CN109988094B - Preparation method of ethanesulfonic acid nintedanib - Google Patents
Preparation method of ethanesulfonic acid nintedanib Download PDFInfo
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- CN109988094B CN109988094B CN201910352138.0A CN201910352138A CN109988094B CN 109988094 B CN109988094 B CN 109988094B CN 201910352138 A CN201910352138 A CN 201910352138A CN 109988094 B CN109988094 B CN 109988094B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/32—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of salts of sulfonic acids
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/42—Separation; Purification; Stabilisation; Use of additives
- C07C303/44—Separation; Purification
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- C—CHEMISTRY; METALLURGY
- 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
Abstract
The invention relates to a preparation method of ethanesulfonic acid nintedanib, which comprises the following steps: the method comprises the following steps: adding 1-acetyl-3- [ methoxy (phenyl) methylene ] -2-oxoindoline-6-carboxylic acid methyl ester (compound A) and N- (4-aminophenyl) -N, 4-dimethyl-1-piperazineacetamide (compound B) into a reaction solvent for reaction, adding pyrrolidine after the reaction is finished for continuing the reaction, crystallizing, stirring and washing a mixed solvent, and drying to generate (3Z) -3- { [ (4- { methyl- [ (4-methylpiperazin-1-yl) acetyl ] amino) phenyl) amino ] - (phenyl) methylene } -2-oxo-2, 3-dihydroindole-6-carboxylic acid methyl ester (compound C); step two: and reacting the compound C with ethanesulfonic acid, crystallizing, filtering and drying to obtain the ethanesulfonic acid nintedanib (compound D). The method obtains the ethanesulfonic acid nintedanib with high purity, good yield and low impurity level through two-step reaction.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a preparation method of ethanesulfonic acid nintedanib.
Background
Idiopathic Pulmonary Fibrosis (IPF) is a chronic, progressive, fibrotic interstitial lung disease with lesions confined to the lungs, well-developed in the elderly population, characterized by common interstitial pneumonia (UIP) with unclear etiology in lung histology and/or high-resolution ct (hrct) of the chest.
There is currently no large-scale epidemiological study of incidence and prevalence of IPF. Overall IPF incidence appears to be a significantly increasing trend. Studies from the uk reported a total incidence of IPF of only 4.6/10 ten thousand, but the incidence of IPF increased by an estimated 11% annually between 1991 and 2003, an increase that appears to be unrelated to an aging population or an increased frequency of confirmed diagnosis in mild patients. According to the latest registered data from the American big sample medical care database, the prevalence rate of IPF in the general population of the United states is estimated to be (14.0-42.7)/10 ten thousand, and the prevalence rate is (6.8-16.3)/10 ten thousand.
The soft capsule of Nidanib ethanesulfonate is an effective drug for treating idiopathic pulmonary fibrosis, is developed and marketed by Boringer Ingerhan of original research company, and has a structural formula shown in formula I.
The Chinese patent application CN101883756A of the original research company discloses a method for preparing ethanesulfonic acid nintedanib, which has the following route:
the preparation method disclosed in the patent comprises the following basic route that 2-oxoindole-6-methyl formate reacts with chloroacetic anhydride, then reacts with trimethyl orthobenzoate, after acetyl group is removed, the obtained product reacts with N- (4-aminophenyl) -N, 4-dimethyl-1-piperazine acetamide to generate nintedanib, and the nintedanib and ethanesulfonic acid undergo salt formation reaction to obtain a finished product of the ethanesulfonic acid nintedanib.
In addition, chinese patent CN105837493A discloses a method for preparing nintedanib and intermediates, the method route is as follows:
the methods disclosed in the above patents have the disadvantages of long route, low total yield, high pressure hydrogenation reaction kettle, unsuitability for industrial production, and poor control of related substances, especially genotoxic impurities.
Genotoxic impurities (also called genotoxic impurities) are DNA mutagens which can induce gene mutation and cause chromosome breakage and rearrangement at any level of concentration, and can cause cancer, because the safety threshold of genotoxic impurities is difficult to determine, and the genotoxic impurities can still cause cancer at extremely low concentration, the harm thereof has attracted extensive attention, compared with common impurities, the risk of genotoxic impurities is higher, and in principle, the introduction of genotoxic impurities in industrial production is reduced or avoided as much as possible, so that higher requirements are provided for production processes and genotoxic impurity control means.
In the preparation process of the nifedipine ethanesulfonate, most process routes use one or more starting raw materials which are possibly introduced with genotoxic impurities, and a plurality of genotoxic impurities are possibly introduced into raw material products. However, the prior art does not sufficiently consider the removal of genotoxic impurities.
Therefore, the prior art lacks a preparation method of the nifedipine ethanesulfonate, which has the advantages of simple and convenient operation, high product yield, good purity, less impurities, particularly genotoxic impurities and suitability for industrial production.
Disclosure of Invention
Aiming at the defects in the prior art, the invention aims to provide the method for preparing the nifedipine ethanesulfonate, which has the advantages of simple operation, mild conditions, high product yield, good purity and low impurity, particularly genotoxic impurity.
The technical scheme of the invention is as follows:
a preparation method of the ethanesulfonic acid nintedanib comprises the following steps:
the method comprises the following steps: adding 1-acetyl-3- [ methoxy (phenyl) methylene ] -2-oxoindoline-6-formic acid methyl ester (compound A) and N- (4-aminophenyl) -N, 4-dimethyl-1-piperazineacetamide (compound B) into a reaction solvent to react at the reaction temperature of 40-60 ℃, adding pyrrolidine to continue the reaction after the reaction is finished, cooling to 20-40 ℃ after the reaction is finished, stirring and crystallizing, filtering, stirring and washing by using a dichloromethane/methanol mixed solvent, and drying to generate (3Z) -3- { [ (4- { methyl- [ (4-methylpiperazin-1-yl) acetyl ] amino) phenyl ] - (phenyl) methylene } -2-oxo-2, 3-indoline-6-carboxylic acid methyl ester (compound C),
step two: (3Z) -3- { [ (4- { methyl- [ (4-methylpiperazin-1-yl) acetyl ] amino) phenyl) amino ] - (phenyl) methylene } -2-oxo-2, 3-indoline-6-carboxylic acid methyl ester (compound C) and ethanesulfonic acid react in a reaction solvent methanol at a temperature of 40-60 ℃, after the reaction is finished, isopropanol is added, the temperature is reduced to 25-35 ℃, crystallization is carried out, filtration and drying are carried out, thus generating ethanesulfonic acid nintedanib (compound D),
preferably, in the first step of the preparation method of the nintedanib ethanesulfonate, the molar ratio of the methyl 1-acetyl-3- [ methoxy (phenyl) methylene ] -2-oxoindoline-6-carboxylate (compound a) to the compound N- (4-aminophenyl) -N, 4-dimethyl-1-piperazineacetamide (compound B) is 1: 1-1: 2.
Further preferably, the molar ratio of the above-mentioned methyl 1-acetyl-3- [ methoxy (phenyl) methylene ] -2-oxoindoline-6-carboxylate (compound a) and the compound N- (4-aminophenyl) -N, 4-dimethyl-1-piperazineacetamide (compound B) is 1: 1.2.
Further, in the preparation method of the esylate nintedanib, in the first step, the reaction solvent is N, N-dimethylformamide or methanol.
Further preferably, the reaction solvent is methanol.
Further preferably, in the preparation method of nintedanib ethanesulfonate, in the first step, the ratio of the methyl 1-acetyl-3- [ methoxy (phenyl) methylene ] -2-oxoindoline-6-carboxylate (compound a) to the reaction solvent is 1:5-1:15 (mass/volume, g/mL).
Preferably, in the first step of the preparation method of the nifedipine ethanesulfonate, the reaction temperature is 45-50 ℃.
Preferably, in the first step of the preparation method of the esylate nintedanib, the reaction time is 2-6 h of initial reaction, and the reaction is continued for 1-2h after the pyrrolidine is added.
Preferably, in the first step of the preparation method of the nintedanib ethanesulfonate, the molar ratio of the methyl 1-acetyl-3- [ methoxy (phenyl) methylene ] -2-oxoindoline-6-carboxylate (compound a) to the pyrrolidine is 1: 1-1: 1.5.
Preferably, in the first step of the preparation method of the nifedipine ethanesulfonate, the crystallization time is 2-3 h.
Further, in the preparation method of the ethanesulfonic acid nintedanib, in the first step, the volume ratio of dichloromethane to methanol in the mixed solvent is 20: 1-10: 1.
Further, in the preparation method of the ethanesulfonic acid nintedanib, in the first step, the temperature for cooling and crystallization is 25-30 ℃.
Furthermore, in the preparation method of the ethanesulfonic acid nintedanib, in the first step, the volume of the added mixed solvent is 4-6 times of the volume of the stirred and washed solid.
Preferably, in the preparation method of the ethanesulfonic acid nintedanib, in the second step, the molar ratio of the (3Z) -3- { [ (4- { methyl- [ (4-methylpiperazin-1-yl) acetyl ] amino) phenyl) amino ] - (phenyl) methylene } -2-oxo-2, 3-indoline-6-carboxylic acid methyl ester (compound C) to the ethanesulfonic acid is 1:1.5-1: 2.
Preferably, the preparation method of the nifedipine ethanesulfonate comprises the step two, wherein the ratio of (3Z) -3- { [ (4- { methyl- [ (4-methylpiperazin-1-yl) acetyl ] amino) phenyl) amino ] - (phenyl) methylene } -2-oxo-2, 3-indoline-6-carboxylic acid methyl ester (compound C) to methanol is 1:10-1:15 (mass/volume, g/mL).
Preferably, in the second step of the method for preparing the ethanesulfonic acid nintedanib, the ethanesulfonic acid is added in the form of an ethanesulfonic acid aqueous solution with a mass percentage of 70%.
Preferably, in the second step of the method for preparing the nintedanib ethanesulfonate, the reaction temperature is 50-55 ℃.
Further, the preparation method of the ethanesulfonic acid nintedanib comprises the step two, wherein the reaction time is 0.5-1 h.
Preferably, in the preparation method of the nifedipine ethanesulfonate, the ratio of (3Z) -3- { [ (4- { methyl- [ (4-methylpiperazin-1-yl) acetyl ] amino) phenyl) amino ] - (phenyl) methylene } -2-oxo-2, 3-indoline-6-carboxylic acid methyl ester (compound C) to isopropanol in the second step is 1:20-1:50 (mass/volume, g/mL).
Preferably, in the second step of the preparation method of the nifedipine ethanesulfonate, the crystallization temperature is 30-35 ℃.
Further, in the preparation method of the ethanesulfonic acid nintedanib, in the second step, the crystallization time is 4-6 h.
The technical scheme of the invention has the following technical effects:
1. according to the technical scheme, the ethanesulfonic acid nintedanib with high purity, good yield and low impurity level is obtained through two-step reaction, the method can effectively remove genotoxic impurities, and meanwhile, the preparation process is simple and convenient, the conditions are mild, and the industrial production is facilitated.
2. Genotoxic impurities are highly biologically active substances that can damage DNA and have potential carcinogenic toxicity, but such substances are difficult to define a safe threshold (concentration) and should therefore be avoided as much as possible. Three genotoxic impurities possibly introduced by the process are also common genotoxic impurities in the prior art of the nifedipine ethanesulfonate, and comprise N- (4-aminophenyl) -N, 4-dimethyl-1-piperazineacetamide (compound B), N-methyl-4-nitroaniline and N-methyl-2- (4-methylpiperazin-1-yl) -N- (4-nitrophenyl) acetamide, and the removal of the impurities can be realized by washing a large amount of solvent or recrystallizing the product for multiple times, but the yield is greatly reduced due to excessive washing and purification. Through a large number of experiments, the invention unexpectedly discovers that the specific mixed solvent is adopted for stirring and washing in the step one, and the crystallization temperature is controlled in the step two, so that the high total yield and purity of the product can be ensured, and the three genotoxic impurities can be completely removed.
3. Through a screening test of a stirring and washing solution, the inventor unexpectedly finds that impurities wrapped in a product can be obviously removed by adopting a mixed solution of dichloromethane and methanol with a volume ratio of 20: 1-10: 1 for stirring and washing, and compared with other comparative solvents, the removal effect on gene toxic impurities with an aniline structure is very obvious, and under the scheme of the invention, N- (4-aminophenyl) -N, 4-dimethyl-1-piperazineacetamide (compound B), N-methyl-4-nitroaniline and N-methyl-2- (4-methylpiperazin-1-yl) -N- (4-nitrophenyl) acetamide are not detected.
4. The reaction in the second step is carried out at the temperature of 40-60 ℃, and another solvent is added for crystallization after the reaction is finished, the inventor of the invention unexpectedly finds that the temperature in the second crystallization step is in the range of 25-35 ℃, the purity of the obtained ethanesulfonic acid nintedanib (compound D) is highest, and the genotoxic impurities N- (4-aminophenyl) -N, 4-dimethyl-1-piperazineacetamide (compound B) (detection limit is 2ppm), N-methyl-4-nitroaniline (detection limit is 10ppm) and N-methyl-2- (4-methylpiperazine-1-yl) -N- (4-nitrophenyl) acetamide (detection limit is 10ppm) are obviously reduced and are not detected.
Detailed Description
The present invention is further described in detail with reference to the following specific examples, but the present invention is not limited to the technical solutions provided in the following examples.
According to the different preparation examples and comparative examples of the present invention, the starting materials, Compound A and Compound B, were used in the same batch, and the batch number and purity were 97.4% for Compound A (batch number 20170501) and 99.7% for Compound B (batch number 20170522), respectively.
Example 1
Adding 900ml of methanol, 90.0g of methyl 1-acetyl-3- [ methoxy (phenyl) methylene ] -2-oxoindoline-6-carboxylate (compound A) and 80.6g of N- (4-aminophenyl) -N, 4-dimethyl-1-piperazineacetamide (compound B) into a 2L glass reaction bottle, heating to 45-50 ℃, reacting for 2 hours, adding 18.2g of pyrrolidine, stirring at 45-50 ℃, reacting for 1 hour, cooling to 25-30 ℃, stirring, crystallizing for 3 hours, filtering, adding dichloromethane with the volume ratio of 10: 1: the mixture was stirred and washed with methanol, and dried to obtain 126.3g of methyl (3Z) -3- { [ (4- { methyl- [ (4-methylpiperazin-1-yl) acetyl ] amino } phenyl } amino } - (phenyl) methylene } -2-oxo-2, 3-indoline-6-carboxylate (Compound C), yield 91.37%, purity 99.89%.
1.2L of anhydrous methanol is added into a 2L glass bottle, 100.0g of (3Z) -3- { [ (4- { methyl- [ (4-methylpiperazin-1-yl) acetyl ] amino } phenyl } amino } - (phenyl) methylene } -2-oxo-2, 3-indoline-6-carboxylic acid methyl ester (compound C) prepared in example 1 is added, the temperature is raised to 50-55 ℃, 58.3g of 70% ethanesulfonic acid is added dropwise, the temperature is controlled to 50-55 ℃, the reaction is carried out for 0.5h, after the reaction is finished, 3.6L of isopropanol is added, the temperature is lowered to 25-30 ℃, crystallization is carried out for 4h, leaching and vacuum drying are carried out, and 109.9g of finished product of ethanesulfonic acid nintedanib (compound D) which is bright yellow crystalline powder is obtained, the yield is 91.27%, and the purity is 99.96%.
The total yield of the above two-step reaction was 83.4%.
Example 2
The same procedures as in example 1 were repeated except for using 900mL of N, N-dimethylformamide instead of methanol as the reaction solvent in the first step to give 124.3g of the compound c in 89.92% yield and 99.85% purity in the second step, and 107.3g of the compound D in the second step in 89.11% yield and 99.93% purity in the first step. The total yield of the two-step reaction was 80.1%.
Example 3
And the temperature of the temperature reduction and crystallization in the second step is controlled to be 30-35 ℃, other operations are the same as those in the first embodiment, 106.2g of the compound D finished product is obtained in the second step, the yield is 88.20%, and the purity is 99.95%. The total yield of the two-step reaction was 80.6%.
Example 4 and comparative examples 1 to 7
The following solvents were used as the agitation solvent in step one, and the other operations were the same as in example 1, to complete example 4 and comparative examples 1 to 7, and the overall yield and product purity were compared with example 1, with the results shown in the following table:
TABLE 1 Trust solvent investigation
Comparative examples 8-11 selection of crystallization temperatures for Nintedanib ethanesulfonate
Comparative examples 8-10 were carried out in the same manner as in example 1 except that the following crystallization temperatures were used to prepare nintedanib ethanesulfonate (compound D), and the results were shown in the following table, in comparison with examples 1 and 3.
TABLE 2 selection of two different crystallization temperatures in the step two
| Numbering | Temperature of crystallization | Purity of Compound D | Overall yield of |
| Comparative example 8 | 0-10℃ | 99.90％ | 89.9％ |
| Comparative example 9 | 10-15℃ | 99.90％ | 87.6％ |
| Comparative example 10 | 15-20℃ | 99.91％ | 85.2％ |
| Example 1 | 25-30℃ | 99.96％ | 83.4％ |
| Example 3 | 30-35℃ | 99.95％ | 80.6％ |
Test example 1
The related substance detection is carried out on the ethanesulfonic acid nintedanib prepared in examples 1-4 and comparative examples 1-10, and the total impurities and three genotoxic impurities are mainly determined, and the results are as follows:
TABLE 3 Nedanib ethanesulfonate impurity detection results
The detection results show that the solvent is preferably stirred and washed and the crystallization temperature of the final product is optimized through the technological process, the product purity is good, related substances are few, and particularly genotoxic impurities can be removed.
Test example 2
The soft capsule preparation prepared by adopting the ethanesulfonic acid nintedanib prepared in the embodiment 1 of the invention and adopting the same prescription as the original formulation is detected for the genotoxic impurity level of the preparation and compared with the reference formulation in the original formulation, and the result is shown in the following table:
TABLE 4 detection results of genotoxic impurities in self-made preparations and reference preparations
The determination result shows that the gene toxic impurities of the preparation prepared from the raw materials of the invention, namely N- (4-aminophenyl) -N, 4-dimethyl-1-piperazineacetamide (compound B) and N-methyl-2- (4-methylpiperazin-1-yl) -N- (4-nitrophenyl) acetamide, are obviously lower than those of a reference preparation.
Claims (9)
1. A preparation method of the ethanesulfonic acid nintedanib comprises the following steps:
the method comprises the following steps: adding 1-acetyl-3- [ methoxy (phenyl) methylene ] -2-oxoindoline-6-formic acid methyl ester (compound A) and N- (4-aminophenyl) -N, 4-dimethyl-1-piperazineacetamide (compound B) into a reaction solvent to react at the reaction temperature of 40-60 ℃, adding pyrrolidine to continue the reaction after the reaction is finished, cooling to 20-40 ℃ after the reaction is finished, stirring and crystallizing, filtering, stirring and washing by using a dichloromethane/methanol mixed solvent, and drying to generate (3Z) -3- { [ (4- { methyl- [ (4-methylpiperazin-1-yl) acetyl ] amino } phenyl) amino ] - (phenyl) methylene } -2-oxo-2, 3-indoline-6-carboxylic acid methyl ester (compound C),
step two: (3Z) -3- { [ (4- { methyl- [ (4-methylpiperazin-1-yl) acetyl ] amino } phenyl) amino ] - (phenyl) methylene } -2-oxo-2, 3-indoline-6-carboxylic acid methyl ester (compound C) and ethanesulfonic acid react in a reaction solvent methanol at a temperature of 40-60 ℃, after the reaction is finished, isopropanol is added, the temperature is reduced to 25-35 ℃, crystallization is carried out, filtration and drying are carried out, thus generating ethanesulfonic acid nintedanib (compound D),
in the first step, the volume ratio of dichloromethane to methanol in the dichloromethane/methanol mixed solvent is 20: 1-10: 1.
2. The method for preparing the nifedipine ethanesulfonate according to claim 1, wherein: in the first step, the molar ratio of 1-acetyl-3- [ methoxy (phenyl) methylene ] -2-oxoindoline-6-carboxylic acid methyl ester (compound A) to the compound N- (4-aminophenyl) -N, 4-dimethyl-1-piperazineacetamide (compound B) is 1: 1-1: 2.
3. The method for preparing the nifedipine ethanesulfonate according to claim 1, wherein: in the first step, the reaction solvent is N, N-dimethylformamide or methanol.
4. The method for preparing the nifedipine ethanesulfonate according to claim 1, wherein: in the first step, the reaction temperature is 45-50 ℃.
5. The method for preparing the nifedipine ethanesulfonate according to claim 1, wherein: in the first step, the molar ratio of the 1-acetyl-3- [ methoxy (phenyl) methylene ] -2-oxoindoline-6-carboxylic acid methyl ester (compound A) to the pyrrolidine is 1: 1-1: 1.5.
6. The method for preparing the nifedipine ethanesulfonate according to claim 1, wherein: in the first step, the temperature for cooling and crystallizing is 25-30 ℃.
7. The process for preparing nintedanib ethanesulfonate according to claim 1, wherein in step two, the molar ratio of methyl (3Z) -3- { [ (4- { methyl- [ (4-methylpiperazin-1-yl) acetyl ] amino } phenyl) amino ] - (phenyl) methylene } -2-oxo-2, 3-indoline-6-carboxylate (compound C) to ethanesulfonic acid is 1:1.5-1: 2.
8. The method for preparing nintedanib ethanesulfonate according to claim 1, wherein the reaction temperature in step two is 50-55 ℃.
9. The method for preparing nintedanib ethanesulfonate according to claim 1, wherein in the second step, the crystallization temperature is 30-35 ℃.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2004013099A1 (en) * | 2002-07-24 | 2004-02-12 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | 3-z-[1-(4-(n-((4-methyl-piperazin-1-yl)-methylcarbonyl)-n-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulphonate and the use thereof as a pharmaceutical composition |
| CN107011241A (en) * | 2017-04-24 | 2017-08-04 | 常州佳德医药科技有限公司 | A kind of preparation method of Nintedanib esilate |
| CN107820487A (en) * | 2015-07-29 | 2018-03-20 | 赞蒂瓦有限合伙公司 | Prepare (Z) 3 [[4 [methyl [2 (piperazinyl of 4 methyl 1) acetyl group] amino] phenyl] amino] phenylmethylene) Oxoindole 6 carboxylate methyl ester (Nintedanib, Ning Tedani) method |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004013099A1 (en) * | 2002-07-24 | 2004-02-12 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | 3-z-[1-(4-(n-((4-methyl-piperazin-1-yl)-methylcarbonyl)-n-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulphonate and the use thereof as a pharmaceutical composition |
| CN107820487A (en) * | 2015-07-29 | 2018-03-20 | 赞蒂瓦有限合伙公司 | Prepare (Z) 3 [[4 [methyl [2 (piperazinyl of 4 methyl 1) acetyl group] amino] phenyl] amino] phenylmethylene) Oxoindole 6 carboxylate methyl ester (Nintedanib, Ning Tedani) method |
| CN107011241A (en) * | 2017-04-24 | 2017-08-04 | 常州佳德医药科技有限公司 | A kind of preparation method of Nintedanib esilate |
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