CN114133318A - Method for reducing and removing propofol impurity O in propofol product - Google Patents
Method for reducing and removing propofol impurity O in propofol product Download PDFInfo
- Publication number
- CN114133318A CN114133318A CN202111504251.XA CN202111504251A CN114133318A CN 114133318 A CN114133318 A CN 114133318A CN 202111504251 A CN202111504251 A CN 202111504251A CN 114133318 A CN114133318 A CN 114133318A
- Authority
- CN
- China
- Prior art keywords
- propofol
- impurity
- solvent
- product
- reducing
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- OLBCVFGFOZPWHH-UHFFFAOYSA-N propofol Chemical compound CC(C)C1=CC=CC(C(C)C)=C1O OLBCVFGFOZPWHH-UHFFFAOYSA-N 0.000 title claims abstract description 139
- 229960004134 propofol Drugs 0.000 title claims abstract description 137
- JNTNBZKUWHRIGW-UHFFFAOYSA-N 2-propan-2-yl-6-propylphenol Chemical compound CCCC1=CC=CC(C(C)C)=C1O JNTNBZKUWHRIGW-UHFFFAOYSA-N 0.000 title claims abstract description 75
- 238000000034 method Methods 0.000 title claims abstract description 34
- 239000002904 solvent Substances 0.000 claims abstract description 55
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 41
- 239000007787 solid Substances 0.000 claims abstract description 29
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 17
- 239000013557 residual solvent Substances 0.000 claims abstract description 15
- 238000001914 filtration Methods 0.000 claims abstract description 12
- 239000002798 polar solvent Substances 0.000 claims abstract description 12
- 150000002576 ketones Chemical class 0.000 claims abstract description 10
- 238000001816 cooling Methods 0.000 claims abstract description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 22
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 14
- 238000002425 crystallisation Methods 0.000 claims description 12
- 230000008025 crystallization Effects 0.000 claims description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- 239000003208 petroleum Substances 0.000 claims description 8
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 5
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 3
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 3
- PHTQWCKDNZKARW-UHFFFAOYSA-N isoamylol Chemical compound CC(C)CCO PHTQWCKDNZKARW-UHFFFAOYSA-N 0.000 claims description 3
- MSXVEPNJUHWQHW-UHFFFAOYSA-N 2-methylbutan-2-ol Chemical compound CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 claims description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- 230000001476 alcoholic effect Effects 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 6
- 239000001257 hydrogen Substances 0.000 abstract description 6
- 238000000746 purification Methods 0.000 abstract description 6
- 238000007710 freezing Methods 0.000 abstract description 4
- 230000008014 freezing Effects 0.000 abstract description 4
- 230000000694 effects Effects 0.000 abstract description 3
- 239000012847 fine chemical Substances 0.000 abstract description 2
- 238000003889 chemical engineering Methods 0.000 abstract 1
- 239000000047 product Substances 0.000 description 49
- 238000001514 detection method Methods 0.000 description 9
- 238000007670 refining Methods 0.000 description 9
- 238000004821 distillation Methods 0.000 description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 150000007524 organic acids Chemical class 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 235000005985 organic acids Nutrition 0.000 description 3
- LCHYEKKJCUJAKN-UHFFFAOYSA-N 2-propylphenol Chemical compound CCCC1=CC=CC=C1O LCHYEKKJCUJAKN-UHFFFAOYSA-N 0.000 description 2
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 2
- 239000005456 alcohol based solvent Substances 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 239000004210 ether based solvent Substances 0.000 description 2
- 239000005453 ketone based solvent Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 2
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 229940090248 4-hydroxybenzoic acid Drugs 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 230000003444 anaesthetic effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000003442 catalytic alkylation reaction Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000003631 expected effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000012423 maintenance Methods 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
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/68—Purification; separation; Use of additives, e.g. for stabilisation
- C07C37/70—Purification; separation; Use of additives, e.g. for stabilisation by physical treatment
- C07C37/84—Purification; separation; Use of additives, e.g. for stabilisation by physical treatment by crystallisation
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Crystallography & Structural Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a method for reducing and removing propofol impurity O in a propofol product, and relates to the technical field of pharmaceutical fine chemical engineering. The method for reducing propofol impurity O in a propofol product provided by the invention comprises the following steps: and dissolving the crude propofol product in the first solvent to form a solution, continuously adding a second solvent, cooling, crystallizing, filtering and collecting a solid, and removing the residual solvent in the solid to obtain a finished propofol product. According to the invention, by utilizing the difference of the molecular polarities of propofol and propofol impurity O, an alcohol solvent, an ether solvent, a ketone solvent and an aprotic polar solvent are introduced in the purification process of a crude propofol product, so that a strong hydrogen bond effect is formed between the propofol impurity O and the solvents, and the freezing point of the propofol impurity O is lower than that of propofol, so that the propofol and the propofol impurity O are separated, and the purity of propofol in the finished propofol product is improved.
Description
Technical Field
The invention relates to the technical field of pharmaceutical fine chemical industry, in particular to a method for reducing propofol impurity O in a propofol product.
Background
Propofol is an epoch-making near-ideal short-acting intravenous anesthetic, is used for surgical anesthesia induction and maintenance, is widely used in clinic at home and abroad, and achieves very good social and economic benefits. The preparation process mainly comprises two steps: (1) the method is characterized in that p-hydroxybenzoic acid and isopropanol are used as raw materials and are obtained through sulfuric acid catalytic alkylation and decarboxylation reactions, a large amount of concentrated sulfuric acid is used in the process, the concentrated sulfuric acid cannot be recycled, and the environmental protection pressure is high; (2) the method takes the propyl phenol, the aluminum powder and the propylene as raw materials, and the propyl phenol, the aluminum powder and the propylene are obtained in one step through alkylation reaction, and the process has more byproducts and higher requirements on purification process.
Patent US5175376 discloses a purification method using petroleum ether or n-hexane as a refining solvent, which is a refining purification method commonly used at present. The propofol prepared by the process contains fifteen impurities (see European pharmacopoeia), most of the impurities can be reduced to the limit meeting the requirements after refining, but propofol impurity O (the chemical name is 2-isopropyl-6-propylphenol) and propofol isomer isomers have extremely similar structures, the propofol impurity O and propofol isomer isomers are difficult to effectively reduce by the existing refining process, the content of the propofol impurity O is required to be less than 0.05% by the pharmacopoeia quality standard, and the propofol impurity O can be reduced to meet the requirements after repeated refining is actually required, so that the production period is long, the yield is low, the cost is greatly improved, and a good refining method is urgently needed to be found to reduce the propofol impurity O.
Chinese patent CN202110766075.0 adopts an induced crystallization method, and adds inducer water, organic acid, ethyl acetate and other solvents to induce propofol to generate a fixed crystal form, thereby achieving the purpose of improving refining efficiency. However, water and organic acids have high polarity, so that the organic acids are difficult to be mixed and dissolved with solvents such as petroleum ether, n-hexane and n-heptane propofol which are low in polarity, and part of the organic acids are solid and poor in solubility, so that expected effects are difficult to achieve.
Disclosure of Invention
The invention mainly aims to provide a method for reducing propofol impurity O in a propofol product, and aims to refine propofol by using a refining method designed by the structural difference and the physicochemical property difference of the propofol impurity O and propofol, and reduce the propofol impurity O, so that propofol refining is realized.
In order to achieve the aim, the invention provides a method for reducing propofol impurity O in a propofol product, which comprises the following steps: dissolving the crude propofol product in a first solvent to form a solution, continuously adding a second solvent, cooling, crystallizing, filtering, collecting a solid, and removing residual solvent in the solid to obtain a finished propofol product, wherein the second solvent is at least one of an alcohol solvent, an ether solvent, a ketone solvent and an aprotic polar solvent.
The propofol (molecular structure shown as formula I) and the propofol impurity O (molecular structure shown as formula II) are similar in chemical structure, and the difference is that substituent groups on one side of a benzene ring are different, the propofol impurity O is n-propyl, and the propofol is isopropyl. The boiling point of the propofol impurity O is higher than that of propofol, and the freezing point is lower than that of propofol; and the polarity of the propofol impurity O is slightly larger than that of propofol, and one side of the propofol impurity O is similar to a linear phenolic hydroxyl group and is easier to form a hydrogen bond with hydroxyl-containing compounds such as alcohol and the like according to the similar phase dissolution principle.
The alcohol solvent, ether solvent, ketone solvent and aprotic polar solvent can be dissolved in petroleum ether, n-hexane and n-heptane, and are ideal solvents. And groups capable of forming hydrogen bonds with phenolic hydroxyl groups exist in alcohol solvents, ether solvents, ketone solvents and aprotic polar solvents. Due to the influence of steric hindrance, the polarity of propofol impurity O is slightly larger than that of propofol, and phenolic hydroxyl of propofol impurity O is easier to form hydrogen bonds with special groups in alcohol solvents, ether solvents, ketone solvents and aprotic polar solvents, so that propofol impurity O is less prone to crystallization at low temperature and is further retained in the solvents to achieve the purpose of separation and removal.
The technical scheme of the invention is just to utilize the difference of propofol and propofol impurity O, in the purification process of the crude propofol product, the crude propofol product is firstly dissolved in a first solvent, and then a second solvent (namely an alcohol solvent, an ether solvent, a ketone solvent and an aprotic polar solvent) is introduced, so that a strong hydrogen bonding effect is formed between the propofol impurity O and the alcohol solvent, the ether solvent, the ketone solvent and the aprotic polar solvent, and the propofol impurity O is separated because the freezing point of the propofol impurity O is lower than that of propofol, so that the content of the propofol impurity O in the propofol finished product is reduced, and the purity of propofol in the propofol finished product is improved.
As a preferred embodiment of the method for removing propofol impurity O from a propofol product, the ratio of the mass of the crude propofol product to the volume of the second solvent is 100: (3-10).
The inventors have found through extensive experiments that when the ratio of the mass of the crude propofol (in g) to the volume of the second solvent (in ml) is 100: (3-10), the yield of the finished propofol product can reach a high level (77-89%), and the content of propofol in the prepared finished propofol product can reach a high level.
As a preferred embodiment of the method for reducing the propofol impurity O in the propofol product, the alcoholic solvent is at least one of methanol, ethanol, isopropanol, n-propanol, propylene glycol, n-butanol, n-pentanol, isoamyl alcohol and tert-pentanol; the ether solvent is at least one of diethyl ether, isopropyl ether and methyl tert-butyl ether; the ketone solvent is at least one of acetone, methyl ethyl ketone and methyl isobutyl ketone; the aprotic polar solvent is at least one of dimethyl sulfoxide, N-dimethylformamide and N, N-dimethylacetamide.
As a preferable embodiment of the method for reducing the propofol impurity O in the propofol product, the first solvent is at least one of petroleum ether, n-hexane and n-heptane.
In the technical scheme of the invention, the first solvent is used for dissolving the crude propofol.
As a preferred embodiment of the method for reducing propofol impurity O in a propofol product, the solvent remaining in the reduced solid is specifically: the solid was melted and the residual solvent was distilled off.
As a preferred embodiment of the method for reducing the propofol impurity O in the propofol product, the temperature in the cooling crystallization process is not higher than-10 ℃.
As a preferred embodiment of the method for reducing propofol impurity O in a propofol product, the content of propofol in the propofol finished product is 99.7-99.9%, and the content of propofol impurity O in the propofol finished product is 0.01-0.04%.
Compared with the prior art, the invention has the beneficial effects that:
(1) according to the technical scheme, by utilizing the difference of the molecular polarities of propofol and propofol impurity O, in the purification process of a crude propofol product, the crude propofol product is dissolved in a first solvent, and then a second solvent (namely an alcohol solvent, an ether solvent, a ketone solvent and an aprotic polar solvent) is introduced, so that a strong hydrogen bonding effect is formed between the propofol impurity O and the alcohol solvent, the ether solvent, the ketone solvent and the aprotic polar solvent, and the freezing point of the propofol impurity O is lower than that of propofol, so that the propofol and the propofol impurity O are separated, and the purity of propofol in a finished propofol product is improved;
(2) the yield of the propofol finished product prepared by the technical scheme of the invention is 77-89%, the content of propofol in the propofol finished product is 99.7-99.9%, and the content of propofol impurity O in the propofol finished product is 0.01-0.04%.
Drawings
FIG. 1 is a high performance liquid chromatogram of a crude propofol product from example 1;
FIG. 2 is a high performance liquid chromatogram of the finished propofol product of example 1.
Detailed Description
To better illustrate the objects, aspects and advantages of the present invention, the present invention will be further described with reference to the following specific examples.
Example 1
Dissolving 1kg of crude propofol (the content of propofol is 97.3 percent, and the content of propofol impurity O is 0.7 percent) in 400ml of n-heptane to form a solution, adding 100ml of methanol into the solution, cooling to below-20 ℃, crystallizing for 12 hours, filtering and collecting solids, melting the solids, and distilling to remove residual solvent to obtain 780g of propofol finished product.
The yield of the finished propofol in this example is 78%. Through detection, the content of propofol in a finished product of propofol is 99.7%, and the content of propofol impurity O is 0.04%.
As can be seen from fig. 1 and 2, the number of impurity peaks in fig. 1 is significantly higher than that in fig. 2, indicating that the impurity species in the propofol finished product are significantly reduced. And the intensity of the characteristic peak of the propofol impurity O is obviously reduced in figure 2, which shows that the content of the propofol impurity O in the propofol finished product is greatly reduced.
Example 2
1kg of crude propofol (the content of propofol is 96.8 percent, and the content of propofol impurity O is 0.9 percent) is dissolved in 400ml of petroleum ether to form a solution, 60ml of ethanol is continuously added into the solution, the solution is cooled to below-10 ℃ for crystallization for 24 hours, the solid is collected by filtration, the solid is melted and the residual solvent is removed by distillation, and 890g of finished propofol product is obtained.
The yield of the finished propofol in this example is 89%. Through detection, the content of propofol in a finished product of propofol is 99.7%, and the content of propofol impurity O is 0.03%.
Example 3
1kg of crude propofol (the content of propofol is 97.6 percent, and the content of propofol impurity O is 0.4 percent) is dissolved in 350ml of n-hexane to form a solution, 40ml of isopropanol is continuously added into the solution, the solution is cooled to the temperature below minus 20 ℃ for crystallization for 12 hours, the solid is collected by filtration, the solid is melted and the residual solvent is removed by distillation, and 850g of finished propofol product is obtained.
The yield of the finished propofol in this example is 85%. Through detection, the content of propofol in a finished product of propofol is 99.8%, and the content of propofol impurity O is 0.03%.
Example 4
1kg of crude propofol (the content of propofol is 98.1 percent, and the content of propofol impurity O is 0.3 percent) is dissolved in 300ml of petroleum ether to form a solution, 30ml of ether is continuously added into the solution, the solution is cooled to below-15 ℃ for crystallization for 20 hours, solid is collected by filtration, the solid is melted and residual solvent is removed by distillation, and 830g of finished propofol product is obtained.
The yield of the finished propofol in this example is 83%. Through detection, the content of propofol in a finished product of propofol is 99.7%, and the content of propofol impurity O is 0.02%.
Example 5
1kg of crude propofol (the content of propofol is 98.5 percent, and the content of propofol impurity O is 0.2 percent) is dissolved in 350ml of n-heptane to form a solution, 80ml of methyl tert-butyl ether is continuously added into the solution, the solution is cooled to the temperature below minus 20 ℃ for crystallization for 18 hours, the solid is collected by filtration, the solid is melted and the residual solvent is removed by distillation, and 880g of propofol finished product is obtained.
The yield of the finished propofol in this example is 88%. Through detection, the content of propofol in a finished product of propofol is 99.9%, and the content of propofol impurity O is 0.01%.
Example 6
1kg of crude propofol (the content of propofol is 96.6 percent, and the content of propofol impurity O is 0.7 percent) is dissolved in 300ml of n-hexane to form a solution, 50ml of acetone is continuously added into the solution, the solution is cooled to below-10 ℃ for crystallization for 24 hours, solid is collected by filtration, the solid is melted and residual solvent is removed by distillation, and 810g of finished propofol product is obtained.
The yield of the finished propofol in this example is 81%. Through detection, the content of propofol in a finished product of propofol is 99.7%, and the content of propofol impurity O is 0.04%.
Example 7
1kg of crude propofol (the content of propofol is 97.9 percent, and the content of propofol impurity O is 0.5 percent) is dissolved in 300ml of petroleum ether to form a solution, 40ml of methyl isobutyl ketone is continuously added into the solution, the solution is cooled to below-10 ℃ for crystallization for 24 hours, the solid is collected by filtration, the solid is melted and the residual solvent is removed by distillation, and 850g of finished propofol product is obtained.
The yield of the finished propofol in this example is 85%. Through detection, the content of propofol in a finished product of propofol is 99.8%, and the content of propofol impurity O is 0.03%.
Example 8
1kg of crude propofol (the content of propofol is 97.2 percent, and the content of propofol impurity O is 0.6 percent) is dissolved in 400ml of n-heptane to form a solution, 30ml of dimethyl sulfoxide is continuously added into the solution, the solution is cooled to the temperature below minus 20 ℃ for crystallization for 12 hours, the solid is collected by filtration, the solid is melted and the residual solvent is removed by distillation, and 770g of finished propofol product is obtained.
The yield of the finished propofol in this example is 77%. Through detection, the content of propofol in a finished product of propofol is 99.8%, and the content of propofol impurity O is 0.03%.
Example 9
1kg of crude propofol (the content of propofol is 97.8 percent, and the content of propofol impurity O is 0.4 percent) is dissolved in 300ml of N-heptane to form a solution, 30ml of N, N-dimethylformamide is continuously added into the solution, the solution is cooled to the temperature below 20 ℃ below zero for crystallization for 12 hours, the solid is collected by filtration, the solid is melted and the residual solvent is removed by distillation, and 790g of propofol finished product is obtained.
The yield of the finished propofol in this example is 79%. Through detection, the content of propofol in a finished product of propofol is 99.8%, and the content of propofol impurity O is 0.03%.
Finally, it should be noted that the above embodiments are only used for illustrating the technical solutions of the present invention and not for limiting the protection scope of the present invention, and although the present invention is described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention.
Claims (10)
1. A method for reducing propofol impurity O in a propofol product is characterized by comprising the following steps: dissolving the crude propofol product in a first solvent to form a solution, continuously adding a second solvent, cooling, crystallizing, filtering, collecting a solid, and removing residual solvent in the solid to obtain a finished propofol product, wherein the second solvent is at least one of an alcohol solvent, an ether solvent, a ketone solvent and an aprotic polar solvent.
2. The method for reducing propofol impurity O in a propofol product as claimed in claim 1, wherein, the ratio of the mass of said crude propofol product to the volume of said second solvent is 100: (3-10).
3. The method for reducing propofol impurity O in a propofol product according to claim 1, wherein said alcoholic solvent is at least one of methanol, ethanol, isopropanol, n-propanol, propylene glycol, n-butanol, n-pentanol, isopentanol, and tert-pentanol.
4. The method for reducing propofol impurity O in propofol product according to claim 1, wherein said ethereal solvent is at least one of ethyl ether, isopropyl ether and methyl tert-butyl ether.
5. The method for reducing propofol impurity O in a propofol product as claimed in claim 1, wherein said ketone solvent is at least one of acetone, methyl ethyl ketone and methyl isobutyl ketone.
6. The method for reducing propofol impurity O in a propofol product according to claim 1, wherein said aprotic polar solvent is at least one of dimethylsulfoxide, N-dimethylformamide and N, N-dimethylacetamide.
7. The method for reducing propofol impurity O in a propofol product according to claim 1, wherein said first solvent is at least one of petroleum ether, n-hexane and n-heptane.
8. The method for reducing propofol impurity O in propofol products as claimed in claim 1, wherein, the residual solvent in said reduced solid is specifically: the solid was melted and the residual solvent was distilled off.
9. The method for reducing propofol impurity O in propofol product according to claim 1, wherein, the temperature during said cooling crystallization is not higher than-10 ℃.
10. The method for reducing propofol impurity O in a propofol product as claimed in claim 1, wherein, propofol content in said finished propofol product is 99.7-99.9%, and propofol impurity O content in said finished propofol product is 0.01-0.04%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111504251.XA CN114133318B (en) | 2021-12-09 | 2021-12-09 | Method for reducing and removing propofol impurity O in propofol product |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111504251.XA CN114133318B (en) | 2021-12-09 | 2021-12-09 | Method for reducing and removing propofol impurity O in propofol product |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114133318A true CN114133318A (en) | 2022-03-04 |
| CN114133318B CN114133318B (en) | 2023-08-29 |
Family
ID=80385537
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202111504251.XA Active CN114133318B (en) | 2021-12-09 | 2021-12-09 | Method for reducing and removing propofol impurity O in propofol product |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114133318B (en) |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5175376A (en) * | 1991-04-30 | 1992-12-29 | Leiras Oy | Process for the purification of 2,6-diisopropyl phenol |
| US5696300A (en) * | 1994-07-01 | 1997-12-09 | Archimica Spa | Propofol purification |
| US20030094417A1 (en) * | 2001-10-31 | 2003-05-22 | Snoble Karel A.J. | Purification of organic solvents |
| WO2006071995A1 (en) * | 2004-12-23 | 2006-07-06 | Xenoport, Inc. | Serine amino acid derived prodrugs of propofol, compositions, uses and crystalline forms thereof |
| US20130316976A1 (en) * | 2011-02-04 | 2013-11-28 | Norbert Roewer | Pharmaceutical preparation |
| CN108530269A (en) * | 2018-04-11 | 2018-09-14 | 南安市创培电子科技有限公司 | A kind of production method of high-purity propofol |
| CN113372198A (en) * | 2021-07-06 | 2021-09-10 | 山东威高药业股份有限公司 | Refining method of high-purity propofol |
-
2021
- 2021-12-09 CN CN202111504251.XA patent/CN114133318B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5175376A (en) * | 1991-04-30 | 1992-12-29 | Leiras Oy | Process for the purification of 2,6-diisopropyl phenol |
| US5696300A (en) * | 1994-07-01 | 1997-12-09 | Archimica Spa | Propofol purification |
| US20030094417A1 (en) * | 2001-10-31 | 2003-05-22 | Snoble Karel A.J. | Purification of organic solvents |
| WO2006071995A1 (en) * | 2004-12-23 | 2006-07-06 | Xenoport, Inc. | Serine amino acid derived prodrugs of propofol, compositions, uses and crystalline forms thereof |
| US20130316976A1 (en) * | 2011-02-04 | 2013-11-28 | Norbert Roewer | Pharmaceutical preparation |
| CN108530269A (en) * | 2018-04-11 | 2018-09-14 | 南安市创培电子科技有限公司 | A kind of production method of high-purity propofol |
| CN113372198A (en) * | 2021-07-06 | 2021-09-10 | 山东威高药业股份有限公司 | Refining method of high-purity propofol |
Non-Patent Citations (4)
| Title |
|---|
| CHINMOY PRAMANIK ET AL.: "Commercial Manufacturing of Propofol: Simplifying the Isolation Process and Control on Related Substances", 《ORG. PROCESS RES. DEV》, vol. 18, pages 152 - 156, XP055814724, DOI: 10.1021/op400300t * |
| YIYAN WANG ET AL.: "Propofol Inhibits Androgen Production in Rat Immature Leydig Cells", 《PROPOFOL INHIBITS ANDROGEN PRODUCTION》, vol. 10, pages 1 - 14 * |
| 刁文瑞: "丙泊酚杂质的研究", 《医学信息》, vol. 26, no. 7, pages 470 - 471 * |
| 陈洪;: "丙泊酚的合成工艺改进", 药学研究, no. 06, pages 325 - 329 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN114133318B (en) | 2023-08-29 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US9126917B2 (en) | Method for purifying vanillin by liquid-liquid extraction | |
| CN113072434B (en) | Method for preparing cyclopropyl methyl ketone by one-step method | |
| CN114133318B (en) | Method for reducing and removing propofol impurity O in propofol product | |
| CN106478339B (en) | Method for separating cyclopentane and 2, 2-dimethylbutane | |
| CN113292409A (en) | Method for separating high-purity 2-methyl-6-acylnaphthalene and 2-methyl-7-acylnaphthalene and application of rectification in method | |
| CN107759467B (en) | Preparation method for improving carnosic acid content in rosemary lipid-soluble antioxidant | |
| CN113372198B (en) | Refining method of high-purity propofol | |
| CN113429283B (en) | Method for recovering phenylacetic acid from medical wastewater | |
| CN105348046B (en) | Method for recovering 4-cumylphenol from phenol tar | |
| CN113831226A (en) | Method for recovering phenol and acetophenone in phenol tar | |
| CN109289930B (en) | Method for efficiently separating and purifying 1-methylnaphthalene | |
| CN114105812A (en) | Method for synthesizing N, N' -bis (salicylidene) -1, 2-propane diamine by using chloropropene byproduct 1, 2-dichloropropane | |
| CN113582850A (en) | Method for purifying 2, 4-dinitrochlorobenzene | |
| CN101575262A (en) | Method for reducing content of 2-methylnaphthalene impurity | |
| CN114805035B (en) | Method for purifying 4,4' -biphenol | |
| CN111302908B (en) | Method for extracting and separating triethylene glycol and triethylene glycol monomethyl ether by using supercritical carbon dioxide | |
| CN110627802A (en) | Method for extracting sesame lignan from by-product generated in sesame oil production | |
| CN105218313A (en) | Containing the methyl alcohol purification process of acetaldehyde impurities | |
| CN114736103B (en) | Method for separating propyl guaiacol and propyl syringol from lignin oil | |
| JP3832837B2 (en) | Method for producing 3,3 ', 5,5'-tetraalkyl-4,4'-biphenol | |
| CN102746148A (en) | Method for purifying dimethyl succinate | |
| CN110407667B (en) | Preparation method of alkoxy aluminum | |
| CN114685402A (en) | Method for preparing high-quality diketene by eutectic crystallization method | |
| CN107459459B (en) | Method for extracting methyl stearate from benzoyl methane stearate residual liquid | |
| CN106608808B (en) | Method for refining 2, 6-diisopropyl naphthalene |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: A method for reducing impurity O in propofol products Effective date of registration: 20231130 Granted publication date: 20230829 Pledgee: Industrial and Commercial Bank of China Co.,Ltd. Qingyuan Economic Development Zone Sub branch Pledgor: GUANGDONG JIABO PHARMACEUTICAL Co.,Ltd. Registration number: Y2023980068637 |
|
| PE01 | Entry into force of the registration of the contract for pledge of patent right |