CN109651260B - Preparation method of 4-amino-5-methoxymethyl-2-propylpyrimidine - Google Patents
Preparation method of 4-amino-5-methoxymethyl-2-propylpyrimidine Download PDFInfo
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Abstract
The invention relates to the technical field of veterinary drugs, and particularly relates to a preparation method of 4-amino-5-methoxymethyl-2-propylpyrimidine, which comprises the following steps: (1) mixing acrylonitrile and a methanol solution of sodium methoxide and an organic solvent, introducing carbon monoxide, and filtering after the reaction is finished to obtain sodium salt of alpha-methoxymethyl-beta-methoxyacrylonitrile; (2) putting the product obtained in the step (1) into an aqueous solution, adding an amination reagent, and obtaining 3-dimethylamino-2-methoxy methacrylonitrile after the reaction is finished; (3) preparing a butylamidine solution; (4) mixing 3-dimethylamino-2-methoxy methacrylonitrile with a butylamidine solution, controlling the reaction temperature and the reaction time, and carrying out operations such as distillation after the reaction is finished to obtain the 4-amino-5-methoxy methyl-2-propyl pyrimidine. The preparation method does not use a methylation reagent, effectively solves the problem of environmental protection, and greatly improves the product yield.
Description
Technical Field
The invention relates to the technical field of veterinary drugs, and in particular relates to a preparation method of 4-amino-5-methoxymethyl-2-propylpyrimidine for a synthesis process of amproline hydrochloride.
Background
4-amino-5-methoxymethyl-2-propylpyrimidine is a key intermediate for producing an anti-coccidiosis drug, namely amproline hydrochloride. The amproline can competitively inhibit the active transport of thiamine and prevent the occurrence of coccidiosis. Has broad spectrum and high efficiency, and is widely used in livestock and poultry breeding, especially in chicken farms.
At present, the preparation methods of 4-amino-5-methoxymethyl-2-propylpyrimidine in the prior art include the following methods: (1) in the presence of organic solution, sodium methoxide and carbon monoxide, acrylonitrile and methyl formate are condensed to generate sodium salt of alpha-methoxymethyl-beta-hydroxyacrylonitrile, and then the sodium salt is further alkylated in the presence of an alkylating agent to obtain the alpha-methoxymethyl-beta-hydroxyacrylonitrile. Then carrying out cyclization reaction with butylamidine to obtain 4-amino-5-methoxymethyl-2-propylpyrimidine. However, in the reaction, a methylating agent which has high toxicity and is difficult to treat three wastes, namely dimethyl sulfate, is required to be used. (2) Patent CN 1491936a, which uses N, N-dimethyl amide as a phase transfer catalyst to promote the formation of sodium salt, but also uses a methylating agent such as dimethyl sulfate, which is a major environmental issue. (3) DE-a 3511273 discloses a process for direct cyclization of acetamidine hydrochloride with the analogous compound, α -formyl- β -carboxamidopropionitrile sodium salt, without requiring either derivatization of any of the above starting materials or release of acetamidine from its hydrochloride salt, but according to the reported experimental conditions used, the highest yield obtained was only 35% (reported 57%) and the starting sodium salt had to have a minimum purity of 92%, making the process economically unattractive. (4) Patent CN 102105438A discloses a method, which can be obtained by reacting sodium salt with sodium chloride, amination, and direct cyclization with nitrile compound under base catalysis. Although the method uses the cheap and environment-friendly raw material ammonium chloride, the reaction conditions need to be strictly controlled in the reaction process, and a strong-alkaline special catalyst needs to be used in the cyclization reaction to obtain the yield of 43.5 percent, and compared with other synthesis routes, the yield is too low. Because of the above problems, it is necessary to establish a method for producing 4-amino-5-methoxymethyl-2-propylpyrimidine.
Disclosure of Invention
The invention aims to: aiming at the defects in the prior art, the preparation method of the 4-amino-5-methoxymethyl-2-propyl pyrimidine is provided, and a methylation reagent is not used in the preparation method, so that the environmental protection problem is effectively solved, and the product yield is greatly improved.
In order to achieve the purpose, the technical scheme of the invention is as follows:
a process for the preparation of 4-amino-5-methoxymethyl-2-propylpyrimidine, which comprises the steps of:
(1) taking a methanol solution of acrylonitrile and sodium methoxide as a reaction raw material, adding an organic solvent, stirring and mixing, introducing carbon monoxide, controlling the reaction temperature, the reaction time and the reaction pressure, and filtering after the reaction is finished to obtain sodium salt of alpha-methoxymethyl-beta-hydroxyacrylonitrile;
(2) putting the sodium salt of the alpha-methoxymethyl-beta-hydroxyacrylonitrile obtained in the step (1) into an aqueous solution, adding an amination reagent, stirring and mixing, controlling the reaction temperature and the reaction time, and obtaining 3-dimethylamino-2-methoxymethyl acrylonitrile after the reaction is finished;
(3) mixing butylamidine hydrochloride with a methanol solution of sodium methoxide, controlling the reaction temperature and the reaction time, and centrifuging after the reaction is finished to obtain a butylamidine solution;
(4) and (3) mixing the 3-dimethylamino-2-methoxy methacrylonitrile in the step (2) with the butylamidine solution in the step (3), controlling the reaction temperature and the reaction time, and after the reaction is finished, carrying out distillation, water washing, extraction and distillation operations to obtain the 4-amino-5-methoxy methyl-2-propyl pyrimidine.
As an improved technical scheme, the organic solvent is toluene, xylene or halogenated hydrocarbon.
As an improved technical scheme, the molar ratio of the methanol solution of sodium methoxide to the acrylonitrile in the step (1) is 1.05-1.1: 1.
As an improved technical scheme, the reaction temperature of the step (1) is 32-40 ℃, the reaction time is 18-22h, and the reaction pressure is 3-5 Mpa.
As an improved technical scheme, the amination reagent is dimethylamine hydrochloride, and the molar ratio of the sodium salt of the alpha-methoxymethyl-beta-hydroxyacrylonitrile to the dimethylamine hydrochloride in the step (1) is 1.1-1.5: 1.
As an improved technical scheme, the reaction temperature of the step (2) is 35-60 ℃, and the reaction time is 15-20 h.
As an improved technical scheme, in the step (3), the butylamidine hydrochloride and a methanol solution of sodium methoxide are mixed according to an equal molar ratio, the reaction temperature is 30-40 ℃, and the reaction time is 3-5 min.
As an improved technical scheme, the molar ratio of the 3-dimethylamino-2-methoxy methacrylonitrile to the butylamidine solution in the step (4) is 1:1-1.5, the reaction temperature is 65-75 ℃, and the reaction time is 2-4 h.
By adopting the technical scheme, compared with the prior art, the invention has the following advantages:
according to the invention, acrylonitrile is used as a raw material, and a product is prepared through the addition reaction in the step (1), the amination reaction in the step (2) and the cyclization reaction in the step (4), wherein an amination reagent is used for replacing a methylation reagent in the step (2), the reaction temperature is controlled to be 35-60 ℃, and compared with the prior art, dimethylamine hydrochloride is used for replacing the methylation reagent, so that the reaction yield is higher, and the toxicity is lower. Compared with a methylation reagent which cannot be recycled and reused and is difficult to treat three wastes, the raw material has high recycling rate; compared with the carcinogenic amination reagent o-chloroaniline, the dimethylamine has lower toxicity and lower risk; in addition, the raw materials are low in price, the production process is simple, the utilization rate of the raw materials is high, the recovery is convenient, the product cost is low, and the total reaction yield is 72.85%. The total yield is improved by more than 12 percent, and the method is suitable for industrial production.
Detailed Description
The present invention will be described in further detail in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
Example 1
500g of toluene and 200g of sodium methoxide methanol solution (purity of 28%) are added into a 1L autoclave, the mixture is uniformly mixed and stirred, ice water is cooled to 10 ℃, and 50g of acrylonitrile is dropwise added. During the dropping process, the reaction temperature is maintained within 15 ℃. After the dropwise addition, the air in the autoclave was purged with carbon monoxide, pressurized to 3MPa, heated to 35 ℃ and stirred for 20 hours. Carbon monoxide is used to maintain the pressure of the reaction system during the reaction process. After the reaction, the reaction mixture was cooled to room temperature, filtered under reduced pressure to obtain a wet product of the sodium salt of α -methoxymethyl- β -hydroxyacrylonitrile, which was dried under vacuum at 70 ℃ for 2 hours to obtain 125g of the sodium salt with a purity of 92% (yield 90.30%). Dissolving all sodium salts in 250mL of purified water, adding 90.26g of dimethylamine hydrochloride for mixed reaction at 45 ℃ for 17h, centrifugally discharging after the condensation reaction is finished, washing the mixture to be neutral by using a large amount of water, centrifuging, and drying the centrifuged material to obtain 111.56g of solid 3-dimethylamino-2-methoxymethyl acrylonitrile (yield 84.47%). 127.43g of butylamidine hydrochloride (purity 92%) are mixed with 184.41g of sodium methoxide in methanol (purity 28%), the mixture is freed at 35 ℃ and, after the reaction has ended, the mixture is discharged by centrifugation, the sodium chloride cake is washed with methanol and the solutions are combined. Adding all the obtained 3-dimethylamino-2-methoxy methacrylonitrile into a solution containing butylamidine, heating to 70 ℃, reacting for 3h, and distilling to recover dimethylamine and methanol; washing the distilled residual substrate with 300g of 15% sodium hydroxide aqueous solution, extracting with dichloromethane solution, and distilling the organic solvent to obtain the product 4-amino-5-methoxymethyl-2-propylpyrimidine, wherein the total mass is 124.4g, and the calculated yield is 72.85%.
Example 2
500g of toluene and 200g of sodium methoxide methanol solution (purity of 28%) are added into a 1L autoclave, the mixture is uniformly mixed and stirred, ice water is cooled to 10 ℃, and 50g of acrylonitrile is dropwise added. During the dropping process, the reaction temperature is maintained within 15 ℃. After the dropwise addition, the air in the autoclave was purged with carbon monoxide, pressurized to 3MPa, heated to 35 ℃ and stirred for 20 hours. Carbon monoxide is used to maintain the pressure of the reaction system during the reaction process. After the reaction, the reaction mixture was cooled to room temperature, filtered under reduced pressure to obtain a wet product of the sodium salt of α -methoxymethyl- β -hydroxyacrylonitrile, which was vacuum-dried at 70 ℃ for 2 hours to obtain 124.85g of the sodium salt having a purity of 91.91% (yield 90.10%). Dissolving all sodium salts in 250mL of purified water, adding 76.20g of dimethylamine hydrochloride for mixed reaction at 45 ℃ for 17 hours, centrifugally discharging after the condensation reaction is finished, washing the mixture to be neutral by using a large amount of water, centrifuging, and drying the centrifuged material to obtain 111.07g of solid 3-dimethylamino-2-methoxymethyl acrylonitrile (yield 83.34%). 125.73g of butylamidine hydrochloride (purity 92%) are mixed with 181.96g of sodium methoxide in methanol (purity 28%), the mixture is freed at 35 ℃ and, after the reaction has ended, the mixture is discharged by centrifugation, the sodium chloride cake is washed with methanol and the solutions are combined. Adding all the obtained 3-dimethylamino-2-methoxy methacrylonitrile into a solution containing butylamidine, heating to 70 ℃, reacting for 3h, and distilling to recover dimethylamine and methanol; washing the distilled residual substrate with 300g of 15% sodium hydroxide aqueous solution, extracting with dichloromethane solution, and distilling the organic solvent to obtain the product 4-amino-5-methoxymethyl-2-propylpyrimidine, wherein the total mass is 122.63g, and the calculated yield is 71.82%.
Example 3
500g of toluene and 200g of sodium methoxide methanol solution (purity of 28%) are added into a 1L autoclave, the mixture is uniformly mixed and stirred, ice water is cooled to 10 ℃, and 50g of acrylonitrile is dropwise added. During the dropping process, the reaction temperature is maintained within 15 ℃. After the dropwise addition, the air in the autoclave was purged with carbon monoxide, pressurized to 3MPa, heated to 35 ℃ and stirred for 20 hours. Carbon monoxide is used to maintain the pressure of the reaction system during the reaction process. After the reaction, the reaction mixture was cooled to room temperature, filtered under reduced pressure to obtain a wet product of the sodium salt of α -methoxymethyl- β -hydroxyacrylonitrile, which was vacuum-dried at 70 ℃ for 2 hours to obtain 124.93g of the sodium salt having a purity of 91.96% (yield 90.20%). Dissolving all sodium salts in 250mL of purified water, adding 104.03g of dimethylamine hydrochloride for mixed reaction at 45 ℃ for 17 hours, centrifugally discharging after the condensation reaction is finished, washing the materials to be neutral by using a large amount of water, centrifuging, and drying the centrifuged materials to obtain 111.63g of solid 3-dimethylamino-2-methoxymethyl acrylonitrile (the yield is 84.52%). 127.5g butylamidine hydrochloride (purity 92%) was mixed with 184.53g sodium methoxide in methanol (purity 28%), and the mixture was subjected to dissociation reaction at 35 ℃ and centrifuged after the reaction was completed, and the sodium chloride cake was washed with methanol and the solution was combined. Adding all the obtained 3-dimethylamino-2-methoxy methacrylonitrile into a solution containing butylamidine, heating to 70 ℃, reacting for 3h, and distilling to recover dimethylamine and methanol; washing the distilled residual substrate with 300g of 15% sodium hydroxide aqueous solution, extracting with dichloromethane solution, and distilling the organic solvent to obtain the product 4-amino-5-methoxymethyl-2-propylpyrimidine, wherein the total mass is 124.55g, and the calculated yield is 72.94%.
Example 4
500g of toluene and 200g of sodium methoxide methanol solution (purity of 28%) are added into a 1L autoclave, the mixture is uniformly mixed and stirred, ice water is cooled to 10 ℃, and 50g of acrylonitrile is dropwise added. During the dropping process, the reaction temperature is maintained within 15 ℃. After the dropwise addition, the air in the autoclave was purged with carbon monoxide, pressurized to 3MPa, heated to 35 ℃ and stirred for 20 hours. Carbon monoxide is used to maintain the pressure of the reaction system during the reaction process. After the reaction, the reaction mixture was cooled to room temperature, filtered under reduced pressure to obtain a wet product of the sodium salt of α -methoxymethyl- β -hydroxyacrylonitrile, which was vacuum-dried at 70 ℃ for 2 hours to obtain 125.16g of the sodium salt having a purity of 92.09% (yield 90.50%). Dissolving all sodium salts in 250mL of purified water, adding 90.46g of dimethylamine hydrochloride to perform mixed reaction at 35 ℃ for 17 hours, centrifugally discharging after the condensation reaction is finished, washing the mixture to be neutral by using a large amount of water, centrifuging, and drying the centrifuged material to obtain 111.16g of solid 3-dimethylamino-2-methoxymethyl acrylonitrile (yield 84.17%). 126.97g of butylamidine hydrochloride (purity 92%) are mixed with 183.76g of sodium methoxide in methanol (purity 28%), the mixture is freed at 35 ℃ and, after the reaction has ended, the mixture is discharged by centrifugation, the sodium chloride cake is washed with methanol and the solutions are combined. Adding all the obtained 3-dimethylamino-2-methoxy methacrylonitrile into a solution containing butylamidine, heating to 70 ℃, reacting for 3h, and distilling to recover dimethylamine and methanol; washing the distilled residual substrate with 300g of 15% sodium hydroxide aqueous solution, extracting with dichloromethane solution, and distilling the organic solvent to obtain the product 4-amino-5-methoxymethyl-2-propylpyrimidine, wherein the total mass is 123.85g, and the calculated yield is 72.53%.
Example 5
500g of toluene and 200g of sodium methoxide methanol solution (purity of 28%) are added into a 1L autoclave, the mixture is uniformly mixed and stirred, ice water is cooled to 10 ℃, and 50g of acrylonitrile is dropwise added. During the dropping process, the reaction temperature is maintained within 15 ℃. After the dropwise addition, the air in the autoclave was purged with carbon monoxide, pressurized to 3MPa, heated to 35 ℃ and stirred for 20 hours. Carbon monoxide is used to maintain the pressure of the reaction system during the reaction process. After the reaction, the reaction mixture was cooled to room temperature, filtered under reduced pressure to obtain a wet product of the sodium salt of α -methoxymethyl- β -hydroxyacrylonitrile, which was vacuum-dried at 70 ℃ for 2 hours to obtain 125.23g of the sodium salt having a purity of 92.14% (yield 90.60%). Dissolving all sodium salts in 250mL of purified water, adding 90.56g of dimethylamine hydrochloride to carry out mixing reaction at 60 ℃ for 20 hours, centrifugally discharging after the condensation reaction is finished, washing the mixture to be neutral by using a large amount of water, centrifuging, and drying the centrifuged material to obtain 112.5g of solid 3-dimethylamino-2-methoxymethyl acrylonitrile (the yield is 85.18%). 128.5g of butylamidine hydrochloride (purity 92%) is mixed with 185.98g of sodium methoxide in methanol (purity 28%), the mixture is freed at 35 ℃ and, after the reaction has ended, the mixture is discharged by centrifugation, the sodium chloride cake is washed with methanol and the solutions are combined. Adding all the obtained 3-dimethylamino-2-methoxy methacrylonitrile into a solution containing butylamidine, heating to 70 ℃, reacting for 3h, and distilling to recover dimethylamine and methanol; washing the distilled residual substrate with 300g of 15% sodium hydroxide aqueous solution, extracting with dichloromethane solution, and distilling the organic solvent to obtain the product 4-amino-5-methoxymethyl-2-propylpyrimidine, wherein the total mass is 125.42g, and the calculated yield is 73.45%.
Example 6
500g of toluene and 200g of sodium methoxide methanol solution (purity of 28%) are added into a 1L autoclave, the mixture is uniformly mixed and stirred, ice water is cooled to 10 ℃, and 50g of acrylonitrile is dropwise added. During the dropping process, the reaction temperature is maintained within 15 ℃. After the dropwise addition, the air in the autoclave was purged with carbon monoxide, pressurized to 3MPa, heated to 35 ℃ and stirred for 20 hours. Carbon monoxide is used to maintain the pressure of the reaction system during the reaction process. After the reaction, the reaction mixture was cooled to room temperature, filtered under reduced pressure to obtain a wet product of the sodium salt of α -methoxymethyl- β -hydroxyacrylonitrile, which was vacuum-dried at 70 ℃ for 2 hours to obtain 124.85g of the sodium salt having a purity of 91.91% (yield 90.10%). Dissolving all sodium salts in 250mL of purified water, adding 90.06g of dimethylamine hydrochloride for mixed reaction at 45 ℃ for 15h, centrifugally discharging after the condensation reaction is finished, washing the mixture to be neutral by using a large amount of water, centrifuging, and drying the centrifuged material to obtain 110.43g of solid 3-dimethylamino-2-methoxymethyl acrylonitrile (the yield is 83.61%). 126.14g of butylamidine hydrochloride (purity 92%) are mixed with 182.55g of sodium methoxide in methanol (purity 28%), the mixture is freed at 35 ℃ and, after the reaction has ended, the mixture is discharged by centrifugation, the sodium chloride cake is washed with methanol and the solutions are combined. Adding all the obtained 3-dimethylamino-2-methoxy methacrylonitrile into a solution containing butylamidine, heating to 70 ℃, reacting for 3h, and distilling to recover dimethylamine and methanol; washing the distilled residual substrate with 300g of 15% sodium hydroxide aqueous solution, extracting with dichloromethane solution, and distilling the organic solvent to obtain the product 4-amino-5-methoxymethyl-2-propylpyrimidine, wherein the total mass is 122.96g, and the calculated yield is 72.01%.
Example 7
500g of toluene and 200g of sodium methoxide methanol solution (purity of 28%) are added into a 1L autoclave, the mixture is uniformly mixed and stirred, ice water is cooled to 10 ℃, and 50g of acrylonitrile is dropwise added. During the dropping process, the reaction temperature is maintained within 15 ℃. After the dropwise addition, the air in the autoclave was purged with carbon monoxide, pressurized to 3MPa, heated to 35 ℃ and stirred for 20 hours. Carbon monoxide is used to maintain the pressure of the reaction system during the reaction process. After the reaction, the reaction mixture was cooled to room temperature, filtered under reduced pressure to obtain a wet product of the sodium salt of α -methoxymethyl- β -hydroxyacrylonitrile, which was vacuum-dried at 70 ℃ for 2 hours to obtain 125.16g of the sodium salt having a purity of 92.09% (yield 90.50%). Dissolving all sodium salts in 250mL of purified water, adding 90.46g of dimethylamine hydrochloride for mixing reaction at 45 ℃ for 20 hours, centrifugally discharging after the condensation reaction is finished, washing the mixture to be neutral by using a large amount of water, centrifuging, and drying the centrifuged material to obtain 112.27g of solid 3-dimethylamino-2-methoxymethyl acrylonitrile (yield is 85%). 128.24g of butylamidine hydrochloride (purity 92%) are mixed with 185.6g of sodium methoxide in methanol (purity 28%), the mixture is freed at 35 ℃ and, after the reaction has ended, the mixture is discharged by centrifugation, the sodium chloride cake is washed with methanol and the solutions are combined. Adding all the obtained 3-dimethylamino-2-methoxy methacrylonitrile into a solution containing butylamidine, heating to 70 ℃, reacting for 3h, and distilling to recover dimethylamine and methanol; washing the distilled residual substrate with 300g of 15% sodium hydroxide aqueous solution, extracting with dichloromethane solution, and distilling the organic solvent to obtain the product 4-amino-5-methoxymethyl-2-propylpyrimidine, wherein the total mass is 125.11g, and the calculated yield is 73.27%.
Example 8
500g of toluene and 191g of sodium methoxide methanol solution (purity of 28%) are added into a 1L autoclave, the mixture is uniformly mixed and stirred, ice water is cooled to 10 ℃, and 50g of acrylonitrile is dropwise added. During the dropping process, the reaction temperature is maintained within 15 ℃. After the dropwise addition, the air in the autoclave was purged with carbon monoxide, pressurized to 3MPa, heated to 35 ℃ and stirred for 20 hours. Carbon monoxide is used to maintain the pressure of the reaction system during the reaction process. After the reaction, the reaction mixture was cooled to room temperature, filtered under reduced pressure to obtain a wet product of the sodium salt of α -methoxymethyl- β -hydroxyacrylonitrile, which was vacuum-dried at 70 ℃ for 2 hours to obtain 119.96g of the sodium salt having a purity of 92.36% (yield 87.00%). Dissolving all sodium salts in 250mL of purified water, adding 86.96g of dimethylamine hydrochloride to perform mixed reaction at 45 ℃ for 17 hours, centrifugally discharging after the condensation reaction is finished, washing the mixture to be neutral by using a large amount of water, centrifuging, and drying the centrifuged material to obtain 107.46g of solid 3-dimethylamino-2-methoxymethyl acrylonitrile (yield 81.36%). 122.74g of butylamidine hydrochloride (purity 92%) are mixed with 177.64g of sodium methoxide in methanol (purity 28%), the mixture is freed at 35 ℃ and, after the reaction has ended, the mixture is discharged by centrifugation, the sodium chloride cake is washed with methanol and the solutions are combined. Adding all the obtained 3-dimethylamino-2-methoxy methacrylonitrile into a solution containing butylamidine, heating to 70 ℃, reacting for 3h, and distilling to recover dimethylamine and methanol; washing the distilled residual substrate with 300g of 15% sodium hydroxide aqueous solution, extracting with dichloromethane solution, and distilling the organic solvent to obtain the product 4-amino-5-methoxymethyl-2-propylpyrimidine, wherein the total mass is 119.59g, and the calculated yield is 70.04%.
To better demonstrate that the preparation process of the present invention can give a higher yield of 4-amino-5-methoxymethyl-2-propylpyrimidine, several comparative examples are given below.
Comparative example 1
Different from the embodiment 5, the sodium salt of the alpha-methoxy methyl-beta-hydroxy acrylonitrile is put into the water solution and mixed with dimethylamine hydrochloride, the reaction temperature is lower than 35 ℃, and the reaction time is 28 h. The rest operation is the same, under the process condition, the yield of the product 4-amino-5-methoxymethyl-2-propylpyrimidine is 72.28%.
Comparative example 2
Different from the embodiment 5, the sodium salt of the alpha-methoxy methyl-beta-hydroxy acrylonitrile is put into the water solution and mixed with dimethylamine hydrochloride, the reaction temperature is higher than 60 ℃, and the reaction time is 20 h. The rest operation is the same, under the process condition, the yield of the product 4-amino-5-methoxymethyl-2-propylpyrimidine is 70.04%.
Comparative example 3
In patent GB953876A, sodium is added into toluene to react with methanol to generate sodium methoxide, methyl formate and acrylonitrile are added to react, CO keeps the pressure at 10atm overnight to obtain sodium salt, dimethyl sulfate is added to carry out methylation, and the sodium salt and butylamidine are subjected to cyclization reaction, wherein the final yield is 40%.
Comparative example 4
Adding solid sodium methoxide, anhydrous methanol and excessive methyl formate into a mixed solution of toluene and kerosene, dropwise adding acrylonitrile into a bottle, transferring reactants into a pressure-resistant kettle to prepare sodium salt after adding, performing methylation by dimethyl sulfate to obtain alpha-methoxymethyl-beta-hydroxyacrylonitrile, and reacting with butylamidine to obtain a product with the yield of 60%.
As can be seen by comparison, the preparation methods of examples 1 to 8 of the present invention do not use a methylating agent, have less contamination and have higher product yields than the preparation methods of comparative examples 3 and 4. Compared with the preparation methods of comparative examples 1 and 2, when the sodium salt of α -methoxymethyl- β -hydroxyacrylonitrile is put into an aqueous solution and mixed with dimethylamine hydrochloride, the reaction temperature is lower than 35 ℃, the reaction time is prolonged, and when the temperature is higher than 60 ℃, the stability of the sodium salt of α -methoxymethyl- β -hydroxyacrylonitrile is deteriorated, resulting in a decrease in the yield of the objective product.
The present patent is not limited to the above-mentioned embodiments, and those skilled in the art can make various changes without creative efforts from the above-mentioned conception, and fall within the protection scope of the present patent.
Claims (8)
1. A preparation method of 4-amino-5-methoxymethyl-2-propylpyrimidine is characterized by comprising the following steps:
(1) taking a methanol solution of acrylonitrile and sodium methoxide as a reaction raw material, adding an organic solvent, stirring and mixing, introducing carbon monoxide, controlling the reaction temperature, the reaction time and the reaction pressure, and filtering after the reaction is finished to obtain sodium salt of alpha-methoxymethyl-beta-hydroxyacrylonitrile;
(2) putting the sodium salt of the alpha-methoxymethyl-beta-hydroxyacrylonitrile obtained in the step (1) into an aqueous solution, adding an amination reagent, stirring and mixing, controlling the reaction temperature and the reaction time, and obtaining 3-dimethylamino-2-methoxymethyl acrylonitrile after the reaction is finished;
(3) mixing butylamidine hydrochloride with a methanol solution of sodium methoxide, controlling the reaction temperature and the reaction time, and centrifuging after the reaction is finished to obtain a butylamidine solution;
(4) and (3) mixing the 3-dimethylamino-2-methoxy methacrylonitrile in the step (2) with the butylamidine solution in the step (3), controlling the reaction temperature and the reaction time, and after the reaction is finished, carrying out distillation, water washing, extraction and distillation operations to obtain the 4-amino-5-methoxy methyl-2-propyl pyrimidine.
2. The process for preparing 4-amino-5-methoxymethyl-2-propylpyrimidine according to claim 1, wherein: the organic solvent is toluene, xylene or halogenated hydrocarbon.
3. The process for preparing 4-amino-5-methoxymethyl-2-propylpyrimidine according to claim 1, wherein: the molar ratio of the sodium methoxide to the acrylonitrile in the step (1) is 1.05-1.1: 1.
4. The process for preparing 4-amino-5-methoxymethyl-2-propylpyrimidine according to claim 1, wherein: the reaction temperature of the step (1) is 32-40 ℃, the reaction time is 18-22h, and the reaction pressure is 3-5 Mpa.
5. The process for preparing 4-amino-5-methoxymethyl-2-propylpyrimidine according to claim 1, wherein: the amination reagent is dimethylamine hydrochloride, and the molar ratio of the sodium salt of the alpha-methoxymethyl-beta-hydroxyacrylonitrile to the dimethylamine hydrochloride in the step (2) is 1.1-1.5: 1.
6. The process for preparing 4-amino-5-methoxymethyl-2-propylpyrimidine according to claim 1, wherein: the reaction temperature of the step (2) is 35-60 ℃, and the reaction time is 15-20 h.
7. The process for preparing 4-amino-5-methoxymethyl-2-propylpyrimidine according to claim 1, wherein: in the step (3), the butylamidine hydrochloride and the sodium methoxide are mixed according to an equal molar ratio, the reaction temperature is 30-40 ℃, and the reaction time is 3-5 min.
8. The process for preparing 4-amino-5-methoxymethyl-2-propylpyrimidine according to claim 1, wherein: the molar ratio of the 3-dimethylamino-2-methoxy methacrylonitrile in the step (4) to the butylamidine solution is 1:1-1.5, the reaction temperature is 65-75 ℃, and the reaction time is 2-4 h.
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