A method for synthesizing a substituted pyrazoloquinazoline derivative

Abstract

The application belongs to the field of chemical industry, and particularly relates to a synthesis method of a substituted pyrazoloquinazoline derivative. The method provided by the application comprises sequentially preparing 2-chloro-5,6,7,8-tetrahydroquinazoline, 2-chloro-6,7-dihydroquinazolin-8(5H)-ketoxime, 2-chloro-6,7-dihydroquinazolin-8(5H)-ketone, 2-(2-methoxy-8-oxo-5,6,7,8-tetrahydroquinazolin-7-yl)-2-oxoacetic acid methyl ester and 1-(2-hydroxyethyl)-8-methoxy-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylic acid methyl ester, and finally obtaining 1-(2-hydroxyethyl)-8-((5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide. By using the method of the application, three reaction steps are reduced, the total yield is increased by nearly one time, and the method is far higher than the original process route; and the application of dangerous reagents such as hydrazine hydrate and iodine is avoided, and the method is easy to scale up.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of chemical industry, and particularly relates to a synthetic method of substituted pyrazoloquinazoline derivatives. BACKGROUND

[0002] Pyrazoloquinazoline derivatives represent Onvansertib (NMS-P937) with the chemical name of 1-(2-hydroxyethyl)-8-(5-(4-methylpiperazin-1-yl)-2-trifluoromethoxyphenyl)amino)-4,5-dihydropyrazolo[4,3-h]quinazoline-3-carboxamide, and a structural formula is as follows:

[0003]

[0004] Onvansertib (NMS-P937) as a selective PLK1 kinase inhibitor drug has a broad spectrum of anticancer activity, and has an inhibitory activity IC50 of 2nM on PlK1, has better selectivity in the PLKs family, and has an inhibitory activity on P1K2 and P1K3 which is 5000 times higher, and has activities on ovarian cancer, colon cancer, pancreatic cancer, lung cancer, breast cancer, prostate cancer, hematopoietic tumors of the bone marrow system, hematopoietic tumors of the lymphatic system, leukemia, osteosarcoma and melanoma. At present, clinical trials involving Onvansertib are being carried out in patients with acute myeloid leukemia (NCT03303339) and prostate cancer (NCT03414034); and in a clinical phase II trial using Onvansertib and F0LFIRI / bevacizumab as a second-line treatment for KRAS-mutated metastatic colorectal cancer (mCRC), the results show that the treatment scheme has better antitumor activity and tolerance than single drug administration. Since the drug plays an indispensable role in the treatment of various cancers, in recent years, it has been applied to various drug combination therapies for tumors. Therefore, people have been committed to the research on the synthesis process of the compounds, and hope to obtain a simple, green and economical synthesis route.

[0005] Patent W02008074788 discloses a synthetic method for preparing substituted pyrazoloquinazoline derivatives, which uses 1,2-cyclohexanedione as a starting material, and obtains a target product through 13 steps, as shown in the following route: Figure 2

[0006] The above synthetic method has the problems of long route and low total yield. SUMMARY

[0007] The main purpose of the present application is to provide a synthetic method of substituted pyrazoloquinazoline derivatives to overcome the deficiencies in the prior art.

[0008] To achieve the above-mentioned purposes, the technical scheme adopted by the present application comprises:​

[0009] According to a first aspect of the embodiments of the present application, a method for synthesizing a substituted pyrazoloquinazoline derivative is provided, comprising the following steps:

[0010] S1, hydroxylamine aqueous solution is added to a solution of 2,4-dichloro-5,6,7,8-tetrahydroquinazoline and zinc powder in ethanol at room temperature, and after stirring uniformly at a temperature of 50-130℃, it is cooled to room temperature, and after filtration, a filtrate and a residue are obtained, the filtrate is extracted to obtain an organic phase, the organic phase is washed and dried, and after filtration, it is concentrated under reduced pressure to obtain a concentrate, and the concentrate is purified to obtain white solid 2-chloro-5,6,7,8-tetrahydroquinazoline;

[0011] S2, potassium tert-butoxide is added to a tetrahydrofuran solution of the 2-chloro-5,6,7,8-tetrahydroquinazoline, and after stirring uniformly at a temperature of -60--90℃, it is warmed to room temperature, and then extracted to obtain an organic phase, which is dried, filtered and evaporated to dryness to obtain yellow solid 2-chloro-6,7-dihydroquinazolin-8(5H)-ketoxime;

[0012] S3, water and acetone are added to a solution of the 2-chloro-6,7-dihydroquinazolin-8(5H)-ketoxime in hydrochloric acid at room temperature, and after reaction, extraction is performed to obtain an organic phase, which is dried, filtered, and after concentration under reduced pressure, a concentrate is obtained, and the concentrate is purified to obtain yellow solid 2-chloro-6,7-dihydroquinazolin-8(5H)-ketone;

[0013] S4, sodium methoxide is added to a solution of the 2-chloro-6,7-dihydroquinazolin-8(5H)-ketone and dimethyl oxalate in methanol at room temperature, and after stirring uniformly at a temperature of 60-80℃, it is cooled, and after concentration under reduced pressure, a concentrate is obtained, and the concentrate is purified to obtain yellow solid methyl 2-(2-methoxy-8-oxo-5,6,7,8-tetrahydroquinazolin-7-yl)-2-oxoacetate;

[0014] S5, 2-hydrazinoethanol is added to a mixture of the methyl 2-(2-methoxy-8-oxo-5,6,7,8-tetrahydroquinazolin-7-yl)-2-oxoacetate in acetic acid, and after stirring uniformly at room temperature, the reaction is quenched with hydrochloric acid and the pH value is adjusted, and after evaporation of the solvent, a crude product is obtained, which is redissolved in water, and after basification, extraction is performed, and the organic phase is collected, which is dried, filtered and concentrated to obtain a concentrate, and the concentrate is purified to obtain yellow solid methyl 1-(2-hydroxyethyl)-8-methoxy-4,5-dihydro-1H-pyrazolo[4,3-h]quinoline-3-carboxylate;

[0015] S6, to the solution of 1-(2-hydroxyethyl)-8-methoxy-4,5-dihydro-1H-pyrazolo[4,3- h]quinazoline-3-carboxylic acid methyl ester and acetyl chloride in dichloromethane, diisopropylethylamine was added, stirred uniformly at room temperature, after the reaction was completed, extraction was carried out, the organic phase was collected, after the organic phase was washed, dried, filtered, and concentrated under reduced pressure, a concentrate was obtained, after the concentrate was purified, yellow solid 1-(2-acetyloxyethyl)-8-methoxy-4,5-dihydro-1H-pyrazolo[4,3- h]quinazoline-3-carboxylic acid methyl ester was obtained;

[0016] S7, to the solution of 1-(2-acetyloxyethyl)-8-methoxy-4,5-dihydro-1H-pyrazolo[4,3- h]quinazoline-3-carboxylic acid methyl ester in N,N-dimethylformamide, phosphorus oxychloride was added at room temperature, stirred uniformly at 90-110°C, after the reaction was completed, extraction was carried out, the organic phase was collected, after the organic phase was washed, dried, filtered, and concentrated under reduced pressure, a concentrate was obtained, after the concentrate was purified, yellow solid 1-(2-acetyloxyethyl)-8-chloro-4,5-dihydro-1H-pyrazolo[4,3- h]quinazoline-3-carboxylic acid methyl ester was obtained;

[0017] S8, to the solution of 5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)aniline, 1-(2- acetyloxyethyl)-8-chloro-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylic acid methyl ester in dioxane, potassium phosphate, Pd2dba3 and 4,5-bis(diphenylphosphino)- 9,9-dimethylxanthene were added at room temperature, stirred uniformly at 100-120°C, after the reaction was completed, extraction was carried out, the organic phase was collected, after the organic phase was washed, dried, filtered, and concentrated under reduced pressure, a concentrate was obtained, after the concentrate was purified, yellow solid 1-(2-acetyloxyethyl)-8-((5-(4-methylpiperazin-1-yl)-2- (trifluoromethoxy)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylic acid methyl ester was obtained;

[0018] S9, to the 1-(2-acetyloxyethyl)-8-((5-(4-methylpiperazin-1-yl)-2- (trifluoromethoxy)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylic acid methyl ester in methanol and water, lithium hydroxide was added, stirred uniformly at room temperature, the pH value was adjusted, after purification, yellow solid 1-(2-hydroxyethyl)-8-((5-(4-methylpiperazin-1-yl)-2- (trifluoromethoxy)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylic acid was obtained;

[0019] S10, 1-(2-hydroxyethyl)-8-((5-(4-methylpiperazin-1-yl)-2- (trifluoromethoxy) phenyl) amino) -4, 5-dihydro-1H-pyrazolo [4, 3-h] quinoline-3- carboxylic acid in N, N-dimethylformamide is added ammonium chloride, 2-(7- azobenzenetriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphate and diisopropylethylamine, stirring at room temperature, after the reaction is completed, purification to obtain yellow solid 1-(2-hydroxyethyl)-8-((5-(4-methylpiperazin-1-yl)-2- (trifluoromethoxy) phenyl) amino) -4, 5-dihydro-1H-pyrazolo [4, 3-h] quinoline-3- carboxamide.

[0020] Further, in step S1, 9-10 g of 2,4-dichloro-5,6,7,8-tetrahydroquinoline, 9.5-10.5 g of zinc powder, and 16.5-17.5 g of a hydroxylamine aqueous solution with a mass percentage of 15-25% correspond to 120 mL of ethanol; the step S1 comprises filtering with diatomite and extracting with ethyl acetate, and the organic phase is washed with brine, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure at 40-50°C, and the concentrate is purified by column chromatography to obtain white solid 2-chloro-5,6,7,8-tetrahydroquinoline.

[0021] Further, in step S2, 5-6 g of 2-chloro-5,6,7,8-tetrahydroquinoline and 3-4 g of potassium tert-butoxide correspond to 400 mL of tetrahydrofuran; the step S2 comprises stirring uniformly at a temperature of -70--86°C, then warming to room temperature, pouring into water / ice acetic acid, extracting with ethyl acetate, drying the organic phase with anhydrous sodium sulfate, filtering and evaporating to dryness to obtain yellow solid 2-chloro-6,7-dihydroquinazoline-8(5H)-ketoxime.

[0022] Further, in step S3, 5-6 g of 2-chloro-6,7-dihydroquinazoline-8(5H)- ketoxime, 260-276 mL of water and 60-74 mL of acetone correspond to 67 mL of hydrochloric acid; the step S3 comprises pouring into sodium carbonate / water after the reaction is completed as detected by LCMS, extracting with ethyl acetate, drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure at 35-45°C, and the concentrate is purified by column chromatography to obtain yellow solid 2-chloro-6,7-dihydroquinazoline-8(5H)-ketone.

[0023] Further, in step S4, 1.5-2.5 g of 2-chloro-6,7-dihydroquinazolin-8(5H)-one, 2.0-3.2 g of dimethyl oxalate, and 3.0-4.8 g of sodium methoxide with a mass percentage of 25-35% in methanol correspond to 30 mL of methanol; after the reaction is completed as detected by LCMS, the reaction mixture is concentrated under reduced pressure at 40-50°C, and the concentrate is purified by column chromatography to obtain 2-(2-methoxy-8-oxo-5,6,7,8-tetrahydroquinazolin-7-yl)-2-oxoacetic acid methyl ester in the form of a yellow solid.

[0024] Further, in step S5, 2.0-2.8 g of 2-(2-methoxy-8-oxo-5,6,7,8-tetrahydroquinazolin-7-yl)-2-oxoacetic acid methyl ester and 0.8-1.2 g of 2-hydrazinoethanol correspond to 4 mL of acetic acid; after the reaction is completed as detected by LCMS, the reaction is quenched with hydrochloric acid, the pH value is adjusted to 5-7, the solvent is evaporated, the crude product is redissolved in water, the solution is basified with 30% aqueous ammonium hydroxide solution, and the product is extracted with dichloromethane; the organic phase is dried over anhydrous sodium sulfate, filtered, concentrated, and the concentrate is purified by flash column chromatography to obtain 1-(2-hydroxyethyl)-8-methoxy-4,5-dihydro-1H-pyrazolo[4,3-h]quinoline-3-carboxylic acid methyl ester in the form of a yellow solid.

[0025] Further, in step S6, 1.2-2.2 g of 1-(2-hydroxyethyl)-8-methoxy-4,5-dihydro-1H-pyrazolo[4,3-h]quinoline-3-carboxylic acid methyl ester, 560-575 mg of acetyl chloride, and 0.7-1.5 g of diisopropylethylamine correspond to 12 mL of dichloromethane; after the reaction is completed as detected by LCMS, water is added to the reaction mixture, and the product is extracted with dichloromethane; the organic phase is washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure at 40-50°C, and the concentrate is purified by column chromatography to obtain 1-(2-acetyloxyethyl)-8-methoxy-4,5-dihydro-1H-pyrazolo[4,3-h]quinoline-3-carboxylic acid methyl ester in the form of a yellow solid.

[0026] Further, in step S7, 1.2-2.0 g of 1-(2-acetyloxyethyl)-8-methoxy-4,5-dihydro-1H- pyrazolo[4,3-h]quinazoline-3-carboxylic acid methyl ester and 3.8-4.6 g of phosphorus oxychloride correspond to 10 mL of N,N-dimethylformamide; the step S7 comprises, after the reaction is completed as detected by LCMS, adding water to the reaction mixture and extracting with ethyl acetate, washing the extracted organic phase with an aqueous ammonium chloride solution, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure at 40-50°C, and purifying the concentrate by column chromatography to obtain 1-(2-acetyloxyethyl)-8-chloro-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylic acid methyl ester in the form of a yellow solid.

[0027] Further, in step S8, 0.8-1.6 g of 5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)aniline, 1.2-1.8 g of 1-(2-acetyloxyethyl)-8-chloro-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylic acid methyl ester, 2.2-3.2 g of potassium phosphate, 388-396 mg of Pd2dba3, and 490-500 mg of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene correspond to 10 mL of dioxane; the step S8 comprises, after the reaction is completed as detected by LCMS, extracting with ethyl acetate, washing the organic phase with brine, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure at 40-50°C, and purifying the concentrate by column chromatography to obtain 1-(2-acetyloxyethyl)-8-((5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylic acid methyl ester in the form of a yellow solid.

[0028] Further, in step S9, 4-8 mL of methanol, 1.2-1.8 mL of water, and 180-186 mg of lithium hydroxide correspond to 1.5 g of 1-(2-acetyloxyethyl)-8-((5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylic acid methyl ester; the step S9 comprises adjusting the pH to 2.5-3.5 with an aqueous HC1 solution, and then purifying by preparative high-performance liquid chromatography to obtain 1-(2-hydroxyethyl)-8-((5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylic acid in the form of a yellow solid.

[0029] Compared with the prior art, the advantages of the present application include:

[0030] This invention provides a method for synthesizing substituted pyrazoloquinazoline derivatives. By using the method of this invention, the reaction steps are reduced by 3, the overall yield is nearly doubled, which is much higher than the original process route; and this invention avoids the use of dangerous reagents such as hydrazine hydrate and elemental iodine, making it easy to scale up. Attached Figure Description

[0031] Various other advantages and benefits will become apparent to those skilled in the art upon reading the following detailed description of preferred embodiments. The accompanying drawings are for illustrative purposes only and are not intended to limit the invention. Furthermore, the same reference numerals denote the same parts throughout the drawings. In the drawings:

[0032] Figure 1 This is a method for synthesizing a substituted pyrazoloquinazoline derivative in a typical embodiment of the present invention;

[0033] Figure 2 The flowchart shows the synthetic method for preparing substituted pyrazoloquinazoline derivatives disclosed in patent WO2008074788. Detailed Implementation

[0034] In view of the shortcomings of the prior art, the inventors of this invention, through long-term research and extensive practice, have proposed the technical solution of this invention. The following will further explain and illustrate this technical solution, its implementation process, and its principles.

[0035] The present invention will now be described in further detail with reference to specific embodiments. The given embodiments are merely illustrative of the invention and not intended to limit its scope. The embodiments provided below can serve as a guide for further improvements by those skilled in the art and do not constitute a limitation on the invention in any way.

[0036] Unless otherwise specified, the experimental methods used in the following examples are conventional methods, performed according to the techniques or conditions described in the literature in this field or according to the product instructions. Unless otherwise specified, the materials and reagents used in the following examples are commercially available.

[0037] Example 1

[0038] This embodiment provides a method for synthesizing a substituted pyrazoloquinazoline derivative, comprising the following steps:

[0039] S1, at room temperature, to the solution of 2,4-dichloro-5,6,7,8-tetrahydroquinazoline and zinc powder in ethanol, add hydroxylamine aqueous solution, after stirring uniformly at temperature of 50℃, reduce to room temperature, filter with diatomite to obtain filtrate and residue, the filtrate is extracted with ethyl acetate, obtain organic phase, after washing with brine, dry with anhydrous sodium sulfate, filter and concentrate under reduced pressure at 40℃, obtain concentrate, the concentrate is purified by column chromatography to obtain white solid 2-chloro-5,6,7,8-tetrahydroquinazoline; wherein, corresponding to 9g 2,4-dichloro-5,6,7,8-tetrahydroquinazoline, 9.5g zinc powder, 16.5g 15% mass fraction hydroxylamine aqueous solution per 120mL ethanol;

[0040] S2, add potassium tert-butoxide to the tetrahydrofuran solution of the 2-chloro-5,6,7,8-tetrahydroquinazoline, after stirring uniformly at temperature of-90℃, warm to room temperature, then pour into water / ice acetic acid, and extract with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, filter and evaporate to dryness to obtain yellow solid 2-chloro-6,7-dihydroquinazolin-8(5H)-ketoxime; wherein, corresponding to 5g 2-chloro-5,6,7,8-tetrahydroquinazoline, 3g potassium tert-butoxide per 400mL tetrahydrofuran;

[0041] S3, at room temperature, to the solution of the 2-chloro-6,7-dihydroquinazolin-8(5H)-ketoxime in hydrochloric acid, add water and acetone, after showing complete reaction by LCMS detection, pour into sodium carbonate / water, extract with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, filter and concentrate under reduced pressure at 35℃, the concentrate is purified by column chromatography to obtain yellow solid 2-chloro-6,7-dihydroquinazolin-8(5H)-ketone; wherein, corresponding to 5g 2-chloro-6,7-dihydroquinazolin-8(5H)-ketoxime, 260mL water and 60mL acetone per 67mL hydrochloric acid;

[0042] S4, at room temperature, to the solution of the 2-chloro-6,7-dihydroquinazolin-8(5H)-ketone and dimethyl oxalate in methanol, add sodium methoxide, after stirring uniformly at temperature of 60℃, after showing complete reaction by LCMS detection, concentrate under reduced pressure at 40℃, the concentrate is purified by column chromatography to obtain yellow solid methyl 2-(2-methoxy-8-oxo-5,6,7,8-tetrahydroquinazolin-7-yl)-2-oxoacetate; wherein, corresponding to 1.5g 2-chloro-6,7-dihydroquinazolin-8(5H)-ketone, 2.0g dimethyl oxalate, 3.0g 25% mass fraction sodium methoxide per 30mL methanol;

[0043] S5, to the mixture of 2-(2-methoxy-8-oxo-5, 6, 7, 8-tetrahydroquinazolin-7-yl)-2- oxoacetic acid methyl ester in acetic acid, 2-hydrazinoethanol was added, stirred uniformly at room temperature, after the reaction was completed, detected by LCMS, the reaction was quenched with hydrochloric acid, and the pH value was adjusted to 5, after the solvent was evaporated, the crude product was dissolved in water, alkalinized with 30% aqueous ammonium hydroxide solution, and extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the concentrate was purified by flash column chromatography to obtain yellow solid 1-(2-hydroxyethyl)-8-methoxy-4, 5-dihydro-1H-pyrazolo[4, 3-h] quinoline-3-carboxylic acid methyl ester; wherein, 2.0 g of 2-(2-methoxy-8-oxo-5, 6, 7, 8-tetrahydroquinazolin-7-yl)-2-oxoacetic acid methyl ester, 0.8 g of 2-hydrazinoethanol correspond to 4 mL of acetic acid;

[0044] S6, to the solution of 1-(2-hydroxyethyl)-8-methoxy-4, 5-dihydro-1H-pyrazolo[4, 3-h] quinoline-3-carboxylic acid methyl ester and acetyl chloride in dichloromethane, diisopropylethylamine was added, stirred uniformly at room temperature, after the reaction was completed, detected by LCMS, water was added to the reaction mixture, and extracted with dichloromethane. After the organic phase was washed with brine and dried over anhydrous sodium sulfate, it was filtered and concentrated under reduced pressure at 40°C, and the concentrate was purified by column chromatography to obtain yellow solid 1-(2-acetyloxyethyl)-8-methoxy-4, 5-dihydro-1H-pyrazolo[4, 3-h] quinoline-3-carboxylic acid methyl ester; wherein, 1.2 g of 1-(2-hydroxyethyl)-8-methoxy-4, 5-dihydro-1H-pyrazolo[4, 3-h] quinoline-3-carboxylic acid methyl ester, 560 mg of acetyl chloride and 0.7 g of diisopropylethylamine correspond to 12 mL of dichloromethane;

[0045] S7, to the solution of 1-(2-acetyloxyethyl)-8-methoxy-4, 5-dihydro-1H-pyrazolo[4, 3-h] quinoline-3-carboxylic acid methyl ester in N, N-dimethylformamide, phosphorus oxychloride was added at room temperature, stirred uniformly at 90°C, after the reaction was completed, detected by LCMS, water was added to the reaction mixture, and extracted with ethyl acetate. The extracted organic phase was washed with aqueous ammonium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure at 40°C, and the concentrate was purified by column chromatography to obtain yellow solid 1-(2-acetyloxyethyl)-8-chloro-4, 5-dihydro-1H-pyrazolo[4, 3-h] quinoline-3-carboxylic acid methyl ester; wherein, 1.2 g of 1-(2-acetyloxyethyl)-8-methoxy-4, 5-dihydro-1H-pyrazolo[4, 3-h] quinoline-3-carboxylic acid methyl ester, 3.8 g of phosphorus oxychloride correspond to 10 mL of N, N-dimethylformamide;

[0046] S8. To the solution of 5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)aniline, the 1-(2-acetyloxyethyl)-8-chloro-4,5-dihydro-1H-pyrazolo[4,3-h]quinoline-3-carboxylic acid methyl ester in dioxane, add potassium phosphate, Pd2dba3 and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene at room temperature, stir uniformly at 100 °C, after LCMS shows the reaction is completed, extract with ethyl acetate, after the organic phase is washed with brine and dried with anhydrous sodium sulfate, filter and concentrate under reduced pressure at 40 °C, the concentrate is purified by column chromatography to obtain 1-(2-acetyloxyethyl)-8-((5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-h]quinoline-3-carboxylic acid methyl ester as a yellow solid; wherein, 0.8 g of 5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)aniline, 1.2 g of 1-(2-acetyloxyethyl)-8-chloro-4,5-dihydro-1H-pyrazolo[4,3-h]quinoline-3-carboxylic acid methyl ester, 2.2 g of potassium phosphate, 388 mg of Pd2dba3 and 490 mg of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene correspond to 10 mL of dioxane;

[0047] S9. To the 1-(2-acetyloxyethyl)-8-((5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-h]quinoline-3-carboxylic acid methyl ester in methanol and water, add lithium hydroxide, stir uniformly at room temperature, then adjust the pH value to 2.5 with aqueous hydrochloric acid, and then purify by preparative high performance liquid chromatography to obtain 1-(2-hydroxyethyl)-8-((5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-h]quinoline-3-carboxylic acid as a yellow solid; wherein, 1.5 g of 1-(2-acetyloxyethyl)-8-((5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-h]quinoline-3-carboxylic acid methyl ester corresponds to 4 mL of methanol, 1.2 mL of water and 180 mg of lithium hydroxide;

[0048] S10, 1-(2-hydroxyethyl)-8-((5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy) phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-h]quinoline-3-carboxylic acid in N,N- dimethylformamide is added ammonium chloride, 2-(7-azobenzenetriazole)-N,N,N',N'- tetramethyluron hexafluorophosphate and diisopropylethylamine, stirred at room temperature, after the reaction is completed, purified by preparative high performance liquid chromatography to obtain 1-(2-hydroxyethyl)-8-((5-(4-methylpiperazin-1-yl)-2- (trifluoromethoxy)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-h]quinoline-3- carboxamide as a yellow solid; wherein, 290 mg of 1-(2-hydroxyethyl)-8-((5-(4- methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3- h]quinoline-3-carboxylic acid, 115 mg of ammonium chloride, 420 mg of 2-(7- azobenzenetriazole)-N,N,N',N'-tetramethyluron hexafluorophosphate and 280 mg of diisopropylethylamine correspond to every 3 mL of N,N-dimethylformamide.

[0049] Example 2

[0050] The present embodiment provides a method for synthesizing a substituted pyrazoloquinoline derivative, comprising the following steps:

[0051] S1, an aqueous solution of hydroxylamine is added to a solution of 2,4-dichloro-5,6,7,8- tetrahydroquinoline and zinc powder in ethanol at room temperature, stirred uniformly at a temperature of 130°C, then reduced to room temperature, filtered with diatomite to obtain filtrate and residue, the filtrate is extracted with ethyl acetate to obtain an organic phase, the organic phase is washed with brine and then dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure at 50°C to obtain a concentrate, the concentrate is purified by column chromatography to obtain 2-chloro-5,6,7,8-tetrahydroquinoline as a white solid; wherein, 10 g of 2,4-dichloro-5,6,7,8-tetrahydroquinoline, 10.5 g of zinc powder, 17.5 g of 25% mass fraction aqueous solution of hydroxylamine correspond to every 120 mL of ethanol;

[0052] S2, potassium tert-butoxide is added to a tetrahydrofuran solution of the 2-chloro-5,6,7,8- tetrahydroquinoline, stirred uniformly at a temperature of -60°C, then warmed to room temperature, then poured into water / ice acetic acid, and extracted with ethyl acetate, the organic phase is dried with anhydrous sodium sulfate, filtered and evaporated to dryness to obtain 2-chloro-6,7-dihydroquinazolin-8(5H)- ketoxime as a yellow solid; wherein, 6 g of 2-chloro-5,6,7,8-tetrahydroquinoline, 4 g of potassium tert-butoxide correspond to every 400 mL of tetrahydrofuran;

[0053] S3, to the solution of 2-chloro-6,7-dihydroquinazolin-8(5H)-on oxime in hydrochloric acid, water and acetone were added at room temperature, and the reaction was detected by LCMS to be completed. The reaction mixture was poured into sodium carbonate / water, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure at 45°C. The concentrate was purified by column chromatography to obtain 2-chloro-6,7-dihydroquinazolin-8(5H)-one as a yellow solid; wherein 6g of 2-chloro-6,7-dihydroquinazolin-8(5H)-on oxime, 276mL of water and 74mL of acetone correspond to 67mL of hydrochloric acid;

[0054] S4, to the solution of 2-chloro-6,7-dihydroquinazolin-8(5H)-one and dimethyl oxalate in methanol, sodium methoxide was added at room temperature, and the mixture was stirred at a temperature of 80°C. The reaction was detected by LCMS to be completed, and the reaction mixture was concentrated under reduced pressure at 50°C. The concentrate was purified by column chromatography to obtain 2-(2-methoxy-8-oxo-5,6,7,8-tetrahydroquinazolin-7-yl)-2-oxoacetic acid methyl ester as a yellow solid; wherein 2.5g of 2-chloro-6,7-dihydroquinazolin-8(5H)-one, 3.2g of dimethyl oxalate and 4.8g of sodium methoxide with a mass percentage of 35% correspond to 30mL of methanol;

[0055] S5, to the mixture of 2-(2-methoxy-8-oxo-5,6,7,8-tetrahydroquinazolin-7-yl)-2-oxoacetic acid methyl ester in acetic acid, 2-hydrazinoethanol was added and stirred at room temperature. The reaction was detected by LCMS to be completed, and the reaction was quenched with hydrochloric acid and the pH value was adjusted to 7. After evaporation of the solvent, the crude product was dissolved in water, alkalized with 30% aqueous ammonium hydroxide solution, and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by flash column chromatography to obtain 1-(2-hydroxyethyl)-8-methoxy-4,5-dihydro-1H-pyrazolo[4,3-h]quinoline-3-carboxylic acid methyl ester as a yellow solid; wherein 2.8g of 2-(2-methoxy-8-oxo-5,6,7,8-tetrahydroquinazolin-7-yl)-2-oxoacetic acid methyl ester and 1.2g of 2-hydrazinoethanol correspond to 4mL of acetic acid;

[0056] S6, to the solution of 1-(2-hydroxyethyl)-8-methoxy-4,5-dihydro-1H-pyrazolo[4,3- h]quinoline-3-carboxylic acid methyl ester and acetyl chloride in dichloromethane, diisopropyl ethylamine was added, stirred uniformly at room temperature, after the reaction was completed, which was detected by LCMS, water was added to the reaction mixture, and extracted with dichloromethane. The organic phase was washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure at 50°C, and the concentrate was purified by column chromatography to obtain yellow solid 1-(2-acetoxyethyl)-8-methoxy-4,5-dihydro-1H-pyrazolo[4,3-h]quinoline-3-carboxylic acid methyl ester; wherein, 2.2g of 1-(2-hydroxyethyl)-8-methoxy-4,5-dihydro-1H-pyrazolo[4,3-h]quinoline-3-carboxylic acid methyl ester, 575mg of acetyl chloride and 1.5g of diisopropyl ethylamine correspond to 12mL of dichloromethane;

[0057] S7, to the solution of 1-(2-acetoxyethyl)-8-methoxy-4,5-dihydro-1H-pyrazolo[4,3- h]quinoline-3-carboxylic acid methyl ester in N,N-dimethylformamide, phosphorus oxychloride was added at room temperature, stirred uniformly at 110°C, after the reaction was completed, which was detected by LCMS, water was added to the reaction mixture, and extracted with ethyl acetate, the extracted organic phase was washed with aqueous ammonium chloride and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure at 50°C, and the concentrate was purified by column chromatography to obtain yellow solid 1-(2-acetoxyethyl)-8-chloro-4,5-dihydro-1H-pyrazolo[4,3-h]quinoline-3-carboxylic acid methyl ester; wherein, 2.0g of 1-(2-acetoxyethyl)-8-methoxy-4,5-dihydro-1H-pyrazolo[4,3-h]quinoline-3-carboxylic acid methyl ester and 4.6g of phosphorus oxychloride correspond to 10mL of N,N-dimethylformamide;

[0058] S8. To the solution of 5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)aniline, the 1-(2-acetyloxyethyl)-8-chloro-4,5-dihydro-1H-pyrazolo[4,3-h]quinoline-3-carboxylic acid methyl ester in dioxane, add potassium phosphate, Pd2dba3 and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene at room temperature, stir uniformly at 120 °C, after LCMS shows the reaction is completed, extract with ethyl acetate, after the organic phase is washed with brine and dried with anhydrous sodium sulfate, filter and concentrate under reduced pressure at 50 °C, the concentrate is purified by column chromatography to obtain 1-(2-acetyloxyethyl)-8-((5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-h]quinoline-3-carboxylic acid methyl ester as a yellow solid; wherein, 1.6 g of 5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)aniline, 1.8 g of 1-(2-acetyloxyethyl)-8-chloro-4,5-dihydro-1H-pyrazolo[4,3-h]quinoline-3-carboxylic acid methyl ester, 3.2 g of potassium phosphate, 396 mg of Pd2dba3 and 500 mg of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene correspond to 10 mL of dioxane;

[0059] S9. To the 1-(2-acetyloxyethyl)-8-((5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-h]quinoline-3-carboxylic acid methyl ester in methanol and water, add lithium hydroxide, stir uniformly at room temperature, then adjust the pH value to 3.5 with aqueous hydrochloric acid, and then purify by preparative high performance liquid chromatography to obtain 1-(2-hydroxyethyl)-8-((5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-h]quinoline-3-carboxylic acid as a yellow solid; wherein, 1.5 g of 1-(2-acetyloxyethyl)-8-((5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-h]quinoline-3-carboxylic acid methyl ester corresponds to 4-8 mL of methanol, 1.8 mL of water and 186 mg of lithium hydroxide;

[0060] S10, 1-(2-hydroxyethyl)-8-((5-(4-methylpiperazin-1-yl)-2- (trifluoromethoxy)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-h]quinoline-3- carboxylic acid in N,N-dimethylformamide was added ammonium chloride, 2-(7- azobenzo-triazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate and diisopropylethylamine, stirred at room temperature, after the reaction was completed, purified by preparative high performance liquid chromatography to obtain 1-(2- hydroxyethyl)-8-((5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)- 4,5-dihydro-1H-pyrazolo[4,3-h]quinoline-3-carboxamide as a yellow solid; wherein, corresponding to 310 mg of 1-(2-hydroxyethyl)-8-((5-(4-methylpiperazin-1-yl)-2- (trifluoromethoxy)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-h]quinoline-3- carboxylic acid, 126 mg of ammonium chloride, 435 mg of 2-(7-azobenzo-triazol-1- yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate and 300 mg of diisopropylethylamine per 3 mL of N,N-dimethylformamide.

[0061] The application will be described in detail below in conjunction with specific experimental examples.

[0062] As shown in the formula (I), the application provides a substituted pyrazoloquinazoline derivative and a synthesis method thereof. Figure 1

[0063] Step 1, at room temperature, 20% aqueous hydroxylamine solution (17.1 g, 97.2 mmol) was added to a solution of 2,4-dichloro-5,6,7,8-tetrahydroquinoline (9.4 g, 46.3 mmol) and zinc powder (9.9 g, 152.8 mmol) in ethanol (120 mL). The reaction mixture was stirred at 110°C for 1 hour. After the reaction mixture was returned to room temperature, it was filtered with diatomite and extracted with ethyl acetate (2 x 100 mL). The organic phase was washed with brine (100 mL x 2) and dried with anhydrous sodium sulfate. After filtration, the concentrate was concentrated under reduced pressure at 45°C. The concentrate was purified by column chromatography (120 g, petroleum ether / tert-butyl methyl ether volume ratio = 100:00-40:60 gradient elution) to obtain 2-chloro-5,6,7,8-tetrahydroquinoline (6.4 g, purity 100%, yield 81%) as a white solid.

[0064] LCMS: Rt = 0.707 min; MS Calcd.: 168.0; MS Found: 169.1 [M+H]+.

[0065] ​Step 2, To a solution of 2-chloro-5,6,7,8-tetrahydroquinazoline (5.4 g, 32.1 mmol) in tetrahydrofuran (400 mL) was added potassium tert-butoxide (3.6 g, 32.1 mmol) and the mixture was stirred at -78 °C for 10 min, then tert-butyl nitrite (15.5 g, 150.9 mmol) was added. After the reaction mixture was allowed to warm to room temperature, 10 min later, it was poured into water / ice acetic acid (800 mL / 1 mL) and extracted with ethyl acetate (300 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to dryness to give 2-chloro-6,7-dihydroquinazolin-8(5H)-one oxime (5.71 g, 74.87% purity, 85% yield) as a yellow solid.

[0066] LCMS: Rt = 0.621 min; MS Calcd. for C9H7CIN2O: 197.0; MS Found: 198.1 [M+H]+.

[0067] Step 3, To a solution of 2-chloro-6,7-dihydroquinazolin-8(5H)-one oxime (5.4 g, 27.4 mmol) in hydrochloric acid (67 mL) was added water (268 mL) and acetone (67 mL) at room temperature. After the reaction was shown to be complete by LCMS, the mixture was poured into sodium carbonate / water (67 g / 300 mL) and extracted with ethyl acetate (400 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure at 40 °C. The concentrate was purified by column chromatography (80 g, gradient elution with dichloromethane / methanol = 100:00 ~ 95:5 by volume) to give 2-chloro-6,7-dihydroquinazolin-8(5H)-one (2.2 g, 94.18% purity, 43% yield) as a yellow solid.

[0068] LCMS: Rt = 0.458 min; MS Calcd. for C9H7CIN2O: 197.0; MS Found: 198.1 [M+H]+.

[0069] Step 4, To a solution of 2-chloro-6,7-dihydroquinazolin-8(5H)-one (2.0 g, 10.9 mmol) and dimethyl oxalate (2.6 g, 21.9 mmol) in methanol (30 mL) was added sodium methoxide (30% by weight, 3.9 g, 21.9 mmol) at room temperature. The reaction mixture was stirred at 70 °C for 1 h. After the reaction was shown to be complete by LCMS, the mixture was concentrated under reduced pressure at 45 °C. The concentrate was purified by column chromatography (80 g, gradient elution with dichloromethane / methanol = 100:00 ~ 90:10 by volume) to give methyl 2-(2-methoxy-8-oxo-5,6,7,8-tetrahydroquinazolin-7-yl)-2-oxoacetate (2.57 g, 82.43% purity, 88% yield) as a yellow solid.

[0070] LCMS: Rt = 0.948 min; MS Calcd.: 264.1 ; MS Found: 265.0 [M+H]+.

[0071] Step 5, To a mixture of methyl 2-(2-methoxy-8-oxo-5,6,7,8-tetrahydroquinazolin-7- yl)-2-oxoacetate (2.4 g, 9.1 mmol) in acetic acid (4 mL) was added 2-hydrazinoethanol (1.0 g, 13.7 mmol). The reaction was stirred at room temperature for 6 hours. Upon completion of the reaction as monitored by LCMS, the reaction was quenched with hydrochloric acid (1 mol / L) and the pH was adjusted to 6, the solvent was evaporated, the crude was re-dissolved in water, basified with 30% aqueous ammonium hydroxide solution and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The concentrate was purified by flash column chromatography (40 g, petroleum ether / tert-butyl methyl ether, volume ratio = 100:0 to 10:90, gradient elution) to give methyl 1-(2-hydroxyethyl)-8-methoxy-4,5-dihydro-1H-pyrazolo[4,3- h]quinazoline-3-carboxylate (2.17 g, purity 80.07%, yield 79%) as a yellow solid.

[0072] LCMS: Rt = 0.609 min; MS Calcd.: 304.1 ; MS Found: 305.2 [M+H]+.

[0073] Step 6, To a solution of methyl 1-(2-hydroxyethyl)-8-methoxy-4,5-dihydro-1H-pyrazolo[4,3- h]quinazoline-3-carboxylate (1.7 g, 5.59 mmol) and acetyl chloride (567 mg, 7.27 mmol) in dichloromethane (12 mL) was added diisopropylethylamine (1.1 g, 8.39 mmol). The reaction mixture was stirred at room temperature for 1 hour. Upon completion of the reaction as monitored by LCMS, water (10 mL) was added to the reaction mixture and extracted with dichloromethane (20 mL x 2). The organic phase was washed with brine (100 mL x 2) and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure at 45 °C. The concentrate was purified by column chromatography (20 g, petroleum ether / ethyl acetate, volume ratio = 100:0 to 10:90, gradient elution) to give methyl 1-(2-acetyloxyethyl)-8-methoxy-4,5-dihydro-1H-pyrazolo[4,3- h]quinazoline-3-carboxylate (1.73 g, purity 88.94%, yield 91%) as a yellow solid.

[0074] LCMS: Rt = 0.732 min; MS Calcd.: 346.1 ; MS Found: 347.2 [M+H]+.

[0075] Step 7: To a solution of methyl 1-(2-acetyloxyethyl)-8-methoxy-4,5-dihydro-1H- pyrazolo[4,3-h]quinoline-3-carboxylate (1.6 g, 4.62 mmol) in N,N- dimethylformamide (10 mL) was added phosphorus oxychloride (4.2 g, 27.75 mmol) at room temperature. The reaction mixture was stirred at 100 °C for 1 h. After the reaction was complete as indicated by LCMS, the reaction mixture was added to water (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with aqueous ammonium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure at 45 °C. The concentrate was purified by column chromatography (20 g, petroleum ether / ethyl acetate, volume ratio = 100:0 to 15:85, gradient elution) to give methyl 1-(2-acetyloxyethyl)-8-chloro-4,5-dihydro-1H-pyrazolo[4,3- h]quinoline-3-carboxylate (1.5 g, 92.34% purity, 93% yield) as a yellow solid.

[0076] Step 8: To a solution of 5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)aniline (1.2 g, 4.29 mmol), methyl 1-(2-acetyloxyethyl)-8-chloro-4,5-dihydro-1H-pyrazolo[4,3- h]quinoline-3-carboxylate (1.5 g, 4.29 mmol) in dioxane (10 mL) was added potassium phosphate (2.7 g, 12.86 mmol), Pd2dba3 (392 mg, 0.43 mmol) and 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene (495 mg, 0.86 mmol) at room temperature. The reaction mixture was stirred at 110 °C for 16 h. After the reaction was complete as indicated by LCMS, it was extracted with ethyl acetate (30 mL x 3). The organic phase was washed with brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure at 45 °C. The concentrate was purified by column chromatography (20 g, dichloromethane / methanol, volume ratio = 100:0 to 93:7, gradient elution) to give methyl 1-(2-acetyloxyethyl)-8-((5-(4-methylpiperazin-1-yl)-2- (trifluoromethoxy)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-h]quinoline-3-carboxylate (1.84 g, 91.91% purity, 65% yield) as a yellow solid.

[0077] LCMS: Rt = 1.771 min; MS Calcd. for C31H31F3N7O4: 589.2; MS Found: 590.0 [M+H]+.

[0078] Step 9, To methyl 1-(2-acetyloxyethyl)-8-((5-(4-methylpiperazin-1-yl)-2- (trifluoromethoxy)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-h]quinoline-3-carboxylate (1.5 g, 2.55 mmol) in methanol (6 mL) and water (1.5 mL) was added lithium hydroxide (183 mg, 7.64 mmol) and stirred at room temperature for 3 h. The pH of the mixture was adjusted to 3 with aqueous HC1 (2 mol / L). The mixture was purified by preparative high performance liquid chromatography to give 1-(2- hydroxyethyl)-8-((5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)-4,5- dihydro-1H-pyrazolo[4,3-h]quinoline-3-carboxylic acid (1.3 g, 82.02% purity, 96% yield) as a yellow solid.

[0079] LCMS: Rt = 0.734 min; MS Calcd. for C26H25F3N7O3: 532.2; MS Found: 533.2 [M+H]+.

[0080] Step 10, To 1-(2-hydroxyethyl)-8-((5-(4-methylpiperazin-1-yl)-2- (trifluoromethoxy)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-h]quinoline-3-carboxylic acid (300 mg, 0.56 mmol) in N,N-dimethylformamide (3 mL) was added ammonium chloride (121 mg, 2.25 mmol), 2-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (428 mg, 1.13 mmol) and diisopropylethylamine (290 mg, 2.25 mmol) and stirred at room temperature for 2 h. After completion of the reaction, the mixture was purified by preparative high performance liquid chromatography to give 1-(2-hydroxyethyl)-8-((5-(4-methylpiperazin-1-yl)-2- (trifluoromethoxy)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-h]quinoline-3-carboxamide (244 mg, 100% purity, 81% yield) as a yellow solid.

[0081] LCMS: Rt = 0.734 min; MS Calcd. for C26H25F3N7O3: 532.2; MS Found: 533.2 [M+H]+.

[0082] 1H NMR (400 MHz, DMSO-d6) δ 8.93 (s, 1H), 8.36 (s, 1H), 7.40 (d, J = 2.8 Hz, 1H), 7.29 (d, J = 8.8 Hz, 1H), 7.11 (br. s, 1H), 7.01 (br. s, 1H), 6.83 (dd, J = 9.2, 3.2 Hz, 1H), 4.64 (t, J = 5.2 Hz, 2H), 4.59 (t, J = 5.6 Hz, 1H), 3.66 - 3.62 (m, 2H), 3.16 (br. s, 4H), 3.07 (t, J = 7.2 Hz, 2H), 2.89 (t, J = 7.2 Hz, 2H), 2.64 (br. s, 4H), 2.33 (s, 3H).

[0083] By using the method of the present application, 2,4-dichloro-6,7-dihydro-5H- cyclopentapyrimidine is used as a starting material, a different synthetic idea from the original route is used, and the construction of a pyrimidine ring is avoided. The reaction steps are 10 steps, and the total yield is increased to 8.8%. The problems of long route and low total yield in the prior art synthesis method are overcome.

[0084] The above only describes some embodiments of the present application. It should be noted that, for those skilled in the art, other modifications and improvements can be made without departing from the inventive concept of the present application, and these all belong to the protection scope of the present application.

Claims

1. A method of synthesizing a substituted pyrazoloquinazoline derivative, characterized by, Comprising the following steps: S1, at room temperature, to the solution of 2,4-dichloro-5,6,7,8-tetrahydroquinazoline and zinc powder in ethanol, add hydroxylamine aqueous solution, after stirring uniformly at temperature of 50-130℃, reduce to room temperature, after filtration, obtain filtrate and residue, the filtrate is extracted, obtain organic phase, after washing and drying, filter and concentrate under reduced pressure, obtain concentrate, purify the concentrate, obtain white solid 2-chloro-5,6,7,8-tetrahydroquinazoline; S2, in the tetrahydrofuran solution of the 2-chloro-5,6,7,8-tetrahydroquinazoline, add potassium tert-butoxide, after stirring uniformly at temperature of-60--90℃, warm to room temperature, then extract, obtain organic phase, after drying, filter and evaporate, obtain yellow solid 2-chloro-6,7-dihydroquinazolin-8(5H)-ketoxime; S3, at room temperature, to the solution of the 2-chloro-6,7-dihydroquinazolin-8(5H)-ketoxime in hydrochloric acid, add water and acetone, after reaction, extract, obtain organic phase, after drying, filter, concentrate under reduced pressure, obtain concentrate, purify the concentrate, obtain yellow solid 2-chloro-6,7-dihydroquinazolin-8(5H)-ketone; S4, at room temperature, to the solution of the 2-chloro-6,7-dihydroquinazolin-8(5H)-ketone and dimethyl oxalate in methanol, add sodium methoxide, after stirring uniformly at temperature of 60-80℃, after reaction, cool, concentrate under reduced pressure, obtain concentrate, purify the concentrate, obtain yellow solid methyl 2-(2-methoxy-8-oxo-5,6,7,8-tetrahydroquinazolin-7-yl)-2-oxoacetate; S5, to the mixture of the methyl 2-(2-methoxy-8-oxo-5,6,7,8-tetrahydroquinazolin-7-yl)-2-oxoacetate in acetic acid, add 2-hydrazinoethanol, after stirring uniformly at room temperature, after reaction, quench with hydrochloric acid, adjust pH value, after evaporation of solvent, obtain crude product, re-dissolve the crude product in water, after alkalization, extract, collect organic phase, after drying, filter and concentrate, obtain concentrate, purify the concentrate, obtain yellow solid methyl 1-(2-hydroxyethyl)-8-methoxy-4,5-dihydro-1H-pyrazolo[4,3-h]quinoline-3-carboxylate; S6, to the solution of the methyl 1-(2-hydroxyethyl)-8-methoxy-4,5-dihydro-1H-pyrazolo[4,3-h]quinoline-3-carboxylate and acetyl chloride in dichloromethane, add diisopropylethylamine, after stirring uniformly at room temperature, after reaction, extract, collect organic phase, after washing, drying, filter, concentrate under reduced pressure, obtain concentrate, purify the concentrate, obtain yellow solid methyl 1-(2-acetyloxyethyl)-8-methoxy-4,5-dihydro-1H-pyrazolo[4,3-h]quinoline-3-carboxylate; S7, at room temperature, to the solution of 1-(2-acetyloxyethyl)-8-methoxy-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylic acid methyl ester in N,N-dimethylformamide, phosphorus oxychloride was added, stirred uniformly at 90-110℃, after the reaction was completed, extraction was carried out, the organic phase was collected, after the organic phase was washed, dried, filtered, and concentrated under reduced pressure, a concentrate was obtained, after the concentrate was purified, yellow solid 1-(2-acetyloxyethyl)-8-chloro-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylic acid methyl ester was obtained; S8, at room temperature, to the solution of 5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)aniline, 1-(2-acetyloxyethyl)-8-chloro-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylic acid methyl ester in dioxane, potassium phosphate, Pd2dba3 and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene were added, stirred uniformly at 100-120℃, after the reaction was completed, extraction was carried out, the organic phase was collected, after the organic phase was washed, dried, filtered, and concentrated under reduced pressure, a concentrate was obtained, after the concentrate was purified, yellow solid 1-(2-acetyloxyethyl)-8-((5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylic acid methyl ester was obtained; S9, to the 1-(2-acetyloxyethyl)-8-((5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylic acid methyl ester in methanol and water, lithium hydroxide was added, after stirring uniformly at room temperature, the pH value was adjusted, after purification, yellow solid 1-(2-hydroxyethyl)-8-((5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylic acid was obtained; S10, to the 1-(2-hydroxyethyl)-8-((5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylic acid in N,N-dimethylformamide, ammonium chloride, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate and diisopropylethylamine were added, stirring was carried out at room temperature, after the reaction was completed, purification was carried out, yellow solid 1-(2-hydroxyethyl)-8-((5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide was obtained.

2. The method of synthesis of pyrazoloquinazoline derivatives according to claim 1, characterized by that: In step S1, 9-10 g of 2,4-dichloro-5,6,7,8-tetrahydroquinazoline, 9.5-10.5 g of zinc powder, and 16.5-17.5 g of a hydroxylamine aqueous solution with a mass percentage of 15-25% correspond to every 120 mL of ethanol; the step S1 comprises filtering with diatomite and extracting with ethyl acetate, and the organic phase is washed with brine, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure at 40-50°C, and the concentrate is purified by column chromatography to obtain 2-chloro-5,6,7,8-tetrahydroquinazoline in the form of a white solid.

3. The method of synthesis of pyrazoloquinazoline derivatives according to claim 1, characterized by that: In step S2, 5-6 g of 2-chloro-5,6,7,8-tetrahydroquinazoline and 3-4 g of potassium tert-butoxide correspond to every 400 mL of tetrahydrofuran; the step S2 comprises stirring uniformly at a temperature of -70--86°C, then warming to room temperature, pouring into water / ice acetic acid, and extracting with ethyl acetate, and the organic phase is dried with anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain 2-chloro-6,7-dihydroquinazolin-8(5H)-one oxime in the form of a yellow solid.

4. The method of synthesis of pyrazoloquinazoline derivatives according to claim 1, characterized by that: In step S3, 5-6 g of 2-chloro-6,7-dihydroquinazolin-8(5H)-one oxime, 260-276 mL of water, and 60-74 mL of acetone correspond to every 67 mL of hydrochloric acid; the step S3 comprises pouring into sodium carbonate / water after the reaction is complete as detected by LCMS, extracting with ethyl acetate, drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure at 35-45°C, and the concentrate is purified by column chromatography to obtain 2-chloro-6,7-dihydroquinazolin-8(5H)-one in the form of a yellow solid.

5. The method of synthesis of pyrazoloquinazoline derivatives according to claim 1, characterized by that: In step S4, 1.5-2.5 g of 2-chloro-6,7-dihydroquinazolin-8(5H)-one, 2.0-3.2 g of dimethyl oxalate, and 3.0-4.8 g of sodium methoxide with a mass percentage of 25-35% correspond to every 30 mL of methanol; the step S4 comprises concentrating under reduced pressure at 40-50°C after the reaction is complete as detected by LCMS, and the concentrate is purified by column chromatography to obtain 2-(2-methoxy-8-oxo-5,6,7,8-tetrahydroquinazolin-7-yl)-2-oxoacetic acid methyl ester in the form of a yellow solid.

6. The method of synthesis of pyrazoloquinazoline derivatives according to claim 1, characterized by that: In step S5, 2.0-2.8 g of 2-(2-methoxy-8-oxo-5,6,7,8-tetrahydroquinazolin-7-yl)-2-oxoacetic acid methyl ester and 0.8-1.2 g of 2-hydrazinoethanol correspond to every 4 mL of acetic acid; the step S5 comprises quenching the reaction with hydrochloric acid after the reaction is complete as detected by LCMS, adjusting the pH to 5-7, evaporating the solvent, redissolving the crude product in water, alkalizing with a 30% aqueous ammonium hydroxide solution, extracting with dichloromethane, drying the organic phase with anhydrous sodium sulfate, filtering, concentrating, and purifying the concentrate by flash column chromatography to obtain 1-(2-hydroxyethyl)-8-methoxy-4,5-dihydro-1H-pyrazolo[4,3-h]quinoline-3-carboxylic acid methyl ester in the form of a yellow solid.

7. The method of synthesis of pyrazoloquinazoline derivatives according to claim 1, wherein: Step S6: 1.2-2.2 g of 1-(2-hydroxyethyl)-8-methoxy-4,5-dihydro-1H-pyrazolo[4,3- h]quinoline-3-carboxylic acid methyl ester, 560-575 mg of acetyl chloride and 0.7-1.5 g of diisopropylethylamine per 12 mL of dichloromethane; the step S6 comprises adding water to the reaction mixture after the completion of the reaction as detected by LCMS and extracting with dichloromethane; the organic phase is washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure at 40-50 °C, and the concentrate is purified by column chromatography to obtain 1-(2-acetyloxyethyl)-8-methoxy-4,5-dihydro-1H-pyrazolo[4,3- h]quinoline-3-carboxylic acid methyl ester as a yellow solid.

8. The method of synthesis of pyrazoloquinazoline derivatives according to claim 1, characterized by that: Step S7: 1.2-2.0 g of 1-(2-acetyloxyethyl)-8-methoxy-4,5-dihydro-1H-pyrazolo[4,3- h]quinoline-3-carboxylic acid methyl ester, 3.8-4.6 g of phosphorus oxychloride per 10 mL of N,N-dimethylformamide; the step S7 comprises adding water to the reaction mixture after the completion of the reaction as detected by LCMS and extracting with ethyl acetate, washing the extracted organic phase with an aqueous ammonium chloride solution, drying over anhydrous sodium sulfate, filtering and concentrating under reduced pressure at 40-50 °C, and purifying the concentrate by column chromatography to obtain 1-(2-acetyloxyethyl)-8-chloro-4,5-dihydro-1H-pyrazolo[4,3- h]quinoline-3-carboxylic acid methyl ester as a yellow solid.

9. The method of synthesis of pyrazoloquinazoline derivatives according to claim 1, characterized by that: Step S8: 0.8-1.6 g of 5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)aniline, 1.2-1.8 g of 1-(2-acetyloxyethyl)-8-chloro-4,5-dihydro-1H-pyrazolo[4,3-h]quinoline-3-carboxylic acid methyl ester, 2.2-3.2 g of potassium phosphate, 388-396 mg of Pd2dba3 and 490-500 mg of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene per 10 mL of dioxane; the step S8 comprises extracting with ethyl acetate after the completion of the reaction as detected by LCMS, washing the organic phase with brine, drying over anhydrous sodium sulfate, filtering and concentrating under reduced pressure at 40-50 °C, and purifying the concentrate by column chromatography to obtain 1-(2-acetyloxyethyl)-8-((5-(4-methylpiperazin-1-yl)-2- (trifluoromethoxy)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-h]quinoline-3-carboxylic acid methyl ester as a yellow solid.

10. The method of synthesis of pyrazoloquinazoline derivatives according to claim 1, wherein: In Step S9, per 1.5 g of 1-(2-acetyloxyethyl)-8-((5-(4-methylpiperazin-1-yl)-2- (trifluoromethoxy)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylic acid methyl ester, 4-8 mL of methanol, 1.2-1.8 mL of water, and 180-186 mg of lithium hydroxide; the Step S9 includes adjusting the pH to 2.5-3.5 with an aqueous HC1 solution, and then purifying by preparative high-performance liquid chromatography to obtain 1-(2-hydroxyethyl)-8-((5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylic acid as a yellow solid.

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