CN114133318B - 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
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- CN114133318B CN114133318B CN202111504251.XA CN202111504251A CN114133318B CN 114133318 B CN114133318 B CN 114133318B CN 202111504251 A CN202111504251 A CN 202111504251A CN 114133318 B CN114133318 B CN 114133318B
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- 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
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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 industry. The method for reducing and removing the propofol impurity O in the propofol product provided by the invention 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 solid, and removing the residual solvent in the solid to obtain a propofol finished product. According to the invention, by utilizing the molecular polarity difference of the propofol and the propofol impurity O, in the purification process of the crude propofol, an alcohol solvent, an ether solvent, a ketone solvent and an aprotic polar solvent are introduced, so that a strong hydrogen bond effect is formed between the propofol impurity O and the solvents, and the propofol impurity O is separated from the propofol impurity O because the solidifying point of the propofol impurity O is lower than that of the propofol, so that the purity of the propofol in the propofol finished 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 and removing propofol impurity O in a propofol product.
Background
Propofol is an epoch-making short-acting intravenous anesthetic which is close to ideal, is used for the induction and maintenance of surgical anesthesia, is widely used in clinic at home and abroad, and achieves good social benefit and economic benefit. The preparation process mainly comprises two steps: (1) The process is obtained by using p-hydroxybenzoic acid and isopropanol as raw materials and carrying out sulfuric acid catalytic alkylation and decarboxylation reaction, and the process needs a large amount of concentrated sulfuric acid, cannot be recycled and has high environmental protection pressure; (2) The propofol, aluminum powder and propylene are used as raw materials, and are obtained through alkylation reaction in one step, so that more byproducts and higher purification process requirements are achieved.
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 through refining, but the propofol impurity O (chemical name is 2-isopropyl-6-propylphenol) and the propofol isomer have extremely similar structures, the existing refining process is difficult to effectively reduce the propofol impurity O, the content of the propofol impurity O is required to be less than 0.05% by the quality standard of the pharmacopoeia, and the propofol impurity O can be reduced to the limit meeting the requirements only through repeated refining for a plurality of times, so that the production period is long, the yield is low, and the cost is greatly improved.
Chinese patent CN202110766075.0 adopts an induced crystallization method, and inducer water, organic acid, ethyl acetate and other solvents are added to induce propofol to produce a fixed crystal form, so as to achieve the purpose of improving refining efficiency. However, because of the large polarity of water and organic acid, the organic acid is difficult to be mixed with weak polar substances such as petroleum ether, n-hexane, n-heptane-propofol and the like, and part of the organic acid is solid, the solubility is poor, and the expected effect is difficult to be achieved.
Disclosure of Invention
The invention mainly aims to provide a method for reducing and removing propofol impurity O in a propofol product, which aims to refine the propofol by utilizing the structural difference and physicochemical property difference of the propofol impurity O and the propofol to design a refining method, so that the propofol impurity O is reduced and removed, and the refining of the propofol is realized.
In order to achieve the above object, the present invention provides a method for reducing and removing propofol impurity O in a propofol product, comprising the steps of: dissolving the crude propofol in a first solvent to form a solution, continuously adding a second solvent, cooling, crystallizing, filtering, collecting solid, and removing residual solvent in the solid to obtain a propofol finished 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 chemical structure of the propofol (the molecular structure is shown as a formula I) is similar to that of the propofol impurity O (the molecular structure is shown as a formula II), and the difference is that substituents 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; according to the principle of similar compatibility, one side of the phenolic hydroxyl group similar to a linear phenolic hydroxyl group is easier to form a hydrogen bond with a hydroxyl-containing compound such as alcohol, and the theory speculates that the mixed solvent containing the linear alcohol, ether, ketone and the like is used for recrystallizing the propofol, so that the impurity O is easy to remain in a mother solution to separate the propofol from the propofol, and the propofol is further purified.
Alcohol solvents, ether solvents, ketone solvents and aprotic polar solvents 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. Under the influence of steric hindrance, the polarity of the propofol impurity O is slightly larger than that of propofol, and the phenolic hydroxyl groups of the propofol impurity O are more prone to form hydrogen bonds with special groups in alcohol solvents, ether solvents, ketone solvents and aprotic polar solvents, so that the propofol impurity O is not prone to crystallization at low temperature, and further remains in the solvents to achieve the purpose of separation and reduction.
According to the technical scheme, the difference between the propofol and the propofol impurity O is utilized, in the purification process of the propofol crude product, the propofol crude product is firstly dissolved in a first solvent, then a second solvent (namely an alcohol solvent, an ether solvent, a ketone solvent and an aprotic polar solvent) is introduced, so that a stronger hydrogen bond 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 from the propofol impurity O because the solidifying point of the propofol impurity O is lower than that of the propofol, the content of the propofol impurity O in the propofol finished product is reduced, and the purity of the propofol in the propofol finished product is improved.
As a preferred embodiment of the method for removing propofol impurity O in a propofol product of the present invention, 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 a number of experiments that when the ratio of the mass (in g) of the crude propofol product to the volume (in ml) of the second solvent is 100: and (3-10), the yield of the finished product of the propofol can reach a higher level (the yield is 77-89%), and the content of the propofol in the prepared finished product of the propofol reaches a higher level.
As a preferred embodiment of the method for reducing the propofol impurity O in the propofol product of the present invention, the alcohol solvent is at least one of methanol, ethanol, isopropanol, n-propanol, propylene glycol, n-butanol, n-pentanol, isopentanol and tert-pentanol; the ether solvent is at least one of diethyl ether, isopropyl ether and methyl tertiary 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 preferred embodiment of the method for removing propofol impurity O in a propofol product according to the present invention, 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 product of the propofol.
As a preferred embodiment of the method for removing propofol impurity O in a propofol product of the present invention, the solvent remaining in the removed solids is specifically: the solid was melted and the residual solvent was distilled off.
As a preferred embodiment of the method for removing propofol impurity O in a propofol product of the present invention, the temperature during the cooling crystallization is not higher than-10 ℃.
As a preferred embodiment of the method for reducing the propofol impurity O in the propofol product, the content of the propofol in the propofol product is 99.7-99.9%, and the content of the propofol impurity O in the propofol product is 0.01-0.04%.
Compared with the prior art, the invention has the beneficial effects that:
(1) According to the technical scheme, the molecular polarity difference of the propofol and the propofol impurity O is utilized, in the purification process of the propofol crude product, the propofol crude 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 stronger hydrogen bond 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 solidifying point of the propofol impurity O is lower than that of the propofol, so that the propofol and the propofol impurity O are separated, and the purity of the propofol in a propofol finished product is improved;
(2) The yield of the finished product of the propofol prepared by the technical scheme of the invention is 77-89%, the content of the propofol in the finished product of the propofol is 99.7-99.9%, and the content of the propofol impurity O in the finished product of the propofol is 0.01-0.04%.
Drawings
FIG. 1 is a high performance liquid chromatogram of crude propofol in example 1;
fig. 2 is a high performance liquid chromatogram of the propofol final product of example 1.
Detailed Description
For a better description of the objects, technical solutions and advantages of the present invention, the present invention will be further described by means of specific examples.
Example 1
1kg of crude propofol product (the content of propofol is 97.3 percent, and the content of propofol impurity O is 0.7 percent) is taken and dissolved in 400ml of n-heptane to form a solution, 100ml of methanol is continuously added into the solution, the solution is cooled to below-20 ℃ for crystallization for 12 hours, the solid is filtered and collected, and 780g of propofol finished product is obtained by melting and distilling the solid to remove residual solvent.
The yield of the finished propofol product in this example was 78%. The detection shows that the content of the propofol in the propofol finished product is 99.7%, and the content of the 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 product is significantly reduced. And the characteristic peak intensity of the propofol impurity O in the figure 2 is obviously reduced, which shows that the content of the propofol impurity O in the propofol finished product is greatly reduced.
Example 2
1kg of crude propofol product (the content of propofol is 96.8 percent, and the content of propofol impurity O is 0.9 percent) is taken and 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 filtered and collected, and the solid is melted and distilled to remove residual solvent, so as to obtain 890g of propofol finished product.
The yield of the finished propofol product in this example was 89%. The detection shows that the content of the propofol in the propofol finished product is 99.7%, and the content of the propofol impurity O is 0.03%.
Example 3
1kg of crude propofol product (the content of propofol is 97.6%, and the content of propofol impurity O is 0.4%) is taken and dissolved in 350ml of normal hexane to form a solution, 40ml of isopropanol is continuously added into the solution, the solution is cooled to below-20 ℃ for crystallization for 12 hours, the solid is collected by filtration, and the solid is melted and distilled to remove residual solvent, so that 850g of propofol finished product is obtained.
The yield of the finished propofol product in this example was 85%. The detection shows that the content of the propofol in the propofol finished product is 99.8%, and the content of the propofol impurity O is 0.03%.
Example 4
1kg of crude propofol product (the content of propofol is 98.1 percent, and the content of propofol impurity O is 0.3 percent) is taken and dissolved in 300ml of petroleum ether to form a solution, 30ml of diethyl ether is continuously added into the solution, the solution is cooled to below-15 ℃ for crystallization for 20 hours, the solid is filtered and collected, and the solid is melted and distilled to remove residual solvent, so that 830g of propofol finished product is obtained.
The yield of the propofol finished product in this example was 83%. The detection shows that the content of the propofol in the propofol finished product is 99.7%, and the content of the propofol impurity O is 0.02%.
Example 5
1kg of crude propofol product (the content of propofol is 98.5%, and the content of propofol impurity O is 0.2%) is taken and dissolved in 350ml of n-heptane to form a solution, 80ml of methyl tertiary butyl ether is continuously added into the solution, the solution is cooled to below-20 ℃ for crystallization for 18 hours, the solid is collected by filtration, and 880g of propofol finished product is obtained by melting and distilling the solid to remove residual solvent.
The yield of the finished propofol product in this example was 88%. The detection shows that the content of the propofol in the propofol finished product is 99.9%, and the content of the propofol impurity O is 0.01%.
Example 6
1kg of crude propofol product (the content of propofol is 96.6 percent, and the content of propofol impurity O is 0.7 percent) is taken and dissolved in 300ml of normal 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, the solid is filtered and collected, and the solid is melted and distilled to remove residual solvent, so that 810g of propofol finished product is obtained.
The yield of the propofol finished product in this example was 81%. The detection shows that the content of the propofol in the propofol finished product is 99.7%, and the content of the propofol impurity O is 0.04%.
Example 7
1kg of crude propofol product (the content of propofol is 97.9%, and the content of propofol impurity O is 0.5%) is taken and 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, and the solid is melted and distilled to remove residual solvent, so that 850g of propofol finished product is obtained.
The yield of the finished propofol product in this example was 85%. The detection shows that the content of the propofol in the propofol finished product is 99.8%, and the content of the propofol impurity O is 0.03%.
Example 8
1kg of crude propofol product (the content of propofol is 97.2 percent, and the content of propofol impurity O is 0.6 percent) is taken and 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 below-20 ℃ for crystallization for 12 hours, the solid is collected by filtration, and the solid is melted and distilled to remove residual solvent, so as to obtain 770g of propofol finished product.
The yield of the finished propofol product in this example was 77%. The detection shows that the content of the propofol in the propofol finished product is 99.8%, and the content of the propofol impurity O is 0.03%.
Example 9
1kg of crude propofol (the content of propofol is 97.8%, and the content of propofol impurity O is 0.4%) is taken and 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 below-20 ℃ for crystallization for 12 hours, the solid is collected by filtration, and the solid is melted and distilled to remove residual solvent, thus 790g of propofol finished product is obtained.
The yield of the finished propofol product in this example was 79%. The detection shows that the content of the propofol in the propofol finished product is 99.8%, and the content of the propofol impurity O is 0.03%.
Finally, it should be noted that the above embodiments are only for illustrating the technical solution of the present invention and not for limiting the scope of the present invention, and although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that the technical solution of the present invention may be modified or substituted equally without departing from the spirit and scope of the technical solution of the present invention.
Claims (8)
1. A method for reducing and removing propofol impurity O in a propofol product, comprising the steps of: dissolving the crude propofol product in a first solvent to form a solution, continuously adding a second solvent, cooling, crystallizing, filtering, collecting solids, and removing residual solvents in the solids to obtain a propofol finished product, wherein the first solvent is at least one of petroleum ether, n-hexane and n-heptane; the second solvent is at least one of an alcohol solvent, an ether solvent, a ketone solvent and an aprotic polar solvent; the aprotic polar solvent is at least one of dimethyl sulfoxide, N-dimethylformamide and N, N-dimethylacetamide.
2. The method for removing propofol impurity O from a propofol product of claim 1, wherein the ratio of the mass of crude propofol to the volume of the second solvent is 100: (3-10).
3. The method for removing propofol impurity O from a propofol product of claim 1, wherein the 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 removing propofol impurity O from a propofol product as claimed in claim 1 wherein, the ether solvent is at least one of diethyl ether, isopropyl ether and methyl tertiary butyl ether.
5. The method for removing propofol impurity O from a propofol product of claim 1, wherein the ketone solvent is at least one of acetone, methyl ethyl ketone, and methyl isobutyl ketone.
6. The method for reducing the propofol impurity O in a propofol product as claimed in claim 1 wherein, the residual solvent in the solids reducing means is specifically: the solid was melted and the residual solvent was distilled off.
7. The method for removing propofol impurity O from a propofol product as claimed in claim 1 wherein, the temperature during cooling crystallization is not higher than-10 o C。
8. The method for reducing the amount of propofol impurity O in a propofol product of claim 1, wherein the amount of propofol in the propofol product is from 99.7 to 99.9%, and wherein the amount of propofol impurity O in the propofol product is from 0.01 to 0.04%.
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Citations (5)
| 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 |
| WO2006071995A1 (en) * | 2004-12-23 | 2006-07-06 | Xenoport, Inc. | Serine amino acid derived prodrugs of propofol, compositions, uses and crystalline forms thereof |
| 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 |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7514588B2 (en) * | 2001-10-31 | 2009-04-07 | Honeywell International Inc. | Purification of organic solvents |
| EP2484350B1 (en) * | 2011-02-04 | 2016-04-20 | Roewer, Norbert, Univ.-Prof. Dr. med. | Pharmaceutical preparation containing a complex of a salt of propofol and a cyclodextrin |
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2021
- 2021-12-09 CN CN202111504251.XA patent/CN114133318B/en active Active
Patent Citations (5)
| 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 |
| WO2006071995A1 (en) * | 2004-12-23 | 2006-07-06 | Xenoport, Inc. | Serine amino acid derived prodrugs of propofol, compositions, uses and crystalline forms thereof |
| 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 (1)
| Title |
|---|
| 丙泊酚的合成工艺改进;陈洪;;药学研究(第06期);第325-329页 * |
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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 |