CN111004141B - New method for synthesizing nintedanib intermediate 2-chloro-N-methyl-N- (4-nitrophenyl) acetamide - Google Patents
New method for synthesizing nintedanib intermediate 2-chloro-N-methyl-N- (4-nitrophenyl) acetamide Download PDFInfo
- Publication number
- CN111004141B CN111004141B CN201911318896.7A CN201911318896A CN111004141B CN 111004141 B CN111004141 B CN 111004141B CN 201911318896 A CN201911318896 A CN 201911318896A CN 111004141 B CN111004141 B CN 111004141B
- Authority
- CN
- China
- Prior art keywords
- chloro
- methyl
- nitrophenyl
- acetamide
- nitrophenylacetamide
- 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.)
- Active
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
A new method of a nintedanib intermediate relates to a preparation method of a specific compound 2-chloro-N-methyl-N- (4-nitrophenyl) acetamide. The method sequentially comprises the following steps: taking p-nitroaniline as a raw material, carrying out acyl chlorination reaction with chloroacetic agent to generate 2-chloro-N-p-nitrophenylacetamide, and carrying out methylation reaction with methylating agent to obtain a target product, namely 2-chloro-N-methyl-N- (4-nitrophenyl) acetamide. The invention provides a brand new synthetic route, the used raw materials have sufficient market supply and wide sources, the reactions in each step are relatively thorough, the reaction conditions are mild, the control is easy, and the method can be applied to large-scale production.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and relates to a new synthesis method of a nintedanib intermediate 2-chloro-N-methyl-N- (4-nitrophenyl) acetamide.
Background
Nintedanib is an oral drug developed by Burlingg Yiger Han company in Germany, is the first and only one tyrosine kinase inhibitor which is approved by FDA for treating idiopathic pulmonary fibrosis, and has been reported in key intermediates 2-chloro-N-methyl-N- (4-nitrophenyl) acetamide patents WO200862182 and WO2018160967 in the synthetic process, as shown in figure 1, p-bromonitrobenzene is taken as a starting material, condensed with monomethylamine under high pressure, and amidated with chloroacetyl chloride to obtain the product.
The method requires high temperature and high pressure in the process of preparing the N-methyl-4-nitroaniline, and has harsh reaction conditions, thereby restricting large-scale industrial production.
The method provides a brand new synthetic route, and the target product 2-chloro-N-methyl-N- (4-nitrophenyl) acetamide is obtained by taking p-nitroaniline as a raw material, carrying out an acyl chlorination reaction with a chloroacetic agent and then carrying out a methylation reaction with dimethyl sulfate. The novel method enables the intermediate to be produced in a large scale through simple process steps and mild reaction conditions, and effectively controls the cost of the product.
Disclosure of Invention
The invention aims to provide a novel synthesis method of a nintedanib intermediate 2-chloro-N-methyl-N- (4-nitrophenyl) acetamide, which has the advantages of simple process and mild reaction conditions and is convenient to operate.
In order to achieve the purpose, a series of experiments are carried out, and a brand new synthetic route is provided.
The technical scheme for realizing the invention is as follows: a new method for synthesizing a nintedanib intermediate 2-chloro-N-methyl-N- (4-nitrophenyl) acetamide is shown in figure 2, and comprises the following steps: taking paranitroaniline as a raw material, carrying out acyl chlorination reaction with chloroacetic agent, and then carrying out methylation reaction with methylating agent to obtain a target product 2-chloro-N-methyl-N- (4-nitrophenyl) acetamide.
Further, the novel method for preparing the nintedanib intermediate 2-chloro-N-methyl-N- (4-nitrophenyl) acetamide is obtained according to the following steps:
preparation of A.2-chloro-N-p-nitrophenylacetamide
Adding 1 time of p-nitroaniline, 2-6 parts by weight of toluene, 1-3 parts by weight of an acid binding agent and 2-4 parts by weight of water into a reaction container, stirring for 20-60 minutes, adding 1-3 parts by weight of a chloroacetic agent at a controlled temperature of 15 ℃, dripping for 1-3 hours, stirring for 1-4 hours at room temperature after dripping, rotatably evaporating the toluene, filtering, and drying to obtain 2-chloro-N-p-nitrophenylacetamide with certain purity;
preparation of 2-chloro-N-methyl-N- (4-nitrophenyl) acetamide
Adding 1 time of 2-chloro-N-p-nitrophenylacetamide, 1 to 3 times of dichloromethane (weight ratio), 1 to 5 times of water (weight ratio) and 1 to 4 times of basic catalyst (mole ratio) into a reactor, dropwise adding a methylating agent 1 to 3 times (mole ratio) at the temperature of 25 to 30 ℃, stirring and keeping the temperature for 2 to 4 hours at the temperature of 50 to 60 ℃ at room temperature after the addition is finished, cooling to 5 to 10 ℃, performing rotary evaporation, filtering, and drying to obtain the 2-chloro-N-methyl-N- (4-nitrophenyl) acetamide.
Further, in the novel method for synthesizing the nintedanib intermediate 2-chloro-N-methyl-N- (4-nitrophenyl) acetamide, the acid-binding agent used in the step A is selected from one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, sodium hydroxide, triethylamine, diisopropanolamine and pyridine.
In a preferred embodiment of the present invention, in the novel method for synthesizing the nintedanib intermediate 2-chloro-N-methyl-N- (4-nitrophenyl) acetamide, the acid-binding agent used in step a is sodium carbonate.
Further, in the new method for synthesizing the nintedanib intermediate 2-chloro-N-methyl-N- (4-nitrophenyl) acetamide, the chloroacetyl chloride used in the step A is selected from chloroacetyl chloride, chloroacetyl bromide and chloroacetic anhydride.
In a preferred embodiment of the present invention, in the novel method for synthesizing 2-chloro-N-methyl-N- (4-nitrophenyl) acetamide, which is an intermediate of nintedanib, the chloroacetyl chloride used in step a is chloroacetyl chloride.
Further, in the novel method for synthesizing the nintedanib intermediate 2-chloro-N-methyl-N- (4-nitrophenyl) acetamide, the alkaline catalyst used in the step B is one or more selected from potassium carbonate, sodium carbonate and sodium hydroxide.
In a preferred embodiment of the present invention, in the new method for synthesizing 2-chloro-N-methyl-N- (4-nitrophenyl) acetamide, which is an intermediate of nintedanib, the basic catalyst used in step B is potassium carbonate.
Further, in the novel method for synthesizing the nintedanib intermediate 2-chloro-N-methyl-N- (4-nitrophenyl) acetamide, the methylating agent used in the step B is selected from methyl chloride, dimethyl sulfate and dimethyl sulfoxide methylene.
In a preferred embodiment of the present invention, in the novel method for synthesizing 2-chloro-N-methyl-N- (4-nitrophenyl) acetamide, which is an intermediate of nintedanib, the methylating agent used in step B is dimethyl sulfate.
Further, in the novel method for synthesizing the nintedanib intermediate 2-chloro-N-methyl-N- (4-nitrophenyl) acetamide, the dichloromethane used in the step B: water (volume ratio) = 5.
Furthermore, in the new method for synthesizing the nintedanib intermediate 2-chloro-N-methyl-N- (4-nitrophenyl) acetamide, the purity of the 2-chloro-N-p-nitrophenylacetamide in the step A is less than 95% through HPLC detection, and the 2-chloro-N-p-nitrophenylacetamide needs to be refined and purified and then is directly put into the reaction in the step B.
Further, in the new method for synthesizing the nintedanib intermediate 2-chloro-N-methyl-N- (4-nitrophenyl) acetamide, in the step A, the refining and purification of the 2-chloro-N-p-nitrophenylacetamide is to pulp the 2-chloro-N-p-nitrophenylacetamide by using a mixed solution of methyl tert-butyl ether and methanol at a temperature of 15 to 25, and to obtain a refined 2-chloro-N-methyl-N- (4-nitrophenyl) acetamide through suction filtration and drying.
Further, the new method for synthesizing the nintedanib intermediate 2-chloro-N-methyl-N- (4-nitrophenyl) acetamide is that the methyl tert-butyl ether: methanol (volume ratio) = 5.
The technical scheme shows that the invention has the following beneficial effects:
1. the invention provides a brand new synthetic route, nitroaniline is used as a raw material, and the nitroaniline has sufficient market supply and wide sources.
2. The synthetic route provided by the invention has the advantages of relatively thorough reaction, mild reaction conditions and easy control, and makes the large-scale production of the final product possible.
Drawings
FIG. 1 is a scheme showing the synthesis scheme of a prior art method for the synthesis of 2-chloro-N-methyl-N- (4-nitrophenyl) acetamide;
FIG. 2 is a scheme showing the synthesis scheme of the process for the synthesis of 2-chloro-N-methyl-N- (4-nitrophenyl) acetamide described herein;
FIG. 3 is a scheme showing the synthesis scheme of 2-chloro-N-methyl-N- (4-nitrophenyl) acetamide described in example 1 of the present invention.
Detailed Description
How this invention can be carried out is further illustrated by the following specific examples:
example 1
A new method for preparing a nintedanib intermediate 2-chloro-N-methyl-N- (4-nitrophenyl) acetamide, as shown in fig. 3, comprising the following steps:
A. preparation of 2-chloro-N-p-nitrophenylacetamide
138g (1.0 mol) of paranitroaniline, 600mL of toluene and 400mL of sodium carbonate (1.59 g (1.5 mol) of water are added into a reaction bottle, the mixture is stirred for 30 minutes, 124g (1.1 mol) of chloroacetyl chloride is slowly dripped at the temperature of 15 +/-5 ℃, the dripping is finished within about 2 hours, the mixture is stirred for 2 hours at room temperature after the dripping is finished, the mixture is filtered and dried to obtain 200g of 2-chloro-N-p-nitrophenylacetamide, the yield is 93 percent, the HPLC purity is 98.3 percent, and the mixture can be directly used for the next reaction without further purification.
B. Preparation of 2-chloro-N-methyl-N- (4-nitrophenyl) acetamide
Adding 215g (1.0 mol) of 2-chloro-N-p-nitrophenylacetamide, 500ml of dichloromethane, 200ml of water and 100g (2.5 mol) of sodium hydroxide into a reaction bottle, controlling the temperature to be 25 to 30 ℃, dropwise adding 247g (2 mol) of dimethyl sulfate, stirring and preserving heat for 3 hours at the temperature of between room temperature and 50 to 60 ℃, concentrating under reduced pressure to remove dichloromethane, cooling to be 5 to 10 ℃, filtering, and drying to obtain 218g of yellow solid, wherein the yield is 95.6%, and the HPLC purity is 99.2%.
A small amount of crude product was purified by methyl tert-butyl ether and methanol (volume ratio) =5, and 1H NMR (DMSO, 300 MHz) δ:3.42 (3H, s), 3.68 (2H, s), 6.99, (2H, m), 8.05 (2H, m). FAB-MS (m/z): 229.5 (M + H).
Example 2
A novel method for preparing a nintedanib intermediate 2-chloro-N-methyl-N- (4-nitrophenyl) acetamide comprises the following steps:
A. preparation of 2-chloro-N-p-nitrophenylacetamide
138g (1.0 mol) of p-nitroaniline, 600mL of toluene and 400mL of sodium carbonate (1.5 mol) and water are added into a reaction bottle, the mixture is stirred for 60 minutes, 191g (1.1 mol) of chloroacetic anhydride is added into the reaction bottle in portions at the temperature of 15 +/-5 ℃, the mixture is stirred for 4 hours at room temperature after the addition is finished, the mixture is filtered and dried to obtain 192kg of 2-chloro-N-p-nitrophenylacetamide, the yield is 89.3 percent, the HPLC purity is 96.8 percent, and the product can be directly used for the next reaction without further purification.
Preparation of 2-chloro-N-methyl-N- (4-nitrophenyl) acetamide in step B
Adding 215g (1 mol) of 2-chloro-N-p-nitrophenylacetamide, 200mL of dichloromethane, 600mL of water and 100g (2.5 mol) of sodium hydroxide into a reaction bottle, dropwise adding 365g (4 mol) of dimethyl sulfoxide methylene at the temperature of 25 to 30 ℃, stirring and preserving heat for 2 hours at the temperature of 50 to 60 ℃, adding 100mL of water, concentrating under reduced pressure to remove dichloromethane, cooling to 5-10 ℃, filtering, and drying to obtain 208g of yellow solid, wherein the yield is 91.2% and the HPLC purity is 99.5%.
A small amount of crude product was purified from methyl tert-butyl ether and methanol (volume ratio) =5, and 1H NMR (DMSO, 300 MHz) δ:3.42 (3H, s), 3.68 (2H, s), 6.99, (2H, m), 8.05 (2H, m). FAB-MS (m/z): 229.5 (M + H).
Example 3
A novel method for preparing a nintedanib intermediate 2-chloro-N-methyl-N- (4-nitrophenyl) acetamide comprises the following steps:
A. preparation of 2-chloro-N-p-nitrophenylacetamide
138g (1.0 mol) of p-nitroaniline, 320mL of toluene and 101g (1.0 mol) of triethylamine water are added into a reaction bottle, stirred for 20 minutes, 112g (1.0 mol) of chloroacetyl chloride is slowly dripped at the temperature of 15 +/-5 ℃ for about 3 hours, and the mixture is stirred for 1 hour at room temperature after the dripping is finished, filtered and dried to obtain 186g of 2-chloro-N-p-nitrophenylacetamide, the yield is 86.5 percent, the HPLC purity is 93.3 percent, and the 2-chloro-N-p-nitrophenylacetamide cannot be directly used for the next reaction. The product needs to be refined and purified, 186g of 2-chloro-N-p-nitrophenylacetamide is put into a reactor, and methyl tert-butyl ether is added: methanol =5, and 600ml of a mixture of methanol =5 was slurried at 15 to 25 ℃, suction-filtered, and dried to obtain 175g of a 2-chloro-N-methyl-N- (4-nitrophenyl) acetamide fine product with an hplc purity of 99.8%.
B. Preparation of 2-chloro-N-methyl-N- (4-nitrophenyl) acetamide
215g (1.0 mol) of 2-chloro-N-p-nitrophenylacetamide, 500ml of dichloromethane, 200ml of water and 40g (1.0 mol) of sodium hydroxide are added into a reaction bottle, 123.5g (1 mol) of dimethyl sulfate is added dropwise at the temperature of 25 to 30 ℃, after the addition is finished, the mixture is stirred and insulated for 4 hours at the temperature of 50 to 60 ℃ at room temperature, the dichloromethane is removed through decompression concentration, the mixture is cooled to 5 to 10 ℃, and is filtered and dried to obtain 206g of yellow solid, the yield is 90.3%, and the HPLC purity is 97.2%.
A small amount of crude product was purified by methyl tert-butyl ether and methanol (volume ratio) =5, and 1H NMR (DMSO, 300 MHz) δ:3.42 (3H, s), 3.68 (2H, s), 6.99, (2H, m), 8.05 (2H, m). FAB-MS (m/z): 229.5 (M + H).
Example 4
A novel method for preparing a nintedanib intermediate 2-chloro-N-methyl-N- (4-nitrophenyl) acetamide comprises the following steps:
A. preparation of 2-chloro-N-p-nitrophenylacetamide
138g (1.0 mol) of p-nitroaniline, 1000mL of toluene and 3.18g (3 mol) of sodium carbonate are added into a reaction bottle with 500mL of water, stirred for 30 minutes, chloroacetyl chloride 448g (4.0 mol) is slowly dripped at the temperature of 15 +/-5 ℃ for about 1 hour, and the mixture is stirred for 2 hours at room temperature after the dripping is finished, filtered and dried to obtain 195g of 2-chloro-N-p-nitrophenylacetamide, the yield is 90.7 percent, the HPLC purity is 98.3 percent, and the 2-chloro-N-p-nitrophenylacetamide can be directly used for the next reaction without further purification.
B. Preparation of 2-chloro-N-methyl-N- (4-nitrophenyl) acetamide
215g (1 mol) of 2-chloro-N-p-nitrophenylacetamide, 150ml of dichloromethane, 1000ml of water and 160g (4 mol) of sodium hydroxide are added into a reaction bottle, 370.5g (1 mol) of dimethyl sulfate is dropwise added at the temperature of 25 to 30 ℃, after the addition is finished, the mixture is stirred and insulated for 3 hours at the temperature of 50 to 60 ℃, the dichloromethane is removed by concentration under reduced pressure, the mixture is cooled to 5 to 10 ℃, and the mixture is filtered and dried to obtain 210g of yellow solid, wherein the yield is 92.1 percent, and the HPLC purity is 96.8 percent.
A small amount of crude product was purified from methyl tert-butyl ether and methanol (volume ratio) =5, and 1H NMR (DMSO, 300 MHz) δ:3.42 (3H, s), 3.68 (2H, s), 6.99, (2H, m), 8.05 (2H, m). FAB-MS (m/z): 229.5 (M + H).
According to the invention, p-nitroaniline is used as a raw material, and is subjected to acyl chlorination reaction with chloroacetic acid to obtain 2-chloro-N-p-nitrophenylacetamide, and then is methylated with dimethyl sulfate to obtain a target product 2-chloro-N-methyl-N- (4-nitrophenyl) acetamide, compared with patent WO2018160967, in the synthetic process of the route, the reaction is thorough, and less impurities are generated, and stable solvents dichloromethane and water are selected in the methylation reaction process, so that the method is economical and practical, the yield of the obtained target product is over 90%, the purity is over 98%, and in patent WO2018160967, ethyl acetate is used as a solvent, the ethyl acetate is easy to decompose under the high-temperature alkaline condition, and the decomposed alcohol and acid can bring impurities to the reaction. The invention provides the thorough synthesis route, has mild reaction conditions and easy control, and makes the large-scale production of the final product possible.
Although the invention has been described and illustrated in some detail by the inventor, it should be understood that modifications and/or alterations to the above-described embodiments, or equivalent alterations thereto, will become apparent to those skilled in the art without departing from the spirit of the invention, and that no limitation to the invention is intended by the terms of the present invention as set forth herein is intended to be exhaustive or understood.
Claims (1)
1. A method for synthesizing a nintedanib intermediate 2-chloro-N-methyl-N- (4-nitrophenyl) acetamide is characterized by comprising the following steps:
A. preparation of 2-chloro-N-p-nitrophenylacetamide
138g of paranitroaniline, 600mL of toluene and 400mL of water containing 1.59g of sodium carbonate are added into a reaction bottle, stirred for 30 minutes, chloroacetyl chloride 124g is slowly dripped at the temperature of 15 +/-5 ℃, the mixture is dripped out after about 2 hours, stirred for 2 hours at room temperature after the dripping, filtered and dried to obtain 2-chloro-N-paranitrophenylacetamide
200g, yield 93% and HPLC purity 98.3%, and the product can be directly used in the next reaction without further purification;
B. preparation of 2-chloro-N-methyl-N- (4-nitrophenyl) acetamide
Adding 215g of 2-chloro-N-p-nitrophenylacetamide, 500ml of dichloromethane, 200ml of water and 100g of sodium hydroxide into a reaction bottle, dropwise adding 247g of dimethyl sulfate at the temperature of 25-30 ℃, stirring and preserving heat for 3 hours at the room temperature of 50-60 ℃, concentrating under reduced pressure to remove dichloromethane, cooling to 5-10 ℃, filtering, and drying to obtain the compound
218g, yield 95.6%, HPLC purity 99.2%, crude product detected after purification of 5 volume ratio of 1 methyl tert-butyl ether to methanol, 1H NMR (DMSO, 300 MHz) δ:3.42 (3H, s), 3.68 (2H, s), 6.99, (2H, m), 8.05 (2H, m), FAB-MS (m/z): 229.5 (M + H).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911318896.7A CN111004141B (en) | 2019-12-19 | 2019-12-19 | New method for synthesizing nintedanib intermediate 2-chloro-N-methyl-N- (4-nitrophenyl) acetamide |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911318896.7A CN111004141B (en) | 2019-12-19 | 2019-12-19 | New method for synthesizing nintedanib intermediate 2-chloro-N-methyl-N- (4-nitrophenyl) acetamide |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN111004141A CN111004141A (en) | 2020-04-14 |
| CN111004141B true CN111004141B (en) | 2022-10-04 |
Family
ID=70117534
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201911318896.7A Active CN111004141B (en) | 2019-12-19 | 2019-12-19 | New method for synthesizing nintedanib intermediate 2-chloro-N-methyl-N- (4-nitrophenyl) acetamide |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111004141B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN118439966B (en) * | 2024-07-05 | 2024-10-11 | 南昌大学 | Synthesis method of p-nitroaniline compound |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4567299A (en) * | 1984-12-24 | 1986-01-28 | Monsanto Company | Herbicidal 2-haloacetanilides |
| CN101883756A (en) * | 2007-12-03 | 2010-11-10 | 贝林格尔.英格海姆国际有限公司 | Process for the manufacture of an indolinone derivative |
| CN106632092A (en) * | 2016-12-22 | 2017-05-10 | 重庆智合生物医药有限公司 | 1,3-dimethyl-7-substituted-quinazolinyl-2,4-diones, and synthesis method and application thereof |
| CN109081819A (en) * | 2017-06-13 | 2018-12-25 | 湖南师范大学 | A kind of 5- aminothiazole derivs and its preparation and use |
-
2019
- 2019-12-19 CN CN201911318896.7A patent/CN111004141B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4567299A (en) * | 1984-12-24 | 1986-01-28 | Monsanto Company | Herbicidal 2-haloacetanilides |
| CN101883756A (en) * | 2007-12-03 | 2010-11-10 | 贝林格尔.英格海姆国际有限公司 | Process for the manufacture of an indolinone derivative |
| CN106632092A (en) * | 2016-12-22 | 2017-05-10 | 重庆智合生物医药有限公司 | 1,3-dimethyl-7-substituted-quinazolinyl-2,4-diones, and synthesis method and application thereof |
| CN109081819A (en) * | 2017-06-13 | 2018-12-25 | 湖南师范大学 | A kind of 5- aminothiazole derivs and its preparation and use |
Non-Patent Citations (1)
| Title |
|---|
| Glycosylated lanthanide cyclen complexes as luminescent probes for monitoring glycosidase enzyme activity;Helen M. Burke等;《Organic & Biomolecular Chemistry》;20160906;第14卷(第38期);第9133-9145页，尤其是第9134页方案1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN111004141A (en) | 2020-04-14 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108424388A (en) | A kind of preparation method of chronic anaemia drug | |
| CN109516998B (en) | Synthesis method of Barosavir intermediate | |
| CN110590635A (en) | Preparation method of levetiracetam and intermediate thereof | |
| CN104402909B (en) | A kind of synthetic method of cefoxitin acid | |
| CN111004141B (en) | New method for synthesizing nintedanib intermediate 2-chloro-N-methyl-N- (4-nitrophenyl) acetamide | |
| CN114539048B (en) | Carlong anhydride intermediate and preparation method of Carlong anhydride | |
| CN114315759A (en) | Preparation method of 2-methyl-1- (4-morpholinylphenyl) -2-morpholinyl-1-acetone | |
| CN108299466B (en) | Improved dolutegravir synthesis method | |
| CN110563699A (en) | Post-treatment purification method of fluoro pranoprazan intermediate | |
| CN115611860B (en) | Method for synthesizing nilaparib | |
| CN115536593A (en) | Scalable production method of 4-hydroxy-N, N, 2-trimethylbenzimidazole-6-formamide | |
| CN113845502A (en) | Preparation method of 3- (benzyloxy) -4-oxo-4H-pyran-2-carboxylic acid | |
| CN111018782B (en) | Preparation method of 9-aminoacridine and derivatives thereof | |
| CN111848423B (en) | Preparation method of tert-butyl 3-oxocyclobutylcarbamate | |
| CN115417816A (en) | Preparation method of 3,6-dibromo-1-chloro-isoquinoline | |
| CN107673994A (en) | A kind of preparation method of arylmethane class compound | |
| CN109369618B (en) | Method for preparing 2-chloro-5- ((2- (nitromethylene) imidazoline-1-yl) methyl) pyridine in one pot | |
| CN108101845B (en) | Preparation method of eltrombopag | |
| US20220235010A1 (en) | Synthesis method for 1-methyl-1h-indazole-6-carboxylic acid | |
| CN110746367B (en) | Synthesis method of 1,2, 4-triazole-3-methyl carboxylate | |
| CN110724098A (en) | Synthetic method of 5, 7-dichloro-1, 2,3, 4-tetrahydroisoquinoline-6-carboxylic acid hydrochloride | |
| CN111138355A (en) | Preparation method of formaldehyde-substituted aza-condensed ring compound | |
| CN116874411B (en) | Synthesis method of 1-bromocarbazole | |
| CN118146182B (en) | Preparation method of 3-benzyloxy-4-oxo-4H-pyran-2-carboxylic acid | |
| CN115231992B (en) | Preparation method of (2-chloro-5-iodophenyl) (4-fluorophenyl) methanone |
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 | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |