CN114456097A - Oseltamivir warning structure impurity and preparation method thereof - Google Patents
Oseltamivir warning structure impurity and preparation method thereof Download PDFInfo
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- CN114456097A CN114456097A CN202210165739.2A CN202210165739A CN114456097A CN 114456097 A CN114456097 A CN 114456097A CN 202210165739 A CN202210165739 A CN 202210165739A CN 114456097 A CN114456097 A CN 114456097A
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- C07D203/00—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom
- C07D203/26—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
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- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
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- G—PHYSICS
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N2030/022—Column chromatography characterised by the kind of separation mechanism
- G01N2030/027—Liquid chromatography
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
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Abstract
The invention discloses an oseltamivir warning structure impurity and a preparation method thereof, wherein the oseltamivir warning structure impurity is shown as a formula I. The preparation method disclosed by the invention is low in cost and simple and convenient to operate, can be synthesized in a large quantity, and provides a reference substance for qualitative and quantitative analysis of oseltamivir warning structure impurities, so that a foundation is laid for quality research of oseltamivir bulk drugs and related preparations.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and relates to a preparation method of an antiviral drug oseltamivir impurity.
Background
Oseltamivir (Oseltamivir) is a specific inhibitor acting on neuraminidase, can inhibit the action of neuraminidase, can inhibit mature influenza viruses from escaping from host cells, and thus can inhibit the transmission of the influenza viruses in human bodies to play a role in treating influenza. Oseltamivir is a successful case of reasonable drug design based on a structure, a large number of means of computer-aided drug design are applied in the research and development process of the drug, and a neuraminidase inhibitor with high efficiency, low toxicity and strong specificity is purposefully designed according to the three-dimensional structure of a target enzyme.
Patent CN1759093A reports the synthetic route of oseltamivir as follows:
wherein, the compound 4 can generate warning structure impurities by hydrolysis in the subsequent synthesis process.
The warning structure impurities in the medicine are usually determined to be in ppm level according to the maximum daily dose, and the existence of the warning structure impurities greatly increases the safe medication risk, so that the quality of the bulk drugs and related preparations is effectively controlled by directionally preparing the target impurities and establishing a corresponding analysis and detection method.
Disclosure of Invention
According to the usual ester hydrolysis method (see comparative example 1), the yield is low and the warning structure impurity of the present invention cannot be obtained in high purity.
The invention provides an oseltamivir warning structure impurity (shown in a formula I) and a preparation method with high yield and high purity.
In one aspect, the invention provides an oseltamivir warning structure impurity, wherein the oseltamivir warning structure impurity is shown as a formula I:
on the other hand, the preparation method of the oseltamivir warning structure impurity comprises the following steps:
1) dissolving the compound represented by the formula II in a lower alkanol or an aqueous solution of a lower alkanol with stirring
2) And adding sodium hydroxide or potassium hydroxide, and performing hydrolysis reaction at a temperature not higher than room temperature to obtain the oseltamivir warning structure impurity shown in the formula I.
In an embodiment of the present invention, the lower alkanol is one or a mixture of two or more of methanol, ethanol and isopropanol, preferably ethanol.
In an embodiment of the present invention, the aqueous solution of the lower alkanol is one or a mixture of two or more of an aqueous methanol solution, an aqueous ethanol solution and an aqueous isopropanol solution, preferably, an aqueous ethanol solution; the concentration of the aqueous solution may be from 50% v/v to 99% v/v.
In an embodiment of the invention, the sodium hydroxide or potassium hydroxide is added in the form of an aqueous solution, e.g. at a concentration of 5% w/w to 25% w/w, preferably 10% w/w.
In an embodiment of the invention, the molar ratio of the compound of formula II to sodium hydroxide or potassium hydroxide is 1 (1.5-3.0), preferably the molar ratio is 1: 2.
In an embodiment of the present invention, the reaction temperature of the hydrolysis reaction is 0 ℃ to 10 ℃.
In an embodiment of the present invention, after the hydrolysis reaction, a post-treatment operation is further included, and the post-treatment operation includes a process of distilling the solvent under reduced pressure and adjusting pH.
The post-treatment operation comprises the steps of firstly adjusting the pH value to be 6-7, and then distilling the solvent under reduced pressure; or distilling the solvent under reduced pressure, and then adjusting the pH value to 6-7 to obtain the compound shown in the formula (I). Preferably, the solvent is distilled under reduced pressure and the pH is adjusted.
The post-treatment also comprises a column chromatography process.
In a third aspect, the invention also provides application of the oseltamivir warning structure impurity shown in the formula I as a reference substance in quality research of an oseltamivir bulk drug or an intermediate compound.
The beneficial results of the invention are:
the invention provides an oseltamivir warning structure impurity (I) and a preparation method thereof, the method has high yield, can prepare the oseltamivir warning structure impurity (I) in large quantity, has the purity of more than 90 percent by an area normalization method, and can be used for the quality research of oseltamivir as a reference substance.
Description of the drawings: the term "room temperature" as used herein means 10 ℃ to 30 ℃.
Drawings
FIG. 1 shows nuclear magnetic hydrogen spectrum of oseltamivir warning structure impurity (I).
FIG. 2 shows the mass spectrum of oseltamivir warning structure impurity (I).
FIG. 3 shows the HPLC for locating the reference substance of the warning structural impurity (I) of oseltamivir.
FIG. 4 shows the HPLC for detecting the warning structural impurity (I) in the oseltamivir product.
Detailed Description
The following examples are intended to illustrate embodiments of the present invention without limiting the scope of the invention.
Formula (II)
The compounds shown are prepared by patent CN1759093A or its equivalent.
Example 1 Synthesis of oseltamivir Warning structural impurity (I)
Adding 5.00g of compound (II) (13.79mmol) and 50mL of ethanol into a reaction bottle at room temperature, stirring for dissolving, cooling to 0-10 ℃, adding 10mL of aqueous solution of 1.1g of sodium hydroxide (27.50mmol), stirring at 0-10 ℃ overnight, distilling the reaction liquid at 50 ℃ under reduced pressure until the reaction liquid is dried, adding 10mL of dichloromethane and 10mL of water into the residue, dropwise adding concentrated hydrochloric acid to adjust the pH to be 6-7, separating out an oily substance, separating out the oily substance, and purifying by column chromatography, wherein an eluent is petroleum ether and ethyl acetate to be 10:1 (volume ratio), so as to obtain 3.23g of the oseltamivir warning structural impurity (I), the yield is 71.1%, and the purity is 99.5%.
MS[M+H]：282.2。
1H-NMR(600MHz，CD3OD) δ 0.91(t, 3H), δ 0.97(t, 3H), δ 1.04(s, 6H), δ 1.56(m, 4H), δ 2.21(d, 1H), δ 2.43(d, 1H), δ 2.57(t, 2H), δ 3.46(m, 1H), δ 4.20(s, 1H), δ 6.76(d, 1H) (hydrogen spectrum as in fig. 1, mass spectrum as in fig. 2).
Example 2 Synthesis of oseltamivir Warning structural impurity (I)
Adding 5.00g of compound (II) (13.79mmol) and 50mL of methanol into a reaction bottle at room temperature, stirring for dissolving, cooling to 0-10 ℃, adding 20mL of aqueous solution of 1.2g of potassium hydroxide (21.43mmol), stirring at 0-10 ℃ overnight, distilling the reaction liquid at 50 ℃ under reduced pressure until the reaction liquid is dried, adding 10mL of dichloromethane and 10mL of water into the residue, dropwise adding concentrated hydrochloric acid to adjust the pH to be 6-7, separating out an oily substance, separating out the oily substance, and purifying by column chromatography, wherein an eluent is petroleum ether and ethyl acetate to be 10:1 (volume ratio), so as to obtain 3.14g of the oseltamivir warning structural impurity (I), the yield is 69.3%, and the purity is 99.8%.
Example 3 detection method of oseltamivir warning structure impurity (I) in product
Instruments and equipment: liquid chromatograph, electronic balance, volumetric flask
Chromatographic conditions are as follows:
and (3) determination:
blank solution: 50% acetonitrile
Control solution: precisely weighing a proper amount of reference substance of the impurity (I), diluting the reference substance with a blank solution to prepare about 10 mu g/ml, and preparing 2 parts in parallel;
test solution: an appropriate amount of oseltamivir sample is weighed precisely, and diluted by blank solution to prepare 1mg/ml solution, and 2 parts of the solution are prepared in parallel.
And (4) quantitative limit: 0.05ug/ml
Detection limit: 0.017ug/ml
And (3) detecting a sample: lower than the detection limit (detection pattern is shown in figure 3 and figure 4)
Comparative example 1 Synthesis of oseltamivir Warning structural impurity (I)
Adding 5.00g of compound (II) (13.79mmol) and methanol (50mL) into a reaction bottle at room temperature, stirring to dissolve, adding 10mL of an aqueous solution of 3.80g of potassium carbonate (27.50mmol), stirring at 30-40 ℃ overnight, adding 10mL of dichloromethane and 10mL of water, dropwise adding concentrated hydrochloric acid to adjust the pH to be 6-7, distilling the reaction solution at 50 ℃ under reduced pressure until the reaction solution is dried, and carrying out column chromatography purification on the residue to obtain 0.50g of oseltamivir warning structure impurity (I), wherein the yield is 11.0% and the purity is 65%.
Comparative example 2 Synthesis of oseltamivir Warning structural impurity (I)
At room temperature, 10.00g of compound (II) (27.58mmol), methanol (50mL) and a stirred supernatant were added to a reaction flask, and 10mL of an aqueous solution of 9.00g of potassium carbonate (65.22mmol) was added thereto, stirred overnight, the solvent was evaporated under reduced pressure, and the resulting oily substance was purified by column chromatography to obtain 0.8g of a mixture having a purity of 57.5% and a MS molecular weight of 282.2 and 561.3, respectively.
Finally, it is noted that the above-mentioned embodiments illustrate rather than limit the invention, and that, while the invention has been described with reference to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims.
Claims (10)
1. An oseltamivir warning structure impurity, formula (I):
2. the method of claim 1 for preparing an impurity of warning structure:
1) dissolving the compound represented by the formula (II) in a lower alkanol or an aqueous solution of a lower alkanol with stirring;
2) and adding sodium hydroxide or potassium hydroxide, and performing hydrolysis reaction at a temperature not higher than room temperature to obtain the oseltamivir warning structure impurity shown in the formula I.
3. The process according to claim 2, wherein the lower alkanol is one or a mixture of two or more of methanol, ethanol and isopropanol, preferably ethanol;
the aqueous solution of the lower alkanol is one or a mixture of more than two of methanol aqueous solution, ethanol aqueous solution and isopropanol aqueous solution, preferably ethanol aqueous solution; the concentration of the aqueous solution may be from 50% v/v to 99% v/v.
4. A method according to claim 2, wherein the sodium hydroxide or potassium hydroxide is added as an aqueous solution, for example at a concentration of 5% w/w to 25% w/w, preferably 10% w/w;
the molar ratio of the compound of the formula II to the sodium hydroxide or the potassium hydroxide is 1 (1.5-3.0), and preferably the molar ratio is 1: 2.
5. The method according to claim 2, wherein the hydrolysis reaction is carried out at a reaction temperature of 0 ℃ to 10 ℃.
6. The method according to claim 2, wherein the treatment operation after the hydrolysis reaction comprises distillation of the solvent under reduced pressure and adjustment of pH.
7. The preparation method according to claim 6, wherein the post-treatment operation comprises adjusting the pH to 6-7, and distilling the solvent under reduced pressure to obtain the compound of formula (I).
8. The method of claim 6, wherein the post-treatment comprises distilling the solvent under reduced pressure and adjusting the pH to 6-7 to obtain the compound of formula (I).
9. The method of claim 7 or 8, wherein the post-treatment further comprises a column chromatography process.
10. The use of a compound of formula I according to claim 1 as a reference for the detection of impurities in the oseltamivir production process.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115326999A (en) * | 2022-10-12 | 2022-11-11 | 深圳市海滨制药有限公司 | Detection method of oseltamivir epoxy intermediate and isomer thereof |
| CN115626885A (en) * | 2022-09-26 | 2023-01-20 | 植恩生物技术股份有限公司 | Oseltamivir warning structure impurity C10-B-ZZ7 as well as preparation method and application thereof |
| CN115656388A (en) * | 2022-11-21 | 2023-01-31 | 深圳市海滨制药有限公司 | Method for detecting oseltamivir starting material and related substances thereof |
| CN115850102A (en) * | 2022-12-29 | 2023-03-28 | 浙江工业大学 | Preparation method of oseltamivir |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108047077A (en) * | 2017-12-27 | 2018-05-18 | 杭州新博思生物医药有限公司 | A kind of preparation method of Oseltamivir chiral impurity |
| CN112625009A (en) * | 2020-12-18 | 2021-04-09 | 植恩生物技术股份有限公司 | Refining method of orlistat key intermediate |
| CN113861057A (en) * | 2021-09-30 | 2021-12-31 | 苏州正济药业有限公司 | Oseltamivir phosphate intermediate impurity compound and preparation method and application thereof |
-
2022
- 2022-02-23 CN CN202210165739.2A patent/CN114456097A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108047077A (en) * | 2017-12-27 | 2018-05-18 | 杭州新博思生物医药有限公司 | A kind of preparation method of Oseltamivir chiral impurity |
| CN112625009A (en) * | 2020-12-18 | 2021-04-09 | 植恩生物技术股份有限公司 | Refining method of orlistat key intermediate |
| CN113861057A (en) * | 2021-09-30 | 2021-12-31 | 苏州正济药业有限公司 | Oseltamivir phosphate intermediate impurity compound and preparation method and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| 邓宇，等: "磷酸奥司他韦起始物料杂质OTg-R1的合成研究", 上海医药, vol. 42, no. 15, pages 72 - 74 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115626885A (en) * | 2022-09-26 | 2023-01-20 | 植恩生物技术股份有限公司 | Oseltamivir warning structure impurity C10-B-ZZ7 as well as preparation method and application thereof |
| CN115326999A (en) * | 2022-10-12 | 2022-11-11 | 深圳市海滨制药有限公司 | Detection method of oseltamivir epoxy intermediate and isomer thereof |
| CN115326999B (en) * | 2022-10-12 | 2022-12-27 | 深圳市海滨制药有限公司 | Detection method of oseltamivir epoxy intermediate and isomer thereof |
| CN115656388A (en) * | 2022-11-21 | 2023-01-31 | 深圳市海滨制药有限公司 | Method for detecting oseltamivir starting material and related substances thereof |
| CN115850102A (en) * | 2022-12-29 | 2023-03-28 | 浙江工业大学 | Preparation method of oseltamivir |
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