A method for synthesizing 3-pyrimidinone-4,5,6,7-tetrahydro-2H-pyrazole[4,3-c]pyridine
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-02-14
- Publication Date
- 2026-08-14
AI Technical Summary
[0003]本发明的目的在于提供一种3-嘧啶酮-4,5,6,7-四氢-2H-吡唑[4,3-c]吡啶的合成方法，用于解决现有技术中3-嘧啶酮-4,5,6,7-四氢-2H-吡唑[4,3-c]吡啶制备反应时间长和产率低的技术问题
[0018]通过在制备过程中使用经甲酸降低活性的RaneyNi，同时利用甲酸作为氢源，还原氰基为醛基，然后原位与胺基发生还原胺化反应，一锅法制备得到了3-嘧啶酮-4,5,6,7-四氢-2H-吡唑[4,3-c]吡啶，从而代替奥格列龙的咪唑酮结构，在此结构的基础上，可以进行大量衍生反应，以筛选更高药效的先导化合物。
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Abstract
Description
Technical Field
[0001] This invention belongs to the field of organic compound preparation technology, specifically relating to a method for synthesizing 3-pyrimidinone-4,5,6,7-tetrahydro-2H-pyrazole[4,3-c]pyridine. Background Technology
[0002] Oligerione, a next-generation GLP-1 receptor agonist, aims to effectively lower blood glucose levels by mimicking the physiological effects of GLP-1, stimulating insulin secretion, and inhibiting glucagon release, thus providing a new treatment option for type 2 diabetes. Compared to traditional GLP-1 analogs, oligrione's non-peptide structure endows it with better oral absorption efficiency and stability, reduces the inconvenience of injection administration, and improves patient compliance and quality of life. 3-Imidazolone-4,5,6,7-tetrahydro-2H-pyrazole[4,3-c]pyridine, as a core intermediate in the oligrione synthesis pathway, is also a key focus for many pharmaceutical R&D companies seeking to further optimize the structure of oligrione to improve efficacy. In this compound structure, 3-pyrimidinone, as an analogue and pharmacodynamic similarity group of 3-imidazolidinone, is widely used as a substitute group for 3-imidazolidinone in the development of small molecule new drugs. Summary of the Invention
[0003] The purpose of this invention is to provide a method for synthesizing 3-pyrimidinone-4,5,6,7-tetrahydro-2H-pyrazole[4,3-c]pyridine, which solves the technical problems of long reaction time and low yield in the preparation of 3-pyrimidinone-4,5,6,7-tetrahydro-2H-pyrazole[4,3-c]pyridine in the prior art.
[0004] To achieve the above objectives, the present invention adopts the following technical solution:
[0005] This invention provides a method for synthesizing 3-pyrimidinone-4,5,6,7-tetrahydro-2H-pyrazole[4,3-c]pyridine, comprising the following steps:
[0006] Step 1: Add cyanoacetamide to a container, add dichloromethane, purge with nitrogen, then place the container in an ice-water bath, slowly add oxaloyl chloride under stirring, purge with nitrogen, heat to react, and after the reaction is complete, obtain compound B;
[0007] Step 2: tert-butyl(S)-3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester was added to a container, tetrahydrofuran was added, nitrogen was purged, and then the container was placed in an ice-water bath. Under stirring, a dichloromethane solution containing compound B was slowly added. After nitrogen purging, the mixture was stirred at room temperature. After stirring, the mixture was diluted, extracted, and the organic phases were combined, washed, dried, filtered, concentrated, and purified to obtain compound C.
[0008] Step 3: Add compound C to the container, then add formic acid, and slowly add Raney Ni under stirring. After nitrogen purging, heat and stir the reaction. After the reaction is complete, filter and concentrate the filtrate to obtain crude oily product. Then add saturated sodium bicarbonate solution and tetrahydrofuran, stir, and then add di-tert-butyl carbonate anhydride. Stir the reaction at room temperature. After the reaction is complete, extract, combine the organic phases, wash, dry, filter, concentrate, and purify to obtain 3-pyrimidinone-4,5,6,7-tetrahydro-2H-pyrazole[4,3-c]pyridine.
[0009] The synthetic reaction formula for 3-pyrimidinone-4,5,6,7-tetrahydro-2H-pyrazole[4,3-c]pyridine in the above process is as follows:
[0010]
[0011] Preferably, in step one, the ratio of cyanoacetamide, dichloromethane, and oxalyl chloride is (1-3)g:(80-120)mL:(4.12-4.64)g.
[0012] Preferably, in step one, after adding dichloromethane, nitrogen is purged 1-2 times, and after adding oxalyl chloride, nitrogen is purged 2-4 times. The reaction temperature is 70-80℃, and the reaction time is 1-2 hours.
[0013] Preferably, in step two, the ratio of tert-butyl(S)-3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester, tetrahydrofuran, compound B, and dichloromethane is (1-1.2) g : (45-55) mL : (0.137-0.393) g : (25-35) mL.
[0014] Preferably, in step two, the nitrogen purging is performed 1-2 times after adding tetrahydrofuran, and 3-5 times after adding dichloromethane solution containing compound B. The stirring time at room temperature is 10-12 hours. Distilled water is added for dilution, and the mixture is extracted with ethyl acetate 3-5 times, washed with saturated sodium chloride solution 1-2 times, and dried with anhydrous sodium sulfate. During the purification process, a mixed solution of petroleum ether and ethyl acetate with a volume ratio of (50-100):(0-50) is used as the eluent for silica gel column chromatography purification.
[0015] Preferably, in step three, the ratio of compound C, formic acid, Raney Ni, saturated sodium bicarbonate solution, tetrahydrofuran, and di-tert-butyl carbonate is (0.95-1.15)g:(40-60)mL:(4-6)mL:(10-12)mL:(8-12)mL:(0.606-0.618)g.
[0016] Preferably, in step three, the heating and stirring reaction temperature is 90-95℃, the reaction time is 10-14h, the stirring reaction time at room temperature is 10-12h, the extraction is performed with ethyl acetate 2-4 times, the washing is performed with saturated sodium chloride solution 1-3 times, and the drying is performed with anhydrous sodium sulfate. During the purification process, a mixed solution of petroleum ether and ethyl acetate with a volume ratio of (50-100):(0-50) is used as the eluent for silica gel column chromatography purification.
[0017] In summary, due to the adoption of the above technical solution, the beneficial effects of the present invention are:
[0018] By using RaneyNi, whose activity is reduced by formic acid, and using formic acid as a hydrogen source to reduce the cyano group to an aldehyde group, followed by in-situ reductive amination with an amino group, 3-pyrimidinone-4,5,6,7-tetrahydro-2H-pyrazole[4,3-c]pyridine was prepared in a one-pot process, thus replacing the imidazolidinone structure of ocglino. Based on this structure, a large number of derivatization reactions can be carried out to screen lead compounds with higher efficacy. Attached Figure Description
[0019] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.
[0020] Figure 1 This is the LCMS spectrum of compound C obtained in Example 1 of the present invention, detected at a wavelength of 214 nm; where the Y-axis represents the milliabsorbance and the X-axis represents the retention time.
[0021] Figure 2 This is the LCMS spectrum of compound 3-pyrimidinone-4,5,6,7-tetrahydro-2H-pyrazole[4,3-c]pyridine obtained in Example 1 of the present invention, detected at a wavelength of 214 nm; where the Y-axis represents the milliabsorbance and the X-axis represents the retention time. Detailed Implementation
[0022] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. 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.
[0023] Example 1: This example discloses a method for synthesizing 3-pyrimidinone-4,5,6,7-tetrahydro-2H-pyrazole[4,3-c]pyridine, comprising the following steps:
[0024] Step 1: Add 2g of cyanoacetamide to a container, add 100mL of dichloromethane, purge with nitrogen once, then place the container in an ice-water bath, slowly add 4.38g of oxaloyl chloride under stirring, purge with nitrogen three times, heat at 75℃ for 1.5h, and after the reaction is complete, compound B is obtained;
[0025] Step 2: 1.1 g of tert-butyl(S)-3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester was added to a container, followed by 50 mL of tetrahydrofuran. The mixture was purged with nitrogen once, and then the container was placed in an ice-water bath. Under stirring, 30 mL of dichloromethane solution containing 0.265 g of compound B was slowly added. After purging with nitrogen three times, the mixture was stirred at room temperature for 12 h. After stirring, the mixture was diluted with distilled water and extracted three times with ethyl acetate. The organic phases were combined, washed once with saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography using a 75:25 (v / v) mixture of petroleum ether and ethyl acetate as the eluent to obtain compound C in 74% yield.
[0026] Step 3: Add 1.05g of compound C to a container, followed by 50mL of formic acid. Slowly add 5mL of Raney Ni under stirring. After nitrogen purging, heat and stir at 90℃ for 12h. After the reaction is complete, filter and concentrate the filtrate to obtain crude oil. Then add 10mL of saturated sodium bicarbonate solution and 10mL of tetrahydrofuran. After stirring, add 0.612g of di-tert-butyl carbonate anhydride and stir at room temperature for 12h. After the reaction is complete, extract twice with ethyl acetate, combine the organic phases, wash once with saturated sodium chloride solution, dry with anhydrous sodium sulfate, filter, concentrate, and use a mixed solution of petroleum ether and ethyl acetate (volume ratio 75:25) as the eluent for silica gel column chromatography purification to obtain 3-pyrimidinone-4,5,6,7-tetrahydro-2H-pyrazole[4,3-c]pyridine, with a yield of 71%.
[0027] See Figure 1 As shown in Table 1, the LCMS spectrum analysis results of compound C in this embodiment are as follows:
[0028] Table 1. Analysis of LCMS spectra of compound C
[0029] Retention time Peak width Peak area Peak height Peak area / % 1.47 0.01 22.31 27.53 1.09 1.55 0.01 11.85 13.95 0.58 1.64 0.02 91.13 66.14 4.44 1.71 0.02 15.31 9.43 0.75 1.88 0.02 1903.14 1743.69 92.79 2.30 0.02 7.27 6.22 0.35
[0030] See Figure 1 As shown in Table 2, the LCMS spectrum analysis results of Example 3-pyrimidinone-4,5,6,7-tetrahydro-2H-pyrazole[4,3-c]pyridine are presented:
[0031] Table 2. Analysis of LCMS spectra of 3-pyrimidinone-4,5,6,7-tetrahydro-2H-pyrazole[4,3-c]pyridine
[0032] Retention time Peak width Peak area Peak height Peak area / % 1.73 0.02 8.72 6.97 0.65 1.82 0.02 1133.21 1078.91 85.04 1.87 0.02 92.37 71.24 6.93 2.05 0.02 98.12 89.48 7.36
[0033] Example 2: This example discloses a method for synthesizing 3-pyrimidinone-4,5,6,7-tetrahydro-2H-pyrazole[4,3-c]pyridine, comprising the following steps:
[0034] Step 1: Add 1g of cyanoacetamide to a container, add 80mL of dichloromethane, purge with nitrogen once, then place the container in an ice-water bath, slowly add 4.12g of oxaloyl chloride under stirring, purge with nitrogen three times, heat at 75℃ for 1.5h, and after the reaction is complete, compound B is obtained;
[0035] Step 2: 1 g of tert-butyl(S)-3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester was added to a container, followed by 45 mL of tetrahydrofuran. The mixture was purged with nitrogen once, and then the container was placed in an ice-water bath. Under stirring, 25 mL of dichloromethane solution containing 0.137 g of compound B was slowly added. After purging with nitrogen three times, the mixture was stirred at room temperature for 12 h. After stirring, the mixture was diluted with distilled water and extracted three times with ethyl acetate. The organic phases were combined, washed once with saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography using a 75:25 (v / v) mixture of petroleum ether and ethyl acetate as the eluent to obtain compound C in 70% yield.
[0036] Step 3: Add 0.95g of compound C to a container, followed by 40mL of formic acid. Slowly add 4mL of Raney Ni under stirring. After nitrogen purging, heat and stir at 90℃ for 12h. After the reaction, filter and concentrate the filtrate to obtain crude oil. Then add 11mL of saturated sodium bicarbonate solution and 8mL of tetrahydrofuran. After stirring, add 0.606g of di-tert-butyl carbonate anhydride and stir at room temperature for 12h. After the reaction, extract twice with ethyl acetate, combine the organic phases, wash once with saturated sodium chloride solution, dry with anhydrous sodium sulfate, filter, concentrate, and use a mixed solution of petroleum ether and ethyl acetate (volume ratio 75:25) as the eluent for silica gel column chromatography purification to obtain 3-pyrimidinone-4,5,6,7-tetrahydro-2H-pyrazole[4,3-c]pyridine with a yield of 68%.
[0037] Example 3: This example discloses a method for synthesizing 3-pyrimidinone-4,5,6,7-tetrahydro-2H-pyrazole[4,3-c]pyridine, comprising the following steps:
[0038] Step 1: Add 3g of cyanoacetamide to a container, add 120mL of dichloromethane, purge with nitrogen once, then place the container in an ice-water bath, slowly add 4.64g of oxaloyl chloride under stirring, purge with nitrogen three times, heat at 75℃ for 1.5h, and after the reaction is complete, compound B is obtained;
[0039] Step 2: 1.2 g of tert-butyl(S)-3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester was added to a container, followed by 55 mL of tetrahydrofuran. The mixture was purged with nitrogen once, and then the container was placed in an ice-water bath. Under stirring, 35 mL of dichloromethane solution containing 0.393 g of compound B was slowly added. After purging with nitrogen three times, the mixture was stirred at room temperature for 12 h. After stirring, the mixture was diluted with distilled water and extracted three times with ethyl acetate. The organic phases were combined, washed once with saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography using a mixed solution of petroleum ether and ethyl acetate at a volume ratio of 75:25 as the eluent to obtain compound C in 72% yield.
[0040] Step 3: Add 1.15g of compound C to a container, followed by 60mL of formic acid. Slowly add 6mL of Raney Ni under stirring. After nitrogen purging, heat and stir at 90℃ for 12h. After the reaction is complete, filter and concentrate the filtrate to obtain crude oil. Then add 12mL of saturated sodium bicarbonate solution and 12mL of tetrahydrofuran. After stirring, add 0.618g of di-tert-butyl carbonate anhydride and stir at room temperature for 12h. After the reaction is complete, extract twice with ethyl acetate, combine the organic phases, wash once with saturated sodium chloride solution, dry with anhydrous sodium sulfate, filter, concentrate, and use a mixed solution of petroleum ether and ethyl acetate (volume ratio 75:25) as the eluent for silica gel column chromatography purification to obtain 3-pyrimidinone-4,5,6,7-tetrahydro-2H-pyrazole[4,3-c]pyridine, with a yield of 62%.
[0041] Example 4: This example discloses a method for synthesizing 3-pyrimidinone-4,5,6,7-tetrahydro-2H-pyrazole[4,3-c]pyridine, comprising the following steps:
[0042] Step 1: Add 1.5g of cyanoacetamide to a container, add 90mL of dichloromethane, purge with nitrogen once, then place the container in an ice-water bath, slowly add 4.2g of oxaloyl chloride under stirring, purge with nitrogen three times, heat at 75℃ for 1.5h, and after the reaction is complete, compound B is obtained;
[0043] Step 2: 1.05 g of tert-butyl(S)-3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester was added to a container, followed by 42 mL of tetrahydrofuran. The mixture was purged with nitrogen once, and then the container was placed in an ice-water bath. Under stirring, 28 mL of dichloromethane solution containing 0.139 g of compound B was slowly added. After purging with nitrogen three times, the mixture was stirred at room temperature for 12 h. After stirring, the mixture was diluted with distilled water and extracted three times with ethyl acetate. The organic phases were combined, washed once with saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography using a mixed solution of petroleum ether and ethyl acetate at a volume ratio of 75:25 as the eluent to obtain compound C in 68% yield.
[0044] Step 3: Add 0.98g of compound C to a container, followed by 45mL of formic acid. Slowly add 4.2mL of Raney Ni under stirring. After nitrogen purging, heat and stir at 90℃ for 12h. After the reaction is complete, filter and concentrate the filtrate to obtain crude oil. Then add 10.2mL of saturated sodium bicarbonate solution and 8.5mL of tetrahydrofuran. After stirring, add 0.608g of di-tert-butyl carbonate anhydride and stir at room temperature for 12h. After the reaction is complete, extract twice with ethyl acetate, combine the organic phases, wash once with saturated sodium chloride solution, dry with anhydrous sodium sulfate, filter, concentrate, and use a mixed solution of petroleum ether and ethyl acetate (volume ratio 75:25) as the eluent for silica gel column chromatography purification to obtain 3-pyrimidinone-4,5,6,7-tetrahydro-2H-pyrazole[4,3-c]pyridine, with a yield of 65%.
[0045] Example 5: This example discloses a method for synthesizing 3-pyrimidinone-4,5,6,7-tetrahydro-2H-pyrazole[4,3-c]pyridine, comprising the following steps:
[0046] Step 1: Add 2.5g of cyanoacetamide to a container, add 110mL of dichloromethane, purge with nitrogen once, then place the container in an ice-water bath, slowly add 4.3g of oxaloyl chloride under stirring, purge with nitrogen three times, heat at 75℃ for 1.5h, and after the reaction is complete, compound B is obtained;
[0047] Step 2: 1.15 g of tert-butyl(S)-3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester was added to a container, followed by 48 mL of tetrahydrofuran. The mixture was purged with nitrogen once, and then the container was placed in an ice-water bath. Under stirring, 32 mL of dichloromethane solution containing 0.142 g of compound B was slowly added. After purging with nitrogen three times, the mixture was stirred at room temperature for 12 h. After stirring, the mixture was diluted with distilled water and extracted three times with ethyl acetate. The organic phases were combined, washed once with saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography using a mixed solution of petroleum ether and ethyl acetate at a volume ratio of 75:25 as the eluent to obtain compound C in 65% yield.
[0048] Step 3: Add 1.13g of compound C to a container, followed by 55mL of formic acid. Slowly add 4.6mL of Raney Ni under stirring. After nitrogen purging, heat and stir at 90℃ for 12h. After the reaction is complete, filter and concentrate the filtrate to obtain crude oil. Then add 10.6mL of saturated sodium bicarbonate solution and 9.5mL of tetrahydrofuran. After stirring, add 0.609g of di-tert-butyl carbonate anhydride and stir at room temperature for 12h. After the reaction is complete, extract twice with ethyl acetate, combine the organic phases, wash once with saturated sodium chloride solution, dry with anhydrous sodium sulfate, filter, concentrate, and use a mixed solution of petroleum ether and ethyl acetate (volume ratio 75:25) as the eluent for silica gel column chromatography purification to obtain 3-pyrimidinone-4,5,6,7-tetrahydro-2H-pyrazole[4,3-c]pyridine with a yield of 68%.
[0049] Example 6: This example discloses a method for synthesizing 3-pyrimidinone-4,5,6,7-tetrahydro-2H-pyrazole[4,3-c]pyridine, comprising the following steps:
[0050] Step 1: Add 1.8g of cyanoacetamide to a container, add 105mL of dichloromethane, purge with nitrogen once, then place the container in an ice-water bath, slowly add 4.46g of oxaloyl chloride under stirring, purge with nitrogen three times, heat at 75℃ for 1.5h, and after the reaction is complete, obtain compound B;
[0051] Step 2: 1.02 g of tert-butyl(S)-3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester was added to a container, followed by 52 mL of tetrahydrofuran. The mixture was purged with nitrogen once, and then the container was placed in an ice-water bath. Under stirring, 29 mL of dichloromethane solution containing 0.159 g of compound B was slowly added. After purging with nitrogen three times, the mixture was stirred at room temperature for 12 h. After stirring, the mixture was diluted with distilled water and extracted three times with ethyl acetate. The organic phases were combined, washed once with saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography using a mixed solution of petroleum ether and ethyl acetate at a volume ratio of 75:25 as the eluent to obtain compound C in 62% yield.
[0052] Step 3: Add 1.08 g of compound C to a container, followed by 42 mL of formic acid. Slowly add 4.8 mL of Raney Ni under stirring. After nitrogen purging, heat and stir at 90 °C for 12 h. After the reaction is complete, filter and concentrate the filtrate to obtain a crude oily product. Then add 10.8 mL of saturated sodium bicarbonate solution and 10.5 mL of tetrahydrofuran. After stirring, add 0.613 g of di-tert-butyl carbonate anhydride and stir at room temperature for 12 h. After the reaction is complete, extract twice with ethyl acetate, combine the organic phases, wash once with saturated sodium chloride solution, dry with anhydrous sodium sulfate, filter, concentrate, and use a mixed solution of petroleum ether and ethyl acetate (volume ratio 75:25) as the eluent for silica gel column chromatography purification to obtain 3-pyrimidinone-4,5,6,7-tetrahydro-2H-pyrazole[4,3-c]pyridine, with a yield of 60%.
[0053] Example 7: This example discloses a method for synthesizing 3-pyrimidinone-4,5,6,7-tetrahydro-2H-pyrazole[4,3-c]pyridine, comprising the following steps:
[0054] Step 1: Add 2.7g of cyanoacetamide to a container, add 85mL of dichloromethane, purge with nitrogen once, then place the container in an ice-water bath, slowly add 4.52g of oxaloyl chloride under stirring, purge with nitrogen three times, heat at 75℃ for 1.5h, and after the reaction is complete, obtain compound B;
[0055] Step 2: 1.08 g of tert-butyl(S)-3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester was added to a container, followed by 53 mL of tetrahydrofuran. The mixture was purged with nitrogen once, and then the container was placed in an ice-water bath. Under stirring, 31 mL of dichloromethane solution containing 0.205 g of compound B was slowly added. After purging with nitrogen three times, the mixture was stirred at room temperature for 12 h. After stirring, the mixture was diluted with distilled water and extracted three times with ethyl acetate. The organic phases were combined, washed once with saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography using a mixed solution of petroleum ether and ethyl acetate at a volume ratio of 75:25 as the eluent to obtain compound C in 63% yield.
[0056] Step 3: Add 1.01 g of compound C to a container, followed by 46 mL of formic acid. Slowly add 5.2 mL of Raney Ni under stirring. After nitrogen purging, heat and stir at 90 °C for 12 h. After the reaction is complete, filter and concentrate the filtrate to obtain a crude oily product. Then add 11.3 mL of saturated sodium bicarbonate solution and 11.5 mL of tetrahydrofuran. After stirring, add 0.615 g of di-tert-butyl carbonate anhydride and stir at room temperature for 12 h. After the reaction is complete, extract twice with ethyl acetate, combine the organic phases, wash once with saturated sodium chloride solution, dry with anhydrous sodium sulfate, filter, concentrate, and use a mixed solution of petroleum ether and ethyl acetate (volume ratio 75:25) as the eluent for silica gel column chromatography purification to obtain 3-pyrimidinone-4,5,6,7-tetrahydro-2H-pyrazole[4,3-c]pyridine, with a yield of 62%.
[0057] Example 8: This example discloses a method for synthesizing 3-pyrimidinone-4,5,6,7-tetrahydro-2H-pyrazole[4,3-c]pyridine, comprising the following steps:
[0058] Step 1: Add 1.6g of cyanoacetamide to a container, add 95mL of dichloromethane, purge with nitrogen once, then place the container in an ice-water bath, slowly add 4.61g of oxaloyl chloride under stirring, purge with nitrogen three times, heat at 75℃ for 1.5h, and after the reaction is complete, compound B is obtained;
[0059] Step 2: 1.12 g of tert-butyl(S)-3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester was added to a container, followed by 46 mL of tetrahydrofuran. The mixture was purged with nitrogen once, and then the container was placed in an ice-water bath. Under stirring, 34 mL of dichloromethane solution containing 0.278 g of compound B was slowly added. After purging with nitrogen three times, the mixture was stirred at room temperature for 12 h. After stirring, the mixture was diluted with distilled water and extracted three times with ethyl acetate. The organic phases were combined, washed once with saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography using a mixed solution of petroleum ether and ethyl acetate at a volume ratio of 75:25 as the eluent to obtain compound C in 67% yield.
[0060] Step 3: Add 1.04 g of compound C to a container, followed by 48 mL of formic acid. Slowly add 5.6 mL of Raney Ni under stirring. After nitrogen purging, heat and stir at 90 °C for 12 h. After the reaction is complete, filter and concentrate the filtrate to obtain a crude oily product. Then add 11.6 mL of saturated sodium bicarbonate solution and 8.8 mL of tetrahydrofuran. After stirring, add 0.611 g of di-tert-butyl carbonate anhydride and stir at room temperature for 12 h. After the reaction is complete, extract twice with ethyl acetate, combine the organic phases, wash once with saturated sodium chloride solution, dry with anhydrous sodium sulfate, filter, concentrate, and use a mixed solution of petroleum ether and ethyl acetate (volume ratio 75:25) as the eluent for silica gel column chromatography purification to obtain 3-pyrimidinone-4,5,6,7-tetrahydro-2H-pyrazole[4,3-c]pyridine, with a yield of 63%.
[0061] Example 9: This example discloses a method for synthesizing 3-pyrimidinone-4,5,6,7-tetrahydro-2H-pyrazole[4,3-c]pyridine, comprising the following steps:
[0062] Step 1: Add 2.3g of cyanoacetamide to a container, add 115mL of dichloromethane, purge with nitrogen once, then place the container in an ice-water bath, slowly add 4.27g of oxaloyl chloride under stirring, purge with nitrogen three times, heat at 75℃ for 1.5h, and after the reaction is complete, obtain compound B;
[0063] Step 2: 1.18 g of tert-butyl(S)-3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester was added to a container, followed by 49 mL of tetrahydrofuran. The mixture was purged with nitrogen once, and then the container was placed in an ice-water bath. Under stirring, 26 mL of dichloromethane solution containing 0.315 g of compound B was slowly added. After purging with nitrogen three times, the mixture was stirred at room temperature for 12 h. After stirring, the mixture was diluted with distilled water and extracted three times with ethyl acetate. The organic phases were combined, washed once with saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography using a 75:25 (v / v) mixture of petroleum ether and ethyl acetate as the eluent to obtain compound C with a yield of 67%.
[0064] Step 3: Add 1.09 g of compound C to a container, followed by 52 mL of formic acid. Slowly add 5.8 mL of Raney Ni under stirring. After nitrogen purging, heat and stir at 90 °C for 12 h. After the reaction is complete, filter and concentrate the filtrate to obtain a crude oily product. Then add 11.9 mL of saturated sodium bicarbonate solution and 11.3 mL of tetrahydrofuran. After stirring, add 0.609 g of di-tert-butyl carbonate anhydride and stir at room temperature for 12 h. After the reaction is complete, extract twice with ethyl acetate, combine the organic phases, wash once with saturated sodium chloride solution, dry with anhydrous sodium sulfate, filter, concentrate, and use a mixed solution of petroleum ether and ethyl acetate (volume ratio 75:25) as the eluent for silica gel column chromatography purification to obtain 3-pyrimidinone-4,5,6,7-tetrahydro-2H-pyrazole[4,3-c]pyridine, with a yield of 66%.
[0065] The above description is only a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the scope of the technology disclosed in the present invention, based on the technical solution and inventive concept of the present invention, should be covered within the scope of protection of the present invention.
[0066] The preferred embodiments of the present invention disclosed above are merely illustrative of the invention. These preferred embodiments do not exhaustively describe all details, nor do they limit the invention to specific implementations. Clearly, many modifications and variations can be made based on the content of this specification. This specification selects and specifically describes these embodiments to better explain the principles and practical applications of the invention, thereby enabling those skilled in the art to better understand and utilize the invention. The invention is limited only by the claims and their full scope and equivalents.
Claims
1. A method for synthesizing 3-pyrimidinone-4,5,6,7-tetrahydro-2H-pyrazole[4,3-c]pyridine, characterized in that, Includes the following steps: Step 1: Add cyanoacetamide to a container, add dichloromethane, purge with nitrogen, then place the container in an ice-water bath, slowly add oxaloyl chloride under stirring, purge with nitrogen, heat to react, and after the reaction is complete, obtain compound B; Step 2: tert-butyl(S)-3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester was added to a container, tetrahydrofuran was added, nitrogen was purged, and then the container was placed in an ice-water bath. Under stirring, a dichloromethane solution containing compound B was slowly added. After nitrogen purging, the mixture was stirred at room temperature. After stirring, the mixture was diluted, extracted, and the organic phases were combined, washed, dried, filtered, concentrated, and purified to obtain compound C. Step 3: Add compound C to the container, then add formic acid, and slowly add Raney Ni under stirring. After nitrogen purging, heat and stir the reaction. After the reaction is complete, filter and concentrate the filtrate to obtain crude oily product. Then add saturated sodium bicarbonate solution and tetrahydrofuran, stir, and then add di-tert-butyl carbonate anhydride. Stir the reaction at room temperature. After the reaction is complete, extract, combine the organic phases, wash, dry, filter, concentrate, and purify to obtain 3-pyrimidinone-4,5,6,7-tetrahydro-2H-pyrazole[4,3-c]pyridine.
2. The method for synthesizing 3-pyrimidinone-4,5,6,7-tetrahydro-2H-pyrazole[4,3-c]pyridine according to claim 1, characterized in that, In step one, the ratio of cyanoacetamide, dichloromethane, and oxalyl chloride is (1-3)g:(80-120)mL:(4.12-4.64)g.
3. The method for synthesizing 3-pyrimidinone-4,5,6,7-tetrahydro-2H-pyrazole[4,3-c]pyridine according to claim 1, characterized in that, In step one, after adding dichloromethane, nitrogen is purged 1-2 times, and after adding oxalyl chloride, nitrogen is purged 2-4 times. The reaction temperature is 70-80℃, and the reaction time is 1-2 hours.
4. The method for synthesizing 3-pyrimidinone-4,5,6,7-tetrahydro-2H-pyrazole[4,3-c]pyridine according to claim 1, characterized in that, In step two, the ratio of tert-butyl(S)-3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester, tetrahydrofuran, compound B, and dichloromethane is (1-1.2) g : (45-55) mL : (0.137-0.393) g : (25-35) mL.
5. The method for synthesizing 3-pyrimidinone-4,5,6,7-tetrahydro-2H-pyrazole[4,3-c]pyridine according to claim 1, characterized in that, In step two, the nitrogen purging is performed 1-2 times after adding tetrahydrofuran, and 3-5 times after adding dichloromethane solution containing compound B. The stirring time is 10-12 hours at room temperature. Distilled water is added for dilution, and the mixture is extracted with ethyl acetate 3-5 times, washed with saturated sodium chloride solution 1-2 times, and dried with anhydrous sodium sulfate. During the purification process, a mixed solution of petroleum ether and ethyl acetate with a volume ratio of (50-100):(0-50) is used as the eluent for silica gel column chromatography purification.
6. The method for synthesizing 3-pyrimidinone-4,5,6,7-tetrahydro-2H-pyrazole[4,3-c]pyridine according to claim 1, characterized in that, In step three, the ratio of compound C, formic acid, Raney Ni, saturated sodium bicarbonate solution, tetrahydrofuran, and di-tert-butyl carbonate anhydride is (0.95-1.15)g:(40-60)mL:(4-6)mL:(10-12)mL:(8-12)mL:(0.606-0.618)g.
7. The method for synthesizing 3-pyrimidinone-4,5,6,7-tetrahydro-2H-pyrazole[4,3-c]pyridine according to claim 1, characterized in that, In step three, the heating and stirring reaction temperature is 90-95℃, the reaction time is 10-14h, the stirring reaction time at room temperature is 10-12h, the extraction is performed with ethyl acetate 2-4 times, the washing is performed with saturated sodium chloride solution 1-3 times, and the drying is performed with anhydrous sodium sulfate. During the purification process, a mixed solution of petroleum ether and ethyl acetate with a volume ratio of (50-100):(0-50) is used as the eluent for silica gel column chromatography purification.