CN116239485A - Preparation method of lopina Wei Sanfu acetyl impurity, prepared impurity and application - Google Patents
Preparation method of lopina Wei Sanfu acetyl impurity, prepared impurity and application Download PDFInfo
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- CN116239485A CN116239485A CN202211499016.2A CN202211499016A CN116239485A CN 116239485 A CN116239485 A CN 116239485A CN 202211499016 A CN202211499016 A CN 202211499016A CN 116239485 A CN116239485 A CN 116239485A
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Abstract
The invention discloses a preparation method of lopinavir Wei Sanfu acetyl impurity, in particular to a preparation method of lopinavir Wei Sanfu acetyl impurity by reacting lopinavir intermediate (LPV-2) with trifluoroacetic anhydride or trifluoroacetic ester in a solvent under alkaline condition and taking 4-dimethylaminopyridine as a catalyst; the invention also discloses the lopina Wei Sanfu acetyl impurity prepared by the method and the application thereof; the invention provides a new thought for the synthesis of lopina Wei Sanfu acetyl impurity, the reaction condition of the synthesis route is simple and mild, the yield and purity are higher, the preparation requirement of the impurity can be met, and the method has important significance for the research of lopinavir.
Description
Technical Field
The invention relates to the technical field of medicine synthesis, in particular to a preparation method of lopina Wei Sanfu acetyl impurities, the prepared impurities and application.
Background
Lopinavir (Lopinavir), developed by Abbot corporation in the united states, approved by the FDA in the united states at month 3 in 1996, marketed first in the united states, and subsequently marketed as Lopinavir/ritonavir complex formulation at month 9 in 2000. In 2007, the Chinese market is called chocolate ganoderma (kalett), and is mainly used for treating AIDS clinically. Wherein the cultural name is (2S, 3S, 5S) -2- (2, 6-dimethyl phenoxy acetyl) amino-3-hydroxy-5- [2S- (1-tetrahydropyrimidine-2-ketone) -3-methyl butyryl ] amino-1, 6-diphenyl n-hexane, and the structural formula is as follows:
lopinavir is a protease inhibitor of human immunodeficiency diseases HIV-1 and HIV-2. The mechanism of action is to block the cleavage of the gag-pol polyprotein, resulting in the production of immature, non-viable viral particles. Lopinavir, ritonavir and other antiretroviral drugs are used in combination to treat HIV-1 infection. Patent WO9721685 discloses a preparation method thereof, and the synthetic route is as follows:
in the process of synthesizing lopinavir bulk drug by adopting the route reaction, in the step of deaminating protective group of trifluoroacetic acid, a byproduct with the content of approximately 2-5% is detected by LC-MS, and the impurity is found to be 543.2 ([ M+H)] + ) Is characterized by a molecular ion peak of (2),the acetyl impurity of lopina Wei Sanfu is presumed. The impurity directly affects the quality of lopinavir bulk drug products, and in order to facilitate the quality research of lopinavir bulk drug, the preparation method of lopina Wei Sanfu acetyl impurity is urgently needed to be provided, and aims to efficiently and conveniently obtain a lopina Wei Sanfu acetyl impurity reference substance with higher purity, which has important significance for registration reporting and quality control of lopinavir bulk drug. However, the prior art does not disclose a process for the preparation of lopina Wei Sanfu acetyl impurities.
Disclosure of Invention
The invention aims to provide a preparation method of lopina Wei Sanfu acetyl impurity, the prepared impurity and application thereof, so as to solve the problems in the background technology.
In order to achieve the above purpose, the present invention provides the following technical solutions:
a preparation method of lopina Wei Sanfu acetyl impurity, which comprises the following steps: lopinavir intermediate (LPV-2) reacts with trifluoroacetic anhydride or trifluoroacetic ester in a solvent under alkaline condition by using 4-dimethylaminopyridine as a catalyst to obtain lopina Wei Sanfu acetyl impurity, wherein the synthetic route is as follows:
As a further scheme of the invention: the alkali is any one of organic alkali or inorganic alkali; the organic base is any one of triethylamine, N-diisopropylethylamine and pyridine; the inorganic base is any one of sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate.
As a further scheme of the invention: the reaction solvent is any one of tetrahydrofuran, ethyl acetate, dichloromethane, N-dimethylformamide, dimethyl sulfoxide and N-methylpyrrolidone.
As a further scheme of the invention: the trifluoro acetate is any one of trifluoro methyl acetate, trifluoro ethyl acetate, trifluoro isopropyl acetate, trifluoro allyl acetate, trifluoro pentafluorophenyl acetate and trifluoro trimethyl silicon acetate.
As a further scheme of the invention: the invention also discloses a lopina Wei Sanfu acetyl impurity prepared by the method, and preferably, the structure of the lopina Wei Sanfu acetyl impurity is as follows:
as a further scheme of the invention: the invention also discloses the application of the lopina Wei Sanfu acetyl impurity prepared by the preparation method in detecting and/or controlling the quality of lopinavir.
Compared with the prior art, the invention has the beneficial effects that: the preparation of the lopina Wei Sanfu acetyl impurity is completed by applying a new synthetic route; the synthesis method has the advantages of easily obtained starting materials, simple and mild reaction conditions, higher yield, simple reaction operation, safe and environment-friendly reaction; the synthesis of the lopina Wei Sanfu acetyl impurity solves the difficulty of being purchased in the market, the prepared lopina Wei Sanfu acetyl impurity has high purity, the impurity analysis for lopinavir bulk drug is satisfied, and the method has important significance for the quality research of lopinavir.
Drawings
FIG. 1 is a synthetic route diagram of the acetyl impurity of lopina Wei Sanfu according to the examples of the present invention;
FIG. 2 is a nuclear magnetic resonance hydrogen spectrum of an acetyl impurity of lopina Wei Sanfu according to an embodiment of the present invention;
FIG. 3 is a nuclear magnetic carbon spectrum of an acetyl impurity of lopina Wei Sanfu according to an embodiment of the present invention;
FIG. 4 is a LC-MS spectrum of an acetyl impurity of lopina Wei Sanfu according to the examples of the invention.
Detailed Description
The technical solutions of the present invention will be clearly and completely described below in connection with specific embodiments, and it is obvious that the described embodiments are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Unless otherwise indicated, the starting materials and reagents used in the following examples were either commercially available or may be prepared by known methods.
Referring to fig. 1, the invention discloses a preparation method of lopina Wei Sanfu acetyl impurity, which specifically comprises the following steps: lopinavir intermediate (LPV-2) reacts with trifluoroacetic anhydride or trifluoroacetic ester in a solvent under alkaline conditions with 4-dimethylaminopyridine as a catalyst to obtain lopina Wei Sanfu acetyl impurity. Specific examples are as follows:
example 1
LPV-2 (5 g,11.2 mmol) and 4-dimethylaminopyridine (0.1 g,0.9 mmol) were put into a 100ml reaction flask, 50ml of methylene chloride was dissolved by stirring, triethylamine (3.7 g,37.0 mmol) was added, the temperature was lowered to 0-5℃and trifluoroacetic anhydride (11.1 g,52.9 mmol) was slowly added dropwise thereto, and the mixture was stirred at room temperature overnight. After the reaction is finished, the reaction solution is sequentially washed by 2N HCl (50 ml), saturated sodium bicarbonate (50 ml) and saturated sodium chloride (50 ml), reduced pressure is carried out at the temperature of less than or equal to 45 ℃, ethyl acetate 20ml is added into the residue, the temperature is increased to 60-65 ℃, the solution is clear, N-heptane 10ml is dripped into the residue, the temperature is slowly reduced to 0-5, solid precipitation is carried out, suction filtration is carried out, a filter cake is leached by a small amount of ethyl acetate, vacuum drying is carried out at the temperature of 45 ℃, and 5.6g of trifluoroacetyl impurity is obtained, the yield is 92.3%, and the purity is 94.8%.
Example 2
LPV-2 (5 g,11.2 mmol), THF (50 ml), triethylamine (1.1 g,11.2 mmol) and stirred solution are put into a reaction bottle, cooled to 0-5 ℃, ethyl trifluoroacetate (1.6 g,11.2 mmol) is slowly dripped into the bottle, the reaction is carried out at 0-5 ℃ for 1h after the dripping, and then the reaction is carried out at 20-25 ℃ for 1h. Evaporating under reduced pressure, adding ethyl acetate 20ml into the residue, heating to 60-65deg.C for dissolving, slowly cooling to 0-5, precipitating solid, vacuum filtering, leaching filter cake with small amount of ethyl acetate, vacuum drying at 45deg.C to obtain trifluoroacetyl impurity 4.7g, yield 77.4%, and purity 93.5%.
Example 3
LPV-2 (5 g,11.2 mmol), ethyl acetate (50 ml), triethylamine (1.4 g,13.4 mmol) were charged into the reaction flask, the solution was stirred and cooled to 0-5℃and methyl trifluoroacetate (1.6 g,12.3 mmol) was slowly added dropwise thereto, and the reaction was stirred at room temperature for 2 hours. Evaporating under reduced pressure, adding isopropanol 20ml into the residue, heating to 50-55deg.C for dissolving, slowly cooling to 0-5, precipitating solid, vacuum filtering, leaching filter cake with cold isopropanol, vacuum drying at 45deg.C to obtain trifluoroacetyl impurity 4.3g, yield 70.8%, and purity 93.3%.
Example 4
LPV-2 (5 g,11.2 mmol), THF50ml, potassium carbonate (1.9 g,13.4 mmol) and isopropyl trifluoroacetate (2.6 g,16.8 mmol) were added dropwise thereto under stirring, and the temperature was raised to 50-55℃and the reaction was stirred for 6 hours. Evaporating under reduced pressure, adding isopropanol 20ml into the residue, heating to 50-55deg.C for dissolving, slowly cooling to 0-5, precipitating solid, vacuum filtering, leaching filter cake with cold isopropanol, vacuum drying at 45deg.C to obtain trifluoroacetyl impurity 3.4g, yield 56.0%, purity 91.4%.
Example 5
LPV-2 (5 g,11.2 mmol), DMF15ml, N, N-diisopropylethylamine (1.7 g,13.4 mmol) and trimethylsilyl trifluoroacetate (2.5 g,13.4 mmol) were added dropwise thereto under stirring, and the mixture was heated to 100-110℃and reacted under stirring for 3 hours. Cooling to room temperature, adding 45ml of water and 50ml of dichloromethane, separating liquid, evaporating the organic phase under reduced pressure, adding 20ml of isopropanol into the residue, heating to 50-55 ℃ for dissolving, slowly cooling to 0-5, separating out solid, filtering, leaching a filter cake with a small amount of cold isopropanol, and vacuum drying at 45 ℃ to obtain 1.7g of trifluoroacetyl impurity, wherein the yield is 28.0% and the purity is 90.6%.
Application example
Nuclear magnetic resonance and liquid detection were performed on the lopina Wei Sanfu acetyl impurity obtained in examples 1-5, respectively, and the test results are shown in FIGS. 2-4.
Referring to fig. 2, the nuclear magnetic hydrogen spectrum related data is: 1 H NMR(600MHz，DMSO-d 6 )δ:9.16(d，J＝8.9Hz，1H)，7.55(d，J＝9.5Hz，1H)，7.25(q，6H),7.15(m，4H)，7.02(d，J＝7.5Hz，2H)，6.93(t，1H),5.13(d，J＝5.8Hz，1H)，4.24(q，2H)，4.13-4.07(m，2H)，3.63(q，1H)，2.83(d，J＝7.4Hz，2H)，2.78(dd，1H)，2.71-2.67(dd，1H)，2.15(s，6H)，1.70-1.59(ddt，2H)。
referring to fig. 3, the nuclear magnetic carbon spectrum related data are: 13 C NMR(600MHz，DMSO-d 6 )δ：168.0,155.1,139.4,138.7,130.8,129.6,129.3,128.6,126.7,126.5,124.8,70.8,68.3,53.2,49.2,40.5,39.7,38.9,37.9,16.4。
referring to fig. 4, lc-MS (m/z) related data is: 543.2[ M+H ]] + 。
It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative embodiments, and that the present invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein. Any reference sign in a claim should not be construed as limiting the claim concerned.
Furthermore, it should be understood that although the present disclosure describes embodiments, not every embodiment is provided with a separate embodiment, and that this description is provided for clarity only, and that the disclosure is not limited to the embodiments described in detail below, and that the embodiments described in the examples may be combined as appropriate to form other embodiments that will be apparent to those skilled in the art.
Claims (6)
1. The preparation method of the lopina Wei Sanfu acetyl impurity is characterized by comprising the following steps of: the lopinavir intermediate reacts with trifluoroacetic anhydride or trifluoroacetic ester in a solvent under alkaline condition by taking 4-dimethylaminopyridine as a catalyst to obtain lopina Wei Sanfu acetyl impurity.
2. The method for preparing the lopina Wei Sanfu acetyl impurity according to claim 1, wherein the base is any one of organic base and inorganic base; the organic base is any one of triethylamine, N-diisopropylethylamine and pyridine; the inorganic base is any one of sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate.
3. The method for preparing the lopina Wei Sanfu acetyl impurity according to claim 1, wherein the reaction solvent is any one of tetrahydrofuran, ethyl acetate, dichloromethane, N-dimethylformamide, dimethyl sulfoxide and N-methylpyrrolidone.
4. The method for preparing the lopina Wei Sanfu acetyl impurity according to claim 1, wherein the trifluoroacetate is any one of methyl trifluoroacetate, ethyl trifluoroacetate, isopropyl trifluoroacetate, allyl trifluoroacetate, pentafluorophenyl trifluoroacetate and trimethylsilyl trifluoroacetate.
5. A lopina Wei Sanfu acetyl impurity prepared by the process of any one of claims 1-4, wherein the lopina Wei Sanfu acetyl impurity has the structure:
the nuclear magnetic hydrogen spectrum related data of the lopina Wei Sanfu acetyl impurity are as follows: 1 H NMR(600MHz，DMSO-d 6 )δ:9.16(d，J＝8.9Hz，1H)，7.55(d，J＝9.5Hz，1H)，7.25(q，6H),7.15(m，4H)，7.02(d，J＝7.5Hz，2H)，6.93(t，1H),5.13(d，J＝5.8Hz，1H)，4.24(q，2H)，4.13-4.07(m，2H)，3.63(q，1H)，2.83(d，J＝7.4Hz，2H)，2.78(dd，1H)，2.71-2.67(dd，1H)，2.15(s，6H)，1.70-1.59(ddt，2H)。
6. use of lopina Wei Sanfu acetyl impurities as defined in claim 5 for detecting and/or controlling lopinavir quality.
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