CN1467206A - Method for preparing 2-chloro-4,6-dimethoxy pyrimidine - Google Patents

Abstract

A process for preparing 2-chloro-4,6-dimethoxy pyrimidine including salifying reaction in composite solvent to obtain dimethyl propanediimine dihydrochloride, cyanaminating reaction to obtain 3-amino-3-methoxy-N-cyano-2-propaneimine, and condensation reaction under the action of catalyst to obtain white product crystal. Said composite solvent contains 13 active components including dimethylformacyl, formamide, dimethylacetamide, dimethyl sulfoxide, etc. Its advantages are high output rate, and high purity.

Description

Preparation method of 2-chloro-4, 6-dimethoxypyrimidine

The invention relates to a preparation method of 2-chloro-4, 6-dimethoxypyrimidine.

2-chloro-4, 6-dimethoxy pyrimidine is widely used in chemical fields such as medical intermediates, and for years, three preparation methods of 2-chloro-4, 6-dimethoxy pyrimidine are available:

2-chloro-4, 6-dimethoxypyrimidine is synthesized by diazotizing 2-amino-4, 6-dimethoxypyrimidine, and the method has the defects of low yield (only 30 percent) and the like.

2-mercapto-4, 6-dimethoxypyrimidine is chloridized to synthesize 2-chloro-4, 6-dimethoxypyrimidine, and the method has the defects of difficult preparation of the 2-mercapto-4, 6-dimethoxypyrimidine and the like.

3. Uses malononitrile as raw material, and synthesizes 2-chloro-4, 6-dimethoxy pyrimidine through salifying, cyanamide and condensation, and the method has the defects of low yield (only 55%), low product content (95%) and the like.

The invention aims to provide a preparation method of 2-chloro-4, 6-dimethoxypyrimidine, which has high yield, simple preparation method and high product content.

The preparation method of the 2-chloro-4, 6-dimethoxypyrimidine comprises the following three steps: salifying reaction, cyanamide reaction and condensation reaction.

The method comprises the following specific steps:

A. salt forming reaction:

(Malononitrile)

Adding 10-13 wt% of malononitrile, 11.5-15.5 wt% of methanol and 72-77 wt% of composite solvent into a pressure kettle, stirring, introducing anhydrous hydrogen chloride under 0-20 atm, reacting the mixture at-25-120 ℃ until the hydrochloric acid reaches about 17%, filtering the product, washing the solid with the composite solvent, and drying at room temperature to obtain the dimethyl propyleneimine dihydrochloride.

B. Cyanamide reaction:

under the condition of 0-100 ℃, adding 9-13% of potassium hydroxide into 87-91% of water in a reaction kettle to forman aqueous solution, and adding 1, 3-propanediimine methyl ester dihydrochloride obtained through salt forming reaction; adding about 18.5 percent of 50 percent H2NCN solution into the reaction solution, preserving the heat for 1-10 hours at room temperature to generate 3-amino-3-methoxy-N-cyano-2-propylene imine, washing with water and drying.

C. Condensation reaction:

and (3) adding 95-98% of complexing agent and 2-5% of catalyst into the product, introducing HCl gas (about 1 hour) at the temperature of-25-100 ℃, adding 200 parts of water after the reaction is finished, washing the mixture by using a complex solution, concentrating an organic layer, recrystallizing by using methanol, and drying to obtain a white 2-chloro-4, 6-dimethoxypyrimidine crystal.

The composite solvent is prepared by combining dimethyl formyl, formamide, dimethylacetamide, dimethyl sulfoxide, dimethyl sulfone, 1, 4-dioxane, petroleum ether, isopropanol, isobutanol, cyclohexane, cyclooctane, n-hexane, n-octane and the like.

The innovation of the invention is that the compound solvent and the condensed catalyst are added in the reaction process, and the reaction temperature, the reaction pressure and the material proportion are reasonably selected, thereby achieving the purposes of high yield, simple preparation method and high product content (more than 99 percent).

The present invention will be further described with reference to the following examples.

A. Salt forming reaction:

adding 56 parts of malononitrile, 64 parts of methanol and 350 parts of composite solvent into a pressure kettle, stirring, introducing anhydrous hydrogen chloride under 5atm, reacting the mixture at-15 to-10 ℃ until 80 parts of hydrochloric acid is obtained, continuously reacting for 1 hour, filtering the product, washing the solid with the composite solvent, and drying at room temperature to obtain 173 parts of dimethyl propylenediimine dihydrochloride.

B. Cyanamide reaction:

at the temperature of 20 ℃, adding 50 parts of potassium hydroxide into 400 parts of water in a reaction kettle to form an aqueous solution, and adding 1, 3-propanediimine methyl ester dihydrochloride obtained through salt forming reaction; adding about 84 parts of 50% H2NCN solution into the reaction solution, preserving the heat at room temperature for 1 hour to generate 118 parts of 3-amino-3-methoxy-N-cyano-2-propane imine, washing with water and drying.

C. Condensation reaction:

adding 200 parts of complexing agent and 10 parts of catalyst into the product, introducing HCl gas (about 1 hour) at the temperature of-15 ℃, adding 200 parts of water after the reaction is finished, washing the mixture by using a complex solution, concentrating an organic layer, recrystallizing the organic layer by using methanol, and drying to obtain 97.5 parts of 2-chloro-4, 6-dimethoxypyrimidine white crystals (the content is 99 percent, and the melting point is 103-104 ℃).

Claims (2)

1. A preparation method of 2-chloro-4, 6-dimethoxypyrimidine comprises three steps: salifying reaction, cyanamide reaction and condensation reaction.

The method comprises the following specific steps:

A. salt forming reaction:

(malononitrile) is added with 10-13% (weight percentage, the same below) of malononitrile, 11.5-15.5% of methanol and 72-77% of composite solvent in a pressure kettle and stirred, anhydrous hydrogen chloride is introduced under 0-20 atm, the mixture continues to react for 1-8 hours at the temperature of-25-120 ℃ until the hydrochloric acid reaches about 17%, the product is filtered, the solid is washed by the composite solvent, and the dimethyl propane diimine dihydrochloride is obtained after drying at room temperature.

B. Cyanamide reaction:

under the condition of 0-100 ℃, adding 9-13% of potassium hydroxide into 87-91% of water in a reaction kettle to form an aqueous solution, and adding 1, 3-propanediimine methyl ester dihydrochloride obtained through salt forming reaction; adding about 18.5 percent of 50 percent H2NCN solution into the reaction solution, preserving the heat for 1-10 hours at room temperature to generate 3-amino-3-methoxy-N-cyano-2-propylene imine, washing with water and drying.

C. Condensation reaction:

and (3) adding 95-98% of complexing agent and 2-5% of catalyst into the product, introducing HCl gas (about 1 hour) at the temperature of-25-100 ℃, adding 200 parts of water after the reaction is finished, washing the mixture by using a complex solution, concentrating an organic layer, recrystallizing by using methanol, and drying to obtain a white 2-chloro-4, 6-dimethoxypyrimidine crystal.

2. The method of claim 1, wherein the complex solvent is selected from the group consisting of dimethylformyl, formamide, dimethylacetamide, dimethylsulfoxide, dimethylsulfone, 1, 4-dioxane, petroleum ether, isopropanol, isobutanol, cyclohexane, cyclooctane, n-hexane, and n-octane.