CN111777576A - Preparation method of nintedanib key intermediate - Google Patents
Preparation method of nintedanib key intermediate Download PDFInfo
- Publication number
- CN111777576A CN111777576A CN201910273385.1A CN201910273385A CN111777576A CN 111777576 A CN111777576 A CN 111777576A CN 201910273385 A CN201910273385 A CN 201910273385A CN 111777576 A CN111777576 A CN 111777576A
- Authority
- CN
- China
- Prior art keywords
- solvent
- compound
- ether
- reverse phase
- dosage
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
Abstract
The invention belongs to the technical field of pharmaceutical chemicals, and particularly relates to a preparation method of a nintedanib key intermediate compound II. The adopted reaction condition is mild, high-pressure equipment is avoided, the technical operation is simple, the condition is mild, the process is safer and more environment-friendly, and the feasibility of large-scale production of the nintedanib is greatly improved.
Description
Technical Field
The invention belongs to the technical field of medicinal chemistry, and particularly relates to a preparation method of a key intermediate N- (4-aminophenyl) -N-methyl-2- (4-methylpiperazin-1-yl) acetamide of a tyrosine kinase inhibitor drug nintedanib.
Background
Nintedanib Ethanesulfonate (compound of formula I), known under the english name Nintedanib ethanehanesulfonate, chemical name: (3Z) -2, 3-dihydro-3- [ [ [4- [ methyl [2- (4-methyl-1-piperazinyl) acetyl ] methyl]Amino group]Phenyl radical]Amino group]Benzylidene radical]-2-oxo-1H-indole-6-carboxylic acid methyl ester ethanesulfonate, an oral tyrosine kinase inhibitor developed by Boringer's GmbH, approved by FDA in 2014, under the trade name
Marketed for the treatment of Idiopathic Pulmonary Fibrosis (IPF), became the first Tyrosine Kinase Inhibitor (TKI) approved for the treatment of IPF. The Chinese market was published in 2017, and the Chinese market is currently marketed in a plurality of countries around the world, such as the United states and European Union.
Nedanib ethanesulfonate has been shown to act as a growth factor receptor with potential impact on the pathological mechanisms of pulmonary fibrosis, the most important of which are platelet-derived growth factor receptor (PDGFR), Fibroblast Growth Factor Receptor (FGFR) and Vascular Endothelial Growth Factor Receptor (VEGFR). By blocking these signal transduction pathways involved in the fibrotic process, nintedanib can slow IPF disease progression by reducing the rate of decline in lung function.
The structural formula of the ethanesulfonic acid nintedanib is as follows:
according to the report of the literature, the synthesis of the nifedipine ethanesulfonate is to react an intermediate N- (4-aminophenyl) -N-methyl-2- (4-methylpiperazin-1-yl) acetamide (compound II) with an intermediate methyl 1-acetyl-3- (methoxy (phenyl) methylene) -2-oxoindole-6-carboxylate (compound III) in an organic solvent, then to carry out deprotection on N-acetyl in the presence of piperidine to obtain the nifedipine, and then to form a salt with ethanesulfonic acid to obtain the product, wherein the process route is as follows:
wherein, the preparation of the key intermediate compound (II) needs to be obtained by nitro reduction reaction, and the reaction formula is as follows:
at present, the nitro reduction preparation method of the compound II mainly comprises the following two methods:
(1) palladium on carbon/hydrogenation reduction system
WO2012068441, WO2015153877, WO2018160967 and other patents report that compound IV is subjected to palladium on carbon/hydrogen high pressure hydrogenation to obtain compound II.
The method needs to use a special high-pressure autoclave for high-pressure hydrogenation operation, has extremely high requirements on the gas environment in the system, needs to strictly prevent explosion reaction caused by air mixing, and has extremely high potential safety hazard in industrial mass production.
(2) Reduction of sodium hydrosulfite
CN106467500 reports that compound IV is subjected to reduction reaction by sodium hydrosulfite, and then compound II is obtained after treatment.
Although high-pressure equipment is not needed in the method, sodium hydrosulfite (sodium hydrosulfite) adopted in the reduction reaction is a first-grade moisture inflammable substance, and the sodium hydrosulfite reacts strongly and burns when meeting moisture to generate combustible gases, namely hydrogen sulfide and sulfur dioxide, and once an accident occurs, the danger is huge.
In summary, the reported routes still have the problems of environmental pollution and extremely high safety hazard, and in view of the fact that the drug selection for treating IPF is less for a long time, patients face the threats of fast disease progression and high death risk. Therefore, it is necessary to develop a safe and environment-friendly synthetic route of the nintedanib intermediate which is simple and convenient to operate and more suitable for industrial production.
Disclosure of Invention
The invention aims to provide safe and environment-friendly nintedanib which overcomes the defects of the prior art and is more suitable for industrial production and a preparation method of a key intermediate (II) thereof.
In order to achieve the above technical object, a first technical solution of the present invention is as follows:
and adding an organic solvent, trichlorosilane and organic base into the compound IV to perform a reduction reaction, and after the reaction is finished, adding a reverse phase solvent to crystallize to obtain a compound II.
In the scheme, the organic solvent is selected from chloralkane, preferably one or more of dichloromethane, dichloroethane and trichloromethane;
in the scheme, the organic base is selected from tertiary amine, preferably triethylamine and N, N-diisopropylethylamine;
in the scheme, the reverse phase solvent is selected from ether solvents, alkane solvents or mixtures thereof;
in the scheme, the reverse phase solvent ether solvent is selected from one or more of diethyl ether, isopropyl ether and methyl tert-butyl ether; the alkane solvent is selected from lower alkane, preferably one or more of n-hexane, cyclohexane, n-heptane, and petroleum ether;
in the scheme, the molar ratio of trichlorosilane to compound IV is 2.0-8.0, preferably 3.0-4.0;
in the scheme, the molar ratio of the organic base to the compound IV is 3.0-8.0, preferably 4.0-6.0;
in the scheme, the reduction reaction is carried out at the temperature of 0-50 ℃, preferably 5-40 ℃, and more preferably at room temperature, wherein the room temperature is 10-35 ℃, preferably 15-30 ℃, and more preferably 20-30 ℃.
The second technical scheme of the invention is as follows:
in an alcohol solvent, carrying out nitro reduction reaction on the compound IV under the condition of palladium carbon/ammonium formate until the nitro reduction reaction is complete, filtering, and adding a reverse phase solvent for crystallization to obtain a compound II.
In the scheme, the alcohol solvent can be a lower alcohol of C1-C5, preferably one or more of methanol, ethanol and isopropanol;
in the scheme, the reverse phase solvent is selected from ether solvents, alkane solvents or mixtures thereof;
in the scheme, the reverse solvent ether solvent is selected from one or more of diethyl ether, isopropyl ether and methyl tert-butyl ether; the alkane solvent is selected from lower alkane, preferably one or more of n-hexane, cyclohexane, n-heptane, and petroleum ether;
in the scheme, the mass ratio of the palladium carbon to the compound IV is 0.005-0.1, preferably 0.01-0.05;
in the scheme, the molar ratio of the amine formate to the compound IV is 2.0-8.0, preferably 3.0-5.0;
in this embodiment, the temperature of the reduction reaction is 20 to 80 ℃, preferably 40 to 60 ℃.
The third technical scheme of the invention is as follows:
in an alcohol solvent, carrying out nitro reduction reaction on the compound IV under the conditions of hydrazine hydrate/ferric trichloride/activated carbon until the nitro reduction reaction is complete, filtering, and adding a reverse phase solvent for crystallization to obtain a compound II.
In the scheme, the alcohol solvent can be C1-C5 lower alcohol, preferably one or more of methanol, ethanol and isopropanol;
in the scheme, the reverse phase solvent is selected from ether solvents, alkane solvents or mixtures thereof;
in the scheme, the reverse-phase ether solvent is selected from one or more of diethyl ether, isopropyl ether and methyl tert-butyl ether; the alkane solvent is selected from lower alkane, preferably one or more of n-hexane, cyclohexane, n-heptane, and petroleum ether;
in the scheme, the molar ratio of hydrazine hydrate to the compound IV is 4.0-10.0, preferably 5.0-8.0;
the mass ratio of the ferric trichloride to the compound IV is 0.02-0.1, preferably 0.04-0.08;
the mass ratio of the activated carbon to the compound IV is 0.1-0.5, preferably 0.2-0.3;
in the scheme, the temperature of the reduction reaction is 20-90 ℃, and preferably 30-50 ℃.
In the present invention, unless otherwise specified, the amount of the reaction solvent is the conventional amount for the reaction, and can be determined by those skilled in the art according to the prior art; the reagents used in the invention are conventional reagents and can be purchased in the market, and the used starting materials and reactants can be prepared by the prior art or the published prior documents and can also be purchased in the market; the room temperature in the invention has the technical meaning known in the art, and generally means 20-35 ℃, and the room temperature in the invention is preferably 20-30 ℃, and more preferably 20-25 ℃; the palladium on carbon used in the present invention is palladium on carbon containing water, and the water content is 35 wt%.
Compared with the prior art, the invention has the following beneficial effects:
according to the preparation method of the nintedanib key intermediate compound II, the compound IV is reduced by adopting common reaction reagents under the conditions of normal temperature and normal pressure, so that the high-purity compound II can be conveniently obtained. The adopted reaction condition is mild, high-pressure equipment is avoided, the technical operation is simple, the condition is mild, the process is safer and more environment-friendly, and the feasibility of large-scale production of the nintedanib is greatly improved.
Detailed Description
The foregoing and other aspects of the present invention are achieved by the following detailed description, which should not be construed to limit the claimed subject matter in any way. The technical scheme obtained by simply improving the invention or equivalently replacing the conventional means or components on the basis of the technical scheme of the invention belongs to the protection scope of the invention.
Comparative example 1: preparation of N- (4-aminophenyl) -N-methyl-2- (4-methylpiperazin-1-yl) acetamide (Compound II)
According to the method described in patent WO2015153877A1, Pd/C-H is used2The catalytic system reduces the compound IV to prepare a compound II, which comprises the following steps:
compound IV (5g, 17mmol) was charged to the reactor, methanol 50mL, 0.6g of 10% Pd/C was added, hydrogen was bubbled up to 50psi and reacted at room temperature for 2 hours. After completion of the reaction, filtration was carried out, the filtrate was concentrated under reduced pressure, and the residue was added with ether, stirred, filtered, and dried under vacuum at 50 ℃ to obtain 3.2g of compound II, yield 71.3%, HPLC purity: 98.79 percent.
Example 1: preparation of N- (4-aminophenyl) -N-methyl-2- (4-methylpiperazin-1-yl) acetamide (Compound II)
Adding 100ml of dichloromethane into a reaction bottle, adding 38.5g (131.7mmol) of N- (4-aminophenyl) -N-methyl-2- (4-methylpiperazin-1-yl) acetamide (compound IV), 62g of trichlorosilane (460mmol) and 90ml of triethylamine (647mmol), reacting at room temperature until the TLC detection reaction is completed, adding 300ml of methyl tert-butyl ether into the filtrate, stirring for crystallization, performing suction filtration, and performing vacuum drying at 50 ℃ to obtain 28.4g of off-white solid, wherein the yield is 82.2%, and the HPLC purity: 99.66 percent.
Example 2: preparation of N- (4-aminophenyl) -N-methyl-2- (4-methylpiperazin-1-yl) acetamide (Compound II)
Adding 100ml of trichloromethane into a reaction bottle, adding 38.5g (131.7mmol) of N- (4-aminophenyl) -N-methyl-2- (4-methylpiperazin-1-yl) acetamide (compound IV), 62g of trichlorosilane (460mmol) and 87ml of N, N-diisopropylethylamine (526.8mmol), reacting at room temperature until the TLC detection reaction is completed, adding 300ml of N-hexane, stirring, crystallizing, filtering, and drying in vacuum at 50 ℃ to obtain 28.1g of off-white solid with the yield of 81.3%, the HPLC purity: 99.67 percent.
Example 3: preparation of N- (4-aminophenyl) -N-methyl-2- (4-methylpiperazin-1-yl) acetamide (Compound II)
Adding 100ml of trichloromethane into a reaction bottle, adding 38.5g (131.7mmol) of N- (4-aminophenyl) -N-methyl-2- (4-methylpiperazin-1-yl) acetamide (compound IV), 53.5g of trichlorosilane (395.1mmol) and 90ml of triethylamine (647mmol), reacting at room temperature until TLC detection reaction is completed, adding 300ml of cyclohexane, stirring for crystallization, performing suction filtration, and performing vacuum drying at 50 ℃ to obtain 28.9g of off-white solid, wherein the yield is 83.6%, and the HPLC purity: 99.62 percent.
Example 4: preparation of N- (4-aminophenyl) -N-methyl-2- (4-methylpiperazin-1-yl) acetamide (Compound II)
Adding 20g (68.4mmol) of N- (4-aminophenyl) -N-methyl-2- (4-methylpiperazin-1-yl) acetamide (compound IV), 100ml of isopropanol, 15.0g of palladium carbon with the content of 10% and 15.0g of ammonium formate (238mmol) into a reaction bottle, keeping the temperature at 50-60 ℃ for reaction until the TLC detection is completed, cooling, performing suction filtration, adding dichloromethane for dissolution after the filtrate is concentrated, washing with water, concentrating the filtrate, adding methyl tert-butyl ether after methanol is added for dissolution, stirring for crystallization, performing suction filtration, and performing vacuum drying at 50 ℃ to obtain 14.3g of white-like solid, wherein the yield is 79.7%, and the HPLC purity: 99.67 percent.
Example 5: preparation of N- (4-aminophenyl) -N-methyl-2- (4-methylpiperazin-1-yl) acetamide (Compound II)
Adding 20g (68.4mmol) of N- (4-aminophenyl) -N-methyl-2- (4-methylpiperazin-1-yl) acetamide (compound IV), 100ml of methanol, 15.0g of palladium carbon with the content of 10% and 15.0g of ammonium formate (238mmol) into a reaction bottle, keeping the temperature at 50-60 ℃ for reaction until the TLC detection is completed, cooling, performing suction filtration, adding dichloromethane for dissolution after the filtrate is concentrated, washing with water, concentrating the filtrate, adding N-heptane after the methanol is added for dissolution, stirring for crystallization, performing suction filtration, and performing vacuum drying at 50 ℃ to obtain 14.5g of a white-like solid, wherein the yield is 80.8%, and the HPLC purity: 99.65 percent.
Example 6: preparation of N- (4-aminophenyl) -N-methyl-2- (4-methylpiperazin-1-yl) acetamide (Compound II)
Adding 20g (68.4mmol) of N- (4-aminophenyl) -N-methyl-2- (4-methylpiperazin-1-yl) acetamide (compound IV), 100ml of methanol, 42g of 80% hydrazine hydrate (670mmol), 1.0g of ferric trichloride and 4.0g of activated carbon into a reaction bottle, reacting at room temperature until the TLC detection reaction is complete, performing suction filtration, concentrating the filtrate, adding dichloromethane for dissolving, washing with water, concentrating the organic layer, adding methanol/methyl tert-butyl ether, stirring for crystallization, performing suction filtration, and performing vacuum drying at 50 ℃ to obtain 14.4g of white-like solid, wherein the yield is 80.8%, and the HPLC purity: 99.59 percent.
Example 7: preparation of N- (4-aminophenyl) -N-methyl-2- (4-methylpiperazin-1-yl) acetamide (Compound II)
Adding 20g (68.4mmol) of N- (4-aminophenyl) -N-methyl-2- (4-methylpiperazin-1-yl) acetamide (compound IV), 100ml of isopropanol, 42g of 80% hydrazine hydrate (670mmol), 1.0g of ferric trichloride and 4.0g of activated carbon into a reaction bottle, reacting at 40 ℃ until the TLC detection reaction is complete, performing suction filtration, concentrating the filtrate, adding dichloromethane for dissolving, washing with water, concentrating an organic layer, adding diethyl ether, stirring for crystallization, filtering, and performing vacuum drying at 50 ℃ to obtain 14.2g of white-like solid, wherein the yield is 79.1%, and the HPLC purity: 99.49 percent.
Example 8: preparation of Nintedanib
Adding 50ml of N, N-dimethylformamide into a reaction bottle, adding 8g of compound II (30.5mmol) and 8g of compound III (22.8mmol), controlling the temperature to be 30-40 ℃, and carrying out heat preservation reaction until the TLC detection reaction is completed; adding 5g of piperidine (58.7mmol), keeping the temperature at 30-40 ℃ for reaction until the TLC detection reaction is completed, cooling and crystallizing, filtering, and drying to obtain 9.9g of yellow solid, the yield is 80.6%, and the HPLC purity is as follows: 99.73 percent.
Example 9: preparation of Nintedanib
Adding 80ml of methanol into a reaction bottle, adding 8g of compound II (30.5mmol) and 8g of compound III (22.8mmol), controlling the temperature to be 30-40 ℃, and carrying out heat preservation reaction until the TLC detection reaction is completed; adding 5g of piperidine (58.7mmol), keeping the temperature at 30-40 ℃ for reaction until the TLC detection reaction is completed, cooling and crystallizing, filtering, and drying to obtain 10.6g of yellow solid, wherein the yield is 87.8%, and the HPLC purity is as follows: 99.76 percent.
Example 10: preparation of Nintedanib
Adding 80ml of ethanol into a reaction bottle, adding 8g of compound II (30.5mmol) and 8g of compound III (22.8mmol), controlling the temperature to be 30-40 ℃, and carrying out heat preservation reaction until the TLC detection reaction is completed; adding 5g of piperidine (58.7mmol), keeping the temperature at 30-40 ℃ for reaction until the TLC detection reaction is completed, cooling and crystallizing, filtering, and drying to obtain 10.4g of yellow solid, wherein the yield is 84.6%, and the HPLC purity is as follows: 99.69 percent.
Claims (11)
1. A preparation method of a nintedanib key intermediate II is characterized by comprising the following synthetic route:
the preparation method specifically comprises the following steps:
and adding an organic solvent, trichlorosilane and organic base into the compound IV to perform a reduction reaction, and after the reaction is finished, adding a reverse phase solvent into a reaction system to crystallize to obtain a compound II.
2. The process according to claim 1, wherein the organic solvent is selected from chlorinated alkanes; the organic base is selected from tertiary amines; the reverse phase solvent is selected from ether solvent, alkane solvent or their mixture.
3. The method of claim 2, wherein the chlorinated alkane is one or more of dichloromethane, dichloroethane, and chloroform;
the tertiary amine is triethylamine or N, N-diisopropylethylamine;
the ether solvent is one or more of diethyl ether, isopropyl ether and methyl tert-butyl ether;
the alkane solvent is one or more of n-hexane, cyclohexane, n-heptane and petroleum ether.
4. The method according to claim 1, wherein the amount of trichlorosilane is 2.0 to 8.0 times the molar amount of compound IV; the dosage of the organic base is 3.0 to 8.0 times of the molar dosage of the compound IV.
5. The method according to claim 1, wherein the amount of trichlorosilane is 3.0 to 4.0 times the molar amount of compound IV; the amount of the organic base is 4.0 to 6.0 times of the molar amount of the compound IV.
6. A preparation method of a nintedanib key intermediate II is characterized by comprising the following synthetic route:
the preparation method specifically comprises the following steps:
in an alcohol solvent, carrying out nitro reduction reaction on a compound IV in the presence of palladium carbon and ammonium formate until the nitro reduction reaction is complete, filtering, and adding a reverse phase solvent for crystallization to obtain a compound II.
7. The process according to claim 6, wherein the alcoholic solvent is selected from the group consisting of C1-C5 lower alcohols;
the reverse phase solvent is selected from ether solvent, alkane solvent or their mixture;
the dosage of the palladium carbon is 0.005-0.1 time of the weight of the compound IV;
the amount of the amine formate is 2.0 to 8.0 times of the molar amount of the compound IV.
8. The method according to claim 6, wherein the alcoholic solvent is one or more selected from methanol, ethanol, and isopropanol;
the reverse phase solvent is an ether solvent, and the ether solvent is selected from one or more of diethyl ether, isopropyl ether and methyl tert-butyl ether;
the reverse phase solvent is an alkane solvent, and the alkane solvent is selected from one or more of n-hexane, cyclohexane, n-heptane and petroleum ether;
the dosage of the palladium carbon is 0.01 to 0.05 of the weight of the compound IV;
the amount of the amine formate is 3.0 to 5.0 times of the molar amount of the compound IV.
9. A preparation method of a nintedanib key intermediate II is characterized by comprising the following synthetic route:
the preparation method specifically comprises the following steps:
in an alcohol solvent, carrying out nitro reduction reaction on a compound IV in the presence of hydrazine hydrate, ferric trichloride and activated carbon, filtering after the reaction is finished, and adding a reverse phase solvent for crystallization to obtain a compound II.
10. The process according to claim 9, wherein the alcoholic solvent is selected from the group consisting of lower alcohols of C1-C5;
the reverse phase solvent is selected from ether solvent, alkane solvent or their mixture;
the dosage of hydrazine hydrate is 4.0-10.0 times of the mass of the compound IV;
the dosage of ferric trichloride is 0.02-0.1 time of the mass of the compound IV;
the dosage of the active carbon is 0.1 to 0.5 time of the mass of the compound IV.
11. The method according to claim 9, wherein the alcoholic solvent is one or more of methanol, ethanol, and isopropanol;
the reverse phase solvent is selected from ether solvent, and the ether solvent is one or more of diethyl ether, isopropyl ether and methyl tert-butyl ether;
the reverse phase solvent is selected from alkane solvents, and the alkane solvents are one or more of n-hexane, cyclohexane, n-heptane and petroleum ether;
the dosage of hydrazine hydrate is 5.0 to 8.0 times of the mass of the compound IV;
the dosage of ferric trichloride is 0.04-0.08 times of the mass of the compound IV;
the dosage of the active carbon is 0.2 to 0.3 time of the mass of the compound IV.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910273385.1A CN111777576A (en) | 2019-04-05 | 2019-04-05 | Preparation method of nintedanib key intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910273385.1A CN111777576A (en) | 2019-04-05 | 2019-04-05 | Preparation method of nintedanib key intermediate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN111777576A true CN111777576A (en) | 2020-10-16 |
Family
ID=72755652
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910273385.1A Withdrawn CN111777576A (en) | 2019-04-05 | 2019-04-05 | Preparation method of nintedanib key intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111777576A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113354599A (en) * | 2021-08-09 | 2021-09-07 | 长沙康鹏医药有限公司 | Preparation method of nintedanib key intermediate |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104822642A (en) * | 2012-09-06 | 2015-08-05 | 德克塞勒化学有限公司 | Process for the reduction of nitro derivatives to amines |
-
2019
- 2019-04-05 CN CN201910273385.1A patent/CN111777576A/en not_active Withdrawn
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104822642A (en) * | 2012-09-06 | 2015-08-05 | 德克塞勒化学有限公司 | Process for the reduction of nitro derivatives to amines |
Non-Patent Citations (3)
| Title |
|---|
| ADAM D.ET AL: "Targeting telomerase and telomeres:a click chemistry approach towards highly selective G-quardruplex ligands", 《MOLECULAR BIOSYSTEMS》 * |
| RAMARKRISHNA EDUPUGANTI ET AL: "Discovery of a potent inhibitor of MELK that inhibits expression of the anti-apoptotic protein Mcl-1 and TNBC cell growth", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
| 朱磊等: "瑞替加滨的合成工艺改进", 《中国药物化学杂志》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113354599A (en) * | 2021-08-09 | 2021-09-07 | 长沙康鹏医药有限公司 | Preparation method of nintedanib key intermediate |
| CN113354599B (en) * | 2021-08-09 | 2021-10-26 | 长沙康鹏医药有限公司 | Preparation method of nintedanib key intermediate |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106083691B (en) | A kind of preparation method of arbidol HCl monohydrate | |
| CN112079848A (en) | Synthesis method of baroxavir key intermediate | |
| CN109651371A (en) | A kind of preparation method of valaciclovir hydrochlordide | |
| CN111777576A (en) | Preparation method of nintedanib key intermediate | |
| CN113480492A (en) | Preparation method of epalrestat | |
| CN113636973A (en) | Industrial preparation method of 4- (6-aminopyridine-3-yl) piperazine-1-carboxylic acid tert-butyl ester | |
| CN107298678B (en) | Preparation method of bulk drug suvorexant | |
| CN106279175A (en) | A kind of preparation method of Ertapenem Sodium | |
| CN106674084B (en) | A kind of preparation method of 2- isopropyl oxygroup -5- methyl -4- (piperidin-4-yl) aniline dihydrochloride | |
| CN105085328A (en) | Synthetic method for peramivir trihydrate | |
| CN113698317A (en) | Synthetic method of apatamide, intermediate and synthetic method thereof | |
| CN104326954B (en) | A kind of synthetic method of Fudosteine | |
| CN111100042B (en) | Preparation method of 2-methoxy-5-sulfonamide benzoic acid | |
| CN106432195B (en) | Method for preparing (R) -2- (2-methylpyrrolidine-2-yl) -1H-benzimidazole-4-formamide | |
| AU2014389984A1 (en) | Process of preparing a quinazoline derivative | |
| CN111018782B (en) | Preparation method of 9-aminoacridine and derivatives thereof | |
| CN104910209B (en) | A kind of method for preparing tenofovir | |
| CN114380732A (en) | Preparation method of fluoro-indole carboxylic acid compounds | |
| CN114539084A (en) | Preparation method of mirabegron and intermediate thereof | |
| CN106187864A (en) | A kind of method being prepared high-purity bupivacaine alkali by bupivacaine hydrochloride | |
| IE863270L (en) | Benzamide-heterocyclic derivatives | |
| CN112920054A (en) | Preparation method of 3,3 ', 4, 4' -tetraaminobiphenyl | |
| CN106631962B (en) | A kind of preparation method of (S)-Oxiracetam | |
| CN109810052A (en) | A kind of highly selective Ah pa replaces the simple and convenient process for preparing of Buddhist nun | |
| CN106317064B (en) | The preparation method of methylnaltrexone bromide |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WW01 | Invention patent application withdrawn after publication |
Application publication date: 20201016 |
|
| WW01 | Invention patent application withdrawn after publication |