CN107778290B - Impurity of quinoline derivative and preparation method thereof - Google Patents
Impurity of quinoline derivative and preparation method thereof Download PDFInfo
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Abstract
The invention provides an impurity of quinoline derivatives and a preparation method thereof, in particular to an impurity of a compound shown as a formula I and a preparation method thereofMethods and uses. The impurities of the compound shown in the formula I provided by the invention can be used as a reference marker for impurity inspection of the compound shown in the formula I, the impurity content of the compound shown in the formula I and a preparation thereof can be effectively and conveniently monitored, and the quality of the compound shown in the formula I and the preparation thereof is favorably controlled, so that the safety and the effectiveness of the compound shown in the formula I and the preparation thereof are ensured.
Description
Technical Field
The invention relates to an impurity of quinoline derivatives, a preparation method and application thereof, in particular to an impurity of 1- [ [ [4- (4-fluoro-2-methyl-1H-indol-5-yl) oxy-6-methoxyquinoline-7-yl ] oxy ] methyl ] cyclopropylamine, a preparation method and application thereof.
Background
International patent application WO2008112407 discloses in example 24 the compound 1- [ [ [4- (4-fluoro-2-methyl-1H-indol-5-yl) oxy-6-methoxyquinolin-7-yl ] oxy ] methyl ] cyclopropylamine, the structural formula of which is shown in formula I:
the inhibitor is a multi-target receptor tyrosine kinase inhibitor, can inhibit the kinase activities of vascular endothelial cell growth factor receptors (including VEGFR1, VEGFR2/KDR and VEGFR3), stem cell factor receptors, platelet-derived growth factor receptors and the like, and inhibits downstream signal transduction mediated by VEGFR2, thereby inhibiting tumor angiogenesis, and is a very potential anti-tumor drug.
In order to safely and effectively use the medicine, the quality standard of the medicine has strict regulations on the purity of the effective components of the medicine and the limit of impurities. In the field of pharmaceutical quality analysis techniques, chemical derivatives, synthesis by-products and degradation products of impurities of active pharmaceutical ingredients can be identified or quantified by spectroscopic, chromatographic or other physical methods. Before analyzing impurities in a compound, a substance with higher purity and the same or similar structure as the impurities is used as a reference marker, and the relative position of the reference marker in a chromatogram is taken as the relative position of the impurities in the chromatogram, so as to guide the impurity detection of the compound to be detected. Obviously, the selection and preparation of the reference marker has a direct impact on the scientificity and accuracy of the detection of the impurity content in the active pharmaceutical ingredient.
Disclosure of Invention
In one aspect, the present invention provides a compound of formula II, having the structure:
in some embodiments, the present invention provides a compound of formula II having a purity of 90% or greater; in some exemplary embodiments, the present invention provides a compound of formula II having a purity of 95% or greater.
In another aspect, the present invention provides a process for the preparation of a compound of formula ii, wherein: reacting a compound shown in a formula I with benzaldehyde in a solvent in the presence of a palladium catalyst, hydrogen and acid to prepare a compound shown in a formula II;
in some embodiments, the acid is selected from benzoic acid, p-toluenesulfonic acid, camphorsulfonic acid, trifluoroacetic acid, or mixtures thereof; in some typical embodiments, the acid is selected from camphorsulfonic acid or trifluoroacetic acid.
In some embodiments, the palladium catalyst is selected from Pd/C or Pd (OH)2(ii) a In some typical embodiments, the palladium catalyst is Pd/C; in certain particular embodiments, the palladium catalyst is 5% Pd/C.
In some embodiments, the solvent is selected from tetrahydrofuran, toluene, dichloromethane, or a mixed solvent thereof; in some typical embodiments, the solvent is toluene or dichloromethane.
In some embodiments, the compound of formula i and benzaldehyde are fed in a molar ratio of 1:0.5 to 2; in some typical embodiments, the compound of formula i and benzaldehyde are fed in a molar ratio of 1:1.0 to 1.5; in some more typical embodiments, the compound of formula I and benzaldehyde are fed in a molar ratio of 1: 1.1.
In some embodiments, the compound of formula i and acid are fed in a molar ratio of 1:1.5 to 5; in some typical embodiments, the compound of formula i and the acid are fed in a molar ratio of 1:2 to 5; in some more typical embodiments, the compound of formula I and the acid are fed in a molar ratio of 1: 5.
In some embodiments, the temperature at which the compound of formula I and benzaldehyde are reacted is from-10 ℃ to 25 ℃; in some particular embodiments, the reaction temperature of the compound of formula I and benzaldehyde is-10 ℃ to 10 ℃; in some particular embodiments, the temperature at which the compound of formula I and benzaldehyde are reacted is from 0 ℃ to 5 ℃.
In another aspect, the present invention provides a method for determining the purity of a compound of formula II, wherein:
(1) chromatographic conditions are as follows: octadecylsilane chemically bonded silica is used as a filling agent; taking phosphate buffer solution (0.78 g of sodium dihydrogen phosphate dihydrate is taken and dissolved by adding 900ml of water, adding 5ml of triethylamine and uniformly mixing, adjusting the pH value to 2.9 by using phosphoric acid and diluting to 1000ml by using water) as a mobile phase A, taking acetonitrile as a mobile phase B, and carrying out linear gradient elution according to the following table, wherein the flow rate is 1.0ml per minute; the detection wavelength was 222nm and the column temperature was 30 ℃.
(2) The determination method comprises the following steps: taking a proper amount of the compound shown in the formula II, accurately weighing, dissolving with a solvent, diluting to obtain a solution containing about 0.2mg per 1ml, accurately weighing 20 μ l of the solution as a test solution, injecting into a liquid chromatograph, and recording chromatogram. The purity of the main peak (compound of formula II) in the test solution is calculated by peak area normalization (ignoring peaks with peak area percentage less than 0.02%) and should be not less than 90.0%. The solvent described here is mobile phase A-mobile phase B (80: 20, v/v).
In another aspect, the invention also provides the use of a compound of formula II as a reference marker in the impurity detection of a compound of formula I. In some embodiments, the present invention provides the use of a compound of formula II having a purity of 90% or more as a reference marker in the impurity check of a compound of formula I; in some exemplary embodiments, the present invention provides the use of a compound of formula II having a purity of 95% or more as a reference marker in the impurity check of a compound of formula I.
In some particular embodiments, the use of a compound of formula II as a reference marker in the impurity check of a compound of formula i, characterized in that it comprises the following steps:
system applicability test solution: dissolving appropriate amount of compound of formula I and compound of formula II with solvent, and quantitatively diluting to obtain mixed solution containing about 0.29mg of compound of formula I and 1.45 μ g of compound of formula II per 1 ml. The solvent described here is mobile phase A-mobile phase B (80: 20, v/v).
Preparing a test solution: taking about 14.7mg of the compound shown in the formula I, placing the compound in a 50ml volumetric flask, adding a solvent to dissolve and dilute the compound to a scale, and shaking up the solution to obtain the compound. The solvent described here is mobile phase A-mobile phase B (80: 20, v/v).
Control solution: precisely measuring 1ml of the test solution, placing the test solution in a 100ml volumetric flask, adding a solvent to dilute the test solution to a scale, and shaking up the test solution to obtain the test solution. The solvent described here is mobile phase A-mobile phase B (80: 20, v/v).
Chromatographic conditions are as follows: octadecylsilane chemically bonded silica is used as a filling agent; taking phosphate buffer solution (0.78 g of sodium dihydrogen phosphate dihydrate is taken and dissolved by adding 900ml of water, adding 5ml of triethylamine and uniformly mixing, adjusting the pH value to 2.9 by using phosphoric acid and diluting to 1000ml by using water) as a mobile phase A, taking acetonitrile as a mobile phase B, and carrying out linear gradient elution according to the following table, wherein the flow rate is 1.0ml per minute; the detection wavelength is 222 nm; the column temperature was 30 ℃. And (3) taking 20 mu l of the system applicability test solution, injecting into a liquid chromatograph, and recording a chromatogram map, wherein the separation degree of the compound shown in the formula I and the compound shown in the formula II is more than 1.5.
The determination method comprises the following steps: the detection is carried out by high performance liquid chromatography (China pharmacopoeia 2015 edition of general rules 0512). Under the condition that the system applicability test meets the requirements, precisely measuring 20 mu l of each of the test solution and the reference solution, respectively injecting the solution into a liquid chromatograph, and recording the chromatogram. And calculating the content of the impurity A according to a main component self-comparison method without adding a correction factor.
(8) Calculating the formula:
in the formula, AImpurity A-peak area of impurity a peak in the test sample solution; a. theControlPeak area of the main peak of the control solution (i.e. the peak of the compound of formula I). The impurity A can be a compound of a formula II or other impurities with similar structures with the compound of the formula II.
As used herein, unless otherwise indicated, the purity refers to the purity as determined by the "method of determining the purity of a compound of formula II" herein.
Herein, unless otherwise indicated, reference to a compound of formula I includes a compound of formula I as the free base or a salt thereof, such as the hydrochloride or dihydrochloride salt. Examples of compounds of formula I formulated in "test solutions" include, but are not limited to, freshly prepared or stored bulk drug compounds of formula I, pharmaceutical compositions comprising compounds of formula I.
The invention provides a high-purity compound of formula II, which is an important impurity compound generated in the production process of the compound of formula I. The content of this impurity compound directly affects the pharmaceutical quality of the compound of formula I and its formulations. The high-purity compound of the formula II provided by the invention can effectively improve the scientificity and accuracy of impurity detection of the compound of the formula I and the preparation thereof, can effectively and conveniently monitor the impurity content of the compound of the formula I and the preparation thereof, and is beneficial to the quality control of the compound of the formula I and the preparation thereof, thereby ensuring the safety and effectiveness of the compound of the formula I and the preparation thereof.
Detailed Description
The examples are intended to better illustrate the context of the invention and are not intended to limit the scope of the invention. EXAMPLE 1 preparation of the Compound of formula II
Putting 2.00g of a compound of a formula I, 0.57g of benzaldehyde, 0.10g of 5% palladium carbon, 2.80g of trifluoroacetic acid and 30ml of dichloromethane into a three-mouth reaction bottle, stirring, cooling to 0-5 ℃, introducing hydrogen, and reacting for 3 hours; after the reaction is finished, evaporating the reaction solution under reduced pressure to remove the solvent, adding 50ml of saturated sodium bicarbonate and 50ml of dichloromethane, and separating out an organic phase; the aqueous phase was re-extracted with 50ml of dichloromethane, the organic phases were combined, washed with 50ml of saturated brine and dried over anhydrous sodium sulfate for 2 hours; filtering, and evaporating the filtrate under reduced pressure to remove the solvent to obtain the compound shown in the formula II.
m/z：498.2185[M+H]+。
EXAMPLE 2 preparation of a Compound of formula I (1- [ [ [4- (4-fluoro-2-methyl-1H-indol-5-yl) oxy-6-methoxyquinolin-7-yl ] oxy ] methyl ] cyclopropylamine)
Prepared according to the preparation method disclosed in CN101809012A to obtain 1- (((4- (4-fluoro-2-methyl-1H-indol-5-yl) oxy-6-methoxyquinolin-7-yl) oxy) methyl) cyclopropylcarbamic acid benzyl ester.
2.0g of benzyl 1- (((4- (4-fluoro-2-methyl-1H-indol-5-yl) oxy-6-methoxyquinolin-7-yl) oxy) methyl) cyclopropylcarbamate, 20ml of acetic acid, and 20ml of an acetic acid solution containing 33% by mass of hydrobromic acid were mixed and stirred at room temperature for 1 hour; diluting with ethyl acetate/water, separating out water phase, and alkalifying with sodium carbonate; filtering, and drying the filter cake at 80 ℃ to obtain solid, namely the free alkali of the compound in the formula I.
With reference to the previous method, the content of the compound of formula II in the free base of the compound of formula I was determined to be < 0.3%.
Claims (9)
1. Use of a compound of formula II as a reference marker in the impurity examination of a compound of formula i, characterized in that it comprises the steps of:
system applicability test solution: dissolving appropriate amount of compound of formula I and compound of formula II with solvent, and quantitatively diluting to obtain mixed solution containing about 0.29mg of compound of formula I and 1.45 μ g of compound of formula II per 1 ml; the solvent is mobile phase A-mobile phase B, wherein the volume ratio of the mobile phase A to the mobile phase B is 80: 20;
preparing a test solution: taking about 14.7mg of the compound shown in the formula I, placing the compound in a 50ml volumetric flask, adding a solvent to dissolve and dilute the compound to the scale, and shaking up, wherein the solvent is mobile phase A-mobile phase B, and the volume ratio of the mobile phase A to the mobile phase B is 80: 20;
control solution: precisely measuring 1ml of a sample solution, placing the sample solution in a 100ml volumetric flask, adding a solvent to dilute the sample solution to a scale, and shaking up, wherein the solvent is a mobile phase A-a mobile phase B, and the volume ratio of the mobile phase A to the mobile phase B is 80: 20;
chromatographic conditions are as follows: octadecylsilane chemically bonded silica is used as a filling agent; taking phosphate buffer solution as a mobile phase A and acetonitrile as a mobile phase B, and carrying out linear gradient elution according to the following table, wherein the flow rate is 1.0ml per minute; the detection wavelength is 222 nm; the column temperature is 30 ℃; injecting 20 mu l of the system applicability test solution into a liquid chromatograph, and recording a chromatogram map, wherein the separation degree of the compound of the formula I and the compound of the formula II is more than 1.5; the preparation method of the mobile phase A comprises the following steps: taking 0.78g of sodium dihydrogen phosphate dihydrate, adding 900ml of water for dissolving, adding 5ml of triethylamine, uniformly mixing, adjusting the pH value to 2.9 by using phosphoric acid, and diluting to 1000ml by using water;
the determination method comprises the following steps: detecting with high performance liquid chromatography, and according to 0512 of the four-part general rules of the Chinese pharmacopoeia 2015 edition; precisely measuring 20 mul of each of the test solution and the reference solution under the condition that the system applicability test meets the requirements, respectively injecting into a liquid chromatograph, and recording the chromatogram; calculating the content of the impurity A according to a main component self-contrast method without adding a correction factor;
calculating the formula:
wherein A isImpurity A-peak area of the peak of the compound of formula II in the test sample solution; a. theControl-peak area of the peak of the compound of formula I in the control solution.
2. Use according to claim 1, characterized in that: the purity of the compound shown in the formula II is more than or equal to 90 percent.
3. Use according to claim 1, characterized in that the compound of formula II has a purity of 95% or more.
4. Use according to claim 1, wherein the compound of formula II is prepared by a process characterized in that: reacting a compound shown in a formula I with benzaldehyde in a solvent in the presence of a palladium catalyst, hydrogen and acid to prepare a compound shown in a formula II;
5. the use of claim 4, wherein in the preparation of the compound of formula II, the acid is selected from benzoic acid, p-toluenesulfonic acid, camphorsulfonic acid, trifluoroacetic acid or mixtures thereof.
6. Use according to claim 4, wherein in the preparation of the compound of formula II, the palladium catalyst is selected from Pd/C or Pd (OH)2。
7. The use of claim 4, wherein the solvent is selected from the group consisting of tetrahydrofuran, toluene, dichloromethane, and mixtures thereof in the preparation of the compound of formula II.
8. The use according to claim 4, wherein in the preparation of the compound of formula II, the compound of formula I and benzaldehyde are fed in a molar ratio of 1: 0.5-2.
9. The use according to claim 4, wherein in the preparation of the compound of formula II, the compound of formula I and the acid are fed in a molar ratio of 1: 1.5-5.
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