Preparation method of pyrazolo [1, 5-c]-dihydropyrimidinone

Abstract

The invention relates to a preparation method of pyrazolo [1, 5-c]-dihydropyrimidone, which comprises the following steps: taking a diazo derivative of N-substituted pyrrolidone and alkyne as raw materials, and carrying out [3 + 2] cycloaddition reaction and rearrangement reaction in an organic solvent to obtain a pyrazolo [1, 5-c]-dihydropyrimidone compound. The method has the advantages of high reaction atom economy, easily available raw materials, simple synthesis process, wide substrate application and convenience in industrialization, and can make up the efficiency of the existing multi-step synthesis technology. The invention provides a convenient synthetic method for preparation of pyrazolo [1, 5-c]-dihydropyrimidone and derivatives thereof.

Description

Technical Field

[0001] This invention belongs to the field of organic chemical synthesis technology, and particularly relates to a method for preparing pyrazolo[1,5-c]-dihydropyrimidinone. Background Technology

[0002] Pyrazole-dihydropyrimidinone compounds are widely found in many biologically active natural products and drug prodrugs. Bioorg.Chem 2019, 89 , 103022; Eur.J.Med.Chem. 2021, 225 , 113781). Among them, pyrazolo[1,5-c]dihydropyrimidinone and its derivatives are an important class of compounds, and are structural fragments of many biologically active compounds and drug progeny, such as I, which is a Glycine / NMDA ( N -Methyl- D -aspartic acid) receptor ( Bioorg.Med.Chem. 2005, 13 , 5536.); II can be used to treat cardiovascular and cerebrovascular diseases (CN118063457A); III can be used to treat Alzheimer's disease ( ACS Chem. Neurosci. 2017, 8 , 2522.) The synthesis of this type of compound has long been a focus of attention for chemists and pharmacologists. Due to the complexity of its skeleton, especially its fused ring structure, it is difficult to extract it in large quantities from petroleum feedstocks or natural products. Therefore, finding a simple, rapid, and highly atom-economical method for the synthesis of pyrazolo[1,5-c]dihydropyrimidinones holds great promise for future applications.

[0003] Currently, existing reports on the synthesis of this type of compound mainly involve a multi-step synthetic method, obtaining one of the heterocycles in the pyrazolo[1,5-c]dihydropyrimidinone structure, and then further modifying it to achieve cyclic fusion. For example... Synthesis 2015, 47 The synthetic method shown in 497 starts with commercially available methyl acrylate as a raw material, and obtains a pyrazolium ring through five steps of modification, followed by deprotection and cyclization reactions to obtain a pyrazolo[1,5-c]dihydropyrimidinone structure. However, patent CN118063457A provides a method for synthesizing pyrazolo[1,5-c]dihydropyrimidinone through multiple steps, followed by oxidation. These multi-step synthetic methods use various organic reagents, are cumbersome, do not meet the requirements of modern green chemistry, and have slowed down industrialization.

[0004] Clearly, if the synthesis steps can be shortened to improve the economic efficiency of the steps, and further 100% atom economy can be achieved in the key steps, the difficulties of existing synthesis methods can be effectively overcome and the shortcomings of the synthesis process can be made up. Summary of the Invention

[0005] The purpose of this invention is to address the shortcomings of existing technologies by providing an efficient method for preparing pyrazolo[1,5-c]dihydropyrimidinone.

[0006] To achieve the above objectives, the present invention adopts the following technical solution: A method for preparing a pyrazolo[1,5-c]dihydropyrimidinone includes the following steps: Under the protection of inert gas, N A diazo derivative (I) of a substituted pyrrolidone and an alkyne (II) are mixed in an organic solvent and rearranged at 0 °C to 120 °C to give pyrazolo[1,5-c]dihydropyrimidinone (III). The reaction route is as follows: In the formula, R1 is selected from one of the following groups: substituted or unsubstituted phenyl, thiophene, thiazole; the substituent of the phenyl group is selected from: halogen, methoxy, benzyloxy, sulfonic acid group, ester group; R2 is selected from trimethylsilyl or tert-butyl.

[0007] Furthermore, the aforementioned N The molar ratio of the diazo derivative (I) of the substituted pyrrolidone to the alkyne (II) is 1:10 to 1:80.

[0008] Further, the organic solvent is one or two of N,N-dimethylformamide, N-methylpyrrolidone, toluene, xylene, mesitylene, 1,4-dioxane, acetonitrile, dichloromethane, 1,2-dichloroethane, diethyl ether, ethylene glycol dimethyl ether, methyl tert-butyl ether, tetrahydrofuran, N,N-dimethylacetamide, dimethyl sulfoxide, and n-butanol.

[0009] Furthermore, the inert gas is nitrogen.

[0010] Compared with the prior art, the present invention has the following advantages: 1. This invention does not require a metal catalyst, but only uses... N Using diazo derivatives of substituted pyrrolidone and inexpensive alkynes as raw materials, pyrazolo[1,5-c]dihydropyrimidinone compounds can be efficiently prepared in a single step via [3+2] cycloaddition and further rearrangement. The resulting compounds can play a role in medicinal chemistry.

[0011] 2. The reaction conditions of this invention are mild, the process is simple, the substrate applicability is wide, and the reaction mixture can be separated by simple column chromatography to obtain high-purity products in high yield; at the same time, the reaction can be scaled up to gram level, making it easy to industrialize.

[0012] 3. The reaction of this invention does not require catalysts or other additives, resulting in minimal environmental pollution; the reaction process is clean, achieving 100% atom economy, meeting the requirements of green chemistry, and has significant practical implications and broad application prospects. Attached Figure Description

[0013] The specific embodiments of the present invention will be described in further detail below with reference to the accompanying drawings.

[0014] Figure 1 The product 3a obtained in the embodiments of the present invention 1 H NMR spectrum.

[0015] Figure 2 The product 3a obtained in the embodiments of the present invention 13 C NMR spectrum.

[0016] Figure 3 Product 3b obtained in the embodiments of the present invention 1 H NMR spectrum.

[0017] Figure 4 Product 3b obtained in the embodiments of the present invention 13 C NMR spectrum.

[0018] Figure 5 The product 3c obtained in the embodiments of the present invention 1 H NMR spectrum.

[0019] Figure 6 The product 3c obtained in the embodiments of the present invention 13 C NMR spectrum.

[0020] Figure 7 This is the X-ray single crystal structure of product 3a obtained in the embodiment of the present invention. Detailed Implementation

[0021] The present invention will be further described below with reference to the embodiments.

[0022] As previously stated, this invention provides a method for preparing pyrazolo[1,5-c]-dihydropyrimidinone, wherein the method refers to preparing the pyrazolo[1,5-c]-dihydropyrimidinone under a nitrogen atmosphere. N Using diazo derivatives (I) of substituted pyrrolidone and alkynes (II) as starting materials, a [3+2] cycloaddition reaction is carried out in an organic solvent to yield the product of the general formula: pyrazolo[1,5-c]dihydropyrimidinone(III); The reaction formula is as follows: In the formula, R1 is selected from one of the following groups: substituted or unsubstituted phenyl, thiophene, thiazole; in the substituted or unsubstituted phenyl, the substituent is selected from: halogen, methoxy, benzyloxy, sulfonic acid group, ester group; R2 is selected from one of the following groups: alkyl, aryl, alkoxy, silyl, ester, and can be selected according to actual needs. They follow the same reaction mechanism, and it can be inferred that all substituents within the scope of the present invention can react.

[0023] The N The molar ratio of the diazo derivative of the substituted pyrrolidone to the alkyne is 1:10 to 1:80.

[0024] Organic solvent is N,N -Dimethylformamide, N 1,4-Dioxane, Toluene, Xylene, Trimethylbenzene, Acetonitrile, Dichloromethane, 1,2-Dichloroethane, Diethyl ether, Ethylene glycol dimethyl ether, Methyl tert-butyl ether, Tetrahydrofuran N, N - One or two of dimethylacetamide, dimethyl sulfoxide, and n-butanol.

[0025] In some embodiments, the synthetic method may further include: after the [3+2] cycloaddition reaction, post-processing the obtained reaction mixture to separate compound (III), said post-processing including sequential extraction, washing, drying, and column chromatography. These post-processing methods are known in the art. For example, the extraction reagent may be ethyl acetate, diethyl ether, dichloromethane, etc.; the washing reagent may be saturated brine, saturated ammonium chloride solution, saturated sodium bicarbonate solution, etc.; the drying reagent may be anhydrous sodium sulfate, anhydrous magnesium sulfate, etc.; the eluent for column chromatography separation may be ethyl acetate or a mixture of dichloromethane and petroleum ether (the volume ratio may be 1:100 to 1:1), etc.

[0026] In this embodiment of the invention, R2 uses trimethylsilyl and tert-butyl as examples to prepare more than ten kinds of pyrazolo[1,5-c]dihydropyrimidinone (III) by the above method. The product structural formulas and English names corresponding to those in the embodiments are shown in Table 1: Table 1 Example 1: Preparation of pyrazolo[1,5-c]dihydropyrimidinone derivative 3a Its synthetic route is as follows: Will NA diazo derivative 1a (0.2 mmol) of a substituted pyrrolidone was added to 2.0 mL of tetrahydrofuran solution. After purging with nitrogen three times in a Young's tube, 2.0 mL of trimethylsilyne 2a was added. The reaction was allowed to proceed at room temperature for 24 hours, after which the reaction was stopped. The product was then separated by column chromatography using ethyl acetate / petroleum ether (1:20–1:1) as the eluent to obtain pure pyrazolo[1,5-c]dihydropyrimidinone derivative 3a. The product was a pale yellow solid in 89% yield.

[0027] like Figure 1 As shown, 1 H NMR (400 MHz, CDCl3) δ 7.33–7.44 (m, 4H), 7.20 (t, J = 7.0Hz,1H), 6.21 (s, 1H), 3.88 (t, J = 6.5 Hz, 2H), 3.11 (t, J = 6.4 Hz, 2H), 0.33 (s, 9H). like Figure 2 As shown, 13 C NMR (101 MHz, CDCl3) δ 158.4, 148.3, 141.9, 140.1,129.3, 126.9, 125.5, 110.8, 48.7, 22.3, 1.1. HRMS (ESI) (m / z): calculated for C 15 H 20 N3OSi [M+H] + : 286.1370; found:286.1370. like Figure 7 As shown, this is the X-ray single crystal structure of 3a.

[0028] Example 2: Preparation of pyrazolo[1,5-c]dihydropyrimidinone derivative 3a Will N A diazo derivative 1a (1.8 mmol) of a substituted pyrrolidone was added to 18.0 mL of tetrahydrofuran solution. After purging with nitrogen three times in a Young's tube, 16.0 mL of trimethylsilyne 2a was added. The reaction was allowed to proceed at room temperature for 24 hours, after which the reaction was stopped. The product was then separated by column chromatography using ethyl acetate / petroleum ether (1:20–1:1) as the eluent to obtain pure pyrazolo[1,5-c]dihydropyrimidinone derivative 3a. The product was a pale yellow solid with a yield of 92%.

[0029] Example 3: Preparation of pyrazolo[1,5-c]dihydropyrimidinone derivative 3a Will N A diazo derivative 1a (0.2 mmol) of a substituted pyrrolidone was added to 2.0 mL of tetrahydrofuran solution. After purging with nitrogen three times in a Young's tube, 2.0 mL of trimethylsilyne 2a was added. The reaction was allowed to proceed at room temperature for 24 hours, after which the reaction was stopped. The product was then separated by column chromatography using ethyl acetate / petroleum ether (1:20–1:1) as the eluent to obtain pure pyrazolo[1,5-c]dihydropyrimidinone derivative 3a. The product was a pale yellow solid with a yield of 92%.

[0030] Example 4: Preparation of pyrazolo[1,5-c]dihydropyrimidinone derivative 3a Will N A diazo derivative 1a (0.2 mmol) of a substituted pyrrolidone was added to 2.0 mL of dichloromethane solution. After purging with nitrogen three times in a Young's tube, 2.0 mL of trimethylsilyne 2a was added. The reaction was allowed to proceed at room temperature for 24 hours, after which the reaction was stopped. The product was then separated by column chromatography using ethyl acetate / petroleum ether (1:20–1:1) as the eluent to obtain pure pyrazolo[1,5-c]dihydropyrimidinone derivative 3a. The product was a pale yellow solid in 65% yield.

[0031] Example 5: Preparation of pyrazolo[1,5-c]dihydropyrimidinone derivative 3a Will N A diazo derivative 1a (0.2 mmol) of a substituted pyrrolidone was added to 2.0 mL of toluene solution. After purging with nitrogen three times in a Young's tube, 2.0 mL of trimethylsilyne 2a was added. The reaction was allowed to proceed at room temperature for 24 hours, after which the reaction was stopped. The product was then separated by column chromatography using ethyl acetate / petroleum ether (1:20–1:1) as the eluent to obtain pure pyrazolo[1,5-c]dihydropyrimidinone derivative 3a. The product was a pale yellow solid in 40% yield.

[0032] Example 6 Preparation of pyrazolo[1,5-c]dihydropyrimidinone derivative 3a Will N A diazo derivative 1a (0.2 mmol) of a substituted pyrrolidone was added to 2.0 mL of acetonitrile solution. After purging with nitrogen three times in a Young's tube, 2.0 mL of trimethylsilyne 2a was added. The reaction was allowed to proceed at room temperature for 24 hours, after which the reaction was stopped. The product was then separated by column chromatography using ethyl acetate / petroleum ether (1:20–1:1) as the eluent to obtain pure pyrazolo[1,5-c]dihydropyrimidinone derivative 3a. The product was a pale yellow solid in 52% yield.

[0033] Example 7 Preparation of pyrazolo[1,5-c]dihydropyrimidinone derivative 3a Will NA diazo derivative 1a (0.2 mmol) of a substituted pyrrolidone was added to 2.0 mL of methanol solution. After purging with nitrogen three times in a Young's tube, 2.0 mL of trimethylsilyne 2a was added. The reaction was allowed to proceed at room temperature for 24 hours, after which the reaction was stopped. The product was then separated by column chromatography using ethyl acetate / petroleum ether (1:20–1:1) as the eluent to obtain pure pyrazolo[1,5-c]dihydropyrimidinone derivative 3a. The product was a pale yellow solid in 0% yield.

[0034] Example 8: Preparation of pyrazolo[1,5-c]dihydropyrimidinone derivative 3a Will N A diazo derivative 1a (0.2 mmol) of a substituted pyrrolidone was added to 2.0 mL of tetrahydrofuran solution. After purging with nitrogen three times in a Young's tube, 2.0 mL of trimethylsilyne 2a was added. The reaction was carried out in an ice-water bath for 24 hours, after which the reaction was stopped. With dibromomethane as an internal standard, the NMR yield of pyrazolo[1,5-c]dihydropyrimidinone derivative 3a was 15%.

[0035] Example 9: Preparation of pyrazolo[1,5-c]dihydropyrimidinone derivative 3a Will N A diazo derivative 1a (0.2 mmol) of a substituted pyrrolidone was added to 2.0 mL of tetrahydrofuran solution. After purging with nitrogen three times in a Young's tube, 2.0 mL of trimethylsilyne 2a was added. The reaction was carried out at 60 °C for 24 hours, after which the reaction was stopped. With dibromomethane as an internal standard, the NMR yield of pyrazolo[1,5-c]dihydropyrimidinone derivative 3a was 75%.

[0036] Example 10 Preparation of pyrazolo[1,5-c]dihydropyrimidinone derivative 3a Will N A diazo derivative 1a (0.2 mmol) of a substituted pyrrolidone was added to 2.0 mL of tetrahydrofuran solution. After purging with nitrogen three times in a Young's tube, 2.0 mL of trimethylsilyne 2a was added. The reaction was carried out at 120 °C for 24 hours, after which the reaction was stopped. With dibromomethane as an internal standard, the NMR yield of pyrazolo[1,5-c]dihydropyrimidinone derivative 3a was 55%.

[0037] Example 11 Preparation of pyrazolo[1,5-c]dihydropyrimidinone derivative 3b Its synthetic route is as follows: Will NA diazo derivative 1b (0.2 mmol) of a substituted pyrrolidone was added to 2.0 mL of tetrahydrofuran solution. After purging with nitrogen three times in a Young's tube, 2.0 mL of trimethylsilyne 2a was added. The reaction was allowed to proceed at room temperature for 24 hours, after which the reaction was stopped. The product was then separated by column chromatography using ethyl acetate / petroleum ether (1:20–1:1) as the eluent to obtain pure pyrazolo[1,5-c]dihydropyrimidinone derivative 3a. The product was a pale yellow solid with a yield of 92%.

[0038] like Figure 3 As shown: 1 H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 8.6 Hz, 2H), 7.39 (d, J =8.6 Hz, 2H), 6.23 (s, 1H), 4.32 (q, J = 7.0 Hz, 2H), 3.96 (t, J = 6.4 Hz, 2H), 3.15 (t, J = 6.2 Hz, 2H), 1.33 (t, J = 7.2 Hz, 3H), 0.27 (s, 9H). like Figure 4 As shown: 13 C NMR (101 MHz, CDCl3) δ 166.0, 159.1, 148.1, 145.8,139.9, 130.7, 128.5, 124.7, 111.1, 61.3, 48.3, 22.3, 14.5, 1.2. HRMS (ESI) (m / z): calculated for C 18 H 23 N3O3SiNa [M+Na] + : 380.1401; found: 380.1473. Example 12 Preparation of pyrazolo[1,5-c]dihydropyrimidinone derivative 3c Its synthetic route is as follows: Will NA diazo derivative 1c (0.2 mmol) of a substituted pyrrolidone was added to 2.0 mL of tetrahydrofuran solution. After purging with nitrogen three times in a Young's tube, 2.0 mL of trimethylsilyne 2a was added. The reaction was allowed to proceed at room temperature for 24 hours, after which the reaction was stopped. The product was then separated by column chromatography using ethyl acetate / petroleum ether (1:20–1:1) as the eluent to obtain pure pyrazolo[1,5-c]dihydropyrimidinone derivative 3c. The product was a pale yellow solid in 95% yield.

[0039] like Figure 5 As shown: 1 H NMR (500 MHz, CDCl3) δ 7.28 (d, J = 9.0 Hz, 2H), 6.92 (d, J =9.0 Hz, 2H), 6.28 (s, 1H), 3.91 (t, J = 6.5 Hz, 2H), 3.82 (s, 3H), 3.18 (t, J =6.2 Hz, 2H), 0.33 (s, 9H). like Figure 6 As shown: 13 C NMR (101 MHz, CDCl3) δ 158.4, 158.3, 148.7, 140.1,134.7, 127.0, 114.6, 110.8, 55.6, 49.1, 22.3, 1.2. HRMS(ESI) (m / z): calculated for C 16 H 22 N3O2Si [M+H] + : 338.1295; found:338.1292. Example 13 Preparation of pyrazolo[1,5-c]dihydropyrimidinone derivative 3d Its synthetic route is as follows: Will N A diazo derivative 1d (0.2 mmol) of a substituted pyrrolidone was added to 2.0 mL of tetrahydrofuran solution. After purging with nitrogen three times in a Young's tube, 2.0 mL of trimethylsilyne 2a was added. The reaction was allowed to proceed at room temperature for 24 hours, after which the reaction was stopped. The product was then separated by column chromatography using ethyl acetate / petroleum ether (1:20–1:1) as the eluent to obtain pure pyrazolo[1,5-c]dihydropyrimidinone derivative 3d. The product was a pale yellow solid with a yield of 87%.

[0040] 1 H NMR (400 MHz, CDCl3) δ 7.22 (d, J = 2.3 Hz, 2H), 7.13 (t, J = 2.3 Hz,1H), 6.20 (s, 1H), 3.92 (t, J = 6.5 Hz, 2H), 3.10 (t, J = 6.6 Hz, 2H), 0.25 (s, 9H). 13 C NMR (101 MHz, CDCl3) δ 158.6, 147.6, 139.8, 124.8, 124.0, 114.9,110.9, 48.2, 21.9, 1.1. HRMS (ESI) (m / z): calculated for C 13 H 18 N3OSSi [M+H] + : 292.0934; found:292.0992. Example 14 Preparation of pyrazolo[1,5-c]dihydropyrimidinone derivative 3e Its synthetic route is as follows: Will N A diazo derivative 1e (0.2 mmol) of a substituted pyrrolidone was added to 2.0 mL of tetrahydrofuran solution. After purging with nitrogen three times in a Young's tube, 2.0 mL of trimethylsilyne 2a was added. The reaction was allowed to proceed at room temperature for 24 hours, after which the reaction was stopped. The product was then separated by column chromatography using ethyl acetate / petroleum ether (1:20–1:1) as the eluent to obtain the pure pyrazolo[1,5-c]dihydropyrimidinone derivative 3e. The product was a pale yellow solid in 92% yield.

[0041] 1 H NMR (400 MHz, CDCl3) δ 7.48–7.29 (m, 5H), 7.31–7.22 (m, 2H), 7.06–6.95 (m, 2H), 6.27 (s, J = 1.1 Hz, 1H), 3.89 (t, J = 6.5 Hz, 2H), 3.16 (t, 2H), 0.33 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 158.3, 157.6, 148.6, 140.1, 136.8, 134.9,128.7, 128.2, 127.6, 127.0, 115.5, 110.8, 70.4, 49.0, 22.3, 1.2. HRMS(ESI) (m / z): calculated for C 22 H 26 N3O2Si [M+H] + : 392.1789; found:392.1790. Example 15 Preparation of pyrazolo[1,5-c]dihydropyrimidinone derivative 3f Its synthetic route is as follows: Will N A diazo derivative 1f (0.2 mmol) of a substituted pyrrolidone was added to 2.0 mL of tetrahydrofuran solution. After purging with nitrogen three times in a Young's tube, 2.0 mL of trimethylsilyne 2a was added. The reaction was allowed to proceed at room temperature for 24 hours, after which the reaction was stopped. The product was then separated by column chromatography using ethyl acetate / petroleum ether (1:20–1:1) as the eluent to obtain pure pyrazolo[1,5-c]dihydropyrimidinone derivative 3f. The product was a pale yellow solid in 87% yield.

[0042] 1 H NMR (400 MHz, CDCl3) δ 7.41–7.29 (m, 2H), 7.32–7.27 (m, 2H), 6.28(s, 1H), 3.93 (t, J = 6.5 Hz, 2H), 3.18(t, J = 6.5 Hz, 2H), 0.32 (s, 9H). 13 C NMR (101 MHz, CDCl3) δ 158.8, 148.3, 140.4, 140.0, 132.4, 129.4,126.8, 111.0, 48.6, 22.3, 1.5. HRMS(ESI) (m / z): calculated for C 15 H 19 ClN3OSi [M+H] + : 320.0980; found:320.0980. Example 16 Preparation of 3g of pyrazolo[1,5-c]dihydropyrimidinone derivative Its synthetic route is as follows: Will N 1 g (0.2 mmol) of a diazo derivative of a substituted pyrrolidone was added to 2.0 mL of tetrahydrofuran solution. After purging with nitrogen three times in a Young's tube, 2.0 mL of trimethylsilyne 2a was added. The reaction was allowed to proceed at room temperature for 24 hours, after which the reaction was stopped. Separation was performed by column chromatography using ethyl acetate / petroleum ether (1:20–1:1) as the eluent to obtain 3 g of pure pyrazolo[1,5-c]dihydropyrimidinone derivative. The product was a pale yellow solid with a yield of 87%.

[0043] 1 H NMR (400 MHz, CDCl3) δ 7.58–7.49 (m, 2H), 7.31–7.21 (m, 2H), 6.29(s, 1H), 3.94 (t, J = 6.4 Hz, 2H), 3.20 (t, J = 6.4 Hz, 2H), 0.33 (s, 9H). 13 C NMR (101 MHz, CDCl3) δ 158.9, 148.2, 140.9, 139.9, 132.4, 127.1,120.3, 111.0, 48.6, 22.3. HRMS(ESI) (m / z): calculated for C 15 H 19 BrN3OSi [M+H] + : 364.0475; found:364.0468. Example 17 Preparation of pyrazolo[1,5-c]dihydropyrimidinone derivatives for 3 hours Its synthetic route is as follows: Will N A diazo derivative of a substituted pyrrolidone, 1h (0.2 mmol), was added to 2.0 mL of tetrahydrofuran solution. After purging with nitrogen three times in a Young's tube, 2.0 mL of trimethylsilyne 2a was added. The reaction was allowed to proceed at room temperature for 24 hours, after which the reaction was stopped. Separation was performed by column chromatography using ethyl acetate / petroleum ether (1:20~1:1) as the eluent to obtain the pure pyrazolo[1,5-c]dihydropyrimidinone derivative 3h. The product was a pale yellow solid with a yield of 85%.

[0044] 1 H NMR (400 MHz, CDCl3) δ 7.73–7.65 (m, 2H), 7.13–7.09 (m, 2H), 6.27(s, 1H), 3.92 (t, J = 6.2 Hz, 2H), 3.17 (t, J = 6.2 Hz, 2H), 0.32 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 158.8, 148.1, 141.6, 139.9, 138.3, 127.3,111.0, 91.4, 48.4, 22.2, 1.1. HRMS(ESI) (m / z): calculated for C 15 H 19 IN3OSi [M+H] + : 412.0337; found:412.0336. Example 18 Preparation of pyrazolo[1,5-c]dihydropyrimidinone derivative 3i Its synthetic route is as follows: Will N A diazo derivative 1i (0.2 mmol) of a substituted pyrrolidone was added to 2.0 mL of tetrahydrofuran solution. After purging with nitrogen three times in a Young's tube, 2.0 mL of trimethylsilyne 2a was added. The reaction was allowed to proceed at room temperature for 24 hours, after which the reaction was stopped. The product was then separated by column chromatography using ethyl acetate / petroleum ether (1:20–1:1) as the eluent to obtain pure pyrazolo[1,5-c]dihydropyrimidinone derivative 3i. The product was a pale yellow solid in 89% yield.

[0045] 1 H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 4.0 Hz, 1H), 7.08 (d, J = 3.6 Hz,1H), 6.31 (s, 1H), 4.61 (t, J = 6.6 Hz, 2H), 3.23 (t, J = 6.6 Hz, 2H), 0.33 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 160.3, 159.8, 147.0, 140.1, 137.3, 116.1,111.3, 44.5, 21.4, 1.1. HRMS(ESI) (m / z): calculated for C 12 H 16 N4OSSiNa [M+Na] + : 315.0706; found: 315.0705. Example 19 Preparation of pyrazolo[1,5-c]dihydropyrimidinone derivative 3j Its synthetic route is as follows: Will N A diazo derivative 1j (0.2 mmol) of a substituted pyrrolidone was added to 2.0 mL of tetrahydrofuran solution. After purging with nitrogen three times in a Young's tube, 2.0 mL of trimethylsilyne 2a was added. The reaction was allowed to proceed at room temperature for 24 hours, after which the reaction was stopped. The product was then separated by column chromatography using ethyl acetate / petroleum ether (1:20–1:1) as the eluent to obtain pure pyrazolo[1,5-c]dihydropyrimidinone derivative 3j. The product was a pale yellow solid with a yield of 93%.

[0046] 1 H NMR (400 MHz, CDCl3) δ 7.27–7.25 (m, 4H), 6.27 (s, 1H), 3.92 (t, J =6.4 Hz, 2H), 3.18 (t, J = 6.4 Hz, 2H), 2.49 (s, 3H), 0.32 (s, 9H). 13 C NMR (101 MHz, CDCl3) δ 158.5, 148.4, 140.0, 138.9, 137.2, 127.3,125.9, 110.9, 48.7, 22.2, 16.1, 1.1. HRMS(ESI) (m / z): calculated for C 16 H 21 N3OSSiNa [M+Na] + : 354.1067;found: 354.1067. Example 20 Preparation of pyrazolo[1,5-c]dihydropyrimidinone derivative 3k Its synthetic route is as follows: Will N A diazo derivative 1a (0.2 mmol) of a substituted pyrrolidone was added to 2.0 mL of tetrahydrofuran solution. After purging with nitrogen three times in a Young's tube, 2.0 mL of tri-tert-butylacetylene 2b was added. The reaction was allowed to proceed at room temperature for 24 hours, after which the reaction was stopped. The product was then separated by column chromatography using ethyl acetate / petroleum ether (1:20–1:1) as the eluent to obtain the pure pyrazolo[1,5-c]dihydropyrimidinone derivative 3k. The product was a pale yellow solid in 84% yield.

[0047] 1 H NMR (400 MHz, CDCl3) δ 7.39–7.25 (m, 4H), 7.24–7.16 (m, 1H), 6.04(s, 1H), 3.90 (t, J = 6.4 Hz, 2H), 3.09 (t, J = 6.4 Hz, 2H), 1.29 (s, 9H). 13 C NMR (101 MHz, CDCl3) δ 166.0, 148.3, 142.1, 140.7, 129.3, 126.8,125.5, 102.8, 48.6, 32.7, 30.2, 22.4. HRMS (ESI) (m / z): calculated for C 16 H 20 N3O [M+H] + : 270.1601; found:270.1602. The compounds synthesized above have promising applications in medicinal chemistry, such as drug preparation and drug precursor synthesis.

[0048] This invention is not limited to the specific embodiments described above. Those skilled in the art can make various changes accordingly, but any changes that are equivalent to or similar to this invention should be covered within the scope of the claims of this invention.

Claims

1. A method for preparing pyrazolo[1,5-c]dihydropyrimidinone, characterized in that, The preparation method includes the following steps: Under the protection of inert gas, N A diazo derivative (I) of a substituted pyrrolidone and an alkyne (II) are mixed in an organic solvent and rearranged at 0 °C to 120 °C to give pyrazolo[1,5-c]dihydropyrimidinone (III). The reaction route is as follows: In the formula, R1 is selected from one of the following groups: substituted or unsubstituted phenyl, thiophene, thiazole, benzyl; R2 is selected from trimethylsilyl or tert-butyl.

2. The preparation method according to claim 1, characterized in that, In the substituted or unsubstituted phenyl group, the substituent is selected from one of the following groups: halogen, methoxy, benzyloxy, sulfonic acid group, ester group.

3. The preparation method according to claim 1, characterized in that, The N The molar ratio of the diazo derivative (I) of the substituted pyrrolidone to the alkyne (II) is 1:10~80.

4. The preparation method according to claim 1, characterized in that, The organic solvent is one or two of N,N-dimethylformamide, N-methylpyrrolidone, toluene, xylene, mesitylene, 1,4-dioxane, acetonitrile, dichloromethane, 1,2-dichloroethane, diethyl ether, ethylene glycol dimethyl ether, methyl tert-butyl ether, tetrahydrofuran, N,N-dimethylacetamide, dimethyl sulfoxide, and n-butanol.

5. The preparation method according to claim 4, characterized in that, The organic solvent is tetrahydrofuran.

6. The preparation method according to claim 1, characterized in that, The inert gas is nitrogen.

7. The preparation method according to claim 1, characterized in that, The preparation method also includes post-processing, specifically: after the reaction is complete, extraction, washing, drying and column chromatography are performed sequentially to obtain the final product.

8. The preparation method according to claim 1, characterized in that, The reaction temperature ranges from room temperature to 120°C.

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