CN111004141A - Novel method for synthesizing Nintedanib intermediate 2-chloro-N-methyl-N- (4-nitrophenyl) acetamide - Google Patents
Novel method for synthesizing Nintedanib intermediate 2-chloro-N-methyl-N- (4-nitrophenyl) acetamide Download PDFInfo
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- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
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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 2-chloro-N-p-nitrophenylacetamide
Adding 1 time of p-nitroaniline, 2-6 (weight ratio) of toluene, 1-3 (mole ratio) of an acid-binding agent and 2-4 (weight ratio) of water into a reaction vessel, stirring for 20-60 minutes, adding 1-3 (mole ratio) of a chloroacetic agent at the temperature of 15 ℃, finishing dripping within 1-3 hours, stirring for 1-4 hours at room temperature after finishing dripping, rotationally evaporating to remove 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 2-chloro-N-p-nitrophenylacetamide, 1-3 parts by weight of dichloromethane and 1-5 parts by weight of water to 1-4 parts by mole of an alkaline catalyst into a reactor, controlling the temperature to be 25-30 ℃, dropwise adding 1-3 parts by mole of a methylating agent, stirring and preserving the mixture for 2-4 hours at room temperature to 50-60 ℃, cooling to 5-10 ℃, 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, the chloroacetyl chloride used in step a is chloroacetyl chloride in the above-mentioned novel method for synthesizing nintedanib intermediate 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 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 novel method for synthesizing the nintedanib intermediate 2-chloro-N-methyl-N- (4-nitrophenyl) acetamide, 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, the methylating agent used in step B is dimethyl sulfate in the novel method for synthesizing the nintedanib intermediate 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 dichloromethane used in the step B: water (volume ratio) =5: 2.
Further, in the novel 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% by 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 15-25 ℃, and then to carry out suction filtration and drying, so as to obtain a refined 2-chloro-N-methyl-N- (4-nitrophenyl) acetamide.
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: 1.
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
215g (1.0 mol) of 2-chloro-N-p-nitrophenylacetamide, 500ml of dichloromethane, 200ml of water and 100g (2.5 mol) of sodium hydroxide are added into a reaction bottle, 247g (2 mol) of dimethyl sulfate is dropwise added at the temperature of 25-30 ℃, after the addition is finished, the mixture is stirred and insulated for 3 hours at the temperature of 50-60 ℃, the dichloromethane is removed by concentration under reduced pressure, the mixture is cooled to 5-10 ℃, and the mixture is filtered and dried 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 is taken and purified by methyl tert-butyl ether and methanol (volume ratio) =5:1, and 1H NMR (DMSO, 300MHz) delta: 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 25-30 ℃, stirring and preserving heat for 2 hours at the temperature of 50-60 ℃, adding 100mL of water, decompressing and concentrating 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 is taken and purified by methyl tert-butyl ether and methanol (volume ratio) =5:1, and 1H NMR (DMSO, 300MHz) delta: 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 are added into a reaction bottle with 250mL of water, the mixture is stirred for 20 minutes, 112g (1.0 mol) of chloroacetyl chloride is slowly dripped at the temperature of 15 +/-5 ℃, the dripping is finished after about 3 hours, the mixture is stirred for 1 hour at the room temperature, and the mixture is filtered and dried to obtain 186g of 2-chloro-N-p-nitrophenylacetamide, wherein the yield is 86.5 percent, the HPLC purity is 93.3 percent, and the mixture cannot be directly used for the next reaction. The product is purified by refining, 186g of 2-chloro-N-p-nitrophenylacetamide is placed in a reactor, methyl tert-butyl ether is added: pulping the 600ml mixed solution of methanol =5:1 at 15-25 ℃, filtering, and drying to obtain 175g of refined 2-chloro-N-methyl-N- (4-nitrophenyl) acetamide with the HPLC purity of 99.8%.
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 40g (1.0 mol) of sodium hydroxide into a reaction bottle, dropwise adding 123.5g (1 mol) of dimethyl sulfate at the temperature of 25-30 ℃, stirring and preserving heat for 4 hours at the temperature of 50-60 ℃ after adding, concentrating under reduced pressure to remove dichloromethane, cooling to 5-10 ℃, filtering, and drying to obtain 206g of yellow solid, wherein the yield is 90.3%, and the HPLC purity is 97.2%.
A small amount of crude product is taken and purified by methyl tert-butyl ether and methanol (volume ratio) =5:1, and 1H NMR (DMSO, 300MHz) delta: 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 paranitroaniline, 1000mL of toluene and 3.18g (3 mol) of sodium carbonate are added into a reaction bottle 500mL of water, the mixture is stirred for 30 minutes, 448g (4.0 mol) of chloroacetyl chloride is slowly dripped at the temperature of 15 +/-5 ℃, the dripping is finished within about 1 hour, the mixture is stirred for 2 hours at the room temperature after the dripping is finished, the mixture is 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 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 mol) of 2-chloro-N-p-nitrophenylacetamide, 150ml of dichloromethane, 1000ml of water and 160g (4 mol) of sodium hydroxide into a reaction bottle, controlling the temperature to be 25-30 ℃, dropwise adding 370.5g (1 mol) of dimethyl sulfate, stirring and preserving the temperature for 3 hours at room temperature to 50-60 ℃, decompressing and concentrating to remove dichloromethane, cooling to 5-10 ℃, filtering, drying to obtain 210g of yellow solid, wherein the yield is 92.1%, and the HPLC purity is 96.8%.
A small amount of crude product is taken and purified by methyl tert-butyl ether and methanol (volume ratio) =5:1, and 1H NMR (DMSO, 300MHz) delta: 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 a thorough synthesis route, has mild reaction conditions and easy control, and makes the 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 (10)
1. A new method for synthesizing a nintedanib intermediate 2-chloro-N-methyl-N- (4-nitrophenyl) acetamide is characterized by comprising 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.
2. The novel process for the preparation of nintedanib intermediate 2-chloro-N-methyl-N- (4-nitrophenyl) acetamide according to claim 1, wherein: the preparation method comprises the following steps:
preparation of 2-chloro-N-p-nitrophenylacetamide
Adding 1 time of p-nitroaniline, 2-6 (weight ratio) of toluene, 1-3 (mole ratio) of an acid-binding agent and 2-4 (weight ratio) of water into a reaction vessel, stirring for 20-60 minutes, adding 1-3 (mole ratio) of a chloroacetic agent at the temperature of 15 ℃, finishing dripping within 1-3 hours, stirring for 1-4 hours at room temperature after finishing dripping, rotationally evaporating to remove the toluene, filtering and drying to obtain 2-chloro-N-p-nitrophenylacetamide;
preparation of 2-chloro-N-methyl-N- (4-nitrophenyl) acetamide
Adding 1-time 2-chloro-N-p-nitrophenylacetamide, 1-3 parts by weight of dichloromethane and 1-5 parts by weight of water to 1-4 parts by mole of an alkaline catalyst into a reactor, controlling the temperature to be 25-30 ℃, dropwise adding 1-3 parts by mole of a methylating agent, stirring and preserving the mixture for 2-4 hours at room temperature to 50-60 ℃, cooling to 5-10 ℃, performing rotary evaporation, filtering and drying to obtain the 2-chloro-N-methyl-N- (4-nitrophenyl) acetamide.
3. The novel process for the synthesis of the nintedanib intermediate 2-chloro-N-methyl-N- (4-nitrophenyl) acetamide according to claim 2, characterized in that: the acid-binding agent used in the step A is one or more selected from sodium carbonate, sodium bicarbonate, potassium carbonate, sodium hydroxide, triethylamine, diisopropanolamine and pyridine.
4. The novel process for the synthesis of the nintedanib intermediate 2-chloro-N-methyl-N- (4-nitrophenyl) acetamide according to claim 3, wherein: the chloroacetic agent used in step A is selected from chloroacetyl chloride, chloroacetyl bromide and chloroacetic anhydride.
5. The novel process for the synthesis of the nintedanib intermediate 2-chloro-N-methyl-N- (4-nitrophenyl) acetamide according to claim 2, characterized in that: the alkaline catalyst used in the step B is one or more of potassium carbonate, sodium carbonate and sodium hydroxide.
6. The novel process for the synthesis of the nintedanib intermediate 2-chloro-N-methyl-N- (4-nitrophenyl) acetamide according to claim 5, wherein: the methylating agent used in step B is selected from methyl chloride, dimethyl sulfate and dimethyl sulfoxide methylene.
7. The novel process for the synthesis of the nintedanib intermediate 2-chloro-N-methyl-N- (4-nitrophenyl) acetamide according to claim 2, characterized in that: dichloromethane used in step B: water (volume ratio) =5: 2.
8. The novel process for the synthesis of the nintedanib intermediate 2-chloro-N-methyl-N- (4-nitrophenyl) acetamide according to claim 2, characterized in that: the content of the 2-chloro-N-p-nitrophenylacetamide is less than 95 percent by HPLC detection, and the 2-chloro-N-p-nitrophenylacetamide is put into the reaction in the step B after being refined and purified.
9. The novel process for the synthesis of nintedanib intermediate 2-chloro-N-methyl-N- (4-nitrophenyl) acetamide according to claim 8, wherein: and B, refining and purifying the 2-chloro-N-p-nitrophenylacetamide in the step A, namely pulping the 2-chloro-N-p-nitrophenylacetamide by using a mixed solution of methyl tert-butyl ether and methanol at 15-25 ℃, performing suction filtration, and drying to obtain a refined 2-chloro-N-methyl-N- (4-nitrophenyl) acetamide.
10. The novel process for the synthesis of nintedanib intermediate 2-chloro-N-methyl-N- (4-nitrophenyl) acetamide according to claim 9, wherein: methyl tert-butyl ether: methanol (volume ratio) =5: 1.
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| 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 |
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