A preparation method of tipiracil intermediate

Abstract

The present invention belongs to the technical field of drug synthesis. The present invention provides a method for preparing a tipiracil intermediate, wherein a compound 2, a catalyst, water, a hydrogen acceptor, and a reaction solvent are added into a sealed device for reaction to obtain a tipiracil intermediate. The preparation process of the present invention is simple to operate compared with the prior art, and the obtained target product has a high purity and yield, and is suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and particularly relates to a method for preparing a tipiracil intermediate. Background Art

[0002] Colorectal cancer (CRC), including colon cancer and rectal cancer, is one of the most common malignant tumors. Its incidence and mortality rate are third among digestive tract malignancies, second only to gastric cancer and esophageal cancer. China is a low-incidence region globally, but in recent years, the incidence of colorectal cancer in my country has shown a clear upward trend and has become one of the fastest-growing malignant tumors in my country.

[0003] Due to the lack of obvious early symptoms of colorectal cancer and the lack of early screening measures, most patients have already developed to the middle and late stages when they seek medical treatment. For the treatment of middle and late stage colorectal cancer, the preferred option is internal medicine treatment mainly based on chemotherapy. Among them, the new drug Lonsurf [trifluridine (FTD) / tipiracil hydrochloride (TPI), TAS-102] developed by Taiho Pharmaceutical Co., Ltd., a Japanese pharmaceutical company, which was approved for marketing by the Ministry of Health, Labor and Welfare of Japan on March 24, 2014, has attracted widespread attention in the industry. In clinical practice, FTD and TPI are combined with a molar ratio of 2:1 for the treatment of unresectable or recurrent metastatic colorectal cancer that is ineffective with standard chemotherapy, bringing good news to patients with advanced colorectal cancer who have tolerated or have not responded to standard treatment. Among them, FTD inhibits tumor cell growth by embedding into tumor cell DNA, and TPI inhibits FTD phosphorylation and maintains the effective blood concentration of FTD, thereby achieving the treatment purpose. The chemical structure is shown below:

[0004]

[0005] Tipiracil hydrochloride, its CAS number is 183204-72-0, and its chemical name is 5-chloro-6-[(2-iminopyrrolidin-1-yl)methyl]pyrimidine-2,4(1H,3H)-dione monohydrochloride.

[0006] At present, patents WO9630346, EP0763529, US5744475, CN104945384, CN103980253A, CN106317028A, and CN107298656A disclose methods for synthesizing tipiracil hydrochloride. Although the starting materials are different, they all use various synthetic strategies to prepare the key intermediate 5-chloro-6-(chloromethyl)pyrimidine-2,4(1H,3H)dione (1), which is then reacted with 2-iminopyrrolidine hydrochloride to form a salt to obtain the target product.

[0007]

[0008] However, since 2-iminopyrrolidine hydrochloride is used as a reactant in the above process, impurities are easily generated, resulting in a large amount of impurities in the reaction liquid of the above process, making it difficult to obtain a target product with high purity through a single purification, which results in a low yield of about 35% when the target product is finally prepared.

[0009] In order to improve the yield, other synthetic strategies for preparing thiopyrimidine have been disclosed in recent years:

[0010] Patent CN106366073A uses compound 1 as the starting material, first reacts with tetrahydropyrrole-2-thione to obtain 5-chloro-6-(2-thionetrahydropyrrolyl)methyluracil (1'), and then reacts with ammonia to form a salt to obtain the target product. The reaction route is as follows:

[0011]

[0012] Patent CN106749194A uses 6-(chloromethyl)-2,4-(1H,3H)-pyrimidinedione as the starting material, first undergoes a chlorination reaction to obtain intermediate 1, then undergoes a substitution reaction with α-pyrrolidone in the presence of a strong base (n-butyl lithium) to obtain I, and finally undergoes an aminolysis reaction to obtain tipiracil. The reaction route is as follows:

[0013]

[0014] From the above analysis, it can be seen that compound I, as a key intermediate for the synthesis of tipiramidine, has achieved good results in terms of yield and purity when synthesizing tipiramidine. However, the currently reported preparation method of I requires the use of n-butyl lithium for the reaction, and its reaction conditions are harsh and has strict requirements on water, making the operation more demanding and difficult to scale up for industrial production.

[0015] Therefore, it is still a problem that needs to be solved to study and find a preparation method for the key intermediate compound I of tipiracil with simple operation process, high product yield and high purity, which is suitable for industrial production. Summary of the invention

[0016] In view of the problems existing in the current preparation technology of the key intermediate compound I of tipiramid, the present invention provides a new preparation method. The method has a simple operation process and the obtained target product has a high purity and yield.

[0017] The specific technical solutions of the present invention are as follows:

[0018]

[0019] A method for preparing a key intermediate compound I of tipiracil, comprising the following steps:

[0020] Under the protection of inert gas, compound 2, catalyst, water, hydrogen acceptor and reaction solvent are added to a sealed device, and the temperature is controlled until the reaction is completed. After the reaction liquid is cooled to room temperature, the reaction liquid is added to purified water, extracted with an organic solvent, washed with purified water, dried with anhydrous sodium sulfate, filtered, and the filtrate is concentrated to dryness under reduced pressure, washed with purified water for pulping, filtered, and the obtained solid is rinsed with acetone and dried to obtain the target product I.

[0021] In a preferred embodiment, the catalyst is RuH2(PPh3)4, Ru3(CO) 12 , RuCl2(PPh3)3, CpRuCl(PPh3)2 or a combination thereof, among which RuH2(PPh3)4 is particularly preferred.

[0022] In a preferred embodiment, the hydrogen acceptor is one or a combination of (E)-4-phenyl-3-butene-2-one, (E)-2-butenal, (E)-3-pentene-2-one, 3-methyl-2-cyclohexene-1-one, among which (E)-4-phenyl-3-butene-2-one is particularly preferred.

[0023]

[0024] In a preferred embodiment, the reaction solvent is one of tetrahydrofuran, ethylene glycol dimethyl ether, 1,4-dioxane or a combination thereof, among which ethylene glycol dimethyl ether is particularly preferred.

[0025] In a preferred embodiment, the molar ratio of the compound 2 to the catalyst, water and hydrogen acceptor is 1:3%-8%:1.6-3.5:1.6-3.5, with 1:5%:2.1:2.1 being particularly preferred.

[0026] Preferably, for the temperature-controlled reaction, the sealing device can be placed in a heating device with a temperature of 80 to 130°C; the heating device can be selected from heating devices such as oil bath heating, electric heating jacket, steam heating, electric furnace, etc.; the sealing device can be selected from sealed glass tubes, stainless steel reactors with good sealing performance, sealed Schlenk devices, etc.; the present invention preferably uses a Schlenk device for verification.

[0027] In a preferred embodiment, the organic solvent used for the extraction is one of dichloromethane, chloroform, ethyl acetate or a combination thereof.

[0028] Wherein, the compound 2 can be prepared by other prior art methods or the following method:

[0029]

[0030] 5-Chloro-6-(chloromethyl)pyrimidine-2,4(1H,3H)dione (1), 4-aminobutan-1-ol (SM-2) and an acid-binding agent are added to a reaction solvent, the temperature is controlled until the reaction is completed, the reaction is filtered, the filtrate is added to purified water, extracted with an organic solvent, washed with a dilute hydrochloric acid aqueous solution, washed with purified water, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated to dryness under reduced pressure to obtain compound 2.

[0031] In a preferred embodiment, the acid binding agent is an organic base or an inorganic base, wherein the organic base includes but is not limited to one or a combination of triethylamine (TEA), N,N-diisopropylethylamine (DIPEA), and pyridine (Py); the inorganic base includes but is not limited to one or a combination of potassium carbonate and sodium carbonate, wherein potassium carbonate is particularly preferred.

[0032] In a preferred embodiment, the reaction solvent is one of acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide or a combination thereof, wherein N,N-dimethylformamide is particularly preferred.

[0033] In a preferred embodiment, the molar ratio of the compound 1 to SM-2 and the acid binding agent is 1:1.1-1.6:1.8-3.0, with 1:1.3:2.4 being particularly preferred.

[0034] In a preferred embodiment, the reaction temperature is 80-110°C, with 95-100°C being particularly preferred.

[0035] In a preferred embodiment, the organic solvent used for the extraction is one of dichloromethane, chloroform, ethyl acetate or a combination thereof.

[0036] In the present invention, the inert gas is usually nitrogen or argon, with argon being particularly preferred; and the solvents are all degassed.

[0037] The beneficial effects of the present invention are:

[0038] The invention provides a novel method for synthesizing a key intermediate compound I of tipiramidone. The process is simple to operate, and the obtained target product has high purity and yield, and is suitable for industrial production. DETAILED DESCRIPTION

[0039] The present invention is further illustrated by the following examples. It should be correctly understood that the examples of the present invention are only used to illustrate the present invention, rather than to limit the present invention. Therefore, simple improvements to the present invention based on the method of the present invention all fall within the scope of protection claimed by the present invention.

[0040] The present invention adopts HPLC to determine the purity of the key intermediate compound I of tipiracil, and the chromatographic conditions are as follows:

[0041] Chromatographic column: YMC Triart-C 18 (4.6mm×250mm,5.0μm);

[0042] Mobile phase A: phosphate buffer (0.05 mol / L sodium dihydrogen phosphate, pH adjusted to 6.0 with aqueous ammonia);

[0043] Mobile phase B: acetonitrile;

[0044] Gradient elution:

[0045]

[0046] Column temperature: 30°C;

[0047] Detection wavelength: 275nm;

[0048] Flow rate: 1.0 mL / min;

[0049] Injection volume: 10 μL.

[0050] The retention time of the obtained target product is about 13.6min.

[0051] In the following embodiments, various processes and methods not described in detail are conventional methods known in the art.

[0052] Preparation of compound 2:

[0053] Example 1

[0054] At room temperature, 5-chloro-6-(chloromethyl)pyrimidine-2,4(1H,3H)dione (1, 9.75 g, 0.05 mol), 4-aminobutan-1-ol (SM-2, 5.79 g, 65.0 mmol), and potassium carbonate (16.59 g, 0.12 mol) were added to N,N-dimethylformamide (80 mL), and the reaction was controlled at 95-100 °C. After the reaction was completed, the reaction solution was filtered while hot, and the filtrate was added with purified water (300 mL), extracted with dichloromethane (100 mL×3), washed with hydrochloric acid (1 mol / L, 50 mL×2), and the organic phase was washed with purified water (50 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain compound 2, with a yield of 95.4%, HPLC: 99.5%.

[0055] Example 2

[0056] At room temperature, 5-chloro-6-(chloromethyl)pyrimidine-2,4(1H,3H)dione (1, 9.75 g, 0.05 mol), 4-aminobutan-1-ol (SM-2, 4.90 g, 55.0 mmol), and N,N-diisopropylethylamine (15.51 g, 0.12 mol) were added to N,N-dimethylformamide (80 mL), and the temperature was controlled at 95-100 °C. After the reaction was completed, the reaction solution was filtered while hot, and the filtrate was added with purified water (300 mL), extracted with dichloromethane (100 mL×3), washed with hydrochloric acid (1 mol / L, 50 mL×2), washed with purified water (50 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain compound 2 with a yield of 94.3%, HPLC: 99.6%.

[0057] Example 3

[0058] At room temperature, 5-chloro-6-(chloromethyl)pyrimidine-2,4(1H,3H)dione (1, 9.75 g, 0.05 mol), 4-aminobutan-1-ol (SM-2, 4.68 g, 52.5 mmol), and pyridine (9.48 g, 0.12 mol) were added to N,N-dimethylformamide (80 mL), and the temperature was controlled at 110°C for reaction. After the reaction was completed, the reaction solution was filtered while hot, and the filtrate was added with purified water (300 mL), extracted with dichloromethane (100 mL×3), washed with hydrochloric acid (1 mol / L, 50 mL×2), washed with purified water (50 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain compound 2, with a yield of 93.8%, HPLC: 98.9%.

[0059] Example 4

[0060] At room temperature, 5-chloro-6-(chloromethyl)pyrimidine-2,4(1H,3H)dione (1, 9.75 g, 0.05 mol), 4-aminobutan-1-ol (SM-2, 7.13 g, 80.0 mmol), and triethylamine (12.14 g, 0.12 mol) were added to N,N-dimethylformamide (80 mL), and the reaction was controlled at 95-100 °C. After the reaction was completed, the reaction solution was filtered while hot, and the filtrate was added with purified water (300 mL), extracted with dichloromethane (100 mL×3), washed with hydrochloric acid (1 mol / L, 50 mL×2), washed with purified water (50 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain compound 2 with a yield of 95.2%, HPLC: 99.4%.

[0061] Example 5

[0062] At room temperature, 5-chloro-6-(chloromethyl)pyrimidine-2,4(1H,3H)dione (1, 9.75 g, 0.05 mol), 4-aminobutan-1-ol (SM-2, 7.58 g, 85.0 mmol), and sodium carbonate (12.72 g, 0.12 mol) were added to N,N-dimethylformamide (80 mL), and the reaction was controlled at 95-100 °C. After the reaction was completed, the reaction solution was filtered while hot, and the filtrate was added with purified water (300 mL), extracted with dichloromethane (100 mL×3), washed with hydrochloric acid (1 mol / L, 50 mL×2), washed with purified water (50 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain compound 2 with a yield of 94.4%, HPLC: 99.6%.

[0063] Example 6

[0064] At room temperature, 5-chloro-6-(chloromethyl)pyrimidine-2,4(1H,3H)dione (1, 9.75 g, 0.05 mol), 4-aminobutan-1-ol (SM-2, 5.79 g, 65.0 mmol) and potassium carbonate (12.44 g, 0.09 mol) were added to N,N-dimethylformamide (80 mL). The reaction was controlled at 95-100 °C. After the reaction was completed, the reaction solution was filtered while hot, and the filtrate was added with purified water (300 mL), extracted with ethyl acetate (100 mL×3), washed with hydrochloric acid (1 mol / L, 50 mL×2), washed with purified water (50 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain compound 2 with a yield of 93.4%, HPLC: 99.3%.

[0065] Example 7

[0066] At room temperature, 5-chloro-6-(chloromethyl)pyrimidine-2,4(1H,3H)dione (1, 9.75 g, 0.05 mol), 4-aminobutan-1-ol (SM-2, 5.79 g, 65.0 mmol) and potassium carbonate (20.73 g, 0.15 mol) were added to acetonitrile (80 mL), and the reaction was carried out under temperature-controlled reflux (80°C). After the reaction was completed, the reaction solution was filtered while hot, and the filtrate was added with purified water (300 mL), extracted with dichloromethane (100 mL×3), washed with hydrochloric acid (1 mol / L, 50 mL×2), washed with purified water (50 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain compound 2 with a yield of 94.1%, HPLC: 99.5%.

[0067] Preparation of Compound I:

[0068] Example 8

[0069] Under argon protection, compound 2 (9.91 g, 0.04 mol), RuH2(PPh3)4 (2.30 g, 2.0 mmol), water (1.44 g, 0.08 mol), (E)-4-phenyl-3-butene-2-one (11.70 g, 0.08 mol) and ethylene glycol dimethyl ether (100 mL) were added to a Schlenk apparatus, sealed and placed in an oil bath with a temperature control of 110-115°C for reaction. After the reaction was completed, the reaction solution was cooled to room temperature, added to purified water (400 mL), extracted with dichloromethane (150 mL×3), the extracts were combined, washed with purified water (100 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure, added with purified water (50 mL) for pulping and washing, filtered, and the solid was rinsed with acetone and dried to obtain the target product I with a yield of 96.3%, HPLC: 99.91%.

[0070] Example 9

[0071] Under argon protection, compound 2 (9.91 g, 0.04 mol), RuH2(PPh3)4 (1.38 g, 1.2 mmol), water (1.44 g, 0.08 mol), (E)-2-butenal (5.61 g, 0.08 mol) and ethylene glycol dimethyl ether (100 mL) were added to a Schlenk apparatus, sealed and placed in an oil bath with a temperature control of 115-120°C for reaction. After the reaction was completed, the reaction solution was cooled to room temperature, added to purified water (400 mL), extracted with dichloromethane (150 mL×3), the extracts were combined, washed with purified water (100 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure, added with purified water (50 mL) for pulping and washing, filtered, and the solid was rinsed with acetone and dried to obtain the target product I with a yield of 95.8%, HPLC: 99.89%.

[0072] Example 10

[0073] Under argon protection, compound 2 (9.91 g, 0.04 mol), RuH2(PPh3)4 (1.15 g, 1.0 mmol), water (1.44 g, 0.08 mol), (E)-3-penten-2-one (6.73 g, 0.08 mol) and ethylene glycol dimethyl ether (100 mL) were added to a Schlenk apparatus, sealed and placed in an oil bath with a temperature control of 120-125°C for reaction. After the reaction was completed, the reaction solution was cooled to room temperature, added to purified water (400 mL), extracted with dichloromethane (150 mL×3), the extracts were combined, washed with purified water (100 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure, added with purified water (50 mL) for pulping and washing, filtered, and the solid was rinsed with acetone and dried to obtain the target product I with a yield of 94.7%, HPLC: 99.88%.

[0074] Embodiment 11

[0075] Under argon protection, compound 2 (9.91 g, 0.04 mol), RuH2(PPh3)4 (3.69 g, 3.2 mmol), water (1.44 g, 0.08 mol), 3-methyl-2-cyclohexene-1-one (8.81 g, 0.08 mol) and ethylene glycol dimethyl ether (100 mL) were added to a Schlenk apparatus, sealed and placed in an oil bath with a temperature control of 90-95°C for reaction. After the reaction was completed, the reaction solution was cooled to room temperature, added to purified water (400 mL), extracted with dichloromethane (150 mL×3), the extracts were combined, washed with purified water (100 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure, added with purified water (50 mL) for pulping and washing, filtered, and the solid was rinsed with acetone and dried to obtain the target product I with a yield of 95.7%, HPLC: 99.87%.

[0076] Example 12

[0077] Under nitrogen protection, compound 2 (9.91 g, 0.04 mol), RuH2(PPh3)4 (4.14 g, 3.6 mmol), water (1.44 g, 0.08 mol), (E)-4-phenyl-3-butene-2-one (11.70 g, 0.08 mol) and 1,4-dioxane (100 mL) were added to a Schlenk apparatus, sealed and placed in an oil bath with a temperature control of 80-85 ° C for reaction. After the reaction was completed, the reaction solution was cooled to room temperature, added to purified water (400 mL), extracted with ethyl acetate (150 mL×3), the extracts were combined, washed with purified water (100 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure, added with purified water (50 mL) for pulping and washing, filtered, and the solid was rinsed with acetone and dried to obtain the target product I with a yield of 94.3%, HPLC: 99.86%.

[0078] Embodiment 13

[0079] Under argon protection, compound 2 (9.91 g, 0.04 mol), Ru3(CO) 12(1.28 g, 2.0 mmol), water (1.15 g, 0.064 mol), (E)-4-phenyl-3-butene-2-one (9.36 g, 0.064 mol), and ethylene glycol dimethyl ether (100 mL) were added to a Schlenk apparatus, sealed and placed in an oil bath with a temperature control of 115-120° C. for reaction. After the reaction was completed, the reaction solution was cooled to room temperature, added to purified water (400 mL), extracted with dichloromethane (150 mL×3), the extracts were combined, washed with purified water (100 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure, added with purified water (50 mL) for pulping and washing, filtered, and the solid was rinsed with acetone and dried to obtain the target product I with a yield of 95.4%, HPLC: 99.79%.

[0080] Embodiment 14

[0081] Under argon protection, compound 2 (9.91 g, 0.04 mol), RuCl2(PPh3)3 (1.92 g, 2.0 mmol), water (1.08 g, 0.06 mol), (E)-4-phenyl-3-butene-2-one (8.77 g, 0.06 mol) and ethylene glycol dimethyl ether (100 mL) were added to a Schlenk apparatus, sealed and placed in an oil bath with a temperature control of 120-125°C for reaction. After the reaction was completed, the reaction solution was cooled to room temperature, added to purified water (400 mL), extracted with dichloromethane (150 mL×3), the extracts were combined, washed with purified water (100 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure, added with purified water (50 mL) for pulping and washing, filtered, and the solid was rinsed with acetone and dried to obtain the target product I with a yield of 93.6%, HPLC: 99.83%.

[0082] Embodiment 15

[0083] Under argon protection, compound 2 (9.91 g, 0.04 mol), CpRuCl(PPh3)2 (1.58 g, 2.0 mmol), water (2.52 g, 0.14 mol), (E)-4-phenyl-3-butene-2-one (20.47 g, 0.14 mol) and ethylene glycol dimethyl ether (100 mL) were added to a Schlenk apparatus, sealed and placed in an oil bath with a temperature control of 105-110°C for reaction. After the reaction was completed, the reaction solution was cooled to room temperature, added to purified water (400 mL), extracted with dichloromethane (150 mL×3), the extracts were combined, washed with purified water (100 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure, added with purified water (50 mL) for pulping and washing, filtered, and the solid was rinsed with acetone and dried to obtain the target product I with a yield of 95.6%, HPLC: 99.76%.

[0084] Example 16

[0085] Under nitrogen protection, compound 2 (9.91 g, 0.04 mol), RuH2(PPh3)4 (2.30 g, 2.0 mmol), water (2.59 g, 0.144 mol), (E)-4-phenyl-3-butene-2-one (21.05 g, 0.144 mol) and tetrahydrofuran (100 mL) were added to a Schlenk apparatus, sealed and placed in an oil bath controlled at 100-105°C for reaction. After the reaction was completed, the reaction solution was cooled to room temperature, added to purified water (400 mL), extracted with chloroform (150 mL×3), the extracts were combined, washed with purified water (100 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure, added with purified water (50 mL) for pulping and washing, filtered, and the solid was rinsed with acetone and dried to obtain the target product I with a yield of 95.1%, HPLC: 99.84%.

Claims

1. A method for preparing a tipiramidin intermediate, characterized in that: Compound 2 was used as a raw material to catalyze the synthesis of tipiramidyl intermediate compound I; the route is as follows: ； Specifically, the following steps are included: under the protection of inert gas, compound 2, catalyst, water, hydrogen acceptor and reaction solvent are added into a sealed device, the temperature is controlled until the reaction is completed, the reaction solution is cooled to room temperature, the reaction solution is added into purified water, organic solvent extraction is performed, purified water is washed, dried over anhydrous sodium sulfate, filtered, the filtrate is concentrated to dryness under reduced pressure, purified water is added for pulping and washing, filtered, the obtained solid is rinsed with acetone, and dried to obtain the target product I; The catalyst is RuH2(PPh3)4, Ru3(CO) 12 , RuCl2(PPh3)3, CpRuCl(PPh3)2 or a combination thereof; The hydrogen acceptor is ( E )-4-phenyl-3-butene-2-one, ( E )-2-butenal, ( E )-3-penten-2-one, 3-methyl-2-cyclohexen-1-one or a combination thereof; The temperature-controlled reaction may be performed by placing the sealing device in a heating device at a temperature of 80 to 130°C.

2. The preparation method according to claim 1, characterized in that The reaction solvent is one of tetrahydrofuran, ethylene glycol dimethyl ether, 1,4-dioxane or a combination thereof.

3. The preparation method according to claim 1, characterized in that: The molar ratio of the compound 2 to the catalyst, water and hydrogen acceptor is 1:3% to 8%: 1.6～3.5：1.6～3.5。 4. The preparation method according to claim 1, characterized in that: The organic solvent used for the extraction is one of dichloromethane, chloroform and ethyl acetate or a combination thereof.

5. The preparation method according to claim 1, characterized in that: The compound 2 can be prepared by the following method: ； 5-Chloro-6-(chloromethyl)pyrimidine-2,4(1 H ,3 H )dione (1), 4-aminobutan-1-ol (SM-2), and an acid-binding agent are added to a reaction solvent, the temperature is controlled until the reaction is complete, the reaction is filtered, the filtrate is added to purified water, extracted with an organic solvent, washed with a dilute hydrochloric acid solution, washed with purified water, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated to dryness under reduced pressure to obtain compound 2; The acid binding agent is an organic base or an inorganic base, and the organic base is triethylamine, N , N - one or a combination of diisopropylethylamine and pyridine; the inorganic base is one or a combination of potassium carbonate and sodium carbonate; The reaction temperature is 80-110°C.

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