阅读说明：本技术 一种乙磺酸尼达尼布杂质及其制备方法和应用 (Ethanesulfonic acid nintedanib impurity as well as preparation method and application thereof ) 是由 曹金 杨文彬 游军辉 余俊 张小兵 于 2018-12-19 设计创作，主要内容包括：本发明涉及一种乙磺酸尼达尼布杂质及其制备方法和应用。本发明能够为乙磺酸尼达尼布产品检测提供分析对照品,提高乙磺酸尼达尼布质量标准,为乙磺酸尼达尼布安全用药提供保证。(The invention relates to an ethanesulfonic acid nintedanib impurity and a preparation method and application thereof. The invention can provide an analysis reference substance for detecting the product of the ethanesulfonic acid nintedanib, improve the quality standard of the ethanesulfonic acid nintedanib, and provide guarantee for safe medication of the ethanesulfonic acid nintedanib.)

1. An impurity of nedanib ethanesulfonate represented by formula I:

2. an impurity of nedanib ethanesulfonate represented by formula II:

3. the preparation method of the nifedipine ethanesulfonate impurity shown in the formula I in claim 1 is characterized in that the compound shown in the formula II and the compound shown in the formula IV undergo a condensation reaction in an organic solvent I, and the obtained product and ethanesulfonic acid form a salt in a mixed solvent of alcohol and water to obtain the nifedipine ethanesulfonate impurity shown in the formula I;

wherein R is₂Selected from hydrogen or-COR₃；R₁And R₃Independently selected from linear or branched alkyl groups having 1 to 6 carbon atoms, preferably methyl or ethyl;

optionally, when R₂is-COR₃In this case, the preparation method further comprises adding an alkaline substance after the condensation reaction is completed, and stirring for reaction, wherein the alkaline substance is preferably selected from potassium hydroxide, sodium carbonate, and potassium carbonate, and preferably potassium hydroxide.

4. The method for preparing the nedanib ethanesulfonate impurity of formula I according to claim 3, wherein the organic solvent I is selected from N, N-dimethylformamide, N-dimethylacetamide, N-diethylacetamide, methanol, ethanol or toluene, preferably N, N-dimethylacetamide or N, N-diethylacetamide.

5. The method for preparing the ethanesulfonic acid nintedanib impurity of the formula I as described in claim 3, wherein the molar ratio of the ethanesulfonic acid to the compound of the formula II is 1: 1-1.5: 1, preferably 1.05: 1; the concentration of the ethanesulfonic acid is 50 to 100%, preferably 70 to 100%, and more preferably 80%.

6. The method for preparing the nifedipine ethanesulfonate impurity of formula I according to claim 3, wherein the alcohol is selected from methanol, ethanol, n-propanol, isopropanol, ethylene glycol or propylene glycol, preferably ethanol or isopropanol; the volume ratio of the alcohol to the water is 3: 1-10: 1, preferably 5: 1-7: 1.

7. the method for preparing the nifedipine ethanesulfonate impurity of the formula I as claimed in claim 3, wherein the method for preparing the compound of the formula II comprises the following steps:

a) heating 2-chloro-N-methyl- (4-nitrophenyl) acetamide and piperazine in an organic solvent II and an acid-binding agent to reflux, and carrying out a condensation reaction to obtain a compound shown in a formula III;

b) the compound of the formula III is subjected to reduction reaction in an organic solvent III to prepare a compound of a formula II;

8. the method for preparing the nifedib ethanesulfonate impurity represented by the formula I according to claim 7, wherein the organic solvent II in the step a) is selected from ether or nitrile solvents, preferably methyl tert-butyl ether, tetrahydrofuran; the acid-binding agent is selected from potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, pyridine or triethylamine, preferably cesium carbonate; preferably, the molar ratio of the acid-binding agent to piperazine is 2: 1-15: 1, preferably 7: 1-10: 1.

9. the method for preparing the nifedipine ethanesulfonate impurity according to claim 7, wherein the reducing agent used in the reduction reaction in step b) is ferric chloride hexahydrate-hydrazine hydrate-activated carbon; the organic solvent III is selected from ester solvents, preferably ethyl formate, ethyl acetate or isopropyl acetate; more preferably ethyl acetate.

10. The method for preparing the nifedib ethanesulfonate impurity represented by the formula I as claimed in claim 9, wherein the molar ratio of the compound of the formula III to ferric trichloride hexahydrate is 1: 0.01-1: 0.2, preferably 1: 0.05-1: 0.1, more preferably 1: 0.08; the molar ratio of the compound of formula III to hydrazine hydrate is 1: 1-1: 10, preferably 1: 3-1: 5; more preferably 1: 4.7; the molar ratio of the compound of formula III to the activated carbon is 1: 1-1: 10, preferably 1: 2-1: 5, more preferably 1: 3.

11. the method for preparing the nifedib ethanesulfonate impurity represented by the formula I as claimed in claim 7, wherein the step b) further comprises refluxing and beating the obtained product in isopropanol after the reduction reaction is completed, preferably, the volume molar ratio of the isopropanol to the compound of the formula II is 5: 1-10: 1, more preferably 7: 1.

12. use of the nifedipine ethanesulfonate impurity according to claim 1 or 2 as an impurity control in the preparation of a raw material or formulation of nifedipine ethanesulfonate.

Technical Field

The invention belongs to the field of medicinal chemistry, and particularly relates to an ethanesulfonic acid nintedanib impurity as well as a preparation method and application thereof.

Background

Nintedanib ethanesulfonate, chemical name: (3Z) -3- { [ (4- { N-methyl-2- (4-methylpiperazin-1-yl) acetylamino } phenyl) amino ] (phenyl) methylene } -2-oxo-2, 3-dihydro-1H-indole-6-carboxylic acid methyl ester ethanesulfonate, english name: nintedanib Ethanesulfonate, a multiple tyrosine kinase inhibitor developed by boeriger ingelhem, is used to inhibit growth factor receptors associated with the pathogenesis of Idiopathic Pulmonary Fibrosis (IPF). In 2014 10, 15 days, nedanib ethanesulfonate was approved by the Food and Drug Administration (FDA) for marketing and treatment of Idiopathic Pulmonary Fibrosis (IPF) and non-small cell lung cancer.

The structural formula of the ethanesulfonic acid nintedanib is as follows:

chinese patents CN101883755A and CN101883756A both report methods for synthesizing nifedipine ethanesulfonate, and the synthetic routes are shown as follows:

the synthesis process of the ethanesulfonic acid nintedanib relates to a plurality of intermediates, and generates a plurality of impurities through side reactions. The impurities in the medicine have close relationship with the process, quality research, stability, pharmacology and toxicology and clinical research, and are directly related to the quality and safety of the medicine on the market. Chinese patent CN105001143A reports that the impurity of the ethanesulfonic acid nintedanib is difficult to purify, the yield after refining is low and the like, and the ethanesulfonic acid nintedanib meeting the report limit range of ICH (International conference on coordination of technical requirements for human drug registration) on the impurity in the bulk drug is difficult to obtain. Therefore, the technical problem to be solved in research and development of the nifedipine ethanesulfonate is to provide a finished product detection and analysis reference substance for controlling impurities in the nifedipine ethanesulfonate and provide a safe medication guarantee.

Disclosure of Invention

The invention aims to provide an ethanesulfonic acid nintedanib impurity, a preparation method and an application thereof, wherein the impurity is not reported in documents at home and abroad.

The invention provides an ethanesulfonic acid nintedanib impurity as shown in a formula I.

The precise molecular weight of the ethanesulfonic acid nintedanib impurity shown in the formula I is 964.39, and the result is confirmed by the nuclear magnetic resonance spectrum and the mass spectrum structure as follows:

the mass spectrum shows that the [ M-H ] is]^-The mass-to-nucleus ratio of the peak is 963.33, and the mass spectrum detection result is met; warp beam¹H-NMR、¹H-NMR+D₂O、¹³C-NMR confirmed that the compound of formula I obtained was correct in structure.

The invention also provides an ethanesulfonic acid nintedanib impurity shown as a formula II.

The precise molecular weight of the ethanesulfonic acid nintedanib impurity shown in the formula II is 410.24, and the result is confirmed by the nuclear magnetic resonance spectrum and the mass spectrum structure as follows:

the mass spectrum shows that the [ M + H ] is]+ peak and [ M + Na]The mass-to-nucleus ratios of the + peak are 411.46 and 433.40 respectively, and accord with the mass spectrum detection result; warp beam¹H-NMR of¹H-NMR+D₂O confirms that the compound of formula II is correct in structure.

In the research of the synthesis process of the nifedipine ethanesulfonate, the inventors of the present application found the impurities shown in formula I and formula II. The impurity shown in the formula II is generated in the process of preparing a nintedanib intermediate N- (4-aminophenyl) -N-methyl-2- (4-methylpiperazin-1-yl) acetamide, the impurity shown in the formula I is generated in the subsequent reaction process of preparing the ethanesulfonic acid nintedanib, and the impurity shown in the formula I and the ethanesulfonic acid nintedanib have similar physical and chemical properties and are difficult to remove.

The presence of the impurities of formula I and formula II in the product is as follows:

the invention also provides a preparation method of the ethanesulfonic acid nintedanib impurity shown in the formula I, which comprises the following steps:

the compound of formula I is obtained by condensation reaction of a compound of formula II and a compound of formula IV in an organic solvent I, salification of the obtained product and ethanesulfonic acid in a mixed solvent of alcohol and water,

wherein R is₂Selected from hydrogen or-COR₃，R₁And R₃Independently selected from linear or branched alkyl groups having 1 to 6 carbon atoms, preferably methyl or ethyl;

when R is₂is-COR₃When the preparation method is finished, the preparation method also comprises the steps of adding an alkaline substance after the condensation reaction is finished, and stirring for reaction; preferably, the alkaline substance is selected from potassium hydroxide, sodium carbonate, potassium carbonate, more preferably potassium hydroxide; the molar ratio of the basic substance to the compound of formula II is 1: 1-1: 3, more preferably 1: 2.

the synthesis route of the ethanesulfonic acid nintedanib impurity shown in the formula I is as follows:

wherein R is₁、R₂、R₃As defined above;

according to the preparation method of the present invention, the organic solvent I is selected from N, N-dimethylformamide, N-dimethylacetamide, N-diethylacetamide, methanol, ethanol or toluene, preferably N, N-dimethylacetamide or N, N-diethylacetamide;

the volume mol ratio (L/mol) of the organic solvent I to the compound of the formula II is 5: 1-20: 1, preferably 10: 1-15: 1;

the condensation reaction temperature is 50-100 ℃, and preferably 70-80 ℃;

the molar ratio of the ethanesulfonic acid to the compound of formula II is 1:1 to 1.5:1, preferably 1.05: 1;

the concentration of the ethanesulfonic acid is 50-100%, preferably 70-100%, more preferably 80%;

the alcohol is selected from methanol, ethanol, n-propanol, isopropanol, ethylene glycol or propylene glycol, preferably ethanol or isopropanol;

the volume ratio of the alcohol to the water is 3: 1-10: 1, preferably 5: 1-7: 1.

the invention also provides a preparation method of the ethanesulfonic acid nintedanib impurity shown in the formula II.

The preparation of the impurity of formula II comprises the following steps:

(a) heating 2-chloro-N-methyl- (4-nitrophenyl) acetamide and piperazine in an organic solvent II and an acid-binding agent to reflux, and carrying out a condensation reaction to obtain a compound shown in a formula III;

(b) the compound of the formula III is subjected to reduction reaction in an organic solvent III to prepare a compound of a formula II;

the synthetic route for the impurities of formula II is as follows:

according to the preparation method of the invention, the molar ratio of the 2-chloro-N-methyl- (4-nitrophenyl) acetamide to the piperazine in the step (a) is 3: 1-2: 1, preferably 2.1: 1;

the organic solvent II is selected from ether or nitrile solvents, preferably methyl tert-butyl ether or tetrahydrofuran;

the volume mol ratio (L/mol) of the organic solvent II to the piperazine is 5: 1-10: 1, preferably 7: 1;

the acid-binding agent is selected from potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, pyridine or triethylamine, preferably cesium carbonate;

the molar ratio of the acid-binding agent to the piperazine is 2: 1-15: 1, preferably 7: 1-10: 1;

according to the preparation method of the invention, the reducing agent used in the reduction reaction in the step (b) is ferric chloride hexahydrate-hydrazine hydrate-activated carbon;

the molar ratio of the compound of the formula III to ferric chloride hexahydrate is 1: 0.01-1: 0.2, preferably 1: 0.05-1: 0.1, more preferably 1: 0.08;

the molar ratio of the compound of formula III to hydrazine hydrate is 1: 1-1: 10, preferably 1: 3-1: 7; more preferably 1: 4.7;

the molar ratio of the compound of formula III to the activated carbon is 1: 1-1: 10, preferably 1: 2-1: 5, more preferably 1: 3;

the temperature of the reduction reaction is 25-65 ℃, and preferably 40-50 ℃;

the organic solvent III is selected from ester solvents, preferably ethyl formate, ethyl acetate or isopropyl acetate, more preferably ethyl acetate.

The volume mol ratio (L/mol) of the organic solvent III to the compound shown in the formula III is 10: 1-30: 1, preferably: 15: 1-25: 1.

according to the preparation method, the step (b) further comprises the steps of filtering after the reduction reaction is finished, washing with a mixed solvent of dichloromethane and methanol, concentrating the filtrate at 60-100 ℃ under reduced pressure, adding isopropanol, refluxing, pulping, stirring, filtering and washing to obtain impurities shown in a formula II; preferably, the volume ratio of dichloromethane to methanol is 3: 1-7: 1, more preferably 5:1, the volume molar ratio (L/mol) of isopropanol to the compound of formula II is 5: 1-10: 1, more preferably 7: 1.

the invention also provides application of the ethanesulfonic acid nintedanib impurity shown in the formula I or the formula II as an impurity reference substance in preparation of raw materials or preparations of ethanesulfonic acid nintedanib.

The invention firstly provides the impurities of the ethanesulfonic acid nintedanib shown in the formula I and the formula II, provides an analysis reference substance for detecting the ethanesulfonic acid nintedanib product, improves the quality standard of the ethanesulfonic acid nintedanib, and provides guarantee for safe medication of the ethanesulfonic acid nintedanib. Secondly, the invention provides a method for preparing the ethanesulfonic acid nintedanib impurities shown in the formula I and the formula II, the preparation method has the advantages of easily available raw materials, simple synthesis process and good repeatability, and the obtained ethanesulfonic acid nintedanib impurities have high yield and good purity by solvent screening and reaction condition optimization, and can be effectively applied to qualitative and quantitative analysis research on the ethanesulfonic acid nintedanib raw material medicines and related impurities of preparations thereof.

Drawings

FIG. 1 is a drawing of a compound of formula I prepared in example 1¹H-NMR spectrum.

FIG. 2 is a graphic representation of the compound of formula I prepared in example 1¹H-NMR+D₂And (4) an O spectrum.

FIG. 3 is a drawing showing a preparation process of example 1Preparation of compounds of formula I¹³C-NMR spectrum.

FIG. 4 is a MS spectrum of the compound of formula I prepared in example 1.

FIG. 5 is a photograph of a compound of formula II prepared in example 1¹H-NMR spectrum.

FIG. 6 is a photograph of a compound of formula II prepared in example 1¹H-NMR + D2O spectrum.

FIG. 7 is a MS spectrum of compound of formula II prepared in example 1.

FIG. 8 is an HPLC detection profile of the presence of the impurity of formula I in nintedanib ethanesulfonate.

FIG. 9 is an HPLC chromatogram of the compound of formula I prepared in example 1.

FIG. 10 is an HPLC chromatogram of the compound of formula II prepared in example 1.

FIG. 11 is a HPLC chromatogram of the compound of formula III prepared in example 1.

Detailed Description

For a better understanding of the present invention, reference will now be made to the following examples, which are intended to illustrate, but are not to be construed to limit the scope of the present invention.