the structure is difficult to determine, and the control limit of the impurities needs to be reduced as far as possible.
In the conversion of IM2 to 8DM, 8DM acetate (impurity C) remained largely, with the impurity C structure as follows.
The appearance of the 8DM crude product is green, the effects are poor by adopting means of beating, recrystallization, reaction condition control and the like, the appearance of the 8DM refined product is still green, and the quality problem is a troublesome problem, so that the problem needs to be solved. The analysis shows that: copper ion catalyst in the process of synthesizing IM1 by SM1 is the root cause of greening products.
The solubility of the impurity A, the impurity B, the impurity C and the impurity 8DM in a conventional solvent is relatively small, the impurity A, the impurity B, the impurity C and the impurity 8DM are relatively difficult to remove, and the impurity A, the impurity B, the impurity C and the impurity 8DM are controlled below 0.15 percent with certain difficulty. Aiming at the current technological situation, a reasonable 8DM refining method is specially required to be developed.
Disclosure of Invention
In order to solve the problems in the prior art, the invention aims to provide a refining method of 8DM. The refining method of 8DM provided by the invention can effectively convert the impurity C in the 8DM crude product into 8DM, so that the content of impurity A, B, C is controlled below 0.15%, copper ions in the 8DM crude product can be effectively removed, the final yield reaches more than 95%, and the purity of the obtained 8DM is more than 99%.
The technical scheme of the invention is as follows:
the refining method of 8DM comprises the following steps:
step (1), stirring and dissolving clear: adding the 8DM crude product into a reaction solvent, controlling the temperature to be 30-60 ℃, stirring and dissolving the crude product, and entering the next step;
step (2), removing copper by adsorption: adding an adsorbent into the step (1), controlling the temperature to be 15-35 ℃, stirring and reacting for 10-30 min, and entering the next step;
step (3), reaction impurity removal: adding an alkaline reagent aqueous solution into the step (2), controlling the temperature to be 25-45 ℃, stirring and reacting for 0.5-2 h, converting the impurity C into 8DM through hydrolysis reaction, filtering, treating solid materials as solid waste, and allowing the liquid materials to enter the next step;
step (4), water-dropping crystallization: controlling the temperature of the liquid material obtained in the step (3) to be 45-65 ℃, dripping water, and entering the next step after the dripping is finished;
step (5), cooling and crystallizing: cooling the material obtained in the step (4) to-10 ℃, controlling the temperature for 1-5 h, and entering the next step;
step (6), solid-liquid separation: carrying out solid-liquid separation on the material obtained in the step (5), treating the mother liquor, recovering the reaction solvent, and allowing the solid material to enter the next step;
step (7), vacuum drying: and (3) vacuum drying the solid material obtained in the step (6) at 55-65 ℃ to obtain 8DM refined product.
Further, the appearance of the 8DM crude product is green, wherein the content of the impurity A is 0.15-0.20%, the content of the impurity B is 0.15-0.25%, and the content of the impurity C is 0.2-2.0%.
Further, the reaction equation for converting impurity C in the crude 8DM product in step (3) to 8DM is as follows:
further, in the step (1), the reaction solvent is at least one of DMF (N, N-dimethylformamide) or DMSO (dimethyl sulfoxide);
further, the volume ratio of the mass of the 8DM crude product to the reaction solvent is 1:6-10, wherein the unit of the mass of the 8DM crude product is g, and the unit of the volume of the reaction solvent is mL.
Further, in the step (2), the adsorbent is at least one of activated carbon, fly ash or magnesium silicate;
further, the mass ratio of the 8DM crude product to the adsorbent is 1:0.01-0.1.
Further, the alkaline agent aqueous solution in the step (3) is at least one of sodium hydroxide aqueous solution or potassium carbonate aqueous solution;
further, the mass concentration of the alkaline reagent aqueous solution is 5% -10%.
Further, the mass ratio of the 8DM crude product to the alkaline agent aqueous solution is 1:0.1-0.3.
Further, in the step (4), the mass ratio of the crude 8DM product to water is 1:3-10.
Further, in the step (4), the water is added dropwise for 0.5 to 5.0 hours.
Further, the drying weight loss of the 8DM refined product after the vacuum drying in the step (7) is below 0.5 percent.
Compared with the prior art, the refining method of 8DM provided by the invention has the following advantages:
(1) The invention fully utilizes the characteristics of the impurity C (8 DM acetate) and the 8DM structure, and adopts an alkaline hydrolysis reaction mode to convert the impurity C (8 DM acetate) into 8DM, thereby controlling the impurity C to be below 0.15 percent.
(2) The invention fully utilizes the solubility difference of the impurity A, the impurity B and 8DM in the crystallization solvent, and adopts a DMF-water or DMSO-water crystallization system to control the impurity A and the impurity B below 0.15 percent.
(3) Aiming at the situation that the appearance of the 8DM crude product is greenish and difficult to remove, in the impurity removal process, workers add activated carbon, fly ash or magnesium silicate as an adsorbent, and the problem that the appearance is greenish is effectively solved by adopting an adsorption copper removal technology; in addition, the alkaline reagent added during impurity C is controlled to further reduce the concentration of copper ions.
(4) The refining method of 8DM provided by the invention has the advantages that the appearance is green, the impurity A is 0.15-0.20%, the impurity B is 0.15-0.25%, the impurity C is 0.2-2.0%, the yield of the 8DM crude product is more than 95%, the purity of the 8DM is more than 99%, the impurity A, the impurity B and the impurity C are all below 0.15%, and the other single impurity is below 0.1%. The preparation method has the characteristics of high yield and good product quality, is stable and is easy to realize industrial production.
Drawings
FIG. 1 is a flowchart of a refining method of 8DM in an embodiment of the invention.
Detailed Description
The invention is further illustrated by the following description of specific embodiments, which are not intended to be limiting, and various modifications or improvements can be made by those skilled in the art in light of the basic idea of the invention, but are within the scope of the invention as long as they do not depart from the basic idea of the invention.
In the following examples and comparative examples, the reagents not specifically described were conventional reagents, which were purchased from conventional reagent manufacturing and selling companies, and the methods used, unless otherwise specified, were all prior art.
Example 1A refining method of 8DM
The appearance of the 8DM crude product to be refined is green, the impurity A is 0.15%, the impurity B is 0.25%, the impurity C is 2.0%, and the specific refining method comprises the following steps:
step (1), stirring and dissolving clear: 200g of 8DM crude product is added into 2000mL of DMF, the temperature is controlled at 30 ℃, and the mixture is stirred for dissolving and clearing, and then the next step is carried out;
step (2), removing copper by adsorption: adding 20g of fly ash into the step (1), controlling the temperature to 25 ℃, stirring and reacting for 30min, and entering the next step;
step (3), reaction impurity removal: adding 60g of 10% sodium hydroxide aqueous solution into the step (2), controlling the temperature to be 30 ℃, stirring and reacting for 2 hours, converting the impurity C into 8DM through hydrolysis reaction, and sampling and detecting by adopting HPLC at the moment, wherein the content of the impurity C is remained below 0.15%; filtering, treating the solid material as solid waste, and allowing the liquid material to enter the next step;
step (4), water-dropping crystallization: controlling the temperature of the liquid material obtained in the step (3) to be 55-65 ℃, dripping 2000mL of water for 5.0h, and entering the next step after the dripping is finished;
step (5), cooling and crystallizing: cooling the material obtained in the step (4) to-10 ℃, controlling the temperature for 3 hours, and entering the next step;
step (6), solid-liquid separation: carrying out solid-liquid separation on the material obtained in the step (5), treating the mother liquor, recovering DMF (dimethyl formamide), and allowing the solid material to enter the next step;
step (7), vacuum drying: and (3) vacuum drying the solid material obtained in the step (6) at 55 ℃ to obtain the 8DM refined product, wherein the limit of the drying weight loss is 0.45%.
Through detection, 191.0g of 8DM refined product is obtained by adopting the preparation method of the example 1, the refining yield is 95.5 percent, and the appearance is white. The purity of the 8DM refined product is 99.4%, the impurity A is 0.12%, the impurity B is 0.11%, and the impurity C is 0.12%.
Example 2 refining method of 8DM
In the 8DM crude product to be refined, the appearance is green, the impurity A is 0.20%, the impurity B is 0.15%, and the impurity C is 1.0%. The specific refining method comprises the following steps:
step (1), stirring and dissolving clear: 200g of 8DM crude product is added into 1200mL of DMSO, the temperature is controlled at 60 ℃, and the mixture is stirred for dissolving and clearing, and then the next step is carried out;
step (2), removing copper by adsorption: adding 10g of active carbon into the step (1), controlling the temperature to 35 ℃, stirring and reacting for 10min, and entering the next step;
step (3), reaction impurity removal: adding 40g of 8% potassium carbonate aqueous solution into the step (2), controlling the temperature to be 45 ℃, stirring and reacting for 1h, converting the impurity C into 8DM through hydrolysis reaction, and sampling and detecting by adopting HPLC at the moment, wherein the content of the impurity C is below 0.15%; filtering, treating the solid material as solid waste, and allowing the liquid material to enter the next step;
step (4), water-dropping crystallization: controlling the temperature of the liquid material obtained in the step (3) to be 45-55 ℃, dripping 600mL of water for 0.5h, and entering the next step after the dripping is finished;
step (5), cooling and crystallizing: cooling the material obtained in the step (4) to 0 ℃, controlling the temperature for 5 hours, and entering the next step;
step (6), solid-liquid separation: carrying out solid-liquid separation on the material obtained in the step (5), treating the mother liquor, recovering the reaction solvent, and allowing the solid material to enter the next step;
step (7), vacuum drying: and (3) vacuum drying the solid material obtained in the step (6) at 65 ℃ to obtain the 8DM refined product, wherein the limit of the drying weight loss is 0.35%.
According to detection, 192.0g of 8DM refined product is obtained by adopting the preparation method of the example 2, the refining yield is 96.0%, and the appearance is white. The purity of the 8DM refined product is 99.2%, the impurity A is 0.12%, the impurity B is 0.09%, and the impurity C is 0.10%.
Example 3 refining method of 8DM
In the 8DM crude product to be refined, the appearance is green, the impurity A is 0.17%, the impurity B is 0.20%, and the impurity C is 0.2%. The specific refining method comprises the following steps:
step (1), stirring and dissolving clear: 200g of 8DM crude product is added into 1600mL of DMF, the temperature is controlled at 45 ℃, and the mixture is stirred and dissolved, and then the next step is carried out;
step (2), removing copper by adsorption: adding 2g of magnesium silicate into the step (1), controlling the temperature to 15 ℃, stirring and reacting for 20min, and entering the next step;
step (3), reaction impurity removal: adding 20g of 5% sodium hydroxide aqueous solution into the step (2), controlling the temperature to 25 ℃, stirring and reacting for 0.5h, converting the impurity C into 8DM through hydrolysis reaction, and sampling and detecting by adopting HPLC at the moment, wherein the content of the impurity C is below 0.15%; filtering, treating the solid material as solid waste, and allowing the liquid material to enter the next step;
step (4), water-dropping crystallization: controlling the temperature of the liquid material obtained in the step (3) to be 50-60 ℃, dripping 1200mL of water for 3.5h, and entering the next step after the dripping is finished;
step (5), cooling and crystallizing: cooling the material obtained in the step (4) to 10 ℃, controlling the temperature for 1h, and entering the next step;
step (6), solid-liquid separation: carrying out solid-liquid separation on the material obtained in the step (5), treating the mother liquor, recovering the reaction solvent, and allowing the solid material to enter the next step;
step (7), vacuum drying: and (3) vacuum drying the solid material obtained in the step (6) at 60 ℃ to obtain the 8DM refined product, wherein the limit of the drying weight loss is 0.15%.
Through detection, 190.0g of 8DM refined product is obtained by adopting the preparation method of the example 3, the refining yield is 95.0 percent, and the appearance is white. The purity of the 8DM refined product is 99.4%, the impurity A is 0.11%, the impurity B is 0.12%, and the impurity C is 0.07%.
Comparative example 1 refining method of 8DM
Comparative example 1 was different from example 1 in that the adsorption copper removal of step (2) was not performed, and other parameters and operations were the same as example 1.
Through detection, 191.2g of 8DM refined product is obtained by adopting the preparation method of comparative example 1, the refining yield is 95.6 percent, and the appearance is grey green. The purity of the 8DM refined product is 99.4%, the impurity A is 0.11%, the impurity B is 0.12%, and the impurity C is 0.12%.
The impurity level of comparative example 1 was substantially uniform, but the appearance was grayish green, as compared with example 1, mainly because copper removal operation was not performed.
Comparative example 2 refining method of 8DM
Comparative example 2 is different from example 3 in that the step (3) reaction is not performed to remove impurities, and other parameters and operations are the same as those of example 3
Through detection, 190.0g of 8DM refined product is obtained by adopting the preparation method of comparative example 2, the refining yield is 95.0%, the appearance is white 8DM refined product with purity of 99.3%, the impurity A is 0.11%, the impurity B is 0.12%, and the impurity C is 0.17%.
Compared with example 3, in comparative example 2, impurity C was not reduced to 0.15% or less, and the remaining index was qualified, mainly because impurity C could not be reduced from 0.2% to 0.15% or less by the solvent crystallization technique, and impurity C was converted into 8DM without the step of removing impurities by reaction.
The above embodiments are merely illustrative of the principles of the present invention and its effectiveness, and are not intended to limit the invention. Modifications and variations may be made to the above-described embodiments by those skilled in the art without departing from the spirit and scope of the invention. Accordingly, it is intended that all equivalent modifications and variations of the invention be covered by the claims, which are within the ordinary skill of the art, be within the spirit and scope of the present disclosure.
Claims (9)
1. The refining method of 8DM is characterized by comprising the following steps:
step (1), stirring and dissolving clear: adding the 8DM crude product into a reaction solvent, controlling the temperature to be 30-60 ℃, stirring and dissolving the crude product, and entering the next step;
step (2), removing copper by adsorption: adding an adsorbent into the step (1), controlling the temperature to be 15-35 ℃, stirring and reacting for 10-30 min, and entering the next step;
step (3), reaction impurity removal: adding an alkaline reagent aqueous solution into the step (2), controlling the temperature to be 25-45 ℃, stirring and reacting for 0.5-2 h, converting the impurity C into 8DM through hydrolysis reaction, filtering, treating solid materials as solid waste, and allowing the liquid materials to enter the next step;
step (4), water-dropping crystallization: controlling the temperature of the liquid material obtained in the step (3) to be 45-65 ℃, dripping water, and entering the next step after the dripping is finished;
step (5), cooling and crystallizing: cooling the material obtained in the step (4) to-10 ℃, controlling the temperature for 1-5 h, and entering the next step;
step (6), solid-liquid separation: carrying out solid-liquid separation on the material obtained in the step (5), treating the mother liquor, recovering the reaction solvent, and allowing the solid material to enter the next step;
step (7), vacuum drying: and (3) vacuum drying the solid material obtained in the step (6) at 55-65 ℃ to obtain 8DM refined product.
2. The method of refining 8DM according to claim 1, wherein the crude 8DM product has a greenish appearance, wherein the impurity A is 0.15% to 0.20%, the impurity B is 0.15% to 0.25%, and the impurity C is 0.2% to 2.0%.
3. The method for purifying 8DM according to claim 1, wherein the reaction equation for converting the impurity C in the crude 8DM product in the step (3) into 8DM is as follows:
4. the method for purifying 8DM according to claim 1, wherein in the step (1), the reaction solvent is at least one of DMF or DMSO;
the volume ratio of the mass of the 8DM crude product to the reaction solvent is 1:6-10, wherein the unit of the mass of the 8DM crude product is g, and the unit of the volume of the reaction solvent is mL.
5. The method for purifying 8DM according to claim 1, wherein in the step (2), the adsorbent is at least one of activated carbon, fly ash, and magnesium silicate;
the mass ratio of the 8DM crude product to the adsorbent is 1:0.01-0.1.
6. The method for purifying 8DM according to claim 1, wherein the aqueous alkaline reagent in the step (3) is at least one of an aqueous sodium hydroxide solution and an aqueous potassium carbonate solution;
the mass concentration of the alkaline reagent aqueous solution is 5% -10%;
the mass ratio of the 8DM crude product to the alkaline reagent aqueous solution is 1:0.1-0.3.
7. The method for purifying 8DM according to claim 1, wherein in the step (4), a mass ratio of the crude 8DM product to water is 1:3 to 10.
8. The method for purifying 8DM according to claim 1, wherein in the step (4), the water is added dropwise for 0.5 to 5.0 hours.
9. The method for purifying 8DM according to claim 1, wherein the weight loss on drying of the 8DM refined product obtained by vacuum drying in step (7) is 0.5% or less.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311078844.3A CN117106005A (en) | 2023-08-25 | 2023-08-25 | Refining method of 8DM |
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