Synthesis method of 5-bromo-2-cyclopropyl pyrimidine

Abstract

The invention discloses a synthesis method of 5-bromo-2-cyclopropyl pyrimidine. The synthesis method comprises the following steps: S1, providing phosphorus oxychloride, DMF (Dimethyl Formamide), 2-bromoacetic acid and fluoboric acid according to a molar ratio of 3: 7: (1-1.2): (2.5-3.2); s2, dropwise adding DMF (Dimethyl Formamide) into phosphorus oxychloride in an ice-water bath to form a mixed solution I, removing the ice-water bath, heating the mixed solution I to room temperature, and stirring for 0.5-1 hour to obtain a formylation reagent; the synthesis process is simple to operate, low in production cost and small in environmental pollution.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical intermediates processing, and particularly relates to a synthesis method of 5-bromo-2-cyclopropyl pyrimidine. BACKGROUND

[0002] 5-bromo-2-cyclopropyl pyrimidine (C7H7BrN2) is a novel pharmaceutical intermediate and a widely used molecular building block. A commonly used method for preparing the compound is to react 5-bromo-2-iodopyrimidine with a Grignard reagent, cyclopropyl magnesium bromide, under the catalysis of a palladium catalyst (tetrakis(triphenylphosphine palladium)), and the main by-product is deiodized 5-bromopyrimidine. The reaction uses expensive initial raw material 5-bromo-2-iodopyrimidine, which is generally priced at 3000 yuan / kg on the market, palladium catalyst, and cyclopropyl bromide (which needs to be freshly prepared Grignard reagent cyclopropyl magnesium bromide). The by-product and the product have very similar physicochemical properties such as polarity and boiling point, and it is very difficult to purify and separate them. The methods disclosed in patents such as US201551395, US2018291002, and WO2023146512 are all based on the above method. The raw material cost is high, the reaction process needs to be strictly operated in a water-free and oxygen-free environment, the operation is difficult, the product needs to be separated and purified by column chromatography, and the yield is low. The patents WO2006004532 (yield not reported) of AstraZeneca and CN118852223 of Zhejiang Jiangbei Nanhai Pharmaceutical Co., Ltd. start from mucobromic acid, neutralize the cyclopropyl formamidine hydrochloride salt with sodium ethoxide, condense with mucobromic acid to form an imine, and then treat with sodium ethoxide to dehydrate and ring-close to obtain a 5-bromo-2-cyclopropyl-4-pyrimidine carboxylic acid intermediate. The pyrimidine carboxylic acid intermediate is separated and then heated at high temperature (>140 DEG C) in a xylene solution or under solvent-free conditions to generate 5-bromo-2-cyclopropyl pyrimidine. These synthesis methods require high-temperature conditions, the reaction process releases gas, and high-vacuum concentration is required for post-treatment, which is very risky for large-scale production. Moreover, the impurities in the crude product have similar structures, which greatly increases the difficulty of post-treatment and product purification. In summary, the synthesis methods reported in the literature are harsh in reaction conditions, complicated in operation, or difficult to obtain raw materials, resulting in high cost. Therefore, we propose a simple synthesis method of 5-bromo-2-cyclopropyl pyrimidine. SUMMARY

[0003] The present application aims to provide a synthesis method of 5-bromo-2-cyclopropyl pyrimidine, which is simple in operation, low in production cost, and small in environmental pollution.

[0004] According to the synthesis method of 5-bromo-2-cyclopropyl pyrimidine provided by the present application, the following steps are included: S1: providing trichloro phosphine: DMF: 2-bromoacetic acid: fluoroboric acid = 3:7:1-1.2:2.5-3.2 according to the molar ratio; S2: under ice water bath, DMF is added dropwise into phosphorus oxychloride, after dropwise addition, a mixed solution one is formed, the ice water bath is removed, the mixed solution one is heated to room temperature and stirred for 0.5-1 hours to prepare a formylating reagent; S3: under ice water bath, 2-bromoacetic acid is added into the formylating reagent obtained in step S2, after addition, a mixed solution two is formed, the mixed solution two is heated to 60-80 DEG C and controlled temperature stirring is carried out for 6-8 hours, after 2-bromoacetic acid is detected to be absent, the reaction is stopped, and a reaction liquid one is obtained; S4: the reaction liquid one in step S3 is cooled to 0-5 DEG C, glacial ethanol is added dropwise for quenching reaction to obtain a mixed solution three; S5: the above mixed solution three is cooled to 0-5 DEG C, 50% fluoroboric acid solution is added dropwise, after dropwise addition, natural temperature recovery to 20-25 DEG C is carried out, stirring is carried out for 2-3 hours, the temperature is cooled to 0-5 DEG C again, crystallization is carried out for 8-15 hours, then filtration is carried out, the filter cake is washed, and then drying is carried out in an oven to obtain 2-bromoethylene amidine onium salt solid; S6: according to a molar ratio, 2-bromoethylene amidine onium salt solid: cyclopropyl methyl amidine hydrochloride: sodium methoxide methanol solution = 1:1:2.1-2.3; S7: 2-bromoethylene amidine onium salt solid and cyclopropyl methyl amidine hydrochloride are dissolved in methanol, 30% sodium methoxide methanol solution is added dropwise at room temperature, after dropwise addition, a reaction liquid two is obtained, the reaction liquid two is heated to reflux, stirring is carried out for 5-8 hours, after cyclopropyl methyl amidine hydrochloride residual is detected to be less than 0.5%, the stirring reaction is stopped, and a reaction liquid three is obtained; S8: the reaction liquid three is concentrated and desolvated on a rotary evaporator water pump, the residue is diluted, methyl tert-butyl ether extraction is carried out three times, after the organic phase is combined, washing is carried out once, drying is carried out using a drying agent, then filtration is carried out, and concentration to dryness is carried out to obtain 5-bromo-2-cyclopropyl pyrimidine product.

[0005] Further, in step S3, after 2-bromoacetic acid is detected to be absent using a central control GC, the reaction is stopped.

[0006] Further, in step S7, after cyclopropyl methyl amidine hydrochloride residual is detected to be less than 0.5% using a central control GC, the stirring reaction is stopped.

[0007] Further, in step S5, the filter cake is washed with glacial ethanol.

[0008] Further, in step S8, the residue is diluted with ice water.

[0009] Further, in step S8, after the organic phase is combined, washing is carried out once using saturated brine.

[0010] Further, in step S8, the drying agent is sodium sulfate.

[0011] The beneficial effects of the present application are that: 1. An active formylation reagent is prepared by reacting phosphine oxychloride and DMF, which then reacts with 2-bromoacetic acid to form an imine salt. This imine salt is then prepared using fluoroboric acid to form a 2-bromoethylene ether onium salt, followed by a cyclization reaction with cyclopropylformamidinium hydrochloride in sodium methoxide and methanol to obtain the final product. This method boasts low raw material costs, high overall yield, simple operation, high safety, and meets green chemistry requirements. The obtained 5-bromo-2-cyclopropylpyrimidine exhibits high purity. Furthermore, most reaction steps in this preparation method are carried out at room temperature or under heating, eliminating the need for stringent anhydrous, ultra-low temperature, or high temperature operating conditions. The reactants and solvents are commonly used raw materials. DMF, ethanol, methanol, and methyl tert-butyl ether are commonly used organic solvents in organic chemistry laboratories; phosphine oxychloride and sodium methoxide in methanol solution are inexpensive chemical raw materials; 2-bromoacetic acid and fluoroboric acid are inexpensive; and cyclopropylformamidinium hydrochloride is a commercially available product. Post-reaction processing is relatively simple, resulting in lower production costs and less environmental pollution. The process is economically practical and operable, making it suitable for industrial production. Attached Figure Description

[0012] Figure 1 This is a synthetic route diagram of 5-bromo-2-cyclopropylpyrimidine as described in this invention.

[0013] Figure 2 The image shows the 1H NMR spectrum of 2-bromo-4-cyclopropylpyrimidine.

[0014] Figure 3 This is a liquid chromatogram.

[0015] Figure 4 This is a liquid chromatogram.

[0016] Figure 5 It is liquid chromatography. Detailed Implementation

[0017] To enable those skilled in the art to better understand the present application, the technical solutions in the embodiments of the present application will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present application, and not all embodiments. Based on the embodiments in the present application, all other embodiments obtained by those of ordinary skill in the art without creative effort should fall within the scope of protection of the present application.

[0018] This invention provides a method for synthesizing 5-bromo-2-cyclopropylpyrimidine, comprising the following steps: S1: Provides a molar ratio of phosphine oxychloride:DMF:2-bromoacetic acid:fluoroboric acid = 3:7:1-1.2:2.5-3.2; S2: Add phosphorus oxychloride dropwise to DMF under an ice-water bath. After the addition is complete, a mixture is formed. Remove the ice-water bath, heat the mixture to room temperature and stir for 0.5-1 hour to obtain the formylation reagent. S3: Add 2-bromoacetic acid to the formylation reagent obtained in step S2 under an ice-water bath. After the addition is complete, a second mixture is formed. Heat the second mixture to 60-80℃ and stir the mixture for 6-8 hours under controlled temperature. Stop the reaction when no 2-bromoacetic acid is detected, and obtain the first reaction solution. S4: Cool the reaction solution one from step S3 to 0-5℃, add ice-cold ethanol dropwise to quench the reaction, and then obtain mixture three; S5: Cool the above mixture to 0-5℃, add 50% fluoroboric acid solution dropwise, and after the addition is complete, allow it to naturally warm up to 20-25℃. Stir for 2-3 hours, then cool it again to 0-5℃ and allow it to crystallize for 8-15 hours. Filter the solution, wash the filter cake, and dry it in an oven to obtain 2-bromoethylenemididine salt solid. S6: The molar ratio of 2-bromoethyleneamidine onion salt solid: cyclopropylmethylamidine hydrochloride: sodium methoxide methanol solution = 1:1:2.1-2.3; S7: 2-bromoethyleneamidine onion salt solid and cyclopropylmethylamidine hydrochloride are dissolved in methanol, and 30% sodium methoxide methanol solution is added dropwise at room temperature. After the addition is complete, reaction solution two is obtained. Reaction solution two is heated to reflux and stirred for 5-8 hours. When the residual cyclopropylmethylamidine hydrochloride is detected to be <0.5%, stirring is stopped to obtain reaction solution three. S8: The reaction solution was concentrated and desolventized by a rotary evaporator with a water pump. The residue was diluted, extracted three times with methyl tert-butyl ether, and the organic phases were combined and washed once. After drying with a desiccant, the mixture was filtered and concentrated to dryness to obtain 5-bromo-2-cyclopropylpyrimidine product.

[0019] The reaction was stopped in step S3 after the absence of 2-bromoacetic acid was detected by central GC.

[0020] In step S7, the reaction was stopped when the residual cyclopropanediol hydrochloride was detected to be <0.5% using a central GC.

[0021] In step S5, the filter cake is washed with ice-cold ethanol.

[0022] The residue in step S8 is diluted with ice water.

[0023] In step S8, the organic phases are combined and then washed once with saturated brine.

[0024] The desiccant in step S8 is sodium sulfate.

[0025] It is worth noting that DMF is N,N-dimethylformamide, which is one of the most commonly used solvents in organic synthesis.

[0026] It is worth noting that intermediate control GC is short for intermediate control gas chromatography, which is an analytical technique commonly used in organic synthesis or chemical production to monitor the reaction process in real time. Its core purpose is to take samples for analysis at key stages of the reaction and to quickly detect changes in the content of raw materials, intermediates, products and impurities in the reaction system through gas chromatography.

[0027] Step S2 involves controlling the dropwise addition process using an ice-water bath to avoid the intense exothermic reaction between phosphorus oxychloride (POCl3) and DMF, thus preventing local overheating and side reactions. After the dropwise addition is complete, remove the ice-water bath and stir at room temperature for 0.5-1 hour to allow DMF and POCl3 to fully react and generate a formylation reagent, ensuring the reagent's activity and providing sufficient active ingredients for subsequent acylation reactions.

[0028] Step S3 involves adding the reagent in an ice-water bath to control the initial reaction temperature of 2-bromoacetic acid and the formylation reagent. This avoids excessively vigorous reactions at low temperatures or side reactions of 2-bromoacetic acid at high temperatures. Heating to 60-80°C and stirring for 6-8 hours is the optimal condition for the acylation reaction, promoting electrophilic substitution between the formylation reagent and 2-bromoacetic acid to generate a key intermediate. Central GC detection ensures no residual 2-bromoacetic acid, guaranteeing a complete reaction and preventing unreacted 2-bromoacetic acid from entering subsequent steps, thus reducing the impact of impurities (such as unacylated brominated products) on the final product.

[0029] In step S7, sodium methoxide neutralizes cyclopropylmethylamidine hydrochloride to generate free cyclopropylmethylamidine (containing an active amino group). This free cyclopropylmethylamidine acts as a nucleophile, attacking the α-carbon (or double bond) of 2-bromoethyleneamidine onium salt, initiating a cyclization reaction to generate the core skeleton of 5-bromo-2-cyclopropylpyrimidine. Reflux increases the reaction temperature, accelerates the cyclization rate, and promotes intramolecular dehydration or elimination reactions. Central-controlled GC detection ensures that the residual cyclopropylmethylamidine is <0.5%, guaranteeing almost complete reaction and preventing residual cyclopropylmethylamidine from co-crystallizing with the product or undergoing side reactions (such as hydrolysis) in subsequent steps, thus improving the purity of the final product.

[0030] Example 1: Under an ice-water bath, 66.2 g of phosphine oxychloride was added dropwise to 73.5 g of DMF, with the temperature controlled below 10°C. After the addition was complete, the ice-water bath was removed, and the mixture was heated to room temperature (20-25°C) and stirred for 0.5-1 hour to obtain the formylation reagent. 20 g of solid 2-bromoacetic acid was added in portions to the formylation reagent. After the addition was complete, the mixture was heated to 70-80°C and stirred for 6 hours. The reaction was stopped after the disappearance of 2-bromoacetic acid was detected by HPLC, yielding reaction solution one. Reaction solution one was cooled to 0-5°C, and 400 g of ice-cold ethanol was slowly added dropwise to quench the reaction, taking care to control the temperature and allow the mixture to vent. After stirring for 1 hour, 63 g of DMF was added dropwise while maintaining the temperature at 0-5°C. After adding 50% fluoroboric acid solution, allow it to naturally warm to 20-25℃, stir for 2-3 hours, then cool again to 0-5℃ and stir to crystallize for 18 hours; filter, wash the filter cake with ice-cold ethanol, and dry the solid in an oven to obtain 33g of 2-bromoethylenemidineium salt solid; weigh out 10g Cyclopropylformamidinium hydrochloride was dissolved in 25 ml of methanol, and 34 g of 30% sodium methoxide methanol solution was added dropwise at room temperature. After the addition was complete, the mixture was stirred for 1 h. Then, 24.3 g of 2-bromoethyleneamidinium salt solid was added, yielding reaction solution two. Reaction solution two was heated to 60-65℃ and stirred for 5 h. A sample was taken for HPLC analysis, and the residual cyclopropylformamidinium hydrochloride was found to be <0.5%. The reaction was stopped, yielding reaction solution three. Reaction solution three was concentrated and desolvated using a rotary evaporator under water pump. The residue was diluted with ice water, extracted three times with methyl tert-butyl ether, and the combined organic phases were washed once with saturated brine, dried over sodium sulfate, filtered, and concentrated to dryness to obtain 11.1 g of yellow solid 5-bromo-2-cyclopropylpyrimidine product. The two-step yield was 50%, and the purity was >98% according to HPLC. Figure 3 It can be known that...

[0031] Example 2: Under an ice-water bath, 60.2 g of phosphine oxychloride was added dropwise to 67 g of DMF, maintaining a temperature <10°C. After the addition was complete, the ice-water bath was removed, and the mixture was heated to room temperature (20-25°C) and stirred for 0.5-1 hour to obtain the formylation reagent. 20 g of... Solid 2-bromoacetic acid was added in portions to the formylation reagent described above. After the addition was complete, the mixture was heated to 60-70°C and stirred for 7 hours under controlled temperature. The reaction was stopped after the disappearance of 2-bromoacetic acid was detected by HPLC, yielding reaction solution one. Reaction solution one was cooled to 0-5°C, and 380g of ice-cold ethanol was slowly added dropwise to quench the reaction, while carefully controlling the temperature and venting. After stirring for 1 hour, 75g of 50% fluoroboric acid solution was added dropwise while maintaining the temperature at 0-5°C. After the addition was complete, the mixture was allowed to naturally return to 20-25°C, stirred for 2-3 hours, and then cooled again to 0-5°C and stirred for 16 hours to induce crystallization. The mixture was filtered, and the filter cake was washed with ice-cold ethanol. The solid was dried in an oven to obtain 31g of solid 2-bromoethylenemidazine salt. 10g of the solid was weighed out... Cyclopropylformamidinium hydrochloride was dissolved in 25 ml of methanol, and 34 g of 30% sodium methoxide methanol solution was added dropwise at room temperature. After the addition was complete, the mixture was stirred for 1 h. Then, 24.3 g of 2-bromoethyleneamidinium salt solid was added, yielding reaction solution two. Reaction solution two was heated to 60-65 °C and stirred for 7 h. HPLC analysis showed that the residual cyclopropylformamidinium hydrochloride was <0.5%, at which point the reaction was stopped, yielding reaction solution three. Reaction solution three was concentrated and desolvated using a rotary evaporator with a water pump. The residue was diluted with ice water, extracted three times with methyl tert-butyl ether, and the combined organic phases were washed once with saturated brine, dried over sodium sulfate, filtered, and concentrated to dryness to obtain 11.5 g of a yellow solid, 5-bromo-2-cyclopropylpyrimidine. The two-step yield was 52%, and the purity was >98% according to HPLC. Figure 4 It can be known that...

[0032] Example 3: Under an ice-water bath, 40g of phosphine oxychloride was added dropwise to 73g of DMF. After the addition was complete, the ice-water bath was removed, and the mixture was heated to room temperature (20-25℃) and stirred for 0.5-1 hour to obtain the formylation reagent. 20g of solid 2-bromoacetic acid was added in portions to the formylation reagent. After the addition was complete, the mixture was heated to 65-75℃ and stirred for 8 hours under controlled temperature. The reaction was stopped after the disappearance of 2-bromoacetic acid was detected by HPLC, yielding reaction solution one. Reaction solution one was cooled to 0-5℃, and 400g of ice-cold ethanol was slowly added dropwise to quench the reaction, while carefully controlling the temperature and venting. After stirring for 1 hour, 60g of 50% fluoroboric acid solution was added dropwise while maintaining the temperature at 0-5℃. After the addition was complete, the mixture was allowed to naturally return to 20-25℃, stirred for 2-3 hours, and then cooled again to 0-5℃ and stirred for 15 hours to crystallize. The mixture was filtered, the filter cake was washed with ice-cold ethanol, and the solid was dried in an oven to obtain 22g of solid 2-bromoethylenemidazine. 10g of the solid was weighed out... Cyclopropylformamidinium hydrochloride was dissolved in 25 ml of methanol, and 32 g of 30% sodium methoxide methanol solution was added dropwise at room temperature. After the addition was complete, the mixture was stirred for 1 h. Then, 24.3 g of 2-bromoethyleneamidinium salt solid was added, yielding reaction solution two. Reaction solution two was heated to 60-65 °C and stirred for 6 h. HPLC analysis showed that the residual cyclopropylformamidinium hydrochloride was <0.5%, at which point the reaction was stopped, yielding reaction solution three. Reaction solution three was concentrated and desolvated using a rotary evaporator under water pump. The residue was diluted with ice water, extracted three times with methyl tert-butyl ether, and the combined organic phases were washed once with saturated brine, dried over sodium sulfate, filtered, and concentrated to dryness to obtain 11.2 g of a yellow solid, 5-bromo-2-cyclopropylpyrimidine. The two-step yield was 35%, and the purity was >96% according to HPLC. Figure 5 It can be known that...

[0033] An active formylation reagent was prepared by reacting trichlorfon and DMF, and then reacted with 2-bromoacetic acid to form an imine salt. This imine salt was then prepared with fluoroboric acid to form a 2-bromoethylenemididine salt. Finally, the 2-bromoethylenemididine salt was reacted with cyclopropylformamidinium hydrochloride in sodium methoxide and methanol under heating to obtain the product. The raw material cost is low, the operation is simple, the safety is high, and the obtained 5-bromo-2-cyclopropylpyrimidine product is of high quality.

[0034] Furthermore, most of the reaction steps in this preparation method are carried out at room temperature or under heating, without the need for stringent anhydrous, ultra-low temperature, or high temperature operating conditions. The reactants and solvents are all commonly used raw materials. Among them, DMF, ethanol, methanol, and methyl tert-butyl ether are commonly used organic solvents in organic synthesis laboratories. Phosphorus oxychloride and sodium methoxide methanol solution are inexpensive chemical raw materials. 2-bromoacetic acid and fluoroboric acid have low market prices. The post-reaction processing is relatively simple, which greatly reduces the production cost. It has strong economic practicality and flexibility, and also meets the requirements of green chemistry.

[0035] The process described in this patent application has low production costs, minimal environmental pollution, simple operation, and stable process, resulting in a high-purity 5-bromo-2-cyclopropylpyrimidine product suitable for industrial production. The above description is only a preferred embodiment of this application. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of this application, and these improvements and modifications should also be considered within the scope of protection of this application.

Claims

1. A method for synthesizing 5-bromo-2-cyclopropylpyrimidine, characterized in that, Includes the following steps: S1: Provides a molar ratio of phosphine oxychloride:DMF:2-bromoacetic acid:fluoroboric acid = 3:7:1-1.2:2.5-3.2; S2: Add phosphorus oxychloride dropwise to DMF under an ice-water bath. After the addition is complete, a mixture is formed. Remove the ice-water bath, heat the mixture to room temperature and stir for 0.5-1 hour to obtain the formylation reagent. S3: Add 2-bromoacetic acid to the formylation reagent obtained in step S2 under an ice-water bath. After the addition is complete, a second mixture is formed. Heat the second mixture to 60-80℃ and stir the mixture for 6-8 hours under controlled temperature. Stop the reaction when no 2-bromoacetic acid is detected, and obtain the first reaction solution. S4: Cool the reaction solution one from step S3 to 0-5℃, add ice-cold ethanol dropwise to quench the reaction, and then obtain mixture three; S5: Cool the above mixture to 0-5℃, add 50% fluoroboric acid solution dropwise, and after the addition is complete, allow it to naturally warm up to 20-25℃. Stir for 2-3 hours, then cool it again to 0-5℃ and allow it to crystallize for 8-15 hours. Filter the solution, wash the filter cake, and dry it in an oven to obtain 2-bromoethylenemididine salt solid. S6: The molar ratio of 2-bromoethyleneamidine onion salt solid: cyclopropylmethylamidine hydrochloride: sodium methoxide methanol solution = 1:1:2.1-2.3; S7: 2-bromoethyleneamidine onion salt solid and cyclopropylmethylamidine hydrochloride are dissolved in methanol, and 30% sodium methoxide methanol solution is added dropwise at room temperature. After the addition is complete, reaction solution two is obtained. Reaction solution two is heated to reflux and stirred for 5-8 hours. When the residual cyclopropylmethylamidine hydrochloride is detected to be <0.5%, stirring is stopped to obtain reaction solution three. S8: The reaction solution was concentrated and desolventized by a rotary evaporator with a water pump. The residue was diluted, extracted three times with methyl tert-butyl ether, and the organic phases were combined and washed once. After drying with a desiccant, the mixture was filtered and concentrated to dryness to obtain 5-bromo-2-cyclopropylpyrimidine product.

2. The method for synthesizing 5-bromo-2-cyclopropylpyrimidine according to claim 1, characterized in that, The reaction was stopped in step S3 after the absence of 2-bromoacetic acid was detected by central HPLC.

3. The method for synthesizing 5-bromo-2-cyclopropylpyrimidine according to claim 1, characterized in that, In step S7, the reaction was stopped after the residual cyclopropylformin hydrochloride was detected by HPLC and found to be <0.5%.

4. The method for synthesizing 5-bromo-2-cyclopropylpyrimidine according to claim 1, characterized in that, In step S5, the filter cake is washed with ice-cold ethanol.

5. The method for synthesizing 5-bromo-2-cyclopropylpyrimidine according to claim 1, characterized in that, The residue in step S8 is diluted with ice water.

6. The method for synthesizing 5-bromo-2-cyclopropylpyrimidine according to claim 1, characterized in that, In step S8, the organic phases are combined and then washed once with saturated brine.

7. The method for synthesizing 5-bromo-2-cyclopropylpyrimidine according to claim 1, characterized in that, The desiccant in step S8 is sodium sulfate.

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