CN111377845A - 3- (dimethylamino (phenyl) methylene) -2-oxindole-6-carboxylic acid methyl ester and preparation method and application thereof - Google Patents
3- (dimethylamino (phenyl) methylene) -2-oxindole-6-carboxylic acid methyl ester and preparation method and application thereof Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- NNPORSJJAKPQCR-UHFFFAOYSA-N methyl 3-[dimethylamino(phenyl)methylidene]-2-oxo-1H-indole-6-carboxylate Chemical compound COC(=O)C1=CC=C2C(C(NC2=C1)=O)=C(C1=CC=CC=C1)N(C)C NNPORSJJAKPQCR-UHFFFAOYSA-N 0.000 title abstract description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 39
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- XZXHXSATPCNXJR-ZIADKAODSA-N nintedanib Chemical compound O=C1NC2=CC(C(=O)OC)=CC=C2\C1=C(C=1C=CC=CC=1)\NC(C=C1)=CC=C1N(C)C(=O)CN1CCN(C)CC1 XZXHXSATPCNXJR-ZIADKAODSA-N 0.000 claims abstract description 31
- 239000002994 raw material Substances 0.000 claims abstract description 5
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- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 7
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
- C07D209/34—Oxygen atoms in position 2
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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
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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
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Abstract
The invention discloses 3- (dimethylamino (phenyl) methylene) -2-oxindole-6-carboxylic acid methyl ester and a preparation method and application thereof. The compound provided by the invention can be used as a reference substance for detecting related substances of the nintedanib and used for controlling the purity of a nintedanib raw material or a preparation.
Description
Technical Field
The invention belongs to the technical field of lung cancer resistance, and particularly relates to 3- (dimethylamino (phenyl) methylene) -2-oxindole-6-carboxylic acid methyl ester, a preparation method and application thereof, which are important impurities in a nintedanib raw material or preparation process.
Background
Nintedanib ethaneylate is a small molecule tyrosine kinase inhibitor that inhibits multiple Receptor Tyrosine Kinases (RTKs). platelet-derived growth factor receptors (PDGFR) α and β, Fibroblast Growth Factor Receptors (FGFR)1-3, Vascular Endothelial Growth Factor Receptors (VEGFR)1-3 and Fmas-like tyrosine kinase-3 (FLT 3.) Nintedanib ethanesulfonic acid was originally developed by the pharmaceutical company Boringer Ghan, and is marketed as a soft capsule, first marketed by FDA 10.10.2014, first marketed in the United states, and marketed by EMA 1.2014 for the treatment of Idiopathic Pulmonary Fibrosis (IPF), under the trade name of IPF
The specification was 100mg and 150mg (in nintedanib). In addition, nimidab ethanesulfonate combined with docetaxel was approved by EMA at 11 months of 2014 for the treatment of patients with locally advanced or metastatic recurrent non-small cell lung cancer with adenocarcinoma oncology after first-line chemotherapy, under the trade name
The specification was 100mg and 150mg (in nintedanib).
The chemical structural formula of the nintedanib is shown as formula 1:
the synthetic route of nintedanib is mainly a patent document applied by the pharmaceutical company of bulling-Yiger, the patent ZL03817530.4 reports a synthetic route 1, the patent ZL0880119068.4 reports a synthetic route 2, and the specific synthetic route is as follows.
Scheme 1:
scheme 2:
disclosure of Invention
The invention aims to provide a nintedanib impurity 3- (dimethylamino (phenyl) methylene) -2-oxindole-6-carboxylic acid methyl ester.
It is another object of the present invention to provide a method for preparing said impurities.
It is a final object of the invention to provide for the use of said impurities.
In order to achieve the purpose, the technical scheme provided by the invention is as follows:
the compound of the invention has a structure shown in formula 3:
the chemical name of the compound is 3- (dimethylamino (phenyl) methylene) -2-oxindole-6-carboxylic acid methyl ester, which is an impurity of nintedanib.
The preparation method of the compound with the structure shown in the formula 3 comprises the steps of reacting the compound shown in the formula 2 with N, N-dimethyl amide to obtain the compound shown in the formula 3,
wherein the N, N-dimethylamide is N, N-dimethylformamide, N-dimethylacetamide, N-dimethylpropionamide or N, N-dimethylbutanamide, preferably N, N-dimethylformamide or N, N-dimethylacetamide, the molar ratio of the compound of formula 2 to the N, N-dimethylamide being 1: (1.5-2.5), preferably 1: (1.6-2.1).
Wherein the reaction temperature is 40-80 ℃, preferably 50-65 ℃, further preferably 54-56 ℃, and the reaction time is 6-10 hours, preferably 8-10 hours.
Wherein the reaction solvent is methanol, dichloromethane, ethanol, isopropanol, butanol, ethyl acetate, anisole or toluene, and the ratio of the compound of formula 2 to the reaction solvent is 1 g: (0.5-2.5) ml, preferably 1 g: (1-2) ml, more preferably 1 g: (1.2-1.4) ml.
After the reaction is finished, extracting the reaction solution by using water and an organic solvent, wherein the organic solvent is one or more of ethyl acetate, isopropyl acetate, methyl acetate and butyl acetate.
In the extraction process, the using amount of the water is 5-15 times, preferably 8-12 times, of the volume of the reaction liquid, and the using amount of the organic solvent is 10-20 times, preferably 13-18 times, of the volume of the reaction liquid. The "amount" used herein refers to the total amount of water or organic solvent used in the extraction process.
Preferably, the water is purified water. And mixing the reaction solution with water, stirring for 10-50 min, preferably 30min, and adding an organic solvent for extraction.
Wherein, the compound of formula 3 is obtained after the reaction and the separation by column chromatography, concentration and drying.
Preferably, the column chromatography method uses silica gel for separation, the mobile phase is a mixture of a first solvent and a second solvent, the first solvent is one or more of ethyl acetate, dichloromethane and isopropyl acetate, and the second solvent is one or more of methanol, ethanol and isopropanol.
The volume ratio of the first solvent to the second solvent is (5-100): 1, preferably (10 to 100): 1.
the separation silica gel is silica gel used in conventional column chromatography, and is preferably 100-200 mesh separation silica gel.
The invention relates to application of a compound with a structure shown in a formula 3 in preparation of a nintedanib raw material or preparation impurity reference substance.
The applicant researches and discovers that in the production process of nintedanib, methoxy in the structure of the compound of the key intermediate formula 2 is easily degraded into N, N-dimethyl to generate a compound of a nintedanib process impurity formula 3, so that the quality of a final product is difficult to guarantee.
The invention develops a nintedanib process impurity, namely 3- (dimethylamino (phenyl) methylene) -2-oxoindole-6-carboxylic acid methyl ester, on the basis of preparing nintedanib by referring to a patent ZL0880119068.4, and obtains the 3- (dimethylamino (phenyl) methylene) -2-oxoindole-6-carboxylic acid methyl ester through one-step reaction and purification, thereby solving the problem of convenience and stability of obtaining the impurity; particularly, the invention researches the purification method of the impurities in the nintedanib process in detail, screens out more stable column chromatography separation conditions, and ensures that the purity of the impurities in the nintedanib process can reach more than 95 percent by HPLC. The preparation condition of the invention is mild and controllable, and the 3- (dimethylamino (phenyl) methylene) -2-oxindole-6-carboxylic acid methyl ester can be conveniently prepared.
Has the advantages that: 1. the compound 3- (dimethylamino (phenyl) methylene) -2-oxindole-6-carboxylic acid methyl ester provided by the invention can be used as a reference substance for detecting related substances of the nintedanib and used for quality control of the nintedanib raw material or related preparations thereof. 2. The preparation method of the impurities provided by the invention is convenient to operate, mild and controllable in reaction conditions, high in reaction stability, high in yield of reaction products and high in purity.
Drawings
FIG. 1 is a secondary mass spectrum of a compound of formula 3;
FIG. 2 is a NMR hydrogen spectrum of a compound of formula 3;
FIG. 3 is a carbon spectrum of a compound of formula 3;
FIG. 4 is a liquid phase detection profile of example 1;
FIG. 5 is a controlled HPLC chromatogram for the reaction of example 5.
Detailed Description
The invention will be described in more detail hereinafter by means of examples, which are intended to be illustrative further and should not be construed as limiting the invention.
Preparation of nintedanib process impurities
Example 1:
adding a compound of formula 2 (10g, 0.032mol) and 12ml of methanol into a reaction bottle, mixing and stirring, adding N, N-dimethylformamide (5ml, 0.065mol), heating to 55 ℃, reacting for 8 hours, adding purified water with the volume 10 times that of the reaction liquid, stirring for 30 minutes, adding ethyl acetate with the volume 10 times that of the reaction liquid for extraction, separating out an aqueous phase, extracting the aqueous phase with ethyl acetate with the volume 5 times that of the reaction liquid, combining organic phases, concentrating under reduced pressure, and purifying the concentrated sample by adopting a column chromatography method. The specific column chromatography conditions are as follows: the silica gel is 100-200 mesh common separation silica gel, and the mobile phase is ethyl acetate: methanol (100: 1 by volume) at a flow rate of 2 ml/min, the corresponding fractions were collected, concentrated under reduced pressure below 40 ℃ and dried under vacuum at 40 ℃ to give 6.30g of the compound of formula 3 in 60.6% yield and 98.9% HPLC purity (see fig. 4 for HPLC).
The structure of the compound of formula 3 is confirmed by mass spectrum (figure 1), nuclear magnetic resonance hydrogen spectrum (figure 2) and carbon spectrum (figure 3), and the specific data are shown in table 1 and table 2:
test data
And (3) map analysis:
TABLE 1 Hydrogen spectra of Nintedanib process impurities
TABLE 2 carbon spectra of the Nintedanib process impurities
Example 2:
adding a compound (6.5g, 0.021mol) of a formula 2 into a reaction bottle, mixing and stirring 12ml of ethanol, adding N, N-dimethylformamide (3.2ml, 0.0413mol), heating to 55 ℃, reacting for 8 hours, adding purified water with the volume 10 times that of the reaction liquid, stirring for 30 minutes, adding isopropyl acetate with the volume 10 times that of the reaction liquid for extraction, separating out an aqueous phase, extracting the aqueous phase with isopropyl acetate with the volume 5 times that of the reaction liquid, combining organic phases, concentrating under reduced pressure, and purifying a concentrated sample by adopting a column chromatography method. The specific column chromatography conditions are as follows: the silica gel is a common separation silica gel with a particle size of 100-200 meshes, and the mobile phase is isopropyl acetate: ethanol 100:5 (vol/vol) at a flow rate of 2 ml/min, the corresponding fractions were collected, concentrated under reduced pressure below 40 ℃ and dried under vacuum at 40 ℃ to give 4.30g of the compound of formula 3 in 63.6% yield and 97.8% HPLC purity.
Example 3:
adding a compound of formula 2 (8g, 0.026mol) and 12ml of toluene into a reaction bottle, mixing and stirring, adding N, N-dimethylacetamide (5ml, 0.054mol), heating to 55 ℃, reacting for 9 hours, adding purified water with the volume 10 times that of the reaction liquid, stirring for 30 minutes, adding methyl acetate with the volume 10 times that of the reaction liquid for extraction, separating out an aqueous phase, extracting the aqueous phase with methyl acetate with the volume 5 times that of the reaction liquid, combining organic phases, concentrating under reduced pressure, and purifying the concentrated sample by adopting a column chromatography method. The specific column chromatography conditions are as follows: the silica gel is 100-200 mesh common separation silica gel, and the mobile phase is ethyl acetate: ethanol 100:1 (vol/vol) at a flow rate of 2 ml/min, the corresponding fractions were collected, concentrated under reduced pressure below 40 ℃ and dried under vacuum at 40 ℃ to give 4.82g of the compound of formula 3 in 57.9% yield and 96.8% HPLC purity.
Example 4:
adding a compound of formula 2 (5g, 0.016mol) and 12ml of isopropanol into a reaction flask, mixing and stirring, adding N, N-dimethylacetamide (2.4ml, 0.026mol), heating to 55 ℃, reacting for 10 hours, adding purified water with the volume 10 times that of the reaction solution, stirring for 30 minutes, adding ethyl acetate with the volume 10 times that of the reaction solution, extracting, separating out an aqueous phase, extracting the aqueous phase with ethyl acetate with the volume 5 times that of the reaction solution, combining organic phases, concentrating under reduced pressure to dryness, and purifying the concentrated sample by adopting a column chromatography method. The specific column chromatography conditions are as follows: the silica gel is 100-200 mesh common separation silica gel, and the mobile phase is dichloromethane: methanol 100:10 (vol/vol) at a flow rate of 2 ml/min, the corresponding fractions were collected, concentrated under reduced pressure below 40 ℃ and dried under vacuum at 40 ℃ to give 2.42g of the compound of formula 3 in 48.2% yield and 95.5% HPLC purity.
Example 5:
nintedanib was prepared by reference to the synthetic method reported in patent ZL0880119068.4 (see scheme 2 for details).
The applicant researches and discovers that in the process of preparing the nintedanib by reacting the key intermediate compound of formula 2 with SCR-4308, methoxy in the structure of the key intermediate compound of formula 2 is easily degraded into N, N-dimethyl to generate the nintedanib process impurity compound of formula 3, so that the quality of the final product is difficult to ensure.
The key intermediate compound of formula 2 and SCR-4308 react to prepare Nintedanib by a specific process:
adding the compound shown in the formula 2, SCR-4308, methanol and N, N-dimethylformamide into a reaction kettle, stirring, carrying out nitrogen protection, heating to 55-65 ℃, reacting for 8 hours (taking reaction liquid for detection), cooling to 0-10 ℃ after the reaction is finished, filtering, washing with methanol, and carrying out vacuum drying on the solid at 40 +/-5 ℃ to obtain the nintedanib. The control spectrum of the reaction is shown in FIG. 5, wherein 16.199min is nintedanib, and 17.653min is the nintedanib process impurity compound of formula 3.
The detection conditions of fig. 5 are:
octadecylsilylated bonded silica gel is used as a filler in chromatographic conditions and system applicability tests; taking 10mmol/L ammonium acetate (pH is adjusted to 5.0 by glacial acetic acid) as a mobile phase A, and acetonitrile as a mobile phase B; the flow rate was 1.0ml per minute; the detection wavelength is 242 nm; the column temperature was 35 ℃; the sample volume was 5. mu.l and the elution was performed with a linear gradient as in Table 3 below.
TABLE 3
The assay method comprises taking appropriate amount of the product, adding solvent (acetonitrile: water: 80:20 mixed solution), diluting to obtain solution containing 1mg per 1ml, and making into sample solution. Precisely measuring 5 μ l of the sample solution, injecting into a liquid chromatograph, recording chromatogram, deducting solvent peak and gradient elution peak, and calculating according to area normalization method.
Claims (11)
1. A compound having the structure shown in formula 3:
2. the method for preparing the compound having the structure shown in the formula 3 according to claim 1, which comprises reacting the compound of the formula 2 with N, N-dimethylamide to obtain a compound of the formula 3,
3. the process according to claim 2, wherein the N, N-dimethylamide is N, N-dimethylformamide, N-dimethylacetamide, N-dimethylpropionamide or N, N-dimethylbutanamide, preferably N, N-dimethylformamide or N, N-dimethylacetamide, the molar ratio of the compound of formula 2 to N, N-dimethylamide being 1: (1.5-2.5), preferably 1: (1.6-2.1).
4. The method according to claim 2, wherein the reaction temperature is 40 to 80 ℃, preferably 50 to 65 ℃, further preferably 54 to 56 ℃, and the reaction time is 6 to 10 hours, preferably 8 to 10 hours.
5. The method according to claim 2, wherein the reaction solvent is methanol, dichloromethane, ethanol, isopropanol, butanol, ethyl acetate, anisole or toluene, and the ratio of the compound of formula 2 to the reaction solvent is 1 g: (0.5-2.5) ml, preferably 1 g: (1-2) ml, more preferably 1 g: (1.2-1.4) ml.
6. The method of claim 2, wherein after the reaction is completed, the reaction solution is extracted with water and an organic solvent, wherein the organic solvent is one or more of ethyl acetate, isopropyl acetate, methyl acetate and butyl acetate.
7. The method according to claim 6, wherein the amount of the water used in the extraction process is 5 to 15 times, preferably 8 to 12 times, the volume of the reaction solution, and the amount of the organic solvent used is 10 to 20 times, preferably 13 to 18 times, the volume of the reaction solution.
8. The method of claim 2, wherein the compound of formula 3 is obtained by separating the reaction product by column chromatography, concentrating and drying.
9. The method of claim 8, wherein the column chromatography method uses silica gel for separation, the mobile phase is a mixture of a first solvent and a second solvent, the first solvent is one or more of ethyl acetate, dichloromethane and isopropyl acetate, and the second solvent is one or more of methanol, ethanol and isopropanol.
10. The method of claim 9, wherein: the volume ratio of the first solvent to the second solvent is (5-100): 1, preferably (10 to 100): 1.
11. use of a compound of claim 1 having a structure represented by formula 3 in the preparation of a nintedanib raw material or a formulation impurity control.
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| CN201811614198.7A CN111377845A (en) | 2018-12-27 | 2018-12-27 | 3- (dimethylamino (phenyl) methylene) -2-oxindole-6-carboxylic acid methyl ester and preparation method and application thereof |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101883755A (en) * | 2007-12-03 | 2010-11-10 | 贝林格尔.英格海姆国际有限公司 | Indolinone derivatives and preparation methods thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101883755A (en) * | 2007-12-03 | 2010-11-10 | 贝林格尔.英格海姆国际有限公司 | Indolinone derivatives and preparation methods thereof |
Non-Patent Citations (2)
| Title |
|---|
| GRAEVSKAYA, I. P. 等: ""Synthesis and neurotropic properties of 1-(2,6-dichlorophenyl)-3-amino(alkoxy)methylene-2-indolinone derivatives"", 《KHIMIKO-FARMATSEVTICHESKII ZHURNAL》 * |
| 李正邦 等: ""尼达尼布有关物质测定方法的建立"", 《中国药师》 * |
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