CN111116396A - Preparation method of bosutinib raw material - Google Patents
Preparation method of bosutinib raw material Download PDFInfo
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- CN111116396A CN111116396A CN201911309463.5A CN201911309463A CN111116396A CN 111116396 A CN111116396 A CN 111116396A CN 201911309463 A CN201911309463 A CN 201911309463A CN 111116396 A CN111116396 A CN 111116396A
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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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- C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
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Abstract
The invention relates to a preparation method of a bosutinib raw material, which comprises the steps of preparing 3-methyl (ethyl) acylaminophenol by taking m-aminophenol as a raw material, reacting with potassium (sodium) chloride to generate 2, 4-dichloro-5-methyl (ethyl) acylaminophenol, reacting 2, 4-dichloro-5-methyl (ethyl) acylaminophenol with chloromethane to generate 2, 4-dichloro-5-formamido anisole, and removing formyl groups to generate 2, 4-dichloro-5-methoxyaniline. The invention combines sodium (potassium) chloride and hydrogen peroxide, performs chlorine substitution on a benzene ring, and compared with performing chlorine substitution by using chlorine or sulfonyl chloride, the method has the advantages that phenolic hydroxyl on the benzene ring is methylated, methyl chloride is used for replacing dimethyl sulfate, the reaction condition is mild, the operation environment is good, and the post-treatment is simple.
Description
Technical Field
The invention relates to the technical field of chemistry, and particularly provides a preparation method of a bosutinib raw material.
Background
The 2, 4-dichloro-5-methoxyaniline is a key intermediate for producing bosutinib, and the existing synthetic process route is as follows:
in the existing synthesis process, chlorine or sulfonyl chloride has high danger and strong corrosion to equipment in the processes of storage, transportation and use; dimethyl sulfate belongs to highly toxic substances, is colorless and tasteless, and particularly requires attention to harm to human bodies in the processes of storage, transportation and use; in the process, a large amount of acidic high-salt wastewater is generated, and the pressure on environmental protection is increased.
Disclosure of Invention
The invention aims to solve the technical problem of providing a preparation method of a bosutinib raw material, which has mild reaction conditions, is green and environment-friendly and has no safety risk.
The technical scheme adopted by the invention is as follows:
a preparation method of a bosutinib raw material, wherein the bosutinib raw material is 2, 4-dichloro-5-methoxyaniline, and the method comprises the following steps:
b1, performing amino protection on m-aminophenol to generate 3-methyl (ethyl) acylaminophenol;
b2, reacting 3-methyl (ethyl) acylaminophenol with potassium chloride or sodium chloride to generate 2, 4-dichloro-5-methyl (ethyl) acylaminophenol;
b3, reacting 2, 4-dichloro-5-methyl (ethyl) acylaminophenol with a methylating agent to generate 2, 4-dichloro-5-methyl (ethyl) acylaminoanisole;
b4 removing the nor (acetyl) acyl from 2, 4-dichloro-5-formamido anisole to obtain 2, 4-dichloro-5-methoxyaniline.
Preferably, the chlorine source on the benzene ring in step B2 is sodium chloride or potassium chloride, and the amount of the substance is 2.5-3.5 times of that of m-aminophenol.
Preferably, the oxidant used in the step B2 is hydrogen peroxide, the amount of the hydrogen peroxide is 1.5 to 2.5 times of that of sodium chloride or potassium chloride, and the reaction temperature in the step B2 is 10 to 50 ℃.
Preferably, the methylating agent used in step B3 is methyl chloride. Preferably, the solvent used in step B3 is acetonitrile, dimethylformamide, methanol, ethanol, propanol, isopropanol or a combination thereof, which is 5 to 10 times the weight of 2, 4-dichloro-5-methylaminophenol.
Preferably, the reaction temperature of step B3 is 60-80 ℃. The reaction rate is relatively fast and since the boiling point of acetonitrile is 81.6 ℃.
Preferably, the base used in step B3 is sodium carbonate or potassium carbonate in a mass ratio of
1.2 to 1.5 times of 2, 4-dichloro-5-methyl (ethyl) amido phenol. Sodium carbonate and potassium carbonate are mild acid-binding agents.
High resolution mass spectrum HRMS (ESI) m/z 192.1 for 2, 4-dichloro-5-methoxyaniline, calculated value C7H7Cl2NO: 192.04. see in particular fig. 1, 2.
The invention has the following beneficial effects:
1. the reaction condition is mild, green and environment-friendly, and no safety risk exists.
2. Good reaction selectivity, high atom economy, convenient post-treatment and purification, high yield up to more than 80 percent and relatively low cost. The cost of the prior process is about 610 yuan per kilogram, the cost of the process is about 520 yuan per kilogram, and the reduction is at least more than 15%.
3. In the existing production process, chlorine gas or sulfonyl chloride is used for chlorination, and the chlorine gas is a highly toxic gas with strong pungent smell and has suffocation property. Sulfuryl chloride emits toxic hydrogen chloride and sulfide gas when meeting water, generates toxic sulfide and chloride smog when being heated, and has strong pungent odor. Chlorine or sulfuryl chloride has high danger and strong corrosion to equipment in the processes of storage, transportation and use. In the post-treatment process of the reaction, a large amount of strongly acidic waste water (about 20% of waste acid containing sulfuric acid, hydrochloric acid and acetic acid is generated in one ton of products by adopting sulfonyl chloride, and a large amount of waste hydrochloric acid is generated by adopting chlorine) is generated, so that the environmental protection pressure is increased. To neutralize the waste acid, about 11 tons of 30% liquid caustic soda is consumed, and the cost of producing one ton of product is increased by more than 7700 yuan. In the invention, sodium (potassium) chloride and hydrogen peroxide are combined to perform chlorine substitution on a benzene ring, and compared with the chlorine substitution by using chlorine or sulfonyl chloride, the chlorine substitution method has the advantages that: mild reaction conditions, good operation environment and simple post-treatment.
4. Dimethyl sulfate is a tubular product, is extremely toxic and has been used as a war poison gas. In the invention, methyl chloride is used for replacing dimethyl sulfate, which is safer than dimethyl sulfate.
Drawings
FIG. 12 is a liquid mass spectrum of 4-dichloro-5-methoxyaniline;
FIG. 22 is a liquid mass spectrum of 4-dichloro-5-methoxyaniline.
Detailed Description
Example 1
A preparation method of a bosutinib raw material is disclosed, wherein the bosutinib raw material is 2, 4-dichloro-5-methoxyaniline.
1900mL of glacial acetic acid and 109.0g (1.0mol) of m-aminophenol were added to a 5000mL reaction flask, and dissolved with stirring, heated to 50 ℃ and added 122mL (1.3mol) of acetic anhydride dropwise over 1 hour. After the completion of the dropwise addition, the mixture was stirred continuously, and the completion of the reaction was monitored by TLC (PE: EA ═ 1: 1), and 175.3g (3.0mol) of sodium chloride was added in portions at about 50 ℃, and 510.2g (4.5mol) of 30% hydrogen peroxide was added dropwise over 30min, and the completion of the reaction was monitored by TLC (PE: EA ═ 1: 1), and the mixture was poured into an appropriate amount of ice water, filtered, and the filter cake was washed with water and dried to obtain 204.6g of off-white 2, 4-dichloro-5-acetamidophenol in a yield of 93% and a purity of 99.2%.
To a 3000mL autoclave, 1150mL of dimethylformamide was added, 220g (1.0mol) of 2, 4-dichloro-5-acetamidophenol and 127.2g (1.2mol) of sodium carbonate were added in portions, methyl chloride was introduced, stirring was started, heating was carried out to 80 ℃, the completion of the reaction was monitored by TLC (PE: EA ═ 2: 1), then cooling was carried out to room temperature, the reaction solution was poured into an ice-water mixture, stirred for 1 hour, filtered, washed with water, and dried at 50 ℃ to obtain 229.3g of a pale yellow product, namely N- (2, 4-dichloro-5-methoxybenzene) acetamide solid, with 98% yield and 99.0% purity.
To a 5000mL reaction flask were added 1000mL of ethanol, 1000mL of water, 750mL of 30% hydrochloric acid, 234g (1mol) of N- (2, 4-dichloro-5-methoxybenzene) acetamide, heated to 70 ℃, and stirred for 12 hours to give a brown solution, and the reaction was monitored by dot-and-dash monitoring (PE: EA ═ 2: 1). Cooling the reaction solution to 10 ℃, adding 10% sodium hydroxide solution to adjust the pH value to about 8, distilling off ethanol under reduced pressure, cooling to 5 ℃, separating, filtering, and drying in vacuum at 35 ℃ to obtain 159.4g of light brown yellow product 2, 4-dichloro-5-methoxyaniline, wherein the yield is 88%, and the purity is 98.8%.
The total yield based on m-aminophenol as starting material was 80.20%.
Example 2
A5000 mL reaction flask was charged with 1120mL of glacial acetic acid and 109.0g (1.0mol) of m-aminophenol, and dissolved by stirring, and 153mL (1.5mol) of acetic anhydride was added dropwise at 30 ℃ over 1 hour. After the completion of the dropwise addition, the mixture was stirred continuously, and the completion of the reaction was monitored by TLC (PE: EA ═ 1: 1), and at about 30 ℃, 186.4g (2.5mol) of potassium chloride was added in portions, and at about 30min, 708.5g (6.25mol) of 30% hydrogen peroxide was added dropwise, and the completion of the reaction was monitored by TLC (PE: EA ═ 1: 1), and the mixture was poured into an appropriate amount of ice water, filtered, and the filter cake was washed with water and dried to obtain 206.8g of off-white 2, 4-dichloro-5-acetamidophenol at a yield of 94% and a purity of 99.1%.
To a 5000mL autoclave, 2750mL of acetonitrile is added, 220g (1.0mol) of 2, 4-dichloro-5-acetamidophenol is added in portions, 207.3g (1.5mol) of potassium carbonate is added, methyl chloride is introduced, stirring is started, heating is carried out to 60 ℃, the reaction is monitored by TLC (PE: EA ═ 2: 1) and then cooled to room temperature, solid-liquid separation is carried out, liquid is transferred to a 5000mL three-necked bottle, the temperature of the reaction solution is adjusted to 15 ℃, illumination reaction is carried out, TLC (PE: EA ═ 2: 1) is monitored to be finished, concentration is carried out, acetonitrile is recovered, the solid is recrystallized by a methanol-water mixed solution, and drying is carried out, so that light brown yellow products of 2, 4-dichloro-5-methoxyaniline, 176.6g, the yield is 92%, and the purity.
The total yield based on m-aminophenol as starting material was 86.48%.
Example 3
Adding 545g of formic acid into a 3000mL three-neck flask, starting stirring, adding 109g (1.0mol) of m-aminophenol and 1.1g (6mmol) of vanadium pentoxide in batches, heating to 100 ℃, monitoring the reaction by TLC (PE: EA is 1: 1), then cooling to 40 ℃, adding 175.3g (3.0mol) of sodium chloride in batches, dropwise adding 510.2g (4.5mol) of 30% hydrogen peroxide in 30min, monitoring the reaction by TLC (PE: EA is 1: 1), filtering after the reaction is finished, and recycling the formic acid from the filtrate. The intermediate is directly used for the next reaction without purification. The obtained 2, 4-dichloro-5-formamidophenol was transferred to a 5000mL autoclave, 1750mL of ethanol was added, 206g (1.0mol) of 2, 4-dichloro-5-formamidophenol and 179.7g (1.3mol) of potassium carbonate were added in portions, methyl chloride was introduced, stirring was started, heating was carried out to 70 ℃, the completion of the reaction was monitored by TLC (PE: EA ═ 2: 1), then cooling was carried out to room temperature, solid-liquid separation was carried out, the liquid was transferred to a 5000mL three-necked bottle, 1000mL of 30% hydrochloric acid was added, heating was carried out to reflux, stirring was carried out for 6 hours, a brown solution was obtained, and completion of the reaction was monitored by a dot-plate (PE: EA ═ 2: 1). Cooling the reaction solution to 10 ℃, adding 10% sodium hydroxide solution to adjust the pH value to about 8, distilling off ethanol under reduced pressure, cooling to 5 ℃, separating, filtering, and drying in vacuum at 35 ℃ to obtain 170.9g of light brown yellow product 2, 4-dichloro-5-methoxyaniline, wherein the yield is 84.55%, and the purity is 99.1%.
The total yield based on m-aminophenol as starting material was 84.55%.
Example 4
872g of formic acid was added to a 5000mL three-neck flask, stirring was started, 109g (1.0mol) of m-aminophenol and 5.5g (14.3mmol) of tungsten trioxide were added in portions, the mixture was heated to 90 ℃ and the reaction was monitored by TLC (PE: EA: 1), then cooled to 10 ℃ and 261g (3.5mol) of potassium chloride was added in portions, 30% 997.6g (8.8mol) of hydrogen peroxide was added dropwise over 30min and the reaction was monitored by TLC (PE: EA: 1), after the reaction was completed, the mixture was filtered and formic acid was recovered from the filtrate and recycled. The intermediate is directly used for the next reaction without purification. Transferring the obtained off-white 2, 4-dichloro-5-formamidophenol into a 5000mL autoclave, adding 2050mL of acetonitrile, adding 206g (1.0mol) of 2, 4-dichloro-5-formamidophenol and 179.7g (1.4mol) of sodium carbonate in batches, introducing methyl chloride, stirring, heating to 80 ℃, monitoring the reaction by TLC (PE: EA is 2: 1), cooling to room temperature, performing solid-liquid separation, transferring the liquid into a 5000mL three-neck flask, adjusting the temperature of the reaction liquid to 25 ℃, performing light reaction, monitoring the reaction by TLC (PE: EA is 2: 1), concentrating, recovering acetonitrile, recrystallizing the solid by using a methanol-water mixed solvent, and drying to obtain a light brown yellow product, namely 2, 4-dichloro-5-methoxyaniline, wherein the yield is 92.15% and the purity is 99.5%.
The total yield based on m-aminophenol as starting material was 92.15%.
Comparative example 1
800mL of glacial acetic acid and 109.0g (1.0mol) of m-aminophenol are added into a 5000mL reaction flask, stirred and dissolved, heated to 50 ℃, and 140.8mL (1.5mol) of acetic anhydride is added dropwise in about 1 h. After the addition, the completion of the reaction was monitored by TLC (PE: EA ═ 1: 1), cooled to room temperature, and after about 3 hours, chlorine gas was introduced to the reaction to change the color to light yellow, and the completion of the reaction was monitored by dot plate (PE: EA ═ 1: 1). Pouring the reaction mixture into ice water, stirring for 1h, filtering, washing with water, and drying at 50 ℃ to obtain 189.2g of off-white product 2, 4-dichloro-5-acetamidophenol, wherein the yield is 86% and the purity is 98.9%.
2750mL of methanol is added into a 5000mL reaction bottle, 220g (1.0mol) of 2, 4-dichloro-5-acetamidophenol and 165.9g (1.2mol) of potassium carbonate are added in batches, stirring is carried out at 50 ℃ for 30min, 151.4g (1.2mol) of dimethyl sulfate is added dropwise after 1h, and stirring is carried out at 60 ℃ for 1h to obtain a white suspension. TLC (PE: EA 2: 1) then cooled to room temperature, solid-liquid separated, poured into ice water mixture, stirred for 1h, filtered, washed with water, dried at 50 ℃ to give the light yellow product N- (2, 4-dichloro-5-methoxybenzene) acetamide as a solid 180.2g, 77% yield and 98.9% purity.
234g (1.0mol) of N- (2, 4-dichloro-5-methoxybenzene) acetamide was transferred to a 10000mL three-necked flask, and 2800mL of methanol was added, 1200mL of 30% hydrochloric acid was added, heated to reflux, and stirred for 8 hours to obtain a brown solution, and the reaction was monitored by dot-and-dash monitoring (PE: EA ═ 2: 1). Cooling the reaction solution to 10 ℃, adding 10% sodium hydroxide solution to adjust the pH value to about 8, distilling off methanol under reduced pressure, cooling to 5 ℃, separating, filtering, and drying in vacuum at 35 ℃ to obtain 157.4g of light brown yellow product 2, 4-dichloro-5-methoxyaniline, wherein the yield is 82% and the purity is 99.3%.
The total yield based on m-aminophenol as starting material was 54.30%.
Comparative example 2
3000mL of ethyl formate and 109.0g (1.0mol) of m-aminophenol were added to a 5000mL reaction flask, the mixture was heated under reflux for 30 hours, TLC was used to monitor completion of the reaction (PE: EA: 1), ethyl formate was removed under reduced pressure, the mixture was cooled to room temperature, 700mL of acetic acid was added, 337.4g (2.5mol) of sulfuryl chloride was added dropwise, the mixture was stirred for 10 hours to turn pale yellow, and the completion of the reaction was monitored by a dot plate (PE: EA: 1). Pouring the reaction mixture into ice water, stirring for 1h, filtering, washing with water, and drying at 50 ℃ to obtain 146.3g of offwhite product 2, 4-dichloro-5-formamidophenol, wherein the yield is 71%, and the purity is 98.7%.
To a 3000mL autoclave, 1350mL of acetonitrile was added, 206g (1.0mol) of 2, 4-dichloro-5-formamidophenol and 179.7g (1.4mol) of sodium carbonate were added in portions, methyl chloride was introduced, stirring was started, heating was carried out to 70 ℃, TLC monitoring of completion of the reaction (PE: EA ═ 2: 1), then cooling was carried out to room temperature, solid-liquid separation was carried out, the liquid was transferred to a 3000mL three-necked flask, the temperature of the reaction solution was adjusted to 25 ℃, the reaction was carried out by light irradiation, TLC monitoring of completion of the reaction (PE: EA ═ 2: 1), concentration was carried out, acetonitrile was recovered, the solid was recrystallized with a methanol-water mixed solution, and drying was carried out to obtain a light brown yellow product, 2, 4-dichloro-5-methoxyaniline, 172.8g, yield 90%, and purity 99.
The total yield based on m-aminophenol as starting material was 63.90%.
Comparative example 3
Into a 3000mL three-necked flask, 1091g of formic acid was added, stirring was started, 109g (1.0mol) of m-aminophenol and 5.5g (38mmol) of molybdenum trioxide were added in portions, the mixture was heated to 50 ℃ and the reaction was monitored by TLC (PE: EA: 1), then the mixture was cooled to room temperature, and after about 3 hours, the reaction was carried out by introducing chlorine gas so that the color became pale yellow and the completion of the reaction was monitored by a dot plate (PE: EA: 1). Pouring the reaction mixture into ice water, stirring for 1h, filtering, washing with water, and drying at 50 ℃ to obtain 175.1g of offwhite product 2, 4-dichloro-5-formamidophenol, wherein the yield is 85 percent, and the purity is 99.0 percent.
To a 5000mL autoclave, 2800mL of isopropanol was added, 206g (1.0mol) of 2, 4-dichloro-5-carboxamidophenol and 127.2g (1.2mol) of sodium carbonate were added in portions, methyl chloride was introduced, stirring was started, heating was carried out to 80 ℃, completion of the reaction was monitored by TLC (PE: EA ═ 2: 1), then cooling was carried out to room temperature, solid-liquid separation was carried out, the liquid was transferred to a 10000mL reaction flask, 1000mL of water and 1200mL of 30% hydrochloric acid were added, and heating was carried out to reflux reaction for 12 hours to obtain a brown solution, and completion of the reaction was monitored by a dot plate (PE: EA ═ 2: 1). Cooling the reaction solution to 10 ℃, adding 10% sodium hydroxide solution to adjust the pH value to about 8, distilling off isopropanol under reduced pressure, cooling to 5 ℃, separating, filtering, and drying in vacuum at 35 ℃ to obtain 153.6g of light brown yellow product 2, 4-dichloro-5-methoxyaniline, wherein the yield is 80%, and the purity is 98.8%.
The total yield based on m-aminophenol as starting material was 68%.
Comparative example 4
To a 2000mL three-necked flask, 550g of formic acid was added, stirring was started, 109g (1.0mol) of m-aminophenol and 1.8g (10mmol) of vanadium pentoxide were added in portions, the mixture was heated to 50 ℃ and the reaction was monitored by TLC (PE: EA: 1), followed by cooling to room temperature, 404.9g (3.0mol) of sulfuryl chloride was added dropwise, the mixture was stirred for 10 hours after completion of the addition, the color became pale yellow, and completion of the reaction was monitored by dot plate (PE: EA: 1). Pouring the reaction mixture into a large amount of ice water, stirring for 1h, filtering, washing with water, and drying at 50 ℃ to obtain 177.2g of offwhite product 2, 4-dichloro-5-formamidophenol, wherein the yield is 86% and the purity is 98.7%.
2200mL of acetonitrile is added into a 5000mL autoclave, 206g (1.0mol) of 2, 4-dichloro-5-formamidophenol and 179.7g (1.4mol) of sodium carbonate are added in batches, methyl chloride is introduced, stirring is started, heating is carried out to 60 ℃, TLC (TLC is used for monitoring the completion of the reaction (PE: EA is 2: 1), then cooling is carried out to room temperature, solid-liquid separation is carried out, liquid is transferred into a 5000mL three-neck flask, the temperature of the reaction liquid is adjusted to 25 ℃, the illumination reaction is carried out, TLC is used for monitoring the completion of the reaction (PE: EA is 2: 1), concentration is carried out, acetonitrile is recovered, the solid is recrystallized by a methanol-water mixed solvent, and drying is carried out, thus obtaining 172.8g of light brown yellow product 2, 4-dichloro-5-methoxyaniline, the yield is 90.
The total yield based on m-aminophenol as starting material was 77.40%.
Comparative example 5
900mL of glacial acetic acid and 109.0g (1.0mol) of m-aminophenol were added to a 3000mL reaction flask, and dissolved with stirring, and 157.8mL (2.0mol) of formic acid acetic anhydride was added dropwise at about 1 hour with heating to 50 ℃. After the completion of the dropwise addition, the mixture was stirred continuously, and the completion of the reaction was monitored by TLC (PE: EA ═ 1: 1), 146.1g (2.5mol) of sodium chloride was added in portions at about 50 ℃, and 408.1g (3.6mol) of 30% hydrogen peroxide was added dropwise over 30min, and the completion of the reaction was monitored by TLC (PE: EA ═ 1: 1), and the mixture was poured into an appropriate amount of ice water, filtered, and the cake was washed with water and dried to obtain 187.5g of off-white 2, 4-dichloro-5-carboxamidophenol with a yield of 91% and a purity of 98.7%.
To a 3000mL reaction flask were added 1850mL of dimethylformamide, 206g (1mol) of 2, 4-dichloro-5-carboxamidophenol and 207.3g (1.5mol) of potassium carbonate, and the mixture was stirred at 50 ℃ for 30min, then 164.0g (1.3mol) of dimethyl sulfate was added dropwise over 1 hour, and the mixture was further stirred at 50 ℃ for 1 hour to obtain a white suspension. Pouring the reaction liquid into an ice-water mixture, stirring for 1h, filtering, washing with water, and drying at 50 ℃ to obtain 176g of a light yellow product N- (2, 4-dichloro-5-methoxybenzene) formamide solid, wherein the yield is 80%, and the purity is 98.9%.
To a 5000mL reaction flask were added 1000mL of ethanol, 1000mL of water, 700mL of 30% hydrochloric acid, and 220g (1mol) of N- (2, 4-dichloro-5-methoxybenzene) carboxamide, and the mixture was heated to 70 ℃ and stirred for 15 hours to obtain a brown solution, and the reaction was monitored by dot-and-dash monitoring (PE: EA ═ 2: 1). Cooling the reaction solution to 10 ℃, adding 10% sodium hydroxide solution to adjust the pH value to about 8, distilling off ethanol under reduced pressure, cooling to 5 ℃, separating, filtering, and drying in vacuum at 35 ℃ to obtain 159.4g of light brown yellow product 2, 4-dichloro-5-methoxyaniline, wherein the yield is 83% and the purity is 98.8%.
The total yield based on m-aminophenol as starting material was 60.42%.
Comparative example 6
1000mL of glacial acetic acid and 109.0g (1.0mol) of m-aminophenol were added to a 5000mL reaction flask, and dissolved with stirring, and 126.2mL (1.6mol) of formic acid acetic anhydride was added dropwise over 1 hour by heating to 80 ℃. After the completion of the dropwise addition, stirring was continued, the reaction was monitored by TLC (PE: EA 1: 1), cooled to about 50 ℃, and 223.7g (3.0mol) of potassium chloride was added in portions, 680.2g (6.0mol) of 30% hydrogen peroxide was added dropwise over 30min, and the reaction was monitored by TLC (PE: EA 1: 1), and the mixture was poured into an appropriate amount of ice water, filtered, and the filter cake was washed with water and dried to obtain 185.40g of off-white 2, 4-dichloro-5-carboxamidophenol with a yield of 90% and a purity of 99.1%.
To a 3000mL reaction flask were added 500mL of dimethylformamide, 700mL of ethanol, 206g (1mol) of 2, 4-dichloro-5-carboxamidophenol, 207.3g (1.5mol) of potassium carbonate, followed by stirring at 40 ℃ for 30min, and 189.2g (1.5mol) of dimethyl sulfate was added dropwise over 1 hour, and the mixture was heated to 60 ℃ and stirred for 1 hour to obtain a white suspension. Pouring the reaction liquid into an ice-water mixture, stirring for 1h, filtering, washing with water, and drying at 50 ℃ to obtain 173.8g of a light yellow product N- (2, 4-dichloro-5-methoxybenzene) formamide solid, wherein the yield is 79%, and the purity is 98.9%.
220g (1.0mol) of N- (2, 4-dichloro-5-methoxybenzene) formamide and 1900g of acetonitrile are added into a 5000mL three-necked flask, the temperature of the reaction solution is adjusted to 25 ℃, the reaction is performed by illumination, TLC (PE: EA is 2: 1) monitors the completion of the reaction, concentration is performed, the acetonitrile is recovered, a solid is recrystallized by a methanol-water mixed solvent, and drying is performed to obtain 184.3g of light brown yellow product 2, 4-dichloro-5-methoxyaniline, wherein the yield is 96% and the purity is 99.5%.
The total yield based on m-aminophenol as starting material was 68.26%.
Comparative example 7
Into a 3000mL three-necked flask, 650g of formic acid was added, stirring was started, 109g (1.0mol) of m-aminophenol and 11.6g (50mmol) of tungsten trioxide were added in portions, the mixture was heated to 80 ℃ and the reaction was monitored by TLC (PE: EA: 1), then the mixture was cooled to 20 ℃ and 163.6g (2.8mol) of sodium chloride was added in portions, 30% hydrogen peroxide (725.5 g (6.4mol) was added dropwise over 30min and the reaction was monitored by TLC (PE: EA: 1), and after the reaction was completed, the mixture was filtered and the filtrate was recovered and used as formic acid. The intermediate is directly used for the next reaction without purification. The obtained off-white 2, 4-dichloro-5-formamidophenol was transferred to a 3000mL reaction flask, 600mL acetonitrile, 600mL isopropanol, 206.0g (1.0mol) of 2, 4-dichloro-5-formamidophenol, 137.8g (1.3mol) of sodium carbonate were added, stirred at 40 ℃ for 30min, 164.0g (1.3mol) of dimethyl sulfate was added dropwise over 1h, the temperature was raised to 50 ℃, and stirring was continued for 1h to obtain a white suspension. Pouring the reaction liquid into an ice-water mixture, stirring for 1h, filtering, washing with water, and drying at 50 ℃ to obtain a light yellow product N- (2, 4-dichloro-5-methoxybenzene) formamide solid 180.4g, wherein the yield is 78.72%, and the purity is 98.7%.
To a 5000mL reaction flask were added 1000mL of ethanol, 1000mL of water, 650mL of 30% hydrochloric acid, and 220g (1mol) of N- (2, 4-dichloro-5-methoxybenzene) carboxamide, and the mixture was heated to reflux to obtain a brown solution, and the reaction was monitored by dot-panel monitoring for completion (PE: EA ═ 2: 1). Cooling the reaction solution to 10 ℃, adding 10% sodium hydroxide solution to adjust the pH value to about 8, distilling off ethanol under reduced pressure, cooling to 5 ℃, separating, filtering, and drying in vacuum at 35 ℃ to obtain 155.5g of light brown yellow product 2, 4-dichloro-5-methoxyaniline, wherein the yield is 81%, and the purity is 98.9%.
The total yield based on m-aminophenol as starting material was 63.76%.
Comparative example 8
The method comprises the steps of adding 550g of formic acid into a 3000mL three-neck flask, starting stirring, adding 109g (1.0mol) of m-aminophenol and 2.2g (12mmol) of vanadium pentoxide in batches, heating to 80 ℃, monitoring the completion of the reaction by TLC (PE: EA is 1: 1), then cooling to 20 ℃, adding 260.9g (3.5mol) of potassium chloride in batches, dropwise adding 600.8g (5.3mol) of 30% hydrogen peroxide in 30min, monitoring the completion of the reaction by TLC (PE: EA is 1: 1), filtering after the reaction is finished, and recovering formic acid from the filtrate for recycling. The intermediate is directly used for the next reaction without purification. The obtained off-white 2, 4-dichloro-5-formamidophenol is transferred into a 3000mL reaction bottle, 1500mL propanol, 206g (1.0mol) of 2, 4-dichloro-5-formamidophenol and 165.9g (1.2mol) of potassium carbonate are added, the mixture is stirred for 30min at the temperature of 40 ℃, 151.4g (1.2mol) of dimethyl sulfate is added dropwise after about 1h, the temperature is raised to 50 ℃, and the stirring is continued for 1h, so that a white suspension is obtained. Pouring the reaction liquid into an ice-water mixture, stirring for 1h, filtering, washing with water, and drying at 50 ℃ to obtain 173.8g of a light yellow product N- (2, 4-dichloro-5-methoxybenzene) formamide solid, wherein the yield is 75.05%, and the purity is 98.7%.
In a 3000mL three-necked flask were added 220g (1.0mol) of N- (2, 4-dichloro-5-methoxybenzene) carboxamide and 1200g of acetonitrile, the reaction mixture was warmed to 25 ℃, the reaction was illuminated, TLC monitored for completion of the reaction (PE: EA ═ 2: 1), concentrated, and the acetonitrile was recovered, and the solid was recrystallized from a mixed methanol-water solvent and dried to give 184.3g of 2, 4-dichloro-5-methoxyaniline as a pale brown-yellow product with a yield of 96% and a purity of 99.5%.
The total yield based on m-aminophenol as starting material was 72.05%.
By comparing examples 1, 2, 3, 4, 5, 6, 7, 8 with comparative examples 1, 2, 3, 4, chlorine was combined with sodium chloride or potassium chloride and hydrogen peroxide, and the chlorine was removed with less by-products and high yield because of the milder chlorine removal reagent compared with chlorine and sulfuryl chloride.
By comparing the examples 3, 4, 7 and 8 with the examples 1, 2, 3, 4, 5 and 6, the formic acid is used as an amino protection reagent, and the chlorine is combined by sodium chloride or potassium chloride and hydrogen peroxide, so that the recovered formic acid can be recycled, the post-treatment is simple, the intermediate is directly used for the next step without purification, the material loss of the post-treatment is reduced, the water separation is not needed, and the generation of a large amount of acidic wastewater is reduced, thereby improving the yield and reducing the production cost.
By comparing the examples 1, 2, 3, 4, 2, 3 and 4 with the comparative examples 1, 5, 6, 7 and 8, methyl chloride is used as a methylating agent, because methyl chloride is a gas, a small amount of unreacted methyl chloride is easy to separate from a reaction system, the obtained methylated intermediate can directly carry out the next reaction without separation and purification, and the unreacted dimethyl sulfate needs to be quenched, thereby not influencing the next reaction and reducing the material loss of post-treatment, thereby improving the yield and reducing the production cost.
By comparing the examples 1, 2, 3 and 4 with the comparative examples 1, 2, 3, 4, 5, 6, 7 and 8, the yield is higher because the new process is adopted; by comparing the examples and comparative examples, the yield of example 4 was the highest, reaching 92.15%, and comparative example 1, in which the previous process was completely repeated, gave the lowest yield, only 54.3%.
In addition, it should be noted that the above contents described in the present specification are only illustrations of the contents of the present invention. Equivalent or simple changes in the structure, characteristics and principles of the invention are included in the protection scope of the patent. Various modifications, additions and substitutions for the specific embodiments described may be made by those skilled in the art without departing from the scope of the invention as defined in the accompanying claims.
Claims (7)
1. A preparation method of a bosutinib raw material, wherein the bosutinib raw material is 2, 4-dichloro-5-methoxyaniline, is characterized by comprising the following steps:
b1, amino protection is carried out on m-aminophenol to generate 3-methyl (ethyl) acylaminophenol,
b2 reaction of 3-methyl (ethyl) acylaminophenol with potassium chloride or sodium chloride to obtain 2, 4-dichloro-5-methyl (ethyl) acylaminophenol,
b3 reaction of 2, 4-dichloro-5-methyl (ethyl) acylaminophenol with methylating agent to obtain 2, 4-dichloro-5-methyl (ethyl) acylaminoanisole,
b4 removing the nor (acetyl) acyl from 2, 4-dichloro-5-formamido anisole to generate 2, 4-dichloro-5-methoxyaniline,
2. the process for preparing bosutinib starting material according to claim 1, characterized in that: the chlorine on the benzene ring in the step B2 is derived from sodium chloride or potassium chloride, and the amount of the substance is 2.5-3.5 times of that of m-aminophenol.
3. The process for preparing bosutinib starting material according to claim 1, characterized in that: the oxidant used in the step B2 is hydrogen peroxide, the amount of the oxidant is 1.5 to 2.5 times of sodium chloride or potassium chloride, and the reaction temperature in the step B2 is 10 to 50 ℃.
4. The process for preparing bosutinib starting material according to claim 1, characterized in that: the methylating agent used in step B3 is methyl chloride.
5. The process for preparing bosutinib starting material according to claim 1, characterized in that: the solvent used in step B3 is acetonitrile, dimethylformamide, methanol, ethanol, propanol, isopropanol or their combination, and its weight is 5-10 times of that of 2, 4-dichloro-5-methyl (ethyl) amido phenol.
6. The process for preparing bosutinib starting material according to claim 1, characterized in that: the reaction temperature in step B3 was 60-80 ℃.
7. The process for preparing bosutinib starting material according to claim 1, characterized in that: the base used in the step B3 is sodium carbonate or potassium carbonate, and the mass ratio of the base to the base is 1.2 to 1.5 times of that of the 2, 4-dichloro-5-methyl (ethyl) amido phenol.
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