Synthesis method of 7-chloropyrazolo [1, 5-a] pyrimidine

Abstract

The invention discloses a synthesis method of 7-chloropyrazolo [1, 5-a] pyrimidine, which comprises the following steps: by taking 3H-pyrazole-3-amine as a raw material, converting into an intermediate compound pyrazolo [1, 5-a] pyrimidine-7-alcohol under the action of trans-N, N-dimethylamino ethyl acrylate, and then reacting the pyrazolo [1, 5-a] pyrimidine-7-alcohol with N, N-dimethylamino ethyl acrylate to obtain the 7-chloropyrazolo [1, 5-a] pyrimidine. The target product 7-chloropyrazolo [1, 5-a] pyrimidine is obtained under the action of N, N-dimethylformamide and phosphorus oxychloride. In the key production steps of the synthesis method, trans-N, N-dimethylamino ethyl acrylate is used in a breakthrough manner, an intermediate compound pyrazolo [1, 5-a] pyrimidine-7-alcohol is obtained with high yield, and finally the target 7-chloropyrazolo [1, 5-a] pyrimidine is obtained with high yield through short steps, simple operation and relatively mild reaction conditions.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing 7-chloropyrazolo[1,5-a]pyrimidine. Background Art

[0002] 7-Chloropyrazolo[1,5-a]pyrimidine is an important molecular building block. As a key intermediate, for example, in patent WO2010 / 133836, it is used to synthesize a selective inhibitor of PI3 kinase, which has a wide range of application value in medicine, such as the treatment of inflammatory, autoimmune, cardiovascular, neurodegenerative, metabolic, tumor, injury or ophthalmic diseases. In patent WO2015 / 043492, it is used to synthesize substituted urea derivatives, which can regulate FLT3 kinase activity, inhibit FLT3-ITD, and treat diseases mediated by FLT3 kinase or caused by FLT3-ITD. Therefore, it is of great significance to develop a simple and efficient synthesis method for 7-chloropyrazolo[1,5-a]pyrimidine.

[0003] In the prior art, the conventional synthesis route of 7-chloropyrazolo[1,5-a]pyrimidine is to use 3H-pyrazol-3-amine as a raw material, first synthesize an intermediate compound pyrazolo[1,5-a]pyrimidine-7-ol, and then convert it into 7-chloropyrazolo[1,5-a]pyrimidine. However, metallic sodium is required in the process of synthesizing pyrazolo[1,5-a]pyrimidine-7-ol, which is dangerous, has high safety risks and low yield, and is not suitable for process scale-up production. Summary of the invention

[0004] In view of the above problems existing in the prior art, the purpose of the present invention is to provide a method for synthesizing 7-chloropyrazolo[1,5-a]pyrimidine, wherein the entire synthesis process has low cost, short steps, easy operation, relatively mild reaction conditions, low safety risks and ideal yield.

[0005] To achieve the above object, the technical solution of the present invention is as follows:

[0006] The present invention provides a method for synthesizing 7-chloropyrazolo[1,5-a]pyrimidine, and the synthetic route is as follows:

[0007]

[0008] The specific steps include:

[0009] (1) Compound 1, i.e., 3H-pyrazole-3-amine, is dissolved in an organic solvent I, and compound 2, i.e., trans-N,N-dimethylamino ethyl acrylate, is added thereto, and the mixture is reacted at 70 to 120° C. for 10 to 40 hours. After the reaction is completed, the resulting reaction solution is post-treated to obtain compound 3, i.e., pyrazolo[1,5-a]pyrimidin-7-ol;

[0010] (2) Add N,N-dimethylformamide to a mixture of compound 3 and organic solvent II, and then add phosphorus oxychloride, and react at 10 to 30° C. for 1 to 6 hours. After the reaction is completed, the resulting reaction solution is post-treated to obtain compound 4, i.e., 7-chloropyrazolo[1,5-a]pyrimidine.

[0011] Furthermore, in step (1), the molar ratio of compound 1 to compound 2 is 1:1-3.

[0012] Furthermore, in step (1), the organic solvent I is selected from one or more of ethanol, N,N-dimethylformamide, and dichloromethane.

[0013] Furthermore, in step (1), the mass volume ratio of the compound 1 to the organic solvent I is 1:5 to 40 g / mL.

[0014] Furthermore, in step (1), the post-treatment method comprises: stirring the reaction solution at -5 to 5°C for 30 to 60 minutes after the reaction is completed, filtering after solid precipitation, collecting the filter cake, and drying to obtain compound 3.

[0015] Furthermore, in step (2), the organic solvent II is selected from one or more of tetrahydrofuran, diethyl ether, and methyl tert-butyl ether.

[0016] Furthermore, in step (2), the mass volume ratio of the compound 3 to the organic solvent II is 1:5 to 40 g / mL.

[0017] Furthermore, in step (2), the molar ratio of the compound 3 to N,N-dimethylformamide is 1:1-5.

[0018] Furthermore, in step (2), the molar ratio of compound 3 to phosphorus oxychloride is 1:1-6.

[0019] Furthermore, in step (2), the post-treatment method comprises: adding ethyl acetate to the reaction solution after the reaction is completed, and then adding hydrochloric acid-ethyl acetate solution, stirring for 5-10 minutes until a large amount of solid appears, filtering, washing the filter cake with organic solvent II, collecting the filter cake, and dissolving the obtained solid in a buffer system with a molar concentration ratio of sodium carbonate to sodium bicarbonate of 1M:1M, stirring, extracting with organic solvent III, combining the organic phases, washing, drying, filtering, and concentrating under reduced pressure to obtain compound 4.

[0020] Furthermore, in step (2), the organic solvent III is selected from one or more of ethyl acetate, butyl acetate, chloroform, toluene, dichloromethane, and dichloroethane.

[0021] Compared with the prior art, the present invention has the following beneficial effects:

[0022] The invention provides a method for synthesizing 7-chloropyrazolo[1,5-a]pyrimidine. Compound 1 (3H-pyrazole-3-amine) is used as a raw material, and is converted into an intermediate compound 3 (pyrazolo[1,5-a]pyrimidine-7-ol) under the action of compound 2 (trans-N,N-dimethylamino ethyl acrylate). Compound 3 is then reacted under the action of N,N-dimethylformamide and phosphorus oxychloride to obtain compound 4 (7-chloropyrazolo[1,5-a]pyrimidine). In the key production step of the synthetic method, trans-N,N-dimethylamino ethyl acrylate is used in a breakthrough manner to obtain the intermediate compound pyrazolo[1,5-a]pyrimidine-7-ol with high yield. Finally, the target product 7-chloropyrazolo[1,5-a]pyrimidine is obtained with high yield by short steps, simple operation and relatively mild reaction conditions. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 This is the H NMR spectrum of compound 3 obtained in Example 1.

[0024] Figure 2 This is the H NMR spectrum of compound 4 obtained in Example 1. DETAILED DESCRIPTION

[0025] In order to make the technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below in conjunction with the accompanying drawings of the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the described embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0026] Unless otherwise specified in the following examples, all reagents and materials used were commercially available.

[0027] Example 1

[0028] This example synthesizes a 7-chloropyrazolo[1,5-a]pyrimidine, and the synthesis route is as follows:

[0029]

[0030] The specific steps are:

[0031] (1) Compound 1 (3H-pyrazole-3-amine) (200.00 g, 2.41 mol, 1.00 eq) was dissolved in ethanol (2.0 L), and compound 2 (trans-N,N-dimethylamino ethyl acrylate) (344.64 g, 2.41 mol, 1.00 eq) was added, and the mixture was reacted at 80° C. for 12 hours. After the reaction was completed, the reaction solution was stirred at 0° C. for 30 minutes, and solid precipitated. The solid was filtered, and the filter cake was collected and dried to obtain compound 3 (pyrazolo[1,5-a]pyrimidin-7-ol, light yellow powder, weight 303.60 g, purity 98%, yield 91%).

[0032] The H NMR spectrum of the obtained compound pyrazolo[1,5-a]pyrimidin-7-ol is as follows Figure 1 The obtained characterization data are as follows:

[0033] 1 H NMR (400MHz, dmso) δ12.41 (s, 1H), 7.96-7.78 (m, 2H), 6.18 (d, J = 2.0Hz, 1H), 5.69 (d, J = 7.3Hz, 1H).

[0034] (2) Pyrazolo[1,5-a]pyrimidin-7-ol (100.00 g, 222.18 mmol, 1.0 eq) was added to 2.0 L of tetrahydrofuran, the system temperature was controlled at 15°C, N,N-dimethylformamide (32.48 g, 444.36 mmol, 2.0 eq) was added, phosphorus oxychloride (136.26 g, 888.71 mmol, 4.0 eq) was slowly added dropwise, and after the addition was completed, the mixture was reacted at about 15°C for 1-2 hours. After the reaction was completed, 2.0 L of ethyl acetate in an amount equal to the volume of the solvent was added, and then 4M hydrochloric acid-ethyl acetate solution (100 g) was added, and the mixture was stirred for 5-10 minutes. A large amount of solid appeared, and the mixture was filtered. The filter cake was washed twice with ethyl acetate (200 mL×2), and the filter cake was collected. The solid was dissolved in 1000 mL of a buffer system having a molar concentration ratio of sodium carbonate to sodium bicarbonate of 1M:1M and stirred, extracted twice with ethyl acetate (1600 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain compound 4, i.e., 7-chloropyrazolo[1,5-a]pyrimidine (light yellow solid, weight 109.10 g, purity 98%, yield 94%).

[0035] The H NMR spectrum of the obtained compound 7-chloropyrazolo[1,5-a]pyrimidine is as follows Figure 2 The obtained characterization data are as follows:

[0036] 1H NMR (400MHz, CDCl3) δ8.40(d,J=4.5Hz,1H),8.25(d,J=2.3Hz,1H),6.99(d,J=4.4Hz,1H),6.84(d,J=2.4Hz,1H).

[0037] Embodiments 2 to 5

[0038] Examples 2 to 5 are the same as Example 1, except that the amount of compound 2, organic solvent I, reaction temperature, reaction time, etc. in the reaction are adjusted, as shown in Table 1.

[0039] Through Examples 1 to 5, the effects of various reaction conditions on the reaction yield during the synthesis of 7-chloropyrazolo[1,5-a]pyrimidine were tested. The results are shown in Table 1.

[0040] Table 1

[0041]

[0042] Combination Figure 1 , 2 From Table 1, we can see that

[0043] Comparing Examples 1 and 2, when the molar ratio of raw material 1 to compound 2 is 1:1, the reaction effect is already very good.

[0044] Comparing Examples 1 and 3, the target product can be obtained in both ethanol and N,N-dimethylformamide solvents, and ethanol is more effective as a solvent.

[0045] Comparing Examples 1-4, when the reaction temperature is 80°C, the reaction effect is already very good.

[0046] Comparing Examples 1-5, when the reaction time is 12 h, the reaction effect is already very good.

[0047] The above is a preferred embodiment of the present invention, but the present invention should not be limited to the contents disclosed in the embodiment. Therefore, any equivalent or modification completed without departing from the spirit disclosed in the present invention shall fall within the scope of protection of the present invention.

Claims

1. A method for synthesizing 7-chloropyrazolo[1,5-a]pyrimidine, characterized in that: The synthetic route is as follows: The synthesis method comprises the following steps: (1) Compound 1, i.e., 3H-pyrazole-3-amine, is dissolved in an organic solvent I, and compound 2, i.e., trans-N,N-dimethylamino ethyl acrylate, is added thereto, and the mixture is reacted at 70 to 120° C. for 10 to 40 hours. After the reaction is completed, the resulting reaction solution is post-treated to obtain compound 3, i.e., pyrazolo[1,5-a]pyrimidin-7-ol; (2) First, N,N-dimethylformamide is added to a mixture of compound 3 and organic solvent II, and then phosphorus oxychloride is added, and the mixture is reacted at 10 to 30° C. for 1 to 6 hours. After the reaction is completed, the resulting reaction solution is post-treated to obtain compound 4, i.e., 7-chloropyrazolo[1,5-a]pyrimidine.

2. The method for synthesizing 7-chloropyrazolo[1,5-a]pyrimidine according to claim 1, characterized in that: In step (1), the molar ratio of compound 1 to compound 2 is 1:1-3.

3. The method for synthesizing 7-chloropyrazolo[1,5-a]pyrimidine according to claim 1, characterized in that: In step (1), the organic solvent I is selected from one or more of ethanol, N,N-dimethylformamide, and dichloromethane.

4. The method for synthesizing 7-chloropyrazolo[1,5-a]pyrimidine according to claim 1, characterized in that: In step (1), the mass volume ratio of the compound 1 to the organic solvent I is 1:5-40 g / mL.

5. The method for synthesizing 7-chloropyrazolo[1,5-a]pyrimidine according to claim 1, characterized in that: In step (1), the post-treatment method comprises: stirring the reaction solution at -5 to 5°C for 30 to 60 minutes after the reaction is completed, filtering after solid precipitation, collecting the filter cake, and drying to obtain compound 3.

6. The method for synthesizing 7-chloropyrazolo[1,5-a]pyrimidine according to claim 1, characterized in that: In step (2), the organic solvent II is selected from one or more of tetrahydrofuran, diethyl ether, and methyl tert-butyl ether.

7. The method for synthesizing 7-chloropyrazolo[1,5-a]pyrimidine according to claim 1, characterized in that: In step (2), the mass volume ratio of the compound 3 to the organic solvent II is 1:5 to 40 g / mL.

8. The method for synthesizing 7-chloropyrazolo[1,5-a]pyrimidine according to claim 1, characterized in that: In step (2), the molar ratio of compound 3 to N,N-dimethylformamide is 1:1-5; And / or the molar ratio of compound 3 to phosphorus oxychloride is 1:1-6.

9. The method for synthesizing 7-chloropyrazolo[1,5-a]pyrimidine according to claim 1, characterized in that: In step (2), the post-treatment method includes: first adding ethyl acetate to the reaction solution after the reaction is completed, then adding hydrochloric acid-ethyl acetate solution, stirring for 5-10 minutes until a large amount of solid appears, filtering, washing the filter cake with organic solvent II, collecting the filter cake, dissolving the obtained solid in a buffer system with a molar concentration ratio of sodium carbonate to sodium bicarbonate of 1M:1M, stirring, extracting with organic solvent III, combining the organic phases, washing, drying, filtering, and concentrating under reduced pressure to obtain compound 4.

10. The method for synthesizing 7-chloropyrazolo[1,5-a]pyrimidine according to claim 9, characterized in that: In step (2), the organic solvent III is selected from one or more of ethyl acetate, butyl acetate, chloroform, toluene, dichloromethane and dichloroethane.

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