A process for the preparation of an impurity of an intermediate of urapidil, 1,3-dimethyl-6-(propylamino)pyrimidine-2,4-dione

Abstract

The application relates to the technical field of organic synthesis, and particularly discloses a preparation method of an urapidil intermediate impurity 1,3-dimethyl-6-(propylamino) pyrimidine-2,4-dione. The target product is obtained through three steps of hydrolysis, chlorination and condensation by taking 6-amino-1,3-dimethyl urea pyrimidine as a starting raw material; further, by controlling the types and dosage ratios of reactants, chlorination reagents, acid-binding agents and solvents, reaction temperature and reaction time and post-treatment conditions, the urapidil intermediate impurity with high purity and high yield can be prepared, the urapidil intermediate impurity can be used as a control sample to monitor the quality of urapidil intermediates or urapidil bulk drugs, and has high application value.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of organic synthesis, and particularly relates to a preparation method of an urapidil intermediate impurity 1,3-dimethyl-6-(propylamino) pyrimidine-2,4-dione. BACKGROUND

[0002] Urapidil is a new type of alpha 1 receptor blocker antihypertensive drug, which is mainly used for treating hypertensive crisis, severe and extremely severe hypertension and refractory hypertension, and can also be used for controlling perioperative hypertension.

[0003] The industrial production route of urapidil usually adopts an intermediate 6-(3-hydroxypropyl) amino-1,3-dimethyl uracil prepared through chlorination and condensation, which has an important influence on the synthesis quality of urapidil. However, in the preparation process of the intermediate, the intermediate impurity 1,3-dimethyl-6-(propylamino) pyrimidine-2,4-dione is usually generated in the current method, and the structural formula is as follows:

[0004] Impurities exist not only in the final drug, but also in each intermediate in the synthesis of the drug. In the production process of the drug, the research on the intermediate impurity is an indispensable and very important part. The residual intermediate impurity in the drug will bring potential risks to the later drug product. The existence of these impurities not only affects the drug efficacy, but also causes problems in the production and storage process, and some impurities even have toxic side effects. Therefore, the preparation and research of the intermediate impurity standard are extremely important for the drug efficacy and human health, and it is necessary to synthesize high-purity intermediate impurities.

[0005] At present, there are few reports on the preparation method of the urapidil intermediate impurity 1,3-dimethyl-6-(propylamino) pyrimidine-2,4-dione. In order to better control the quality of the intermediate, a preparation method of high-purity urapidil intermediate impurity 1,3-dimethyl-6-(propylamino) pyrimidine-2,4-dione needs to be researched. SUMMARY

[0006] The application aims to provide a preparation method of high-purity urapidil intermediate impurity 1,3-dimethyl-6-(propylamino) pyrimidine-2,4-dione, which obtains the target product through three steps of hydrolysis, chlorination and condensation, has low material cost, and improves the intermediate impurity purity by using the aprotic solvent and acid binding agent required in the preferred condensation reaction.

[0007] To solve the above technical problems, the technical scheme provided by the application is:

[0008] The preparation method of the urapidil intermediate impurity 1,3-dimethyl-6-(propylamino) pyrimidine-2,4-dione provided by the application comprises the following steps:

[0009] 6-hydroxy-1,3-dimethyl uracil is obtained by hydrolysis reaction of 6-amino-1,3-dimethyl uracil under acidic conditions;

[0010] 6-chloro-1,3-dimethyl uracil is obtained by chlorination reaction of 6-hydroxy-1,3-dimethyl uracil and a chlorination reagent;

[0011] 1,3-dimethyl-6-(propylamino) pyrimidine-2,4-dione is obtained by condensation reaction of 6-chloro-1,3-dimethyl uracil and propylamine in an aprotic solvent with an acid binding agent added; wherein the aprotic solvent is N,N-dimethylformamide or dichloromethane or toluene and acetonitrile in a volume ratio of 2:1-3:1. The synthesis route is as follows:

[0012]

[0013] In the above technical scheme, 6-amino-1,3-dimethyl uracil (compound IV) is used as the raw material, hydrolysis is carried out under acidic conditions to generate 6-hydroxy-1,3-dimethyl uracil (compound III), then chlorination reaction is carried out with a chlorination reagent to generate 6-chloro-1,3-dimethyl uracil (compound II), and then condensation reaction is carried out with n-propylamine in an aprotic solvent with an acid binding agent added to obtain 1,3-dimethyl-6-(propylamino) pyrimidine-2,4-dione (compound I). The aprotic solvent is one of N,N-dimethylformamide, dichloromethane or a mixed solvent of acetonitrile and toluene, and the volume ratio of the mixed solvent of toluene and acetonitrile is preferably 2:1-3:1.

[0014] The application provides a preparation method of a new urapidil intermediate impurity 1,3-dimethyl-6-(propylamino) pyrimidine-2,4-dione.

[0015] Further, the preparation method of the application specifically comprises the following steps:

[0016] In step a, the first step is a hydrolysis reaction, 6-amino-1,3-dimethyl urea pyrimidine is dispersed in a solvent a, an acid solution is added for reflux reaction, cooling and crystallization, filtration and drying are carried out, and 6-hydroxy-1,3-dimethyl urea pyrimidine (compound III) is obtained.

[0017] In step b, the second step is a chlorination reaction, 6-hydroxy-1,3-dimethyl urea pyrimidine is dispersed in a solvent b, a chlorination reagent is added, slow warming and reflux reaction are carried out, cooling, quenching and crystallization are carried out, filtration and drying are carried out, and 6-chloro-1,3-dimethyl urea pyrimidine (compound II) is obtained.

[0018] In step c, the third step is a condensation reaction, 6-chloro-1,3-dimethyl urea pyrimidine is dissolved in an aprotic solvent, an acid binding agent and n-propylamine are added, warming and condensation reaction are carried out, cooling is carried out, filtration is carried out, the obtained reaction liquid is concentrated, cooling and stirring crystallization are carried out, filtration is carried out, beating is carried out, and drying is carried out, and 1,3-dimethyl-6-(propylamino) pyrimidine-2,4-dione (compound I) is obtained.

[0019] The application provides a preparation method of a new urapidil intermediate impurity 1,3-dimethyl-6-(propylamino) pyrimidine-2,4-dione, after reflux reaction and cooling and crystallization of the first two steps of hydrolysis and chlorination, the required product can be obtained, in the third step of condensation reaction, an aprotic solvent is used as a solvent, under the action of an acid binding agent, 6-chloro-1,3-dimethyl urea pyrimidine reacts with n-propylamine, and after post-treatment such as desalting, concentration and crystallization, filtration and beating, the final product compound I is obtained, the whole preparation process has strong operability, simple process, single reaction site of the adopted chemical synthesis method and less by-products.

[0020] Further, in step a, the hydrolysis reaction needs to be carried out under acidic conditions, the acid can be a strong inorganic acid or a strong organic acid, preferably, the acid solution is a sulfuric acid solution or a hydrochloric acid solution, further, the sulfuric acid solution or the hydrochloric acid solution is concentrated sulfuric acid or concentrated hydrochloric acid.

[0021] Further, in step a, the solvent a of the hydrolysis reaction is selected from one of water, methanol or ethanol.

[0022] Further, in step a, the reflux reaction time of the hydrolysis reaction is 1h-5h, preferably 2h-3h.

[0023] Further, in step a, the reflux reaction needs to be cooled to room temperature for 1-2 hours for crystallization.

[0024] Further, in step b, the solvent b for the second step of chlorination reaction is selected from one or more of toluene, ethyl acetate or dichloromethane, preferably toluene or ethyl acetate.

[0025] Further, in step b, the mass-volume ratio of 6-hydroxy-1,3-dimethyluracil (compound III) to solvent in the chlorination reaction is 1:2-6, wherein the unit of mass is g and the unit of volume is mL.

[0026] Further, in step b, the chlorinating agent for the chlorination reaction is selected from one of phosphorus pentachloride, phosphorus oxychloride, thionyl chloride or phenylphosphoryl chloride, more preferably phosphorus oxychloride.

[0027] Further, in step b, the molar ratio of the chlorinating agent phosphorus oxychloride to 6-hydroxy-1,3-dimethyluracil in the chlorination reaction is 1.0:0.6-1.0.

[0028] Further, in step b, the reflux reaction time for the chlorination reaction is 1-8 hours, preferably 2-6 hours.

[0029] Further, in step b, the cooling, quenching and crystallization process after the chlorination reaction needs to be cooled to 10-20℃, and 0.6-3 times the amount of ice water is slowly added to control the temperature below 40℃, and then stirred for 1 hour and cooled to 10-20℃.

[0030] Further, in step c, the mass-volume ratio of 6-chloro-1,3-dimethyluracil (compound II) to aprotic solvent in the third step of condensation reaction is 1:4-6, preferably 1:5, wherein the unit of mass is g and the unit of volume is mL.

[0031] Further, in step c, the molar ratio of the acid binding agent to 6-chloro-1,3-dimethyluracil (compound II) in the condensation reaction is 1.2-1.8:1, preferably 1.5:1.

[0032] Further, in step c, the acid binding agent is one of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate or triethylamine, preferably potassium carbonate.

[0033] Further, in step c, the molar ratio of n-propylamine to 6-chloro-1,3-dimethyluracil (compound II) in the condensation reaction is 1.1-2.0:1, preferably 1.5:1.

[0034] Further, in step c, the reaction temperature for the condensation reaction is 35℃-150℃, preferably 70℃-80℃.

[0035] Further, the reaction time of the condensation reaction in step c is 2-10 hours, preferably 3 hours.

[0036] Further, in the condensation reaction in step c, the reaction liquid is concentrated to 1 / 4-1 / 3 of the original volume in the concentration step in the post-treatment process.

[0037] Further, in the condensation reaction in step c, the crystallization temperature is room temperature and the crystallization time is 3-8 hours, preferably 4 hours, in the stirring crystallization step in the post-treatment process.

[0038] Further, in the condensation reaction in step c, the slurry is prepared, preferably with methyl tert-butyl ether, and the mass / volume ratio of 6-chloro-1,3-dimethyluracil (compound II) to methyl tert-butyl ether is 1:2-4, preferably 1:3, wherein the unit of mass is g and the unit of volume is mL.

[0039] The application provides a preparation method of urapidil intermediate impurity 1,3-dimethyl-6-(propylamino) pyrimidine-2,4-dione, and further controls the types and dosages of reactants, chlorinating reagents, acid-binding agents and solvents, reaction temperature and reaction time, and post-treatment conditions, such as crystallization temperature and time and the dosage of slurry solvent methyl tert-butyl ether, to ensure that the prepared urapidil intermediate impurity 1,3-dimethyl-6-(propylamino) pyrimidine-2,4-dione has a purity of more than 98%, and the method is simple, easy to operate and highly feasible.

[0040] The urapidil intermediate impurity prepared by the method has high purity, can be used as a control for qualitative and quantitative analysis, and can be used for monitoring the quality of prepared urapidil intermediates or urapidil bulk drugs, and has high application value. BRIEF DESCRIPTION OF DRAWINGS

[0041] Figure 1 is a liquid chromatogram of the intermediate impurity 1,3-dimethyl-6-(propylamino) pyrimidine-2,4-dione prepared in Example 1;

[0042] Figure 2 is a liquid chromatogram of the intermediate impurity 1,3-dimethyl-6-(propylamino) pyrimidine-2,4-dione prepared in Example 1; 1 HNMR spectrum;

[0043] Figure 3 is a liquid chromatogram of the intermediate impurity 1,3-dimethyl-6-(propylamino) pyrimidine-2,4-dione prepared in Example 1; 13 CNMR spectrum;

[0044] Figure 4is a mass spectrum of the intermediate impurity 1,3-dimethyl-6-(propylamino)pyrimidine-2,4-dione prepared in Example 1. DETAILED DESCRIPTION

[0045] In order to make the objectives, technical solutions and advantages of the present application clearer, the present application will be further described in details below with reference to the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present application and not used to limit the present application.

[0046] In order to make the objectives, technical solutions and advantages of the present application clearer, the present application will be further described in details below with reference to the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present application and not used to limit the present application.

[0047] Example 1

[0048] The present example provides a preparation method of an intermediate impurity 1,3-dimethyl-6-(propylamino)pyrimidine-2,4-dione of urapidil, comprising the following steps:

[0049] Step a: hydrolysis reaction to prepare 6-hydroxy-1,3-dimethyluracil (compound III)

[0050] Into a 1L reaction bottle, 6-amino-1,3-dimethyluracil 100g was added and dispersed in 400ml purified water, and concentrated sulfuric acid 32.87g was added dropwise at room temperature, and refluxed for 2h, cooled to room temperature, crystallized for 1h, filtered, and oven dried to obtain 6-hydroxy-1,3-dimethyluracil 76.28g, with a yield of 75.80%.

[0051] Step b: chlorination reaction to prepare 6-chloro-1,3-dimethyluracil (compound II)

[0052] Into a reaction bottle, 6-hydroxy-1,3-dimethyluracil 50g obtained in step a was added and dispersed in toluene 100ml, and phosphorus oxychloride 58.92g was added dropwise, and slowly warmed to reflux, and refluxed for 2h, and cooled to 10-20℃, and slowly added ice water 200ml, and controlled the temperature below 40℃, and stirred for 1h, and then cooled to 10-20℃, and filtered, and oven dried to obtain 6-chloro-1,3-dimethyluracil 36.21g, with a yield of 64.77%.

[0053] Step c: condensation reaction to prepare 1,3-dimethyl-6-(propylamino)pyrimidine-2,4-dione (compound I)

[0054] The 6-chloro-1,3-dimethyluracil 30 g obtained in step b was put into a reaction bottle, dissolved in 150 mL of a mixed solvent of toluene and acetonitrile in a volume ratio of 2.5:1, potassium carbonate 35.62 g and n-propylamine 15.24 g were added at room temperature, the temperature was raised to 75°C and kept at 70-80°C, the reaction was carried out for 3 h, the temperature was lowered to room temperature, the salt was filtered out, the obtained reaction liquid was concentrated to 1 / 4 of the original reaction liquid volume, and the obtained solid was added into 90 mL of methyl tert-butyl ether for slurry, and dried to obtain 1,3-dimethyl-6-(propylamino) uracil-2,4-dione product 30.26 g, with a yield of 89.28% and a purity of 99.34%.

[0055] The product passed the identification of HPLC, 1 H NMR spectrum, 13 C NMR spectrum and mass spectrum, and the spectra are shown in Figures 1-4 The retention time of the urapidil intermediate impurity 1,3-dimethyl-6-(propylamino) uracil-2,4-dione in the HPLC spectrum is 19.258 minutes. The urapidil intermediate impurity 1,3-dimethyl-6-(propylamino) uracil-2,4-dione product prepared in Example 1 was detected by liquid chromatography at the same time as the urapidil intermediate, and the liquid chromatogram is shown in Figure 1 As shown in the figure, the urapidil intermediate impurity and the urapidil intermediate have good separation degree.

[0056] Example 2

[0057] The present embodiment provides a preparation method of a urapidil intermediate impurity 1,3-dimethyl-6-(propylamino) uracil-2,4-dione, comprising the following steps:

[0058] Step a: hydrolysis reaction to prepare 6-hydroxy-1,3-dimethyluracil (compound III)

[0059] A 1 L reaction bottle was added with 6-amino-1,3-dimethyluracil 100 g, which was dispersed in 400 mL of ethanol, and concentrated hydrochloric acid 68.61 g was added dropwise at room temperature, and the reaction was carried out under reflux for 3 h, the temperature was lowered to room temperature, and the crystal was precipitated for 2 h, then filtered and dried to obtain 6-hydroxy-1,3-dimethyluracil 77.32 g, with a yield of 76.84%.

[0060] Step b: chlorination reaction to prepare 6-chloro-1,3-dimethyluracil (compound II)

[0061] Into a 1 L reaction flask was placed 6-amino-1,3-dimethyluracil 100 g, dispersed in 400 mL of methanol, and concentrated sulfuric acid 37.93 g was added dropwise at room temperature. The reaction was refluxed for 3 h, cooled to room temperature, and crystals were precipitated for 2 h. The crystals were filtered and dried to obtain 6-hydroxy-1,3-dimethyluracil 76.92 g in a yield of 76.44%.

[0062] Step c: Condensation reaction to prepare 1,3-dimethyl-6-(propylamino) uracil-2,4-dione (Compound I)

[0063] Into a 1 L reaction flask was placed 6-amino-1,3-dimethyluracil 100 g, dispersed in 400 mL of methanol, and concentrated sulfuric acid 37.93 g was added dropwise at room temperature. The reaction was refluxed for 3 h, cooled to room temperature, and crystals were precipitated for 2 h. The crystals were filtered and dried to obtain 6-hydroxy-1,3-dimethyluracil 76.92 g in a yield of 76.44%.

[0064] Example 3

[0065] The present example provides a method for preparing 1,3-dimethyl-6-(propylamino) uracil-2,4-dione, an intermediate impurity of urapidil, comprising the following steps:

[0066] Step a: Hydrolysis reaction to prepare 6-hydroxy-1,3-dimethyluracil (Compound III)

[0067] Into a 1 L reaction flask was placed 6-amino-1,3-dimethyluracil 100 g, dispersed in 400 mL of methanol, and concentrated sulfuric acid 37.93 g was added dropwise at room temperature. The reaction was refluxed for 3 h, cooled to room temperature, and crystals were precipitated for 2 h. The crystals were filtered and dried to obtain 6-hydroxy-1,3-dimethyluracil 76.92 g in a yield of 76.44%.

[0068] Step b: Chlorination reaction to prepare 6-chloro-1,3-dimethyluracil (Compound II)

[0069] Into a 1 L reaction flask was placed 6-amino-1,3-dimethyluracil 100 g, dispersed in 400 mL of methanol, and concentrated sulfuric acid 37.93 g was added dropwise at room temperature. The reaction was refluxed for 3 h, cooled to room temperature, and crystals were precipitated for 2 h. The crystals were filtered and dried to obtain 6-hydroxy-1,3-dimethyluracil 76.92 g in a yield of 76.44%.

[0070] Step c: condensation reaction to prepare 1,3-dimethyl-6-(propylamino) pyrimidine-2,4-dione (compound I)

[0071] The 6-chloro-1,3-dimethyl urea pyrimidine 30 g obtained in step b was put into a reaction bottle and dissolved in 150 mL of N,N-dimethylformamide. Potassium carbonate 28.50 g and n-propylamine 20.31 g were added at room temperature. The temperature was raised to reflux and reacted for 2 h. The temperature was lowered to room temperature. The salt was filtered out. The obtained reaction liquid was concentrated to 1 / 3 of the original reaction liquid volume. Crystallization was carried out at room temperature for 8 h. The obtained solid was filtered and added to 120 mL of methyl tert-butyl ether for slurry. After drying, 1,3-dimethyl-6-(propylamino) pyrimidine-2,4-dione product 28.69 g was obtained with a yield of 84.65% and a purity of 98.18%.

[0072] Comparative Example 1

[0073] The preparation method of the present comparative example is different from that of Example 1 in that the aprotic solvent used in the third step of condensation reaction is toluene, so as to compare the influence of aprotic solvent on the purity of the final product. The specific preparation method comprises the following steps:

[0074] Step a: hydrolysis reaction to prepare 6-hydroxy-1,3-dimethyl urea pyrimidine (compound III)

[0075] A 1 L reaction bottle was added with 6-amino-1,3-dimethyl urea pyrimidine 100 g, which was dispersed in 400 mL of purified water. Concentrated sulfuric acid 32.85 g was added dropwise at room temperature. The reaction was carried out at reflux for 2 h. The temperature was lowered to room temperature. Crystallization was carried out for 1 h. After filtration and drying, 6-hydroxy-1,3-dimethyl urea pyrimidine 75.03 g was obtained.

[0076] Step b: chlorination reaction to prepare 6-chloro-1,3-dimethyl urea pyrimidine (compound II)

[0077] The 6-hydroxy-1,3-dimethyl urea pyrimidine 50 g obtained in step a was put into a reaction bottle and dispersed in toluene 100 mL. Phosphorus oxychloride 58.88 g was added dropwise. The temperature was slowly raised to reflux. The reaction was carried out at reflux for 2 h. The temperature was lowered to 10-20 °C. Ice water 200 mL was slowly added while controlling the temperature below 40 °C. After stirring for 1 h, the temperature was lowered to 10-20 °C. Filtration and drying were carried out. 6-Chloro-1,3-dimethyl urea pyrimidine 36.11 g was obtained.

[0078] Step c: condensation reaction to prepare 1,3-dimethyl-6-(propylamino) pyrimidine-2,4-dione (compound I)

[0079] The 6-chloro-1,3-dimethyluracil 30 g obtained in step b was put into a reaction bottle, dissolved in 150 mL of toluene, potassium carbonate 35.65 g and n-propylamine 15.19 g were added at room temperature, and the temperature was increased to reflux for 3 h. After cooling to room temperature, the salt was filtered out, and the obtained reaction liquid was concentrated to 1 / 4 of the original reaction liquid volume. After stirring at room temperature for 4 h, the filter was obtained. The solid obtained by filtration was added to 90 mL of methyl ether for slushing, and dried to obtain 1,3-dimethyl-6-(propylamino) pyrimidine-2,4-dione product 29.33 g, purity 90.13%.

[0080] Comparative Example 2

[0081] The preparation method of the present comparative example is different from that of Example 1 in that the aprotic solvent used in the third step of condensation reaction is acetonitrile, in order to compare the influence of aprotic solvent on the purity of the final product. The specific preparation method comprises the following steps:

[0082] Step a: hydrolysis reaction to prepare 6-hydroxy-1,3-dimethyluracil (compound III)

[0083] A 1 L reaction bottle was added with 6-amino-1,3-dimethyluracil 100 g, which was dispersed in 400 mL of purified water. Concentrated sulfuric acid 32.69 g was added dropwise at room temperature, and refluxed for 2 h. After cooling to room temperature, it was crystallized for 1 h, filtered and dried to obtain 6-hydroxy-1,3-dimethyluracil 74.53 g.

[0084] Step b: chlorination reaction to prepare 6-chloro-1,3-dimethyluracil (compound II)

[0085] The 6-hydroxy-1,3-dimethyluracil 50 g obtained in step a was put into a reaction bottle, dispersed in 100 mL of toluene, and phosphorus oxychloride 58.98 g was added dropwise. The temperature was slowly increased to reflux, and refluxed for 2 h. After cooling to 10-20°C, 200 mL of ice water was slowly added, and the temperature was controlled below 40°C. After stirring for 1 h, the temperature was cooled to 10-20°C, filtered and dried to obtain 6-chloro-1,3-dimethyluracil 36.61 g.

[0086] Step c: condensation reaction to prepare 1,3-dimethyl-6-(propylamino) pyrimidine-2,4-dione (compound I)

[0087] The 6-chloro-1,3-dimethyluracil 30 g obtained in step b was put into a reaction bottle, dissolved in 150 mL of acetonitrile, and potassium carbonate 35.75 g and n-propylamine 15.35 g were added at room temperature. The temperature was raised to reflux and reacted for 3 h. The temperature was lowered to room temperature, and the salt was filtered out. The obtained reaction liquid was concentrated to 1 / 4 of the original reaction liquid volume, and stirred at room temperature for 4 h to crystallize. The filter obtained solid was added to 90 mL of methyl ether for slushing, and dried to obtain 1,3-dimethyl-6-(propylamino) pyrimidine-2,4-dione product 30.68 g, with a purity of 95.22%.

[0088] Comparative Example 3

[0089] The preparation method of the present comparative example is different from that of Example 1 in that dichloroethane is used as the aprotic solvent in the third step of condensation reaction, in order to compare the influence of aprotic solvent on the purity of the final product. The specific preparation method comprises the following steps:

[0090] Step a: hydrolysis reaction to prepare 6-hydroxy-1,3-dimethyluracil (compound III)

[0091] A 1 L reaction bottle was added with 6-amino-1,3-dimethyluracil 100 g, which was dispersed in 400 mL of purified water. Concentrated sulfuric acid 33.55 g was added dropwise at room temperature, and refluxed for 2 h. The temperature was lowered to room temperature, and crystallized for 1 h. After filtration and drying, 6-hydroxy-1,3-dimethyluracil 76.63 g was obtained.

[0092] Step b: chlorination reaction to prepare 6-chloro-1,3-dimethyluracil (compound II)

[0093] The 6-hydroxy-1,3-dimethyluracil 50 g obtained in step a was put into a reaction bottle, and stirred and dispersed in 100 mL of toluene. Phosphorus oxychloride 57.25 g was added dropwise, and the temperature was slowly raised to reflux. The reaction was refluxed for 2 h, and the temperature was lowered to 10-20°C. 200 mL of ice water was slowly added, and the temperature was controlled below 40°C. After stirring for 1 h, the temperature was lowered to 10-20°C, and filtered. After drying, 6-chloro-1,3-dimethyluracil 33.91 g was obtained.

[0094] Step c: condensation reaction to prepare 1,3-dimethyl-6-(propylamino) pyrimidine-2,4-dione (compound I)

[0095] The 6-chloro-1,3-dimethyl-uracil 30 g obtained in step b was put into a reaction bottle, dissolved in 150 mL of dichloroethane, and then potassium carbonate 37.35 g and n-propylamine 17.01 g were added at room temperature. The reaction was heated to reflux for 3 h, and then cooled to room temperature. The salt was filtered out, and the obtained reaction liquid was concentrated to a volume of 1 / 4 of the original reaction liquid. Crystallization was performed at room temperature for 4 h, and then the obtained solid was filtered out, added into 90 mL of methyl tert-butyl ether for slurry, and then dried to obtain 1,3-dimethyl-6-(propylamino)uracil-2,4-dione product 30.87 g with a purity of 93.68%.

[0096] The above description is merely preferred embodiments of the present application, but not to limit the present application. Any modification, equivalent replacement or improvement made in the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. A process for the preparation of urapidil intermediate impurity 1,3-dimethyl-6- (propylamino)pyrimidine-2,4-dione, characterized in that, Comprising the following steps: hydrolysis reaction of 6-amino-1,3-dimethyluracil under acidic conditions to obtain 6-hydroxy-1,3-dimethyluracil; chlorination reaction of 6-hydroxy-1,3-dimethyluracil with a chlorinating agent to obtain 6-chloro-1,3-dimethyluracil; condensation reaction of 6-chloro-1,3-dimethyluracil with n-propylamine in aprotic solvent with the addition of an acid binding agent to obtain 1,3-dimethyl-6-(propylamino)pyrimidine-2,4-dione; wherein the aprotic solvent is N,N-dimethylformamide or dichloromethane or toluene and acetonitrile in a volume ratio of 2:1-3:1; the acid binding agent is potassium carbonate; the reaction temperature of the condensation reaction is 35℃-150℃, and the reaction time of the condensation reaction is 2h-10h.

2. Process for the preparation of the urapidil intermediate impurity 1,3-dimethyl-6- (propylamino)pyrimidine-2,4-dione according to claim 1, characterized in that, Specifically comprising the following steps: Step a, dissolving 6-amino-1,3-dimethyluracil in solvent a, adding an acid solution, refluxing, cooling and crystallizing, filtering, and drying to obtain 6-hydroxy-1,3-dimethyluracil; Step b, dissolving 6-hydroxy-1,3-dimethyluracil in solvent b, adding a chlorinating agent, refluxing, cooling, quenching, crystallizing, filtering, and drying to obtain 6-chloro-1,3-dimethyluracil; Step c, dissolving 6-chloro-1,3-dimethyluracil in an aprotic solvent, adding an acid binding agent and n-propylamine, warming to perform condensation reaction, cooling, filtering to obtain a reaction liquid, concentrating the reaction liquid, cooling, stirring and crystallizing, filtering, beating, and drying to obtain 1,3-dimethyl-6-(propylamino)pyrimidine-2,4-dione.

3. Process for the preparation of urapidil intermediate impurity 1,3-dimethyl-6- (propylamino)pyrimidine-2,4-dione according to claim 2, characterized in that, In step a, the acid solution is a sulfuric acid solution or a hydrochloric acid solution, and / or The solvent a is at least one of water, methanol or ethanol.

4. Process for the preparation of urapidil intermediate impurity 1,3-dimethyl-6- (propylamino)pyrimidine-2,4-dione according to claim 2 or 3, characterized in that, In step a, the refluxing time is 1h-5h, and / or In step a, the cooling and crystallizing time is 1-2h.

5. A process for the preparation of urapidil intermediate impurity 1,3-dimethyl-6- (propylamino)pyrimidine-2,4-dione according to claim 2, characterized in that, In step b, the solvent b is one or more of toluene, ethyl acetate or dichloromethane, and / or In step b, the chlorinating agent is one of phosphorus pentachloride, phosphorus oxychloride, thionyl chloride or phenylphosphoryl chloride.

6. Process for the preparation of urapidil intermediate impurity 1,3-dimethyl-6- (propylamino)pyrimidine-2,4-dione according to claim 2 or 5, characterized in that, In step b, the mass-volume ratio of 6-hydroxy-1,3-dimethyluracil to solvent a is 1:2-6, wherein the unit of mass is g and the unit of volume is mL; and / or In step b, the molar ratio of the chlorinating agent to 6-hydroxy-1,3-dimethyluracil is 1.0:0.6-1.

0.

7. A process for the preparation of urapidil intermediate impurity 1,3-dimethyl-6- (propylamino)pyrimidine-2,4-dione according to claim 2, characterized in that, In step c, the molar ratio of the acid binding agent to 6-chloro-1,3-dimethyluracil is 1.2-1.8:1; and / or In step c, the molar ratio of n-propylamine to 6-chloro-1,3-dimethyluracil is 1.1-2.0:

1.

8. Process for the preparation of the urapidil intermediate impurity 1,3-dimethyl-6- (propylamino)pyrimidine-2,4-dione according to claim 2 or 7, characterized in that, In step c, the reaction liquid is concentrated to a residual volume of 1 / 4-1 / 3 of the original reaction liquid volume, and / or In step c, the stirring and crystallizing time is 3h-8h.

9. A process for the preparation of urapidil intermediate impurity 1,3-dimethyl-6- (propylamino)pyrimidine-2,4-dione according to claim 8, characterized in that, In step c, methyl tert-butyl ether is added to the filtered solid for beating, and the mass-volume ratio of 6-chloro-1,3-dimethyluracil to methyl tert-butyl ether is 1:2-4, wherein the unit of mass is g and the unit of volume is mL.

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