7-substituted pyrazolo[1,5-a]pyrimidines and methods for their preparation

Abstract

The application discloses a preparation method of a 7-position-hydrogen-substituted pyrazolo[1,5-a]pyrimidine compound. The preparation method comprises the following steps: contacting a compound shown in a formula (I) with a compound shown in one of formula (II) or formula (III), a thiocyanate, an iodine-containing oxidant and a solvent to react. The preparation method has the characteristics of simple operation, low cost of raw materials, wide application range of substrates and high yield, and the obtained product is an important pharmaceutical intermediate.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, and specifically relates to a method for preparing 7-hydrogen-substituted pyrazolo[1,5-a]pyrimidine compounds. Background Technology

[0002] Nitrogen-containing heterocycles are important structural units in many natural products, drugs, and biomolecules, and are widely found in various natural and synthetic drug molecules. They have practical applications in materials, pharmaceuticals, organic pesticides, and dyes. In recent years, pyrazolo[1,5-a]pyrimidines have also received increasing attention. Pyrazolo[1,5-a]pyrimidine compounds are very important nitrogen-containing heterocyclic compounds, serving as a valuable backbone in medicinal chemistry. They possess excellent biological activity and can be used as central nervous system drugs, anti-infectives, and anti-tumor drugs. Marketed clinical drugs with pyrazolo[1,5-a]pyrimidine as their core include osceproline (patent document US20110245275A1) for treating anxiety and alogliptin (patent document US20180235966A1) for treating hyperglycemia. The representative drug of 7-hydro-substituted pyrazolo[1,5-a]pyrimidine is larotrectinib sulfate, a Trk kinase inhibitor used for cancer (patent document US2015005499A1), which has attracted widespread attention from researchers in many fields such as organic synthesis, medicine and biology.

[0003] Several methods for preparing 7-hydro-substituted pyrazolo[1,5-a]pyrimidine compounds have been reported. Tiwari and colleagues reported that using palladium chloride as a catalyst, one molecule of aminopyrazole reacts with two molecules of phenylacetaldehyde to yield 7-hydro-substituted pyrazolo[1,5-a]pyrimidine compounds (ACS Omega, 2017, 2, 11-19). Additionally, a cobalt chloride catalyst with 1.2 equivalents of zinc bromide as an additive has been disclosed, in which a haloaryral hydrocarbon undergoes a cross-coupling reaction with an arylboronic acid ester lithium salt to generate a diaryl compound. One example of this involves the synthesis of 7-hydro-substituted pyrazolo[1,5-a]pyrimidine (Organic Chemistry. Fronters, 2016, 6, 2630-2634). Furthermore, there is a document that discloses the preparation of 7-chloropyrazolo[1,5-a]pyrimidine compounds by using 7-chloropyrazolo[1,5-a]pyrimidine as a raw material, palladium on carbon as a catalyst, and hydrogen as a reducing agent through a reductive dechlorination reaction (Patent document US2007072879A1).

[0004] However, the methods described above for synthesizing 7-hydro-substituted pyrazolo[1,5-a]pyrimidine heterocyclic compounds have relatively harsh reaction conditions, requiring stoichiometric metal salts, palladium or cobalt transition metal catalysts, or lengthy synthetic routes. These methods are cumbersome, costly, and leave transition metal residues in the product, hindering the synthesis of 7-hydro-substituted pyrazolo[1,5-a]pyrimidine compounds, which are important intermediates in drug synthesis. These problems limit the further development and application of 7-hydro-substituted pyrazolo[1,5-a]pyrimidine compounds. Summary of the Invention

[0005] In view of the shortcomings of the prior art, the present invention provides a method for preparing 7-hydro-substituted pyrazolo[1,5-a]pyrimidine compounds that is simple to operate, uses inexpensive and readily available raw materials, has a wide range of applicable substrates, and has a high yield.

[0006] The technical solution of this invention is as follows:

[0007] A method for preparing a 7-hydro-substituted pyrazolo[1,5-a]pyrimidine compound of formula (IV) includes: contacting the compound of formula (I) with a compound of formula (II) or (III), a thiocyanate, an iodine-containing oxidant, and a solvent to cause a reaction;

[0008]

[0009] Among them, R 1 It is selected from one of C2-C6 ester group, morpholinone group, C1-C6 alkanoamide group, and cyano group;

[0010] R 2 Selected from one of phenyl, C1-C6 alkyl-substituted phenyl, C1-C6 alkoxy-substituted phenyl, halogen-substituted phenyl, nitro-substituted phenyl, and furanyl;

[0011] R 3 It is selected from hydrogen, C1-C6 alkyl groups, and halogens.

[0012] According to a specific embodiment of the present invention, R 1 It is selected from one of the following groups: ethyl formate, methyl formate, morpholinone, formamido, and cyano.

[0013] According to a specific embodiment of the present invention, R 2 The R is selected from one of phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl, 2-chlorophenyl, 2-methoxyphenyl, and furanyl. 3 It is selected from one of hydrogen, methyl, and bromine.

[0014] According to a specific embodiment of the present invention, the compound shown in formula (II) is selected from any one of the following compounds:

[0015]

[0016] According to a specific embodiment of the present invention, the compound shown in formula (III) is selected from any one of the following compounds:

[0017]

[0018] According to a specific embodiment of the present invention, the molar ratio of the compound shown in formula (I), the compound shown in one of formulas (II) and (III), the thiocyanate and the iodine-containing oxidant is 1:2:1.25:0.75.

[0019] According to a specific embodiment of the present invention, the thiocyanate is selected from one of ammonium thiocyanate, potassium thiocyanate, and sodium thiocyanate, and the iodine-containing oxidant is selected from one of iodine pentoxide, elemental iodine, and sodium iodate.

[0020] According to a specific embodiment of the present invention, the solvent is selected from dimethyl sulfoxide, acetonitrile, and toluene; preferably, the molar volume ratio of the compound shown in formula (I) to the solvent is 1 mmol / L: 7.5 mL.

[0021] According to a specific embodiment of the present invention, the reaction temperature is 40–100°C and the reaction time is 12 h.

[0022] According to a specific embodiment of the present invention, the reaction product is further separated and purified using conventional methods.

[0023] The beneficial effects of this invention are as follows:

[0024] The preparation method provided by this invention does not require the participation of transition metals. The compound shown in formula (I), the compound shown in formula (II) and one of formula (III), and the thiocyanate can be directly oxidized and cyclized to obtain 7-hydro-substituted pyrazolo[1,5-a]pyrimidine compounds. The preparation method has mild reaction conditions, inexpensive and readily available raw materials, high atom economy, is green and sustainable, and is simple to operate. It can significantly reduce production costs and improve production safety. The obtained product is an important pharmaceutical intermediate. Detailed Implementation

[0025] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0026] In the following examples, the reaction formulas of Examples 1-19 are shown in reaction formula (a), and the reaction formulas of Examples 20-25 are shown in reaction formula (b). Compounds I-1 to I-25 have the general formula structure shown in formula (I), compounds II-1 to II-19 have the general formula structure shown in formula (II), and compounds III-1 to III-6 have the general formula structure shown in formula (III). The substituents of each compound are shown in Table 1.

[0027] The reaction formula (a) is:

[0028]

[0029] Reaction (b) is:

[0030]

[0031] Table 1

[0032]

[0033]

[0034] Example 1

[0035] 3-Ethyl carbamate-5-phenylpyrazolo[1,5-a]pyrimidine, with the following structural formula:

[0036]

[0037] Preparation method: First, add thiocyanate (NH4SCN, 0.5 mmol), solvent (DMSO, 3 mL), compound I-1 (0.4 mmol), compound II-1 (0.8 mmol), and oxidant (I2O) sequentially to a dry, thick-walled pressure-resistant tube. 5, 0.3 mmol) was mixed and stirred at room temperature for a short time, and then the reaction solution was placed in an oil bath at 100 °C and stirred for 12 h. After the reaction was completed, 10% sodium thiosulfate aqueous solution was added to the reaction solution, and the reaction solution was extracted with ethyl acetate. The organic phase was dried with anhydrous Na2SO4, filtered, and the solvent was removed by vacuum distillation. Then, the solution was separated by column chromatography with silica gel as the packing material (the eluent was a mixture of petroleum ether and ethyl acetate) to obtain compound IV-1, which is ethyl 3-carboxylate-5-phenylpyrazolo[1,5-a]pyrimidine, with a yield of 79%. 1HNMR(600MHz,Chloroform-d)δ8.73(d,J=6.6Hz,1H),8.56(s,1H),8.22(dd,J=6.1, 3.1Hz,2H),7.52(s,3H),7.46(d,J=7.0Hz,1H),4.44(q,J=7.6Hz,2H),1.44(s,2H); 13 C NMR(150MHz,Chloroform-d)δ162.7,159.3,148.4,147.8,136.4,136.1,131.5,129.2,127.81,106.8,103.3,60.2,14.2.HRMS(ESI):m / z[M+H] + Calcd for C 15 H 14 N3O2 + :268.1081; found:268.1079.

[0038] Example 2

[0039] 3-Ethyl carbamate-5-phenylpyrazolo[1,5-a]pyrimidine, with the following structural formula:

[0040]

[0041] Preparation method: First, add thiocyanate (KSCN, 0.4 mmol), solvent (DMSO, 3 mL), compound I-2 (0.4 mmol), compound II-2 (0.6 mmol), and oxidant (I₂O) sequentially to a dry, thick-walled pressure-resistant tube. 5, 0.4 mmol), mixed and stirred at room temperature for a short time, then placed the reaction solution in an oil bath at 100°C and stirred for 12 h. After the reaction was completed, the operation steps were the same as in Example 1, yielding compound IV-1, which is ethyl 3-carboxylate-5-phenylpyrazolo[1,5-a]pyrimidine, with a yield of 41%. 1 HNMR(600MHz,Chloroform-d)δ8.73(d,J=6.6Hz,1H),8.56(s,1H),8.22(dd,J=6.1, 3.1Hz,2H),7.52(s,3H),7.46(d,J=7.0Hz,1H),4.44(q,J=7.6Hz,2H),1.44(s,2H); 13C NMR(150MHz,Chloroform-d)δ162.7,159.3,148.4,147.8,136.4,136.1,131.5,129.2,127.81,106.8,103.3,60.2,14.2.HRMS(ESI):m / z[M+H] + Calcd for C 15 H 14 N3O2 + :268.1081; found:268.1079.

[0042] Example 3

[0043] 3-Ethyl carbamate-5-phenylpyrazolo[1,5-a]pyrimidine, with the following structural formula:

[0044]

[0045] Preparation method: First, add thiocyanate (NH4SCN, 0.5 mmol), solvent (acetonitrile, 3 mL), compound I-3 (0.4 mmol), compound II-3 (0.6 mmol), and oxidant (I2O) sequentially to a dry, thick-walled pressure-resistant tube. 5, 0.3 mmol), mixed and stirred at room temperature for a short time, then placed the reaction solution in an oil bath at 100°C and stirred for 12 h. After the reaction was completed, the operation steps were the same as in Example 1, yielding compound IV-1, which is ethyl 3-carboxylate-5-phenylpyrazolo[1,5-a]pyrimidine, with a yield of 31%. 1 HNMR(600MHz,Chloroform-d)δ8.73(d,J=6.6Hz,1H),8.56(s,1H),8.22(dd,J=6.1, 3.1Hz,2H),7.52(s,3H),7.46(d,J=7.0Hz,1H),4.44(q,J=7.6Hz,2H),1.44(s,2H); 13 C NMR(150MHz,Chloroform-d)δ162.7,159.3,148.4,147.8,136.4,136.1,131.5,129.2,127.81,106.8,103.3,60.2,14.2.HRMS(ESI):m / z[M+H] + Calcd for C 15 H 14 N3O2 + :268.1081; found:268.1079.

[0046] Example 4

[0047] 3-Ethyl carbamate-5-phenylpyrazolo[1,5-a]pyrimidine, with the following structural formula:

[0048]

[0049] Preparation method: Thiocyanate (NH4SCN, 0.5 mmol), solvent (DMSO, 3 mL), compound I-4 (0.4 mmol), compound II-4 (0.6 mmol), and oxidant (I2, 0.4 mmol) were added sequentially to a dry, thick-walled, pressure-resistant tube. After mixing and stirring at room temperature for a short time, the reaction solution was placed in an oil bath at 100°C and stirred for 12 h. After the reaction was completed, the operation steps were the same as in Example 1, yielding compound IV-1, which is ethyl 3-carboxylate-5-phenylpyrazolo[1,5-a]pyrimidine, with a yield of 27%. 1 HNMR(600MHz,Chloroform-d)δ8.73(d,J=6.6Hz,1H),8.56(s,1H),8.22(dd,J=6.1, 3.1Hz,2H),7.52(s,3H),7.46(d,J=7.0Hz,1H),4.44(q,J=7.6Hz,2H),1.44(s,2H); 13 C NMR(150MHz,Chloroform-d)δ162.7,159.3,148.4,147.8,136.4,136.1,131.5,129.2,127.81,106.8,103.3,60.2,14.2.HRMS(ESI):m / z[M+H] + Calcd for C 15 H 14 N3O2 + :268.1081; found:268.1079.

[0050] Example 5

[0051] 5-(p-Tolyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester, with the following structural formula:

[0052]

[0053] Preparation method: Thiocyanate (NH4SCN, 0.5 mmol), solvent (DMSO, 3 mL), compound I-5 (0.4 mmol), compound II-5 (0.8 mmol), and oxidant (I2O5, 0.3 mmol) were added sequentially to a dry, thick-walled, pressure-resistant tube. After mixing and stirring at room temperature for a short time, the reaction solution was placed in an oil bath at 100°C and stirred for 12 h. After the reaction was completed, the operation steps were the same as in Example 1, yielding compound IV-2, which is ethyl 5-(p-tolyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate, with a yield of 74%. 1H NMR(600MHz,Chloroform-d)δ8.69(d,J=7.4Hz,1H),8.54(s,1H),8.15–8.08(m,2H),7.43(d,J= 7.4Hz,1H),7.31(d,J=8.0Hz,2H),4.43(q,J=7.1Hz,2H),2.42(s,3H),1.45(t,J=7.1Hz,3H); 13C NMR(150MHz,Chloroform-d)δ162.8,159.2,148.2,147.8,142.0,135.9,133.6,129.9,127.7,106.6,103.0,60.3,21.6,14.3.HRMS(ESI):m / z[M+H]+Calcd for C16H16N3O2+:282.1234; found:282.1237.

[0054] Example 6

[0055] 5-(4-methoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester, with the following structural formula:

[0056]

[0057] Preparation method: Thiocyanate (NH4SCN, 0.5 mmol), solvent (DMSO, 3 mL), compound I-6 (0.4 mmol), compound II-6 (0.8 mmol), and oxidant (I2O5, 0.3 mmol) were added sequentially to a dry, thick-walled, pressure-resistant tube. After mixing and stirring at room temperature for a short time, the reaction solution was placed in an oil bath at 100°C and stirred for 12 h. After the reaction was completed, the operation steps were the same as in Example 1, yielding compound IV-3, which is ethyl 5-(4-methoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid, with a yield of 66%. 1H NMR(600MHz,Chloroform-d)δ8.66(d,J=7.3Hz,1H),8.52(s,1H),8.21–8.16(m,2H),7.38(d, 13C NMR(150MHz,Chloroform-d)δ162.9,162.5,158.8,148.2,147.9,135.8,129.5,128.8,114.5,106.2,102.8,60.3,55.6,14.6.HRMS(ESI):m / z[M+H]+Calcdfor C16H16N3O3:298.1186; found:298.1185.

[0058] Example 7

[0059] 5-(4-fluorophenyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester, with the following structural formula:

[0060]

[0061] Preparation method: Thiocyanate (NH4SCN, 0.5 mmol), solvent (DMSO, 3 mL), compound I-7 (0.4 mmol), compound II-7 (0.8 mmol), and oxidant (I2O5, 0.3 mmol) were added sequentially to a dry, thick-walled, pressure-resistant tube. After mixing and stirring at room temperature for a short time, the reaction solution was placed in an oil bath at 100°C and stirred for 12 h. After the reaction was completed, the operation steps were the same as in Example 1, yielding compound IV-4, which is ethyl 5-(4-fluorophenyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate, with a yield of 62%. 1H NMR(600MHz,Chloroform-d)δ8.74(d,J=7.3Hz,1H),8.57(s,1H),8.28–8.21(m,2H),7.42 (d,J=7.3Hz,1H),7.22(t,J=8.5Hz,2H),4.44(q,J=7.1Hz,2H),1.46(t,J=7.1Hz,3H); 13C NMR(150MHz,Chloroform-d)δ165.9,164.2,162.7,158.1,148.4,147.7,136.2,132.6(d,J=3.2Hz ),129.97(d,J=8.9Hz),116.3(d,J=90Hz),106.4,103.3,60.4,14.6.HRMS(ESI):m / z[M+H]+Calcd for C15H13FN3O2+:286.0986; found:286.0987.

[0062] Example 8

[0063] 5-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester, with the following structural formula:

[0064]

[0065] Preparation method: Thiocyanate (NH4SCN, 0.5 mmol), solvent (DMSO, 3 mL), compound I-8 (0.3 mmol), compound II-8 (0.8 mmol), and oxidant (I2O5, 0.3 mmol) were added sequentially to a dry, thick-walled, pressure-resistant tube. After mixing and stirring at room temperature for a short time, the reaction solution was placed in an oil bath at 100°C and stirred for 12 h. After the reaction was completed, the operation steps were the same as in Example 1, yielding compound IV-5, which is ethyl 5-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid, with a yield of 75%. 1H NMR(600MHz,Chloroform-d)δ8.76(d,J=7.3Hz,1H),8.58(s,1H),8.21–8.15(m,2H),7. 54–7.48(m,2H),7.43(d,J=7.3Hz,1H),4.44(q,J=7.1Hz,2H),1.46(t,J=7.1Hz,3H); 13C NMR(150MHz,Chloroform-d)δ162.6,157.9,148.5,147.719,137.9,136.3,134.8,129.4,129.1,106.4,103.4,60.5,14.6.HRMS(ESI):m / z[M+H]+Calcd for C15H13ClN3O2+:302.0691; found:302.0691.

[0066] Example 9

[0067] 5-(4-bromophenyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester, with the following structural formula:

[0068]

[0069] Preparation method: Thiocyanate (NH4SCN, 0.5 mmol), solvent (DMSO, 3 mL), compound I-9 (0.4 mmol), compound II-9 (0.8 mmol), and oxidant (I2O5, 0.3 mmol) were added sequentially to a dry, thick-walled, pressure-resistant tube. After mixing and stirring at room temperature for a short time, the reaction solution was placed in an oil bath at 100°C and stirred for 12 h. After the reaction was completed, the operation steps were the same as in Example 1, yielding compound IV-6, which is ethyl 5-(4-bromophenyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid, with a yield of 72%. 1H NMR(600MHz,Chloroform-d)δ8.76(d,J=7.2Hz,1H),8.60(s,1H),7.89–7.84(m,1H),7 .53–7.46(m,2H),7.46–7.40(m,2H),4.42(q,J=7.1Hz,2H),1.41(t,J=7.1Hz,3H); 13C NMR(150MHz,Chloroform-d)δ162.6,158.0,148.5,147.7,136.3,135.2,132.4,129.3,126.4,106.4,103.4,60.5,29.8,14.6.HRMS(ESI):m / z[M+H]+Calcd for C15H13BrN3O2+:346.0186; found:346.0187.

[0070] Example 10

[0071] 5-(4-nitrophenyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester, with the following structural formula:

[0072]

[0073] Preparation method: Thiocyanate (NH4SCN, 0.5 mmol), solvent (DMSO, 3 mL), compound I-10 (0.4 mmol), compound II-10 (0.8 mmol), and oxidant (I2O5, 0.3 mmol) were added sequentially to a dry, thick-walled, pressure-resistant tube. After mixing and stirring at room temperature for a short time, the reaction solution was placed in an oil bath at 100°C and stirred for 12 h. After the reaction was completed, the operation steps were the same as in Example 1, yielding compound IV-7, which is ethyl 5-(4-nitrophenyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid, with a yield of 73%. 1H 13C NMR(150MHz,Chloroform-d)δ162.4,156.5,149.5,148.9,147.6,142.0,136.7,128.7,124.3,106.8,104.1,60.6,29.8,14.6.HRMS(ESI):m / z[M+H]+Calcd for C15H13N4O4+:313.0931; found:313.0932.

[0074] Example 11

[0075] 5-(2-methoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester, with the following structural formula:

[0076]

[0077] Preparation method: Thiocyanate (NH4SCN, 0.8 mmol), solvent (DMSO, 3 mL), compound I-11 (0.4 mmol), compound II-11 (0.8 mmol), and oxidant (I2O5, 0.3 mmol) were added sequentially to a dry, thick-walled, pressure-resistant tube. After mixing and stirring at room temperature for a short time, the reaction solution was placed in an oil bath at 100°C and stirred for 12 h. After the reaction was completed, the operation steps were the same as in Example 1, yielding compound IV-8, which is ethyl 5-(2-methoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid, with a yield of 68%. 1H NMR(600MHz,Chloroform-d)δ8.65(d,J=5.6Hz,1H),8.55(s,1H),8.19(d,J=7.0Hz,1H),7.75(d,J=7.5Hz,1H),7.47 13C NMR(150MHz,Chloroform-d)δ162.8,159.2,158.1,147.9,134.5,132.4,131.9,126 .4,121.6,111.7(d,J=6.6Hz),103.0,60.3,55.8,14.6.HRMS(ESI):m / z[M+H]+Calcd for C16H16N3O3+:298.1186; found:298.1185.

[0078] Example 12

[0079] 5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester, with the following structural formula:

[0080]

[0081] Preparation method: Thiocyanate (NH4SCN, 0.5 mmol), solvent (DMSO, 3 mL), compound I-12 (0.4 mmol), compound II-12 (0.8 mmol), and oxidant (I2O5, 0.3 mmol) were added sequentially to a dry, thick-walled, pressure-resistant tube. After mixing and stirring at room temperature for a short time, the reaction solution was placed in an oil bath at 100°C and stirred for 12 h. After the reaction was completed, the operation steps were the same as in Example 1, yielding compound IV-9, which is ethyl 5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid, with a yield of 74%. 1H NMR(600MHz,Chloroform-d)δ8.76(d,J=7.3Hz,1H),8.58(s,1H),8.14–8.08(m,2H),7. 70–7.64(m,2H),7.43(d,J=7.4Hz,1H),4.44(q,J=7.1Hz,2H),1.46(t,J=7.1Hz,3H); 13C NMR(150MHz,Chloroform-d)δ162.5,159.6,148.2,147.7,136.9,134.9,132.5,1 32.3,131.4,130.5,127.5,111.5,103.7,60.5,14.6.HRMS(ESI):m / z[M+H]+Calcd forC15H13ClN3O2+:302.0691; found:302.0691.

[0082] Example 13

[0083] 6-Methyl-5-phenylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester, with the following structural formula:

[0084]

[0085] Preparation method: Thiocyanate (NH4SCN, 0.8 mmol), solvent (DMSO, 3 mL), compound I-13 (0.4 mmol), compound II-13 (0.8 mmol), and oxidant (I2O5, 0.3 mmol) were added sequentially to a dry, thick-walled, pressure-resistant tube. After mixing and stirring at room temperature for a short time, the reaction solution was placed in an oil bath at 100°C and stirred for 12 h. After the reaction was completed, the operation steps were the same as in Example 1, yielding compound IV-10, which is ethyl 6-methyl-5-phenylpyrazolo[1,5-a]pyrimidine-3-carboxylate, with a yield of 71%. 1H NMR (600MHz, Chloroform-d) δ8.60 (d, J = 3.0Hz, 1H), 8.51 (s, 1H), 7.69 (q, J = 3.6Hz, 2H), 7.47 (t, J = 4.0Hz, 3H), 4.38 (t, J = 7.7Hz, 2H), 2.43 (s, 3H); 13C NMR(150MHz,Chloroform-d)δ162.9,162.7,147.7,146.6,138.1,135.0,129.8,129.2,128.5,118.3,102.8,60.3,18.0,14.6.HRMS(ESI):m / z[M+H]+Calcd for C16H16N3O2+:282.1237; found:282.1237.

[0086] Example 14

[0087] 6-Bromo-5-phenylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester, with the following structural formula:

[0088]

[0089] Preparation method: Thiocyanate (NH4SCN, 0.5 mmol), solvent (DMSO, 3 mL), compound I-14 (0.4 mmol), compound II-14 (0.8 mmol), and oxidant (I2O5, 0.3 mmol) were added sequentially to a dry, thick-walled, pressure-resistant tube. After mixing and stirring at room temperature for a short time, the reaction solution was placed in an oil bath at 100°C and stirred for 12 h. After the reaction was completed, the operation steps were the same as in Example 1, yielding compound IV-11, which is ethyl 6-bromo-5-phenylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid, with a yield of 26%. 1H NMR(600MHz,Chloroform-d)δ8.74(d,J=7.4Hz,1H),8.57(s,1H),8.24–8.20(m,2H),7.53 (d,J=3.1Hz,2H),7.47(d,J=7.3Hz,1H),4.45(q,J=7.1Hz,2H),1.46(t,J=7.1Hz,3H); 13C NMR(150MHz,Chloroform-d)δ162.8,159.3,148.4,147.8,136.4,136.1,131.5,129.2,127.8,106.8,103.3,60.4,14.6.HRMS(ESI):m / z[M+H]+Calcd forC15H13BrN3O2+:346.0186; found:346.0189.

[0090] Example 15

[0091] 5-(furan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester, with the following structural formula:

[0092]

[0093] Preparation method: Thiocyanate (NH4SCN, 0.5 mmol), solvent (DMSO, 3 mL), compound I-15 (0.4 mmol), compound II-15 (0.8 mmol), and oxidant (I2O5, 0.3 mmol) were added sequentially to a dry, thick-walled, pressure-resistant tube. After mixing and stirring at room temperature for a short time, the reaction solution was placed in an oil bath at 100°C and stirred for 12 h. After the reaction was completed, the operation steps were the same as in Example 1, yielding compound IV-12, which is ethyl 5-(furan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid, with a yield of 60%. 1H NMR(600MHz,Chloroform-d)δ8.67(d,J=6.7Hz,1H),8.52(s,1H),7.64(s,1H),7.44(s,1 H),7.39(d,J=7.3Hz,1H),6.62(s,1H),4.42(q,J=7.4Hz,2H),1.44(t,J=7.0Hz,3H); 13C NMR(150MHz,Chloroform-d)δ162.7,151.7,150.8,148.3,145.9,136.1,113.9,113.2,105.5,102.8,60.4,14.6.HRMS(ESI):m / z[M+H]+Calcd for C13H12N3O3+:258.0873; found:258.0872.

[0094] Example 16

[0095] 5-Phenyrazolo[1,5-a]pyrimidine-3-carboxylic acid methyl ester, with the following structural formula:

[0096]

[0097] Preparation method: Thiocyanate (NH4SCN, 0.5 mmol), solvent (DMSO, 3 mL), compound I-16 (0.4 mmol), compound II-16 (0.8 mmol), and oxidant (I2O5, 0.3 mmol) were added sequentially to a dry, thick-walled, pressure-resistant tube. After mixing and stirring at room temperature for a short time, the reaction solution was placed in an oil bath at 100°C and stirred for 12 h. After the reaction was completed, the operation steps were the same as in Example 1, yielding compound IV-13, which is methyl 5-phenylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid, with a yield of 88%. 1H 13C NMR(150MHz,Chloroform-d)δ163.2,159.5,148.5,147.7,136.4,136.1,131.5,129.2,127.9,106.9,103.0,51.4.HRMS(ESI):m / z[M+H]+Calcd for C14H12N3O2+:254.0924; found:254.0925.

[0098] Example 17

[0099] 5-Phenylonpyrazolo[1,5-a]pyrimidine-3-carboxamide, with the following structural formula:

[0100]

[0101] Preparation method: Thiocyanate (NH4SCN, 0.5 mmol), solvent (DMSO, 3 mL), compound I-17 (0.4 mmol), compound II-17 (0.8 mmol), and oxidant (I2O5, 0.3 mmol) were added sequentially to a dry, thick-walled, pressure-resistant tube. After mixing and stirring at room temperature for a short time, the reaction solution was placed in an oil bath at 100°C and stirred for 12 h. After the reaction was completed, the operation steps were the same as in Example 1, yielding compound IV-14, which is 5-phenylpyrazolo[1,5-a]pyrimidine-3-carboxamide, with a yield of 75%. 1HNMR(600MHz,Chloroform-d)δ8.80(d,J=7.3Hz,1H),8.68(s,1H),8.10(dd,J=7.4,2 .3Hz,2H),7.98(s,1H),7.58(d,J=1.9Hz,3H),7.45(d,J=7.4Hz,1H),6.04(s,1H); 13C NMR(150MHz,Chloroform-d)δ164.2,158.7,147.7,146.3,136.5,136.1,131.7,129.4,127.7,106.7,105.6.HRMS(ESI):m / z[M+H]+Calcd for C13H11N4O+:239.0927; found:239.0927.

[0102] Example 18

[0103] Morpholino(5-phenylpyrazolo[1,5-a]pyrimidin-3-yl) methyl ketone, with the following structural formula:

[0104]

[0105] Preparation method: Thiocyanate (NH4SCN, 0.5 mmol), solvent (DMSO, 3 mL), compound I-18 (0.4 mmol), compound II-18 (0.8 mmol), and oxidant (I2O5, 0.3 mmol) were added sequentially to a dry, thick-walled, pressure-resistant tube. After mixing and stirring at room temperature for a short time, the reaction solution was placed in an oil bath at 100°C and stirred for 12 h. After the reaction was completed, the operation steps were the same as in Example 1, yielding compound IV-15, which is morpholino(5-phenylpyrazolo[1,5-a]pyrimidin-3-yl) methyl ketone, with a yield of 65%. 1H NMR (600MHz, Chloroform-d) δ8.73(d,J=7.3Hz,1H),8.46(s,1H),8.10(s,2H),7.58–7.49(m,3H),7.39(d,J=7.2Hz,1H),3.82(s,8H); 13C NMR(150MHz,Chloroform-d)δ163.4,157.9,148.3,144.4,136.2(d,J=78.7Hz),131 .3,129.2,127.4,106.2(d,J=4.3Hz),67.2,48.4,31.3.HRMS(ESI):m / z[M+H]+Calcd for C17H17N4O2+:309.1346; found:309.1346.

[0106] Example 19

[0107] 5-Phenylonpyrazolo[1,5-a]pyrimidine-3-cyano, with the following structural formula:

[0108]

[0109] Preparation method: Thiocyanate (NH4SCN, 0.5 mmol), solvent (DMSO, 3 mL), compound I-19 (0.4 mmol), compound II-19 (0.8 mmol), and oxidant (I2O5, 0.3 mmol) were added sequentially to a dry, thick-walled, pressure-resistant tube. After mixing and stirring at room temperature for a short time, the reaction solution was placed in an oil bath at 100°C and stirred for 12 h. After the reaction was completed, the operation steps were the same as in Example 1, yielding compound IV-16, which is 5-phenylpyrazolo[1,5-a]pyrimidine-3-cyano, with a yield of 86%. 1HNMR (600MHz, Chloroform-d) δ8.76 (d, J=7.3Hz, 2H), 8.37 (s, 2H), 8.21 (dd, J=7.5, 2.2Hz, 4H), 7.57 (s, 4H), 7.56–7.53 (m, 4H); 13C NMR(150MHz,Chloroform-d)δ164.2,158.7,147.7,146.3,136.5,136.1,131.7,129.4,127.7,106.7,105.6.HRMS(ESI):m / z[M+H]+Calcd for C13H9N4+:221.0822; found:221.0820.

[0110] Example 20

[0111] 3-Ethyl carbamate-5-phenylpyrazolo[1,5-a]pyrimidine, with the following structural formula:

[0112]

[0113] Preparation method: Thiocyanate (NH4SCN, 0.5 mmol), solvent (DMSO, 3 mL), compound I-20 (0.4 mmol), compound III-1 (0.8 mmol), and oxidant (I2O5, 0.3 mmol) were added sequentially to a dry, thick-walled, pressure-resistant tube. After mixing and stirring at room temperature for a short time, the reaction solution was placed in an oil bath at 100 °C and stirred for 12 h. After the reaction was completed, 10% sodium thiosulfate aqueous solution was added to the reaction solution, and the reaction solution was extracted with ethyl acetate. The organic phase was dried with anhydrous Na2SO4, filtered, and the solvent was removed by vacuum distillation. Then, the solution was separated by column chromatography with silica gel as the packing material (eluent was a mixture of petroleum ether and ethyl acetate) to obtain compound IV-1, which is ethyl 3-carboxylate-5-phenylpyrazolo[1,5-a]pyrimidine, with a yield of 76%. 1HNMR(600MHz,Chloroform-d)δ8.73(d,J=6.6Hz,1H),8.56(s,1H),8.22(dd,J=6.1,3 .1Hz,2H),7.52(s,3H),7.46(d,J=7.0Hz,1H),4.44(q,J=7.6Hz,2H),1.44(s,2H); 13C NMR(150MHz,Chloroform-d)δ162.7,159.3,148.4,147.8,136.4,136.1,131.5,129.2,127.81,106.8,103.3,60.2,14.2.HRMS(ESI):m / z[M+H]+Calcd for C15H14N3O2+:268.1081; found:268.1079.

[0114] Example 21

[0115] 6-Methyl-5-phenylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester, with the following structural formula:

[0116]

[0117] Preparation method: Thiocyanate (NH4SCN, 0.8 mmol), solvent (DMSO, 3 mL), compound I-21 (0.4 mmol), compound III-2 (0.8 mmol), and oxidant (I2O5, 0.3 mmol) were added sequentially to a dry, thick-walled, pressure-resistant tube. After mixing and stirring at room temperature for a short time, the reaction solution was placed in an oil bath at 100°C and stirred for 12 h. After the reaction was completed, the operation steps were the same as in Example 20, yielding compound IV-10, which is ethyl 6-methyl-5-phenylpyrazolo[1,5-a]pyrimidine-3-carboxylate, with a yield of 71%. 1H NMR (600MHz, Chloroform-d) δ8.60 (d, J = 3.0Hz, 1H), 8.51 (s, 1H), 7.69 (q, J = 3.6Hz, 2H), 7.47 (t, J = 4.0Hz, 3H), 4.38 (t, J = 7.7Hz, 2H), 2.43 (s, 3H); 13C NMR(150MHz,Chloroform-d)δ162.9,162.7,147.7,146.6,138.1,135.0,129.8,129.2,128.5,118.3,102.8,60.3,18.0,14.6.HRMS(ESI):m / z[M+H]+Calcd for C16H16N3O2+:282.1237; found:282.1237.

[0118] Example 22

[0119] 5-(2-methoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester, with the following structural formula:

[0120]

[0121] Preparation method: Thiocyanate (NH4SCN, 0.8 mmol), solvent (DMSO, 3 mL), compound I-22 (0.4 mmol), compound III-3 (0.8 mmol), and oxidant (I2O5, 0.3 mmol) were added sequentially to a dry, thick-walled, pressure-resistant tube. After mixing and stirring at room temperature for a short time, the reaction solution was placed in an oil bath at 100°C and stirred for 12 h. After the reaction was completed, the operation steps were the same as in Example 20, yielding compound IV-8, which is ethyl 5-(2-methoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid, with a yield of 66%. 1H NMR(600MHz,Chloroform-d)δ8.65(d,J=5.6Hz,1H),8.55(s,1H),8.19(d,J=7.0Hz,1H),7.75(d,J=7.5Hz,1H),7.47 13C NMR(150MHz,Chloroform-d)δ162.8,159.2,158.1,147.9,134.5,132.4,131.9,126 .4,121.6,111.7(d,J=6.6Hz),103.0,60.3,55.8,14.6.HRMS(ESI):m / z[M+H]+Calcd for C16H16N3O3+:298.1186; found:298.1185.

[0122] Example 23

[0123] 5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester, with the following structural formula:

[0124]

[0125] Preparation method: Thiocyanate (NH4SCN, 0.5 mmol), solvent (DMSO, 3 mL), compound I-23 (0.4 mmol), compound III-4 (0.8 mmol), and oxidant (I2O5, 0.3 mmol) were added sequentially to a dry, thick-walled, pressure-resistant tube. After mixing and stirring at room temperature for a short time, the reaction solution was placed in an oil bath at 100°C and stirred for 12 h. After the reaction was completed, the operation steps were the same as in Example 20, yielding compound IV-9, which is ethyl 5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate, with a yield of 69%. 1H NMR(600MHz,Chloroform-d)δ8.76(d,J=7.3Hz,1H),8.58(s,1H),8.14–8.08(m,2H),7. 70–7.64(m,2H),7.43(d,J=7.4Hz,1H),4.44(q,J=7.1Hz,2H),1.46(t,J=7.1Hz,3H); 13C NMR(150MHz,Chloroform-d)δ162.5,159.6,148.2,147.7,136.9,134.9,132.5,1 32.3,131.4,130.5,127.5,111.5,103.7,60.5,14.6.HRMS(ESI):m / z[M+H]+Calcd forC15H13ClN3O2+:302.0691; found:302.0691.

[0126] Example 24

[0127] 5-Phenylonpyrazolo[1,5-a]pyrimidine-3-carboxamide, with the following structural formula:

[0128]

[0129] Preparation method: Thiocyanate (NH4SCN, 0.5 mmol), solvent (DMSO, 3 mL), compound I-24 (0.4 mmol), compound III-5 (0.8 mmol), and oxidant (I2O5, 0.3 mmol) were added sequentially to a dry, thick-walled, pressure-resistant tube. After mixing and stirring at room temperature for a short time, the reaction solution was placed in an oil bath at 100°C and stirred for 12 h. After the reaction was completed, the operation steps were the same as in Example 20, yielding compound IV-14, which is 5-phenylpyrazolo[1,5-a]pyrimidine-3-carboxamide, with a yield of 75%. 1HNMR(600MHz,Chloroform-d)δ8.80(d,J=7.3Hz,1H),8.68(s,1H),8.10(dd,J=7.4,2 .3Hz,2H),7.98(s,1H),7.58(d,J=1.9Hz,3H),7.45(d,J=7.4Hz,1H),6.04(s,1H); 13C NMR(150MHz,Chloroform-d)δ164.2,158.7,147.7,146.3,136.5,136.1,131.7,129.4,127.7,106.7,105.6.HRMS(ESI):m / z[M+H]+Calcd for C13H11N4O+:239.0927; found:239.0927.

[0130] Example 25

[0131] 5-Phenylonpyrazolo[1,5-a]pyrimidine-3-cyano, with the following structural formula:

[0132]

[0133] Preparation method: Thiocyanate (NH4SCN, 0.5 mmol), solvent (DMSO, 3 mL), compound I-25 (0.4 mmol), compound III-6 (0.8 mmol), and oxidant (I2O5, 0.3 mmol) were added sequentially to a dry, thick-walled, pressure-resistant tube. After mixing and stirring at room temperature for a short time, the reaction solution was placed in an oil bath at 100°C and stirred for 12 h. After the reaction was completed, the operation steps were the same as in Example 20, yielding compound IV-16, which is 5-phenylpyrazolo[1,5-a]pyrimidine-3-cyano, with a yield of 85%. 1HNMR (600MHz, Chloroform-d) δ8.76 (d, J=7.3Hz, 2H), 8.37 (s, 2H), 8.21 (dd, J=7.5, 2.2Hz, 4H), 7.57 (s, 4H), 7.56–7.53 (m, 4H); 13C NMR(150MHz,Chloroform-d)δ164.2,158.7,147.7,146.3,136.5,136.1,131.7,129.4,127.7,106.7,105.6.HRMS(ESI):m / z[M+H]+Calcd for C13H9N4+:221.0822; found:221.0820.

[0134] The preferred embodiments of the present invention have been described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the scope of the technical concept of the present invention, various simple modifications can be made to the technical solution of the present invention, and these simple modifications all fall within the protection scope of the present invention.

Claims

1. A method for preparing the 7-hydrogen-substituted pyrazolo[1,5-a]pyrimidine compound shown in formula (IV), characterized in that, The preparation method includes: contacting the compound shown in formula (I) with the compound shown in formula (II) or formula (III), thiocyanate, iodine-containing oxidant and solvent to cause a reaction; Among them, R 1 It is selected from one of C2-C6 ester group, morpholinone group, C1-C6 alkanoamide group, and cyano group; R 2 Selected from one of phenyl, C1-C6 alkyl-substituted phenyl, C1-C6 alkoxy-substituted phenyl, halogen-substituted phenyl, nitro-substituted phenyl, and furanyl; R 3 Selected from hydrogen, C1-C6 alkyl groups, and halogens; The iodine-containing oxidant is diiodine pentoxide, and the solvent is dimethyl sulfoxide.

2. The preparation method according to claim 1, characterized in that, The R 1 It is selected from one of the following groups: ethyl formate, methyl formate, morpholinone, formamido, and cyano.

3. The preparation method according to claim 1, characterized in that, The R 2 The R is selected from one of phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl, 2-chlorophenyl, 2-methoxyphenyl, and furanyl. 3 It is selected from one of hydrogen, methyl, and bromine.

4. The preparation method according to claim 3, characterized in that, The compound represented by formula (II) is selected from any one of the following compounds:

5. The preparation method according to claim 3, characterized in that, The compound represented by formula (III) is selected from any one of the following compounds:

6. The preparation method according to claim 1, characterized in that, The molar ratio of the compound shown in formula (I) to the compound shown in formula (II) or (III), the thiocyanate and the iodine-containing oxidant is 1:2:1.25:0.

75.

7. The preparation method according to claim 1, characterized in that, The thiocyanate is selected from one of ammonium thiocyanate, potassium thiocyanate, and sodium thiocyanate.

8. The preparation method according to claim 1, characterized in that, The molar volume ratio of the compound shown in formula (I) to the solvent is 1 mmol / L: 7.5 mL.

9. The preparation method according to claim 1, characterized in that, The reaction temperature is 40~100 ℃, and the reaction time is 12 h.

10. The preparation method according to claim 1, characterized in that, It also includes the separation and purification of reaction products.

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