阅读说明：本技术 一种2,4-二胺基-6-氯嘧啶的制备方法 (Preparation method of 2, 4-diamino-6-chloropyrimidine ) 是由 周海亮 梁志寿 高慧丽 于 2021-10-26 设计创作，主要内容包括：本发明提供一种2,4-二胺基-6-氯嘧啶的制备方法,以2,4-二氨基-6-羟基嘧啶为原料在三氯氧磷作用下氯代,采用醇类淬灭,通过有机溶剂分散得到2,4-二氨基-6-羟基嘧啶盐酸盐,盐酸盐使用氨水中和得到2,4-二氨基-6-羟基嘧啶。本发明使用醇淬灭三氯氧磷,使淬灭更加安全,另外加入极性较低的分散剂将产物析出,回收率大于70％,最高回收率可达82％,且生成的磷酸酯比磷酸的沸点更低,易于回收,成本优势明显。(The invention provides a preparation method of 2, 4-diamino-6-chloropyrimidine, which comprises the steps of using 2, 4-diamino-6-hydroxypyrimidine as a raw material to be chlorinated under the action of phosphorus oxychloride, quenching by adopting alcohols, dispersing by using an organic solvent to obtain 2, 4-diamino-6-hydroxypyrimidine hydrochloride, and neutralizing the hydrochloride by using ammonia water to obtain the 2, 4-diamino-6-hydroxypyrimidine. The method uses alcohol to quench phosphorus oxychloride, so that the quenching is safer, in addition, a dispersing agent with lower polarity is added to separate out a product, the recovery rate is more than 70 percent, the highest recovery rate can reach 82 percent, and the generated phosphate ester has lower boiling point than phosphoric acid, is easy to recover and has obvious cost advantage.)

1. A preparation method of 2, 4-diamino-6-chloropyrimidine is characterized by comprising the following steps:

step S1: reacting 2, 4-diamino-6-hydroxypyrimidine (abbreviated as DAHP) serving as a starting material with phosphorus oxychloride at a first temperature to obtain 2, 4-di (dichlorophosphoryl) amino-6-chloropyrimidine, and distilling off redundant phosphorus oxychloride after the reaction is finished;

step S2: quenching with alcohol at a second temperature, adding a dispersing agent, heating for continuous reaction, and filtering at a third temperature to obtain 2, 4-diamino-6-chloropyrimidine hydrochloride and a filtrate, wherein the filtrate is used for recovering a solvent and a phosphate compound;

step S3: adding purified water and ammonia water to the 2, 4-diamino-6-chloropyrimidine hydrochloride in the step S2 for neutralization, extracting with ethyl acetate, and concentrating to obtain 2, 4-diamino-6-chloropyrimidine.

2. The process for preparing 2, 4-diamino-6-chloropyrimidine according to claim 1, wherein: the weight ratio of the 2, 4-diamino-6-hydroxypyrimidine to the phosphorus oxychloride is 3.5-5: 1.

3. The process for preparing 2, 4-diamino-6-chloropyrimidine according to claim 1, wherein: the first temperature is 90-110 ℃, and the second temperature is 0-40 ℃.

4. The process for preparing 2, 4-diamino-6-chloropyrimidine according to claim 1, wherein: the alcohol is selected from lower alcohol of C1-C4 or benzyl alcohol.

5. The process for preparing 2, 4-diamino-6-chloropyrimidine according to claim 4 wherein: the molar ratio of the alcohol to the phosphorus oxychloride is 3-5: 1.

6. The process for preparing 2, 4-diamino-6-chloropyrimidine according to claim 5, wherein: the temperature for the temperature rise continuous reaction is 30-85 ℃.

7. The process for preparing 2, 4-diamino-6-chloropyrimidine according to claim 1, wherein: the dispersant is an organic solvent which is mutually soluble with phosphate; the volume ratio of the dispersing agent to the phosphate ester is 8-10: 1.

8. The process for preparing 2, 4-diamino-6-chloropyrimidine according to claim 7 wherein: the dispersing agent is selected from one or a mixture of methanol, ethanol, benzyl alcohol, isopropanol, diethyl ether, methyl tertiary ether, ethyl acetate, acetone and acetonitrile.

9. The process for preparing 2, 4-diamino-6-chloropyrimidine according to claim 1, wherein: the third temperature is-20 ℃ to 30 ℃.

10. The process for preparing 2, 4-diamino-6-chloropyrimidine according to claim 9 wherein: the pH value of the ammonia water neutralization is 6-7.

Technical Field

The invention belongs to the technical field of preparation of medical raw materials, and particularly relates to a preparation method of 2, 4-diamino-6-chloropyrimidine.

Background

The organic compound 2, 4-Diamino-6-chloropyrimidine (English name: 2, 4-Diamino-6-chloropyrimidine, abbreviated as DACP) is a main raw material for synthesizing Minoxidil, and is also used as an auxiliary material in the electrolysis industry, according to the existing literature reports, the DACP obtained by chlorinating 2, 4-Diamino-6-hydroxypyrimidine under phosphorus oxychloride in the production process generally has the advantages of low yield, complex process, large amount of phosphorus-containing wastewater and high cost.

The existing production process is roughly divided into two types, firstly (the research on synthesis of minoxidil in the fifteenth volume of 1996 in Shandong pharmaceutical industry), water quenching and neutralization are carried out after reaction is finished, and ethyl acetate is used for extraction, the method uses a large amount of phosphorus oxychloride, and neutralization treatment is carried out by using several times of alkali after quenching, so that huge amount of waste water is easily generated, and experiments prove that the extraction efficiency is extremely low, 30-40 times of ethyl acetate is needed for extraction, so that the utilization rate of equipment is low, and the yield cannot be improved.

And secondly, although some methods disclosed by the prior patent methods are simple and convenient in introduction process and easy to industrialize, the described yield is greatly different from the actual yield, the product content is low, and the problems of high cost and poor market competitiveness exist at all. Therefore, the invention provides a preparation method of 2, 4-diamino-6-chloropyrimidine.

Disclosure of Invention

The invention aims to overcome the defects of the prior art, provides a more optimized preparation method for preparing 2, 4-diamino-6-chloropyrimidine, greatly improves the yield, reduces the operation difficulty, ensures the safety of phosphorus oxychloride quenching, is suitable for industrial mass production, is easy to recover phosphate generated in production, and has lower comprehensive cost.

In order to achieve the purpose, the preparation method of the 2, 4-diamino-6-chloropyrimidine provided by the invention specifically comprises the following steps:

step S1: 2, 4-diamino-6-hydroxypyrimidine (abbreviated as DAHP) is used as a starting material and reacts with phosphorus oxychloride at a first temperature to obtain 2, 4-di (dichlorophosphoryl) amino-6-chloropyrimidine, and after the reaction is finished, redundant phosphorus oxychloride is distilled out, wherein the phosphorus oxychloride can be recycled, and the reaction formula is as follows:

step S2: quenching with alcohol at a second temperature, adding a dispersant, heating to continue reaction, and filtering at a third temperature to obtain 2, 4-diamino-6-chloropyrimidine hydrochloride and a filtrate, wherein the filtrate is used for recovering a solvent and a phosphate compound, and the reaction formula is as follows:

step S3: adding pure water and ammonia water into the 2, 4-diamino-6-chloropyrimidine hydrochloride in the step S2 for neutralization, then extracting with ethyl acetate, and concentrating to obtain the 2, 4-diamino-6-chloropyrimidine, wherein the reaction formula is as follows:

further, the weight ratio of the 2, 4-diamino-6-hydroxypyrimidine to the phosphorus oxychloride is 3.5-5: 1, and the preferable weight ratio is 3.5: 1;

further, the first temperature is 90-110 ℃, the optimal temperature is 105 ℃, the reaction time is 4-8 hours, and the optimal reaction time is 6 hours;

further, the second temperature is 0-40 ℃, the alcohol is selected from C1-C4 lower alcohol or benzyl alcohol, the lower alcohol has an enrichment effect compared with water quenching, alcohol quenching is safer and smoother, and the best alcohol is ethanol;

further, the molar ratio of the alcohol to the phosphorus oxychloride is 3-5: 1, and the optimal molar ratio is 3: 1;

further, the temperature for raising the temperature to continue the reaction is 30-80 ℃, and the optimal temperature is the temperature for refluxing the alcohol;

further, the dispersing agent is an organic solvent which is mutually soluble with phosphate ester, and is selected from one or a mixture of methanol, ethanol, benzyl alcohol, isopropanol, diethyl ether, methyl tert-ether, ethyl acetate, acetone and acetonitrile; the most preferred organic solvent is ethyl acetate; the volume ratio of the dispersing agent to the phosphate is 8-10: 1(V/V), and the preferable ratio is 8: 1;

further, the third temperature is-20-30 ℃, the optimal temperature is 20-30 ℃, the filtrate obtained by filtering is subjected to reduced pressure distillation to recover hydrochloric acid, alcohol and phosphate, and the phosphate has a lower boiling point, is not easy to decompose and is easy to recover compared with phosphoric acid generated by quenching with water;

furthermore, the pH value of ammonia water neutralization is 6-7, so that complete DACP can be fully extracted under the pH condition, and the ammonia water consumption is effectively saved.

Compared with the prior art, the invention has the following beneficial effects: according to the invention, the phosphorus oxychloride is quenched by using alcohol, so that on one hand, the quenching is safer and smoother, and the material cannot be washed, on the other hand, a dispersing agent with lower polarity is added to separate out the product, so that the yield is improved, the recovery rate is more than 70%, the highest yield can reach 82%, the boiling point of the generated phosphate is lower than that of phosphoric acid, the temperature stability is high, the recovery is easier, and the cost advantage is obvious.

Drawings

FIG. 1 shows the preparation of 2, 4-diamino-6-chloropyrimidine according to the invention¹H-NMR graph;

FIG. 2 is a MS plot of a 2, 4-diamino-6-chloropyrimidine according to the present invention;

FIG. 3 is a HPLC plot of a 2, 4-diamino-6-chloropyrimidine of this invention.

Detailed Description

In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail below with reference to examples, so that those skilled in the art can fully understand the technical contents of the present invention. It should be understood that the following examples are intended to further illustrate the present invention and should not be construed as limiting the scope of the present invention, and that certain insubstantial modifications and adaptations of the invention by those skilled in the art based on the foregoing description are intended to be covered by the present invention. The specific process parameters and the like of the following examples are also only one example of suitable ranges, i.e., those skilled in the art can select the appropriate ranges through the description herein, and are not limited to the specific values exemplified below.

Example 1:

2, 4-diamino-6-hydroxypyrimidine (12.6g) was weighed into a three-necked flask, and POCl was added₃(53.5g) was added to the reaction flask, and the mixture was stirred for 6 hours while the temperature was raised to 105 ℃. After the reaction was complete, excess POCl was distilled off₃Temperature is reduced to 30 &Slowly adding ethanol (37ml) dropwise at 40 ℃, heating to reflux reaction for 2h after the ethanol is completely added dropwise, cooling, and adding ethyl acetate (96 ml). Cooling, stirring for 2h, and filtering. 17.8g of DACP hydrochloride was obtained.

Adding DACP hydrochloride into water (40ml), heating to 70 ℃ to dissolve, neutralizing with ammonia water to pH 6-7, extracting with ethyl acetate, drying and concentrating to obtain 11.8g of DACP pure product with yield of 82.0%, and performing HPLC: 99.2 percent. [ M + H + ] -145.1, H-NMR (DMSO-d 6): δ 6.64(S, NH2), δ 6.42(S, NH2), δ 5.73(S, Ar-H).

Example 2:

2, 4-diamino-6-hydroxypyrimidine (12.6g) was weighed into a three-necked flask, and POCl was added₃(76.5g) was added to the reaction flask, the temperature was raised to 105 ℃ and stirred for 6 hours. After the reaction was complete, excess POCl was distilled off₃And cooling to 30-40 ℃, slowly dripping ethanol (60ml), heating to reflux reaction for 2 hours after dripping, cooling, and adding acetone (60 ml). Cooling, stirring for 2h, and filtering. 15.4g of DACP hydrochloride was obtained.

Adding DACP hydrochloride into water (40ml), heating to 70 ℃ to dissolve, neutralizing with ammonia water to pH 6-7, extracting with ethyl acetate, drying and concentrating to obtain 10.5g of DACP pure product with yield of 73.0%.

Example 3:

2, 4-diamino-6-hydroxypyrimidine (12.6g) was weighed into a three-necked flask, and POCl was added₃(76.5g) was added to the reaction flask, the temperature was raised to 105 ℃ and stirred for 6 hours. After the reaction was complete, excess POCl was distilled off₃And cooling to 30-40 ℃, slowly dripping methanol (40ml), heating to reflux reaction for 2 hours after dripping, cooling, and adding acetonitrile (60 ml). Cooling, stirring for 2h, and filtering. 16.2g of DACP hydrochloride was obtained.

Adding DACP hydrochloride into water (40ml), heating to 70 ℃ to dissolve, neutralizing with ammonia water to pH 6-7, extracting with ethyl acetate, drying and concentrating to obtain 11.1g of DACP with yield of 77.1%.

Example 4:

2, 4-diamino-6-hydroxypyrimidine (12.6g) was weighed into a three-necked flask, and POCl was added₃(53.5g) was added to the reaction flask, and the mixture was stirred for 6 hours while the temperature was raised to 105 ℃. After the reaction was complete, excess POCl was distilled off₃Cooling to 30-40 ℃, and slowly dropping AAlcohol (40ml), after dripping, heating to reflux reaction for 2h, cooling, and adding tetrahydrofuran (60 ml). Cooling, stirring for 2h, and filtering. 16.6g of DACP hydrochloride was obtained.

Adding DACP hydrochloride into water (40ml), heating to 70 ℃ to dissolve, neutralizing with ammonia water to pH 6-7, extracting with ethyl acetate, drying and concentrating to obtain 10.8g of DACP pure product with yield of 75.0%.

It should be noted that the above-mentioned preferred embodiments are merely illustrative of the technical concepts and features of the present invention, and are intended to enable those skilled in the art to understand the contents of the present invention and implement the present invention, and not to limit the scope of the present invention. All equivalent changes and modifications made according to the spirit of the present invention should be covered within the protection scope of the present invention.