CN109988172B - A kind of synthetic method of pyrazolo[1,5-A]pyrimidine heterocyclic compound and derivative - Google Patents

Abstract

The invention relates to a method for synthesizing pyrazolo[1,5-A]pyrimidine heterocyclic compounds and derivatives. The steps are: (1) preparing tert-butyl 4-aminocyclohexylcarbamate; (2) preparing 2-formyl- 3-methyl-butyronitrile; (3) preparation of 4-isopropyl-1H-pyrazole-5-amine; (4) preparation of 3-isopropylpyrazolo[1,5-a]pyrimidine-5,7-diol ; (5) Preparation of 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrimidine; (6) Using 5,7-dichloro-3-isopropylpyrazolo[1,5-a] ] pyrimidine to prepare 5,7-dibromo-3-isopropylpyrazolo[1,5-a]pyrimidine; ⑺ prepare 4-(5-bromo-3-isopropylpyrazolo[1,5-a] ] Pyrimidine-7-ylamino)-N, N-dimethylbenzenesulfonamide; (8) Preparation of 4-(5-(4-(1,1-dimethylethoxy)carbonyl)-aminocyclohexylamino) -3-Isopropylpyrazolo[1,5-a]pyrimidin-7-ylamino)-N,N-dimethylbenzenesulfonamide. The invention optimizes the reaction process, simplifies the reaction steps, and is beneficial to improve the reaction conversion rate and product yield.

Description

A kind of synthetic method of pyrazolo[1,5-A]pyrimidine heterocyclic compound and derivative

technical field

The invention belongs to the technical field of chemical preparation, and relates to a method for synthesizing pyrazolo[1,5-A]pyrimidine heterocyclic compounds and derivatives.

Background technique

It is well known that the biological activity of nitrogen-containing heterocyclic compounds has always been concerned by scientists, and the aromatic heterocyclic or multi-substituted aromatic rings introduced into the structure of pyrazole ring compounds show higher activity. In recent years, scientists have devoted themselves to the study of pyrazolopyrimidine compounds with high efficiency, low toxicity, structural diversity and broad biological activity. Among them, pyrazolopyrimidine compounds with substituents are heterocyclic compounds with high biological and medicinal activities, such as bactericidal, herbicidal, insecticidal and medicinal activities, and have important research and application value. Pyrazolopyrimidines are also important intermediates in organic synthesis, widely used in the synthesis of aromatic and heterocyclic compounds. Pyrazolopyrimidine derivatives have a variety of synthetic methods and exhibit numerous biological activities, which have aroused extensive research interests of researchers. Constantly searching and trying the synthetic methods of such compounds has great theoretical and application significance for the development of new drugs.

Pyrazolo[1,5-a]pyrimidine is an important heterocyclic compound whose structure exists in a variety of drugs and pesticides, such as Zaleplon (formula 1) with hypnotic effect, Ocinaplon (formula 1), an anxiolytic drug. 2) and the central structural units of Pyrazophos (formula 3) with bactericidal and insecticidal effects are all pyrazolo[1,5-a]pyrimidines.

In recent years, some pyrazolo[1,5-a]pyrimidine derivatives have also been found to have anti-cancer, anti-tumor, anti-anxiety, antibacterial and other activities, and these compounds can also be used as hepatitis C inhibitors, estrogen Hormone receptor ligands, CRF antagonists and COX-2 inhibitors, etc. Based on these remarkable and extensive biological activities, the research on the synthesis of pyrazolo[1,5-a]pyrimidines has also attracted the attention of synthetic chemists.

There are many synthetic methods for pyrazolo[1,5-a]pyrimidines, but most of these synthetic methods have some disadvantages, such as: harsh reaction conditions, relatively low yield, poor regioselectivity or complicated synthesis steps etc., therefore, synthetic chemists are still working on developing new methods for the efficient and mild synthesis of pyrazolo[1,5-a]pyrimidines.

SUMMARY OF THE INVENTION

The purpose of the present invention is to provide a synthesis method of pyrazolo[1,5-A]pyrimidine heterocyclic compounds and derivatives, optimize the reaction process, shorten the reaction time, increase the production capacity, improve the conversion rate and selectivity of the reactants and product yield.

The technical scheme of the present invention is: a method for synthesizing pyrazolo[1,5-A]pyrimidine heterocyclic compounds and derivatives, the compound is 4-(5-(4-(1,1-dimethylethoxy) ) carbonyl)-aminocyclohexylamino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-ylamino)-N,N-dimethylbenzenesulfonamide, comprising the following steps:

(1) Preparation of tert-butyl 4-aminocyclohexylcarbamate: slowly add the CHCl solution of di-tert _- butyl dicarbonate to the CHCl solution of trans _- 1,4-diaminocyclohexane and stir for 16 hours to react. The temperature was -5°C; then CHCl ₃ was distilled off under reduced pressure, and CH ₂ Cl ₂ and saturated Na ₂ CO ₃ solution were added to the white distillation residue; the organic layer was washed with saturated Na ₂ CO ₃ solution and dried with Na ₂ SO ₄ , then concentrated in vacuo to white solid tert-butyl 4-aminocyclohexylcarbamate;

(2) Preparation of 2-formyl-3-methyl-butyronitrile: at -78 °C, add n-BuLi solution dropwise to the THF solution of diisopropylamine, and stir the reactant at -78 °C for 30 minutes ; Isovaleronitrile was added and the reaction was stirred for 10 minutes; at -78°C, the reaction mixture was added to a solution of ethyl formate in THF, stirred at -78°C for 30 minutes, then warmed to room temperature and stirred for reaction 16 hr; adjusted to pH=3 with dilute hydrochloric acid, and extracted the product with EtOAc; the organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , then concentrated in vacuo and purified by chromatography to give compound 2-formyl-3-methyl base-butyronitrile;

(3) Preparation of 4-isopropyl-1H-pyrazol-5-amine: at a temperature of -5°C in an ice-salt bath, 2-formyl-3-methyl-butyronitrile mixed in 100 ml of diethyl ether slowly increased to 85% Add dropwise to the ether solution of hydrazine hydrate for about 1 hour, remove the ice-salt bath, and stir at room temperature for 3 hours; add 50 ml of water to the reaction solution, stir for 15 minutes, extract the ether layer, wash three times with 25 ml of water, dry Dry over magnesium sulfate and concentrate on a rotary evaporator to obtain 4-isopropyl-1H-pyrazol-5-amine as white snowflake crystals;

(4) Preparation of 3-isopropylpyrazolo[1,5-a]pyrimidine-5,7-diol: Dissolve sodium in EtOH, add 4-isopropyl-1H-pyrazole-5- Amine and dimethyl malonate were refluxed for 16 hours, and the reaction temperature was 80 °C; the reaction solution was concentrated and dissolved in water; then adjusted to pH=3 with dilute hydrochloric acid, and the formed precipitate was collected by filtration; the precipitated solid was water Washing and drying in vacuo gave the product 3-isopropylpyrazolo[1,5-a]pyrimidine-5,7-diol as an off-white solid;

(5) Preparation of 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrimidine: 3-isopropylpyrazolo[1,5-a]pyrimidine-5,7-diol and N,N-dimethylaniline was suspended in POCl ₃ , heated to 110 °C in a microwave reactor, and reacted for 15 min; the reaction product was concentrated to dryness, the concentrate was poured into ice, and extracted with CH ₂ Cl ₂ 3 -5 times, the extract was washed with brine, dried _over anhydrous _Na2SO4 , and concentrated in vacuo; the concentrate was purified by column chromatography to give 5,7-dichloro-3-isopropylpyrazolo[1 ,5-a]pyrimidine compound;

(6) Use 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrimidine to prepare 5,7-dibromo-3-isopropylpyrazolo[1,5-a]pyrimidine: 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrimidine 0.02mol, trimethylbromosilane 0.1mol, and acetonitrile 60mL were added to the round-bottomed flask in turn, in a microwave reactor Heat to 150°C, react for 15 min, evaporate the solvent under reduced pressure, and recrystallize the residue from petroleum ether and ethyl acetate to obtain 5,7-dibromo-3-isopropylpyrazolo[1,5- a] pyrimidine product;

(7) Preparation of 4-(5-bromo-3-isopropylpyrazolo[1,5-a]pyrimidin-7-ylamino)-N,N-dimethylbenzenesulfonamide: to 5,7-dibromo 4-Amino-N,N-dimethylbenzenesulfonamide was added to the EtOH solution of -3-isopropylpyrazolo[1,5-a]pyrimidine, and the reaction was refluxed for 2h. The reaction product was concentrated and the concentrate was triturated with hot MeOH to give the product 4-(5-bromo-3-isopropylpyrazolo[1,5-a]pyrimidin-7-ylamino)-N,N- as a white solid dimethylbenzenesulfonamide;

(8) Preparation of 4-(5-(4-(1,1-dimethylethoxy)carbonyl)-aminocyclohexylamino)-3-isopropylpyrazolo[1,5-a]pyrimidine-7- ylamino)-N,N-dimethylbenzenesulfonamide: 4-(5-bromo-3-isopropylpyrazolo[1,5-a]pyrimidin-7-ylamino)-N,N-di Acetonitrile, tert-butyl 4-aminocyclohexylcarbamate and triethylamine were added to the dioxane solution of methylbenzenesulfonamide; the reaction was heated by microwave and reacted at 180°C for 1 hour in a sealed tube; the reaction mixture was subjected to chromatography Purification to give compound 4-(5-(4-(1,1-dimethylethoxy)carbonyl)-aminocyclohexylamino)-3-isopropylpyrazolo[1,5-a]pyrimidine- 7-ylamino)-N,N-dimethylbenzenesulfonamide.

The reaction formula of step (1) is as follows:

The reaction formulas of steps ⑵～⑻ are as follows:

Step (3) can be replaced by: adding hydrazine hydrate and AcOH to the EtOH solution of 2-formyl-3-methyl-butyronitrile, refluxing for 16h, and the reaction temperature is 80°C; after concentrating the reaction product, use saturated Na ₂ Diluted with CO ₃ solution, extracted with CH ₂ Cl ₂ 3-5 times. The extract was washed with brine, dried over anhydrous _Na2SO4 , and concentrated in vacuo to give compound ₄ -isopropyl-lH-pyrazol-5-amine.

Step (5) can be replaced by: 3-isopropylpyrazolo[1,5-a]pyrimidine-5,7-diol and N,N-dimethylaniline are suspended in POCl ₃ for reflux reaction for 16h, the reaction temperature was 108 °C; the reaction product was concentrated to dryness, and the concentrate was poured into ice _; extracted with _CH2Cl2 3-5 times. The extract was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo, and the product was purified by chromatography to give 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrimidine compound .

The intermediate process of the present invention, the product testing instrument and the testing conditions are:

①The nuclear magnetic resonance spectrum was measured with BrukerAC 300 nuclear magnetic resonance instrument, TMS was the internal standard, and DMSO-d ₆ or CDCl ₃ was the solvent;

②High-resolution mass spectrometry was measured by BruckermicroTOF mass spectrometer;

③The melting point was measured by Kofler micro melting point tester.

The method for synthesizing pyrazolo[1,5-A]pyrimidine heterocyclic compounds and derivatives of the present invention optimizes the reaction process, shortens the reaction time, and improves the production capacity by improving the reaction conditions and adopting the microwave catalytic reaction in step (5), It is beneficial to improve the conversion rate, selectivity and product yield of reactants. Conversion from 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrimidine to 5,7-dibromo-3-isopropylpyrazolo because bromine is more reactive than chlorine The synthesis reaction of [1,5-a]pyrimidine is beneficial to increase the yield and speed up the reaction rate.

Detailed ways

The present invention will be described in detail below with reference to the embodiments. The protection scope of the present invention is not limited to the embodiments, and any changes made by those skilled in the art within the scope defined by the claims also belong to the protection scope of the present invention.

The method for synthesizing pyrazolo[1,5-A]pyrimidine heterocyclic compounds and derivatives of the present invention, the compound is 4-(5-(4-(1,1-dimethylethoxy)carbonyl)-amino Cyclohexylamino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-ylamino)-N,N-dimethylbenzenesulfonamide, the synthesis steps are as follows:

(1) Preparation of tert-butyl 4-aminocyclohexylcarbamate: slowly add a solution of di-tert-butyl dicarbonate (2.86 g, 13.1 mmol) in CHCl ₃ (70 mL) to trans-1,4-diaminocyclohexane ( 3 g, 26.3 mmol) of CHCl ₃ (50 mL) solution in CHCl 3 (50 mL) to accept the milky white suspension, and the reaction was stirred for 16 hours at a reaction temperature of 80° C., and then CHCl ₃ was distilled off under reduced pressure. To the white distillation residue was added _CH2Cl2 and _{saturated Na2CO3 solution} . The organic layer was washed with saturated _Na2CO3 solution, dried _{over Na2SO4} , and then concentrated in vacuo to 2.2 g of tert-butyl ₄ -aminocyclohexylcarbamate as a white solid in a yield of 39.1% by mass. ¹ H NMR (300MHz, CDCl ₃ ) δ 1.10-1.26 (m, 4H), 1.44 (s, 9H), 1.84-2.07 (m, 4H), 2.59-2.64 (m, 1H), 3.38 (m, 1H) ), 3.39(br,1H), 4.33(br,1H).

(2) Preparation of 2-formyl-3-methyl-butyronitrile: at -78 ℃, to diisopropylamine (28 mL, 0.2 mol) in THF (100 mL) solution was added dropwise n-BuLi (2.5 M of acetylene) solution, 80 mL) solution, and the reaction was stirred at -78°C for 30 minutes. Isovaleronitrile (18.9 mL, 0.18 mol) was added and the reaction was stirred at -78°C for 10 minutes. The reaction mixture was added to a solution of ethyl formate (15.3 mL, 0.19 mol) in THF (100 mL) at -78°C and the reaction was stirred at -78°C for 30 minutes, then warmed to room temperature and stirred for 16 hours. The reaction product was adjusted to pH=3 with 1M dilute hydrochloric acid (300 mL). The product was extracted with EtOAc, the organic layer was washed with brine, dried _over anhydrous _Na2SO4 , and concentrated to dryness in vacuo. The product was purified by chromatography (eluent EtOAc:PE=1:4) to give 18 g of compound 2-formyl-3-methylbutyronitrile with a yield of 90.2% by mass. ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.08(d,3H), 1.15(d,3H), 2.44-2.48(m,1H), 3.39(d,1H), 9.51(d,1H).

(3) Preparation of 4-isopropyl-1H-pyrazol-5-amine: 2-formyl-3-methyl-butyronitrile (18 g, 0.162 mol) mixed in 100 ml of ether at a temperature of -5 °C in an ice-salt bath ) was slowly added dropwise to the ether solution of 85% hydrazine hydrate (10.6 g of hydrazine hydrate, 0.211 mol, 30 ml of ether) for about 1 hour, the ice-salt bath was removed, and the mixture was stirred at room temperature for 3 hours. Add 50ml of water to the reaction solution, increase stirring for 15 minutes, extract the ether layer, wash three times with 25ml of water, dry over anhydrous magnesium sulfate, and concentrate on a rotary evaporator to obtain 13g of white snowflake crystals to prepare 4-isopropyl-1H-pyridine. oxazol-5-amine, the yield was 64.2% by mass. ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.19 (s, 3H), 1.22 (s, 3H), 2.67-2.72 (m, 1H), 5.13 (br, 3H), 7.12 (s, 1H).

(4) Preparation of 3-isopropylpyrazolo[1,5-a]pyrimidine-5,7-diol: Dissolve sodium (2.4 g, 0.106 mol) in EtOH (500 mL), add 4-isopropyl to the solution Propyl-1H-pyrazol-5-amine (10 g, 0.08 mol) and dimethyl malonate (14 g, 0.088 mol) were reacted under reflux for 16 h, and the reaction temperature was 80 °C. The reaction product was concentrated to dryness, and the residue was dissolved in water. The reaction product was acidified to pH=3 with dilute hydrochloric acid (2N) and the resulting precipitate was collected by filtration. The solid was washed with water and dried in vacuo to give 11 g of 3-isopropylpyrazolo[1,5-a]pyrimidine-5,7-diol product as an off-white solid in a yield of 71% by mass. ¹ HNMR(300MHz,DMSO)δ1.17-1.18(m,12H),2.94-3.04(m,2H),3.75(s,2H),4.88(s,1H),7.67(s,1H),7.78( s, 1H), 11.36 (br, 1H).

(5) Preparation of 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrimidine: 3-isopropylpyrazolo[1,5-a]pyrimidine-5,7-diol (3.95 g, 0.02 mol) and N,N-dimethylaniline (1.75 mL, 0.014 mol) were suspended in _POCl3 (38.1 mL, 0.41 mol). It was heated to 110°C in a microwave reactor and reacted for 15min. The reaction was concentrated and the residue was poured into ice. _Extract 3-5 times with _CH2Cl2 . The extract was washed with brine, dried _over anhydrous _Na2SO4 , and concentrated in vacuo. The product was purified by column chromatography (eluent EtOAc:PE=1:20) to give 4.3 g of compound 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrimidine in yield 92% (mass). ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.35-1.37 (d, 6H), 3.26-3.36 (m, 1H), 6.91 (s, 1H), 8.09 (s, 1H).

(6) Use 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrimidine to prepare 5,7-dibromo-3-isopropylpyrazolo[1,5-a]pyrimidine: 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrimidine 0.02mol, trimethylbromosilane 0.1mol, and acetonitrile 60mL were added to the round-bottomed flask in turn, in a microwave reactor Heated to 150°C, reacted for 15 min, evaporated the solvent under reduced pressure, and recrystallized the residue from petroleum ether and ethyl acetate to obtain 5.9 g of 5,7-dibromo-3-isopropylpyrazolo[1,5-a] Pyrimidine pale yellow solid, yield 92.4%, MS m/z (M) 316; ¹ H NMR (300 MHz, CDCl ₃ ): δ 7.45 (d, J=7.5 Hz, 2H), 7.18 (d, J=7.5 Hz, 2H), 2.46 (s, 3H).

(7) Preparation of 5-bromo-3-isopropylpyrazolo[1,5-a]pyrimidin-7-ylamino)-N,N-dimethylbenzenesulfonamide: to 5,7-dibromo-3- To a solution of isopropylpyrazolo[1,5-a]pyrimidine (2.10 g, 6.6 mmol) in EtOH (200 mL) was added 4-amino-N,N-dimethylbenzenesulfonamide (1.46 g, 7.3 mmol) . The reaction was refluxed for 2h, and the reaction temperature was 80°C. The reaction was concentrated and the residue was triturated with hot MeOH to give 4.3 g of white 5-bromo-3-isopropylpyrazolo[1,5-a]pyrimidin-7-ylamino)-N,N-dimethyl Benzenesulfonamide solid product, the yield is 89% (mass). ¹ H NMR (300MHz, DMSO)δ1.32(d,6H), 2.66(d,6H), 3.47(m,1H), 6.46(s,1H), 7.72-7.75(m,2H), 7.80-7.83 (m, 2H), 8.18 (s, 1H), 10.59 (s, 1H).

(8) Preparation of 4-(5-(4-(5-(4) using 4-(5-bromo-3-isopropylpyrazolo[1,5-a]pyrimidin-7-ylamino)-N,N-dimethylbenzenesulfonamide -(1,1-Dimethylethoxy)carbonyl)-aminocyclohexylamino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-ylamino)-N,N-di Methylbenzenesulfonamide: To 4-(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-ylamino)-N,N-dimethylbenzenesulfonamide (0.4g , 1.02 mmol) in dioxane (3 mL) was added acetonitrile (1 mL), tert-butyl 4-aminocyclohexylcarbamate (0.7 g, 3.3 mmol) and triethylamine (0.71 mL, 3.3 mmol). The reaction was heated by microwave at 180°C in a sealed tube for 1 hour. The reaction mixture was purified by chromatography to give 90 mg of compound 4-(5-(4-(1,1-dimethylethoxy)carbonyl)-aminocyclohexylamino)-3-isopropylpyrazolo[1, 5-a]pyrimidin-7-ylamino)-N,N-dimethylbenzenesulfonamide, yield 16%, (mass). ¹ HNMR (300MHz, CDCl ₃ ) δ 1.25-1.35(m, 10H), 1.45(s, 9H), 2.04-2.21(m, 4H), 2.75(s, 6H), 3.10(m, 1H), 3.47 (br,1H),3.80(br,1H),4.40(d,2H),5.70(s,1H),7.42(d,2H),7.70(s,1H),7.81(d,2H),8.04( s, 1H). LCMS: [M+H]=572, >98%.

The method of the present invention is used to prepare pyrazolo[1,5-A]pyrimidine heterocyclic compounds and derivatives, the reaction process is optimized, the reaction time is shortened, and the yield is increased and the reaction rate is accelerated. Table 1 shows the present invention Preparation of 4-(5-(4-(1,1-dimethylethoxy)carbonyl)-aminocyclohexylamino)-3-isopropylpyrazolo[1,5-a]pyrimidine with prior art -7-ylamino)-N,N-dimethylbenzenesulfonamide reaction time and product yield comparison.

Table 1 reaction time and product yield comparison

Claims (3)

1. A synthetic method of pyrazolo [1,5-A ] pyrimidine heterocyclic compounds and derivatives thereof is disclosed, wherein the compounds are 4- (5- (4- (1, 1-dimethylethoxy) carbonyl) -aminocyclohexylamino) -3-isopropylpyrazolo [1,5-a ] pyrimidin-7-ylamino) -N, N-dimethylbenzenesulfonamide, and the synthetic method is characterized in that: the method comprises the following steps:

⑴ preparation of 4-aminocyclohexyl carbamic acid tert-butyl ester CHCl of di-tert-butyl dicarbonate₃The solution was slowly added to CHCl of trans-1, 4-diaminocyclohexane₃Stirring the solution for reaction for 16 hours, wherein the reaction temperature is-5 ℃; then removing CHCl by reduced pressure distillation₃Adding CH to the white residue₂Cl₂And saturated Na₂CO₃A solution; saturated Na for organic layer₂CO₃Washing with Na₂SO₄Drying and then vacuum concentrating to obtain white solid tert-butyl 4-aminocyclohexylcarbamate;

⑵ preparation of 2-formyl-3-methyl-butyronitrile by adding n-BuLi solution dropwise to diisopropylamine in THF at-78 deg.C, stirring the reaction at-78 deg.C for 30 min, adding isovaleronitrile, stirring the reaction for 10 min, adding the reaction mixture to ethyl formate in THF at-78 deg.C, stirring at-78 deg.C for 30 min, heating to room temperature and stirring for 16h, adjusting pH =3 with dilute hydrochloric acid, extracting the product with EtOAc, washing the organic layer with brine, extracting with anhydrous Na₂SO₄Drying, vacuum concentrating, and purifying by chromatography to obtain 2-formyl-3-methyl-butyronitrile;

preparing 4-isopropyl-1H-pyrazole-5-amine: slowly dripping 2-formyl-3-methyl-butyronitrile mixed in 100ml of diethyl ether into diethyl ether solution of hydrazine hydrate at the temperature of ice salt bath-5 ℃, finishing dripping for about 1 hour, removing the ice salt bath, and stirring for 3 hours at room temperature; adding 50ml of water into the reaction solution, stirring for 15 minutes, extracting an ether layer, washing with 25ml of water for three times, drying by anhydrous magnesium sulfate, and concentrating by a rotary evaporator to obtain white snowflake-shaped crystals of 4-isopropyl-1H-pyrazol-5-amine;

preparation of 3-isopropylpyrazolo [1,5-a ] pyrimidine-5, 7-diol: dissolving sodium in EtOH, adding 4-isopropyl-1H-pyrazole-5-amine and dimethyl malonate into the solution, and carrying out reflux reaction for 16H at the reaction temperature of 80 ℃; concentrating the reaction solution and dissolving in water; adjusting the pH to =3 with dilute hydrochloric acid and collecting the precipitate formed by filtration; the precipitate solid was washed with water and dried under vacuum to give 3-isopropylpyrazolo [1,5-a ] pyrimidine-5, 7-diol product as an off-white solid;

⑸ preparation of 5, 7-dichloro-3-isopropylpyrazolo [1,5-a ]]Pyrimidine: 3-isopropyl pyrazolo [1, 5-a)]Pyrimidine-5, 7-diol and N, N-dimethylaniline suspended in POCl₃Heating to 110 ℃ in a microwave reactor, and reacting for 15 min; the reaction product was concentrated to dryness, the concentrate was poured into ice and washed with CH₂Cl₂Extracting for 3-5 times, washing the extractive solution with brine, and adding anhydrous Na₂SO₄Drying, and then concentrating in vacuum; purifying the concentrate by column chromatography to obtain 5, 7-dichloro-3-isopropylpyrazolo [1,5-a]A pyrimidine compound;

sixthly, preparing 5, 7-dibromo-3-isopropyl pyrazolo [1,5-a ] pyrimidine by using 5, 7-dichloro-3-isopropyl pyrazolo [1,5-a ] pyrimidine: sequentially adding 0.02mol of 5, 7-dichloro-3-isopropylpyrazolo [1,5-a ] pyrimidine, 0.1mol of trimethyl bromomonosilane and 60mL of acetonitrile into a round-bottom flask, heating to 150 ℃ in a microwave reactor, reacting for 15min, evaporating the solvent under reduced pressure, and recrystallizing the residue with petroleum ether and ethyl acetate to obtain a light yellow solid 5, 7-dibromo-3-isopropylpyrazolo [1,5-a ] pyrimidine product;

preparation of 4- (5-bromo-3-isopropylpyrazolo [1,5-a ] pyrimidin-7-ylamino) -N, N-dimethylbenzenesulfonamide: adding 4-amino-N, N-dimethylbenzenesulfonamide into an EtOH solution of 5, 7-dibromo-3-isopropyl pyrazolo [1,5-a ] pyrimidine, and carrying out reflux reaction for 2 hours; the reaction product was concentrated and the concentrate triturated with hot MeOH to give the product 4- (5-bromo-3-isopropylpyrazolo [1,5-a ] pyrimidin-7-ylamino) -N, N-dimethylbenzenesulfonamide as a white solid;

and preparation of 4- (5- (4- (1, 1-dimethylethoxy) carbonyl) -aminocyclohexylamino) -3-isopropylpyrazolo [1,5-a ] pyrimidin-7-ylamino) -N, N-dimethylbenzenesulfonamide: adding acetonitrile, tert-butyl 4-aminocyclohexylcarbamate and triethylamine to a solution of 4- (5-bromo-3-isopropylpyrazolo [1,5-a ] pyrimidin-7-ylamino) -N, N-dimethylbenzenesulfonamide in dioxane; the reaction is carried out by microwave heating, and the reaction is carried out for 1 hour at 180 ℃ in a sealed tube; the reaction mixture was purified by chromatography to give the compound 4- (5- (4- (1, 1-dimethylethoxy) carbonyl) -aminocyclohexylamino) -3-isopropylpyrazolo [1,5-a ] pyrimidin-7-ylamino) -N, N-dimethylbenzenesulfonamide.

2. Pyrazolo [1,5-a according to claim 1]The synthesis method of the pyrimidine heterocyclic compound and the derivative is characterized in that in the step ⑶, hydrazine hydrate and hydrazine hydrate are added into EtOH solution of 2-formyl-3-methyl-butyronitrileAcOH, refluxing and reacting for 16h at the reaction temperature of 80 ℃; the reaction product was concentrated and then saturated Na was added₂CO₃Diluting the solution with CH₂Cl₂Extracting for 3-5 times, washing the extractive solution with brine, and adding anhydrous Na₂SO₄Drying and vacuum concentration to obtain the compound 4-isopropyl-1H-pyrazole-5-amine.

3. Pyrazolo [1,5-a according to claim 1]The method for synthesizing the pyrimidine heterocyclic compound and the derivative is characterized in that in the step ⑸, 3-isopropyl pyrazolo [1,5-a ] is replaced]Pyrimidine-5, 7-diol and N, N-dimethylaniline suspended in POCl₃Carrying out medium reflux reaction for 16h at the reaction temperature of 108 ℃; concentrating the reaction product to dryness and pouring the concentrate into ice; by CH₂Cl₂Extracting for 3-5 times, washing the extractive solution with brine, and adding anhydrous Na₂SO₄Drying, then vacuum concentrating, and purifying the product by chromatography to obtain 5, 7-dichloro-3-isopropyl pyrazolo [1,5-a]A pyrimidine compound.