1. A synthesis process of methyl/ethyl 2-amino, 2-cyanoacetate is characterized by comprising the following steps:

the liquid 2-nitroso, 2-cyano methyl acetate/ethyl ester is subjected to a pressure catalytic hydrogenation reaction to generate 2-amino, 2-cyano methyl acetate/ethyl ester.

2. The process for synthesizing methyl/ethyl 2-amino, 2-cyanoacetate as claimed in claim 1, wherein the liquid methyl/ethyl 2-nitroso, 2-cyanoacetate is generated by nitrosation of methyl/ethyl cyanoacetate with sodium nitrite.

3. Methyl 2-amino, 2-cyanoacetate synthesized by the synthesis process of any one of claims 1 or 2.

4. A process for synthesizing 2-amino, 2-cyanoacetic acid, which comprises the following steps:

reacting methyl/ethyl 2-amino, 2-cyanoacetate with sodium hydroxide to generate sodium 2-amino, 2-cyanoacetate;

2-amino, 2-sodium cyanoacetate reacts with hydrochloric acid to generate 2-amino, 2-cyanoacetic acid;

the methyl/ethyl 2-amino, 2-cyanoacetate is synthesized by the process of claim 1 or 2.

5. The synthesis process of 2-amino, 2-cyanoacetic acid according to claim 4, wherein in the process of reacting methyl/ethyl 2-amino, 2-cyanoacetate with sodium hydroxide to produce sodium 2-amino, 2-cyanoacetate, the temperature is controlled to be 0-20 ℃, and the pH value is controlled to be 10-11;

in the process of reacting 2-amino, 2-cyanosodium acetate with hydrochloric acid to generate 2-amino, 2-cyanoacetic acid, the temperature is controlled to be 50-70 ℃, and the PH value is controlled to be 3-6.

6. 2-amino, 2-cyanoacetic acid synthesized by the process of claim 4.

Background

2,4, 5-triamino-6-hydroxypyrimidine is an important intermediate of vitamin folic acid and other series of high-efficiency and low-toxicity antiviral drugs such as acyclovir, famciclovir and the like.

At present, the traditional synthetic route of the 2,4, 5-triamino-6-hydroxypyrimidine is adopted:

(1) guanidine hydrochloride/guanidine nitrate + sodium methoxide/methanol ═ free guanidine + methanol solution;

(2) free guanidine + methyl cyanoacetate/ethyl cyanoacetate ═ 2, 4-diamino-6-hydroxypyrimidine;

(3)2, 4-diamino-6-hydroxypyrimidine + sodium nitrite ═ 2, 4-diamino-5-nitroso-6-hydroxypyrimidine;

(4)2, 4-diamino-5-nitroso-6-hydroxypyrimidine + H₂(catalyst) ═ 2,4, 5-triamino-6-hydroxypyrimidine.

However, the synthetic route of the 2,4, 5-triamino-6-hydroxypyrimidine has the following defects:

wherein, the 2, 4-diamino-5-nitroso-6-hydroxypyrimidine generated in the step (3) is a solid substance and has extremely low water solubility, the solubility under different treatment conditions is 5-10%, the dissolved 2, 4-diamino-5-nitroso-6-hydroxypyrimidine is subjected to a pressure catalytic hydrogenation process to convert the 2, 4-diamino-5-nitroso-6-hydroxypyrimidine into a final product 2,4, 5-triamino-6-hydroxypyrimidine, and the water consumption in the process is 20-25 times (20-25 tons of water are consumed for producing one ton of 2,4, 5-triamino-6-hydroxypyrimidine product). If an organic solvent is used instead of water, the cost for treating the residual solvent is also extremely high, and it is not economically feasible.

Disclosure of Invention

The invention aims to solve the first technical problem of providing an intermediate for synthesizing 2,4, 5-triamino-6-hydroxypyrimidine and a synthesis process of the intermediate, so that the water consumption in the synthesis process of the 2,4, 5-triamino-6-hydroxypyrimidine is greatly reduced, and the wastewater yield is also greatly reduced, thereby overcoming the defects of large water consumption and large wastewater yield in the conventional synthesis process of the 2,4, 5-triamino-6-hydroxypyrimidine.

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

the invention adopts a new intermediate for synthesizing 2,4, 5-triamino-6-hydroxypyrimidine, and the intermediate is 2-amino, 2-cyanoacetic acid methyl ester/ethyl ester.

The synthesis process of the intermediate 2-amino, 2-cyano methyl acetate/ethyl ester comprises the following steps:

the liquid 2-nitroso, 2-cyano methyl acetate/ethyl ester is subjected to a pressure catalytic hydrogenation reaction to generate 2-amino, 2-cyano methyl acetate/ethyl ester.

In the synthesis process of 2,4, 5-triamino-6-hydroxypyrimidine, the traditional synthesis process is changed, so that a solid intermediate 2, 4-diamino-5-nitroso-6-hydroxypyrimidine is not generated, instead, a liquid compound 2-nitroso, 2-cyano methyl acetate/ethyl ester is utilized to perform catalytic hydrogenation reaction to generate a new intermediate 2-amino, 2-cyano methyl acetate/ethyl ester, and the substance can be applied to generate the 2,4, 5-triamino-6-hydroxypyrimidine by directly cyclizing with guanidyl. Therefore, a large amount of water is not consumed in the hydrogenation step, and a large amount of wastewater is not generated.

As a further improvement of the invention, the liquid 2-nitroso, 2-cyanoacetic acid methyl ester/ethyl ester is generated by nitrosation reaction of cyanoacetic acid methyl ester/ethyl ester and sodium nitrite.

By the above-mentioned nitrosation reaction, liquid methyl/ethyl 2-nitroso, 2-cyanoacetate can be simply and rapidly produced.

Based on the discovery of the above novel intermediate (methyl/ethyl 2-amino, 2-cyanoacetate), the present invention further develops other applications of the above intermediate.

The invention provides a synthesis process of 2-amino, 2-cyanoacetic acid, which comprises the following steps:

reacting methyl/ethyl 2-amino, 2-cyanoacetate with sodium hydroxide to generate sodium 2-amino, 2-cyanoacetate;

2-amino, 2-sodium cyanoacetate reacts with hydrochloric acid to generate 2-amino, 2-cyanoacetic acid;

the 2-amino, 2-cyano methyl acetate/ethyl ester is synthesized by adopting the synthesis process.

Further, in the process of reacting methyl/ethyl 2-amino, 2-cyanoacetate with sodium hydroxide to generate sodium 2-amino, 2-cyanoacetate, the temperature is controlled to be 0-20 ℃, and the PH value is controlled to be 10-11; in the process of reacting 2-amino, 2-cyanosodium acetate with hydrochloric acid to generate 2-amino, 2-cyanoacetic acid, the temperature is controlled to be 50-70 ℃, and the PH value is controlled to be 3-6.

The invention also provides the 2-amino, 2-cyanoacetic acid synthesized by the method.

The invention has the following beneficial effects:

1. the invention changes the mode of cyclization, nitritation and catalytic hydrogenation in the traditional synthesis process of 2,4, 5-triamino-6-hydroxypyrimidine, but the mode of nitritation, catalytic hydrogenation and final cyclization reaction, and the liquid 2-nitroso group and 2-methyl/ethyl cyanoacetate are utilized to carry out catalytic hydrogenation reaction to generate 2-amino, 2-methyl/ethyl cyanoacetate, and the substance can be directly cyclized with guanidyl to generate 2,4, 5-triamino-6-hydroxypyrimidine. Therefore, a large amount of water is not required to be consumed in the hydrogenation reaction step, a large amount of waste water is not generated, and great economic significance and environmental protection significance are achieved.

2. Based on the discovery of the novel intermediate (methyl/ethyl 2-amino, 2-cyanoacetate), the invention further develops the application of the intermediate, and the intermediate can be used for synthesizing 2-amino, 2-cyanoacetic acid in addition to the compound used for generating 2,4, 5-triamino-6-hydroxypyrimidine through guanidyl cyclization, thereby opening a new path for synthesizing 2-amino, 2-cyanoacetic acid.

Detailed Description

EXAMPLE 12 Synthesis of methyl amino, 2-cyanoacetate

The following reaction formula is adopted:

1) methyl cyanoacetate + sodium nitrite ═ 2-nitroso, methyl 2-cyanoacetate;

2) 2-nitroso, 2-cyanoacetic acid methyl ester + H₂(catalyst) ═ 2-amino, 2-cyanoacetic acid methyl ester.

Firstly, carrying out nitrosation reaction on methyl cyanoacetate and sodium nitrite to generate 2-nitroso, 2-methyl cyanoacetate and generate 2-nitroso, wherein the 2-methyl cyanoacetate is in a liquid state; in the nitrosation reaction process, the reaction dripping mode is not limited, the reaction container is not limited, the dripping speed is not limited, the dripping proportion is not limited, and the temperature is controlled to be-20-100 ℃; the completion of the reaction is not affected by the dripping mode, speed and proportion, the reaction can be realized at the temperature of-20-100 ℃, but the temperature is preferably 0-20 ℃.

Then, carrying out pressurized catalytic hydrogenation reaction on the liquid 2-nitroso, 2-cyano methyl acetate to generate 2-amino, 2-cyano methyl acetate; for the catalytic hydrogenation step, noble metals such as nickel, palladium, platinum, rhodium and the like can be selected and used as catalysts, and the concentration and form of the catalysts are not limited. The pressure in the catalytic reaction process is 0.1-10 Mpa, the time is 1-1000 minutes, any type of reaction vessel is not limited, and the reaction temperature is 0-150 ℃; the method can be realized under different catalytic conditions, but the platinum catalyst is preferred, the pressure is 1-2 Mpa, and the temperature is preferably in the range of 50-80 ℃.

In addition to the intermediate methyl 2-amino, 2-cyanoacetate, free guanidine can be further added to produce 2,4, 5-triamino-6-hydroxypyrimidine. The following reaction formula can be adopted:

free guanidine + 2-amino, 2-cyanoacetic acid methyl ester ═ 2,4, 5-triamino-6-hydroxypyrimidine;

by using methyl 2-amino, 2-cyanoacetate obtained by the above-mentioned special synthesis process as an intermediate, 2,4, 5-triamino-6-hydroxypyrimidine was further synthesized, wherein water consumption and wastewater yield were 0.5 times (about 0.5 ton per one ton of 2,4, 5-triamino-6-hydroxypyrimidine produced). If the conventional synthesis process in the background art is adopted, the water consumption and the wastewater yield are 25 times (about 25 tons of water and wastewater are consumed for producing one ton of 2,4, 5-triamino-6-hydroxypyrimidine).

EXAMPLE 22 Synthesis of Ethyl amino, 2-cyanoacetate

The difference between the present example and example 1 is that all methyl esters are replaced by ethyl esters, and the others are unchanged.

EXAMPLE 32 Synthesis of amino, 2-cyanoacetic acid

The following reaction formula is adopted:

1) methyl/ethyl cyanoacetate + sodium nitrite 2-nitroso, methyl/ethyl 2-cyanoacetate;

2) 2-nitroso, methyl/ethyl 2-cyanoacetate + H2 ═ 2-ammonia, methyl/ethyl 2-cyanoacetate;

3) 2-amino, 2-cyanoacetic acid methyl/ethyl ester + sodium hydroxide ═ 2-amino, 2-cyanoacetic acid sodium salt

4) 2-amino, 2-cyanoacetic acid sodium salt + 2-amino, 2-cyanoacetic acid hydrochloride;

namely, the intermediate 2-amino, 2-cyanoacetic acid methyl ester or 2-amino, 2-cyanoacetic acid ethyl ester is synthesized first according to the synthesis process of example 1 or example 2.

Then 2-amino, 2-cyano methyl acetate/ethyl ester reacts with sodium hydroxide to generate 2-amino, 2-cyano sodium acetate; in the process, the temperature is controlled to be 0-20 ℃, and the PH value is controlled to be 10-11; and finally, reacting the 2-amino, 2-cyanosodium acetate with hydrochloric acid to generate a target product 2-amino, 2-cyanoacetic acid, wherein the temperature is controlled to be 50-70 ℃, and the pH value is controlled to be 3-6 in the process.