CN117586194A - Preparation method of 4-amino-2, 6-dimethoxy pyrimidine - Google Patents

Abstract

The invention provides a preparation method of 4-amino-2, 6-dimethoxy pyrimidine, which comprises the following steps: step S1, in a dichloromethane system, carrying out addition reaction on 6-amino uracil and 3, 4-dihydropyran under the action of an acid catalyst to generate a first intermediate, wherein the first intermediate is an alcohol compound; s2, in a dichloromethane system, enabling the first intermediate to react with triphenylphosphine and carbon tetrachloride to generate a second intermediate, wherein the second intermediate is a chlorinated hydrocarbon compound; and S3, removing dihydropyran from the second intermediate and sodium methoxide in a methanol system to perform substitution reaction to generate 4-amino-2, 6-dimethoxy pyrimidine. According to the preparation method, raw materials are cheap and easy to obtain, no special dangerous reaction exists, and the operability is high; and the product has high yield and good purity.

Description

Preparation method of 4-amino-2, 6-dimethoxy pyrimidine

Technical Field

The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of 4-amino-2, 6-dimethoxy pyrimidine.

Background

The sulfa Mo Tuoxin commonly known as bacteriocin is a long-acting sulfa original drug, has an antibacterial spectrum similar to sulfadiazine, has a strong antibacterial effect, and is suitable for bacillary dysentery, enteritis, tonsillitis, urinary tract infection, cellulitis, skin suppuration infection and other diseases. Sulfanilamide medicines (SAs) are a class of antibacterial and anti-inflammatory medicines commonly used in modern medicine, refer to a generic name of a class of medicines with a p-aminobenzenesulfonamide structure, and are a class of chemotherapeutic medicines for preventing and treating bacterial infectious diseases. The SAs can be thousands of kinds, and tens of kinds of SAs have wide application and certain curative effects. Wherein, the common pharmaceutical intermediates for preparing sulfa Mo Tuoxin comprise 4-amino-2, 6-dimethoxy pyrimidine.

At present, the preparation method of the 4-amino-2, 6-dimethoxy pyrimidine mainly comprises the following steps:

1) The method takes 2-methoxyformamidine and methyl cyanoacetate as initial raw materials, and performs cyclization reaction, phosphorus oxychloride chlorination and methoxylation reaction to obtain a target product 4-amino-2, 6-dimethoxy pyrimidine. However, the first step of cyclization reaction is solvent-free heating, and the reaction heat is not easy to control; the use of the strong corrosive reagent phosphorus oxychloride has high requirements on production conditions and is a hindrance to safe production.

2) The preparation method takes compounds such as cyanoacetate, urea and the like which are cheap and easy to obtain as starting materials, and is prepared through four steps of cyclization, acidification, chlorination and methylation. However, the method has long steps, the purity of the intermediate is difficult to control, and more wastewater containing halogen and phosphorus is produced, which is not friendly to the environment.

3) The barbituric acid is taken as a raw material to prepare a product through chlorination, ammoniation and methoxylation. However, the purification of the intermediate is affected by byproducts generated in the ammonification step in the preparation method, so that the route has the defects of poor reaction parallelism, low yield and the like.

4) The catalyst is prepared from malononitrile, methanol and hydrogen chloride gas serving as raw materials through four-step reactions of addition, condensation, cyclization and methoxylation. However, the method uses hydrogen chloride gas in both the addition and cyclization steps, and has the disadvantages of high operation difficulty and high equipment requirement in production.

Disclosure of Invention

In view of the above, the present invention aims to provide a process for producing 4-amino-2, 6-dimethoxypyrimidine which has the advantages of low cost and availability of raw materials, no special dangerous reaction, high operability, high yield and high purity of the obtained product.

In order to solve the technical problems, the invention adopts the following technical scheme:

the preparation method of the 4-amino-2, 6-dimethoxy pyrimidine comprises the following steps:

step S1, in a dichloromethane system, carrying out addition reaction on 6-amino uracil and 3, 4-dihydropyran under the action of an acid catalyst to generate a first intermediate, wherein the first intermediate is an alcohol compound;

s2, in a dichloromethane system, enabling the first intermediate to react with triphenylphosphine and carbon tetrachloride to generate a second intermediate, wherein the second intermediate is a chlorinated hydrocarbon compound;

and S3, removing dihydropyran from the second intermediate and sodium methoxide in a methanol system to perform substitution reaction to generate 4-amino-2, 6-dimethoxy pyrimidine.

In some embodiments of the invention, in step S1, the acidic catalyst is p-toluenesulfonic acid monohydrate, pyridine p-toluenesulfonate, or a mixture thereof.

Further, the acid catalyst is pyridine p-toluenesulfonate, and the molar ratio of the 6-aminouracil to the 3, 4-dihydropyran to the pyridine p-toluenesulfonate is 1.0 (1.1-2.0) (0.02-0.1).

Still further, the step S1 includes:

and (3) dropwise adding the 3, 4-dihydropyran into a dichloromethane solution of 6-aminouracil and pyridine p-toluenesulfonate to generate the first intermediate, wherein the temperature of dropwise adding the 3, 4-dihydropyran is 20-30 ℃ and the reaction time is 2-3 hours.

Still further, the step S1 further includes:

after the reaction, pyridine p-toluenesulfonate was washed with a 10% aqueous sodium bicarbonate solution, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain the treated first intermediate.

In some embodiments of the present invention, in the step S2, the molar ratio of the first intermediate to triphenylphosphine and carbon tetrachloride is 1.0 (2.1-2.5): 2.1-2.5.

Further, the step S2 includes:

adding the first intermediate and triphenylphosphine into dichloromethane, and dropwise adding carbon tetrachloride into the dichloromethane to generate the second intermediate, wherein the temperature of dropwise adding carbon tetrachloride is 15-20 ℃, and the reaction time is 3-4 hours.

In some embodiments of the invention, in the step S3, a molar ratio of the second intermediate to sodium methoxide is 1.0: (3.5-4.0).

Further, the step S3 includes:

sodium methoxide is added to the methanol solution of the second intermediate in batches, and the mixture is heated and refluxed to generate 4-amino-2, 6-dimethoxy pyrimidine, and the reaction time is 4-6 hours.

Still further, the step S3 further includes:

after the reaction is finished, adding active carbon into the reaction solution for decoloring, filtering, concentrating and drying filtrate, pouring ice water for pulping, filtering and drying to obtain the high-purity 4-amino-2, 6-dimethoxy pyrimidine.

The technical scheme of the invention has at least one of the following beneficial effects:

according to the preparation method provided by the embodiment of the invention, the raw materials are cheap and easy to obtain, no special dangerous reaction exists, and the operability is high; the obtained product has high yield, good purity and high feasibility of industrial production.

Detailed Description

In order to make the objects, technical solutions and advantages of the embodiments of the present invention more clear, the technical solutions of the present invention will be clearly and completely described below in connection with the embodiments of the present invention. It will be apparent that the described embodiments are some, but not all, embodiments of the invention. All other embodiments, which are obtained by a person skilled in the art based on the described embodiments of the invention, fall within the scope of protection of the invention.

The preparation method of the 4-amino-2, 6-dimethoxy pyrimidine according to the embodiment of the invention is specifically described below, and comprises the following steps:

step S1, in a dichloromethane system, carrying out addition reaction on 6-amino uracil and 3, 4-dihydropyran under the action of an acid catalyst to generate a first intermediate, wherein the first intermediate is an alcohol compound.

That is, a first intermediate of an alcohol compound (hereinafter, also referred to as intermediate a) is prepared by first subjecting 6-aminouracil and 3, 4-dihydropyran to an addition reaction.

Specifically, the reaction formula is shown in the following formula (1):

further, the acidic catalyst is p-toluenesulfonic acid monohydrate, pyridine p-toluenesulfonate, or a mixture thereof.

Further, the acid catalyst is pyridine p-toluenesulfonate, and the molar ratio of the 6-aminouracil to the 3, 4-dihydropyran to the pyridine p-toluenesulfonate is 1.0 (1.1-2.0) (0.02-0.1). The amino protective agent DHP can be reacted better by using a catalytic amount of an acid catalyst.

Further, the step S1 includes:

and (3) dropwise adding the 3, 4-dihydropyran into a dichloromethane solution of 6-aminouracil and pyridine p-toluenesulfonate to generate the first intermediate, wherein the temperature of dropwise adding the 3, 4-dihydropyran is 20-30 ℃ and the reaction time is 2-3 hours.

In addition, the step S1 may further include:

after the reaction, pyridine p-toluenesulfonate was washed with a 10% aqueous sodium bicarbonate solution, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain the treated first intermediate.

And S2, in a dichloromethane system, enabling the first intermediate to react with triphenylphosphine and carbon tetrachloride to generate a second intermediate, wherein the second intermediate is a chlorinated hydrocarbon compound.

That is, after the first intermediate of the alcohol compound is obtained, an Appel reaction is further performed to convert the alcohol into chlorinated hydrocarbon, thereby obtaining a second intermediate compound (hereinafter, also referred to as intermediate B).

Specifically, the reaction formula is represented by the following formula (2):

the method uses Appel reaction for chlorination, has simple operation and mild reaction, and avoids using chloridizing reagents such as phosphorus pentachloride, phosphorus oxychloride, thionyl chloride and the like with strong acid property.

Further, in the step S2, the molar ratio of the first intermediate to triphenylphosphine to carbon tetrachloride is 1.0 (2.1-2.5).

In some embodiments of the invention, the step S2 includes:

adding the first intermediate and triphenylphosphine into dichloromethane, and dropwise adding carbon tetrachloride into the dichloromethane to generate the second intermediate, wherein the temperature of dropwise adding carbon tetrachloride is 15-20 ℃, and the reaction time is 3-4 hours.

Still further, step S2 may further include: after the reaction is completed, the reaction solution is washed by water, washed by saturated salt water, dried, filtered and concentrated to obtain a crude product, the product is dissolved out by methyl tertiary butyl ether at low temperature, the by-product phosphorus trioxide is removed by filtration, and the filtrate is concentrated to dryness to obtain an intermediate B.

And S3, removing dihydropyran from the second intermediate and sodium methoxide in a methanol system to perform substitution reaction to generate 4-amino-2, 6-dimethoxy pyrimidine.

That is, after the chlorinated hydrocarbon is obtained, it is further subjected to substitution reaction to obtain the objective compound 4-amino-2, 6-dimethoxypyrimidine.

Specifically, the reaction formula is represented by the following formula (3):

in this step sodium methoxide is used for the methoxylation, and the protecting group can be removed at the same time. That is, the step one-pot method realizes the protection of methoxylation and THP removal, and has high efficiency.

Further, in the step S3, a molar ratio of the second intermediate to sodium methoxide is 1.0: (3.5-4.0).

In some embodiments of the invention, the step S3 includes:

sodium methoxide is added to the methanol solution of the second intermediate in batches, and the mixture is heated and refluxed to generate 4-amino-2, 6-dimethoxy pyrimidine, and the reaction time is 4-6 hours.

Further, the step S3 may further include:

after the reaction is finished, adding active carbon into the reaction solution for decoloring, filtering, concentrating and drying filtrate, pouring ice water for pulping, filtering and drying to obtain the high-purity 4-amino-2, 6-dimethoxy pyrimidine.

According to the preparation method disclosed by the embodiment of the invention, the raw materials are cheap and easy to obtain, no special dangerous reaction exists, and the operability is relatively strong; the obtained product has high yield, good purity and high feasibility of industrial production.

The present invention will be further described in detail with reference to examples so that those skilled in the art can better understand the technical aspects of the present invention.

Experimental example 1: preparation of 4-amino-2, 6-dimethoxy pyrimidine compound

The first step: a250 ml three-necked flask was charged with methylene chloride (105 ml, 3P) and 6-aminouracil (35 g,0.275mol,1.0 eq) and pyridine p-toluenesulfonate (3.52 g,0.014mol,0.05 eq), 3, 4-dihydropyran (34.74 g,0.413mol,1.5 eq) was added dropwise, and the reaction was carried out at room temperature of 20-30℃for 2 hours. After completion of the reaction, the reaction mixture was washed with 50mL of an aqueous sodium hydrogencarbonate solution (10%) and then with 50mL of saturated brine, and then dried over anhydrous sodium sulfate, filtered and concentrated to give 56.6g of intermediate A in 97.5% yield.

And a second step of: a500 mL three-port reaction flask was taken, and intermediate A (56.6 g,0.268mol,1.0 eq), triphenylphosphine (154.76 g,0.59mol,2.2 eq) and methylene chloride (280 mL, 5P) were added dropwise with carbon tetrachloride (90.76 g,0.59mol,2.2 eq) and the ice water bath was cooled to 15-20deg.C, and the reaction was carried out at a constant temperature for 3 hours. After the reaction, the reaction mixture was washed with 100mL of water, 100mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated to dryness to obtain a solid, 300mL of methyl tert-butyl ether was added, stirred at 10-15℃and then filtered, and the filtrate was concentrated to dryness to obtain 57.32g of intermediate 2 in 86.2% yield.

And a third step of: a500 ml three-necked flask was charged with intermediate 2 (57.32 g,0.231mol,1.0 eq) and methanol (390 ml, 5P), and sodium methoxide (43.7 g,0.809mol,3.5 eq) was added in portions, followed by refluxing at elevated temperature for 5 hours. After the reaction is finished, 4g of active carbon is added into the reaction solution for decoloration, filtration and concentration are carried out, 100g of ice water is added for stirring and pulping, filtration is carried out, a filter cake is dried at 50 ℃ to obtain 32.62g of product, the melting point is 148.5-150 ℃, the purity is 99.6%, and the yield is 91%.

The nuclear magnetic resonance experiment is carried out on the reactant to confirm the structure of the product, and the data are as follows:

1H NMR (model: AVANCE III HD 400M, CDCl3, 400 MHz) delta=5.45 (s, 1H), 4.83 (s, 2H), 3.93-3.87 (d, 6H), the detection result was identical to the structure.

Experimental example 2: preparation of 4-amino-2, 6-dimethoxy pyrimidine compound

The first step: A1L three-necked flask was charged with methylene chloride (330 ml, 3P) and 6-aminouracil (109.19 g,0.865mol,1.0 eq) and pyridine p-toluenesulfonate (10.81 g,0.043mol,0.05 eq), 3, 4-dihydropyran (109.2 g,1.298mol,1.5 eq) was added dropwise thereto, and the reaction was carried out at room temperature of 20-30℃for 3 hours. After completion of the reaction, 160mL of aqueous sodium hydrogencarbonate (10%) was added to the reaction mixture to wash it with 160mL of saturated brine, and then dried over anhydrous sodium sulfate, filtered and concentrated to give 175.4g of intermediate A in 96% yield.

And a second step of: A2L three-port reaction flask was taken, and intermediate A (175.4 g,0.83mol,1.0 eq), triphenylphosphine (478.94 g, 1.426 mol,2.2 eq) and methylene chloride (660 mL, 5P) were added dropwise with carbon tetrachloride (280.88 g, 1.426 mol,2.2 eq) and the ice water bath was cooled to 15-20deg.C, and the reaction was continued for 4 hours. After the reaction, the reaction solution was washed with 250mL of water, 250mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated to dryness to obtain a solid, 1L of methyl tert-butyl ether was added, stirred at 10-15℃and then filtered, and the filtrate was concentrated to dryness to obtain 180.2g of intermediate 2 in 87.5% yield.

And a third step of: A2L three-necked flask was charged with intermediate 2 (180.2 g,0.726mol,1.0 eq) and methanol (900 ml, 5P), and sodium methoxide (137.26 g,2.541mol,3.5 eq) was added in portions, followed by refluxing at elevated temperature for 5 hours. After the reaction is finished, 10g of active carbon is added into the reaction liquid for decolorization, filtration and concentration are carried out, 300g of ice water is added for stirring and pulping, filtration is carried out, a filter cake is dried at 50 ℃ to obtain 103.86g of product, the melting point is 148.8-150.1 ℃, the purity is 99.5%, and the yield is 92.2%.

The nuclear magnetic resonance experiment is carried out on the reactant to confirm the structure of the product, and the data are as follows:

1H NMR (model: AVANCE III HD 400M, CDCl3, 400 MHz) delta=5.45 (s, 1H), 4.84 (s, 2H), 3.91-3.87 (d, 6H), the detection result was identical to the structure.

While the foregoing is directed to the preferred embodiments of the present invention, it will be appreciated by those skilled in the art that various modifications and adaptations can be made without departing from the principles of the present invention, and such modifications and adaptations are intended to be comprehended within the scope of the present invention.

Claims (10)

1. A method for preparing 4-amino-2, 6-dimethoxy pyrimidine, which is characterized by comprising the following steps:

step S1, in a dichloromethane system, carrying out addition reaction on 6-amino uracil and 3, 4-dihydropyran under the action of an acid catalyst to generate a first intermediate, wherein the first intermediate is an alcohol compound;

s2, in a dichloromethane system, enabling the first intermediate to react with triphenylphosphine and carbon tetrachloride to generate a second intermediate, wherein the second intermediate is a chlorinated hydrocarbon compound;

and S3, removing dihydropyran from the second intermediate and sodium methoxide in a methanol system to perform substitution reaction to generate 4-amino-2, 6-dimethoxy pyrimidine.

2. The method according to claim 1, wherein in the step S1, the acidic catalyst is p-toluenesulfonic acid monohydrate, pyridine p-toluenesulfonate, or a mixture thereof.

3. The preparation method according to claim 2, wherein the acidic catalyst is pyridine p-toluenesulfonate, and the molar ratio of the 6-aminouracil to the 3, 4-dihydropyran to the pyridine p-toluenesulfonate is 1.0 (1.1-2.0) (0.02-0.1).

4. A method according to claim 3, wherein step S1 comprises:

and (3) dropwise adding the 3, 4-dihydropyran into a dichloromethane solution of 6-aminouracil and pyridine p-toluenesulfonate to generate the first intermediate, wherein the temperature of dropwise adding the 3, 4-dihydropyran is 20-30 ℃ and the reaction time is 2-3 hours.

5. The method according to claim 4, wherein the step S1 further comprises:

after the reaction, pyridine p-toluenesulfonate was washed with a 10% aqueous sodium bicarbonate solution, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain the treated first intermediate.

6. The method according to claim 1, wherein in the step S2, the molar ratio of the first intermediate to triphenylphosphine and carbon tetrachloride is 1.0 (2.1-2.5): 2.1-2.5.

7. The method according to claim 6, wherein the step S2 comprises:

adding the first intermediate and triphenylphosphine into dichloromethane, and dropwise adding carbon tetrachloride into the dichloromethane to generate the second intermediate, wherein the temperature of dropwise adding carbon tetrachloride is 15-20 ℃, and the reaction time is 3-4 hours.

8. The method according to claim 1, wherein in the step S3, the molar ratio of the second intermediate to sodium methoxide is 1.0: (3.5-4.0).

9. The method according to claim 8, wherein the step S3 comprises:

sodium methoxide is added to the methanol solution of the second intermediate in batches, and the mixture is heated and refluxed to generate 4-amino-2, 6-dimethoxy pyrimidine, and the reaction time is 4-6 hours.

10. The method according to claim 9, wherein the step S3 further comprises:

after the reaction is finished, adding active carbon into the reaction solution for decoloring, filtering, concentrating and drying filtrate, pouring ice water for pulping, filtering and drying to obtain the high-purity 4-amino-2, 6-dimethoxy pyrimidine.