Synthesis method of pyrazole tricyclic compound

Abstract

The invention belongs to the technical field of medicine synthesis, and particularly relates to a synthesis method of a pyrazole tricyclic compound, a target compound is synthesized by simplifying a synthesis route of the pyrazole tricyclic compound and adopting a one-step synthesis method, the synthesis method has the characteristics of simplicity in operation, short reaction time, easiness in separation and purification and high yield, and the production efficiency can be improved.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and specifically relates to a method for synthesizing a pyrazole tricyclic compound. Background Art

[0002] The pyrazole ring structural unit is an important component of many drugs and pesticides. Pyrazole tricyclic compounds are widely used in the fields of medicine and pesticides due to their structural variability and high-efficiency and broad-spectrum biological activity. In the field of medicine, pyrazole tricyclic compounds are mainly manifested in antibacterial, antitumor, anticancer and other aspects. For example, Srihari reported a pyrazole tricyclic compound that can be used for anti-allergic treatment (Srihari P. et al, New and practical synthesis of 1,4-dihydrobenzopyranopyrazoles. Tetrahedron Lett., 2001, 42, 6599-6601); in the field of pesticides, pyrazole tricyclic compounds are mainly manifested in insecticides, fungicides and herbicides. Li-Gang et al. reported antibacterial drugs containing pyrazole tricyclics (Li-Gang Yu et al, The synthesis and antibacterial activity of pyrazole-fused tricyclic diterpene derivatives, Eur. J. Med. Chem., 2015, 90, 10-20). In recent years, pyrazole fused ring compounds have attracted more and more attention due to their high efficiency, low toxicity, structural diversity and wide biological activity, and the interest in pyrazole compounds has increased dramatically. At present, the synthesis method of pyrazole tricyclic compounds is cumbersome, the byproducts are complex, the separation and purification are difficult, and the yield is low. Therefore, overall, the synthesis economic benefits of pyrazole tricyclic compounds are low, which seriously restricts the production and application of pyrazole tricyclic compounds. (Tomita et al, Structure-based discovery of cellular-active allosteric inhibitors of FAK. Bioorg. Med. Chem. Lett., 2013, 23, 1779–1785; Iwatani M. et al. Discovery and characterization of novel allosteric FAK inhibitors. Eur. J. Med. Chem., 2013, 61, 49-60). Summary of the invention

[0003] In view of this, the object of the present invention is to provide a method for synthesizing pyrazole tricyclic compounds, which is a one-step synthesis method with few steps, high yield and easy separation.

[0004] To achieve the above object, the present invention provides the following technical solution: a method for synthesizing a pyrazole tricyclic compound, wherein the synthesis method comprises:

[0005] 3-bromomethylpyrazole is reacted with an acyl chloride reagent in a strong acid solvent, first in the strong acid solvent for more than 2 hours at a temperature of 100° C., then, when the temperature is cooled to 80° C., the acyl chloride reagent is added to the solution and reacted for more than 1 hour to obtain compound 2;

[0006] S102. Compound 2 reacts with alkaline reagent 1 (methylamine tetrahydrofuran solution) in organic solvent 1 (dichloromethane) to obtain compound 3;

[0007] S103. Compound 3 reacts with alkaline reagent 2 (potassium phosphate) in an organic solvent 2 (1,4-dioxane), and then a palladium catalyst is added to obtain the pyrazole tricyclic compound.

[0008] Preferably, the mass ratio of 3-bromomethylpyrazole to the volume ratio of the strong acid solvent is 1 g / (2-7) mL.

[0009] Preferably, the mass ratio of 3-bromomethylpyrazole to the volume ratio of the strong acid solvent is 1 g / 3 mL.

[0010] Preferably, the mass ratio of 3-bromomethylpyrazole to the volume ratio of the acyl chloride reagent is: 1 g / (0.5-3) mL.

[0011] Preferably, the mass ratio of 3-bromomethylpyrazole to the volume ratio of the acyl chloride reagent is 1 g / 2 mL.

[0012] Preferably, the strong acid solvent is chlorosulfonic acid.

[0013] Preferably, the acyl chlorination agent is one or more of thionyl chloride, phosphorus oxychloride, and phosphorus oxychloride pentachloride.

[0014] Preferably, the mass ratio of the compound 2 to the alkaline reagent 1 is 1:0.1-2.

[0015] Preferably, the mass ratio of the compound 2 to the alkaline reagent 1 is 1:0.3.

[0016] Preferably, the organic solvent 1 is one or more of dichloromethane, tetrahydrofuran (THF), 2-methyltetrahydrofuran, and methyl tert-butyl ether.

[0017] Preferably, the alkaline reagent 1 is any one of methylamine (THF), ethylamine, and deuterated methylamine.

[0018] Preferably, the organic solvent 2 is 1,4-dioxane.

[0019] Preferably, the alkaline reagent 2 is potassium phosphate.

[0020] Preferably, the mass ratio of the compound 3 to the palladium catalyst is 1:0.005-0.05.

[0021] Preferably, the mass ratio of the compound 3 to the palladium catalyst is 1:0.01.

[0022] Preferably, the palladium catalyst is Pd(dppf)Cl2 or tetrakistriphenylphosphine palladium.

[0023] Compared with the prior art, the present invention has the following beneficial effects:

[0024] 1. The invention simplifies and optimizes the technical route and synthesizes the target compound by a one-step synthesis method, which is simple to operate, short in reaction time, easy to separate and purify, high in yield, and improves production efficiency.

[0025] 2. The present invention only requires one step of reaction to prepare the target compound from compound 3, which is convenient and practical. Compound 3 has the advantages of being simple and quick to prepare and easy to store. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 It is a synthetic route map of existing pyrazole tricyclic compounds;

[0027] Figure 2 This is a synthetic route diagram of the first pyrazole tricyclic compound of the present invention;

[0028] Figure 3 The second synthetic route of the pyrazole tricyclic compound of the present invention is shown in FIG.

[0029] Figure 4 The third synthetic route of the pyrazole tricyclic compound of the present invention is shown in FIG. DETAILED DESCRIPTION

[0030] In order to make the purpose, technical solution and advantages of the embodiments of the present invention clearer, the technical solution in the embodiments of the present invention will be clearly and completely described in combination with 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 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.

[0031] like Figure 1The figure shows the existing synthesis route of pyrazole tricyclic compounds. As can be seen from the figure, the existing synthesis route has the problems of cumbersome synthesis steps, complex by-products, difficult separation and purification, low yield, etc., which further reduces the economic benefits of the synthesis of pyrazole tricyclic compounds. In order to overcome the above problems, the present invention proposes a method for synthesizing pyrazole tricyclic compounds. For the convenience of description, the marks in the synthesis route of the present invention are now explained. In the figure, 1 is compound 1, i.e. 3-bromomethylpyrazole, 5a is the target compound, i.e. pyrazole tricyclic compound, and other numbers or combinations of numbers and letters represent the names of corresponding compounds, such as 2 represents chemical 2, and 3b represents compound 3b.

[0032] To this end, we provide three implementation examples to demonstrate the applicability of our experimental method, and different substrates can be synthesized in one step.

[0033] Embodiment 1:

[0034] like Figure 2 An embodiment of the present invention is shown, and the specific steps are as follows:

[0035] Step 1: Synthesis of compound 2

[0036] Dissolve compound 1 (1 g) in chlorosulfonic acid (2 mL), cool to 0 ° C, add thionyl chloride (2 mL) under nitrogen protection, and heat the mixture to 80 ° C and stir for 5 h. After the raw materials are completely reacted, slowly add the reaction solution dropwise into ice H2O to quench and dilute. Extract the mixture with dichloromethane (20 mL × 3), combine the obtained organic phases, add saturated brine to wash, and dry over anhydrous sodium sulfate. Filter the obtained organic phase under reduced pressure and concentrate in vacuo. The target compound 2 is directly used in the next step (1 g, yield 62%).

[0037] Step 2: Synthesis of compound 3

[0038] Compound 2 (100 mg) was dissolved in dichloromethane (1 mL), methylamine tetrahydrofuran solution (0.5 mL) was slowly added dropwise, and the mixture was stirred at room temperature for 1.5 h. The mixture was concentrated in vacuo, and the crude product was purified by preparative plate chromatography (PE / EA=2:1) ​​to obtain compound 3 (50 mg, yield 51.2%).

[0039] LCMS m / z:254.20[M+H] + .

[0040] Step 3: Synthesis of compound 5a

[0041] Compound 3 (350 mg, 1.37 mmol) was dissolved in 1,4-dioxane (5 mL), 4 (750 mg, 2.75 mmol), potassium phosphate (492 mg, 2.328 mmol) were added, nitrogen was replaced three times, Pd(dppf)Cl2 (60 mg, 0.08 mmol) was added, and the mixture was heated to 50 °C and stirred for 8 h. After the reaction was completed, 10 mL of H2O was added to the reaction solution to quench the reaction. The mixture was extracted with DCM (30 mL × 3), all organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The obtained organic phase was filtered under reduced pressure and concentrated in vacuo. The crude product was purified by preparative plate chromatography (PE / EA = 1:1) to obtain the target compound 5a (211 mg, yield 52%).

[0042] LCMS m / z:295.35[M+H] + .

[0043] 1 H NMR (400MHz, CHLOROFORM-D) δ8.24(dd,J=1.5,7.8Hz,1H),7.91(dd,J=1.5,8.1Hz,1H),7.89(s,1H),7.54(t,J=8.0Hz,1H),4.07(s,3H),3.13(s,3H).

[0044] Embodiment 2:

[0045] like Figure 3 Another embodiment of the present invention is shown, which is specifically implemented as follows:

[0046] Step 1: Synthesis of compound 3b

[0047] Compound 2 (500 mg) was dissolved in dichloromethane (5 mL), deuterated methylamine hydrochloride (272 mg, 3.85 mmol) and TEA (1 g, 9.6 mmol) were added under nitrogen protection, and the mixture was stirred at room temperature for 1.5 h. The mixture was filtered under reduced pressure and concentrated in vacuo. The crude product was purified by preparative plate chromatography (PE / EA=2:1) ​​to obtain compound 3b (380 mg, yield 76.7%).

[0048] Step 2: Synthesis of compound 5b

[0049] Compound 3 (200 mg, 0.78 mmol) was dissolved in 1,4-dioxane (5 mL), 4 (412 mg, 1.55 mmol), potassium phosphate (492 mg, 2.328 mmol) were added, nitrogen was replaced three times, Pd(dppf)Cl2 (60 mg, 0.08 mmol) was added, and the mixture was heated to 50 °C and stirred for 8 h. After the reaction was completed, 10 mL of H2O was added to the reaction solution to quench the reaction. The mixture was extracted with DCM (30 mL × 3), all organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The obtained organic phase was filtered under reduced pressure and concentrated in vacuo. The crude product was purified by preparative plate chromatography (PE / EA = 1:1) to obtain the target compound 5b (120 mg, yield 51%).

[0050] LCMS m / z:298.30[M+H] + .

[0051] 1 H NMR (400MHz, CHLOROFORM-D) δ8.24 (dd, J=1.5, 7.8Hz, 1H), 7.93–7.89 (m, 2H), 7.54 (t, J=8.0Hz, 1H), 4.07 (s, 3H).

[0052] Embodiment three:

[0053] like Figure 4 The third embodiment of the present invention is shown, and its specific implementation is as follows:

[0054] Step 1: Synthesis of compound 3c

[0055] Compound 2 (100 mg, 1.93 mmol) was dissolved in dichloromethane (2 mL), ethylamine (260 mg, 5.8 mmol) was slowly added dropwise, and the mixture was stirred at room temperature for 0.5 h. The mixture was concentrated in vacuo, and the crude product was purified by preparative plate chromatography (PE / EA=2:1) ​​to obtain compound 3c (50 mg, yield 48.5%).

[0056] Step 2: Synthesis of compound 5c

[0057] Compound 3c (50 mg, 0.186 mmol) was dissolved in 1,4-dioxane (5 mL), 4 (99 mg, 0.37 mmol), potassium phosphate (119 mg, 0.56 mmol) were added, nitrogen was replaced three times, Pd(dppf)Cl2 (15 mg, 0.02 mmol) was added, and the mixture was heated to 50 °C and stirred for 8 h. After the reaction was completed, 10 mL of H2O was added to the reaction solution to quench the reaction. The mixture was extracted with DCM (30 mL × 3), all organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The obtained organic phase was filtered under reduced pressure and concentrated in vacuo. The crude product was purified by preparative plate chromatography (PE / EA = 1:1) to obtain the target compound 5c (25 mg, yield 44%).

[0058] LCMS m / z:309.20[M+H] + .

[0059] 1 H NMR (400MHz, CDCl3) δ8.19 (d, J = 7.6Hz, 1H), 7.86–7.78 (m, 2H), 7.48 (t, J = 8.0Hz, 1H), 4.01 (s, 3H), 3.61 (q, J = 7.2Hz, 2H), 0.82 (t, J = 7.2Hz, 3H).

[0060] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit the same. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that the technical solutions described in the aforementioned embodiments may still be modified, or some of the technical features may be replaced by equivalents. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for synthesizing a pyrazole tricyclic compound, characterized in that: The method comprises the following steps: S101. 3-bromomethylpyrazole is reacted with an acyl chloride reagent in a strong acid solvent, first in the strong acid solvent for more than 2 hours at a temperature of 100° C., then, when the temperature is cooled to 80° C., the acyl chloride reagent is added to the solution and reacted for more than 1 hour to obtain compound 2; S102. Compound 2 reacts with alkaline reagent 1 in organic solvent 1 to obtain compound 3; S103. Compound 3 reacts with alkaline reagent 2 in organic solvent 2, and then a palladium catalyst is added to obtain the pyrazole tricyclic compound.

2. The method for synthesizing a pyrazole tricyclic compound according to claim 1, characterized in that: The mass ratio of 3-bromomethylpyrazole to the volume ratio of the strong acid solvent is: 1 g / (2-7) mL.

3. The method for synthesizing a pyrazole tricyclic compound according to claim 2, characterized in that: The mass ratio of 3-bromomethylpyrazole to the volume of the strong acid solvent is: 1 g / 3 mL.

4. The method for synthesizing a pyrazole tricyclic compound according to claim 1, characterized in that: The mass ratio of 3-bromomethylpyrazole to the volume ratio of the acyl chloride reagent is: 1 g / (0.5-3) mL.

5. The method for synthesizing a pyrazole tricyclic compound according to claim 4, characterized in that: The mass ratio of 3-bromomethylpyrazole to the volume ratio of the acyl chloride reagent is: 1 g / 2 mL.

6. The method for synthesizing a pyrazole tricyclic compound according to claim 1, characterized in that: The strong acid solvent is chlorosulfonic acid.

7. The method for synthesizing a pyrazole tricyclic compound according to claim 1, characterized in that: The acyl chloride reagent is one or more of thionyl chloride, phosphorus oxychloride, and phosphorus oxychloride pentachloride.

8. The method for synthesizing a pyrazole tricyclic compound according to claim 1, characterized in that: The mass ratio of the compound 2 to the alkaline reagent 1 is 1:0.1-2.

9. The method for synthesizing a pyrazole tricyclic compound according to claim 1, characterized in that: The mass ratio of the compound 2 to the alkaline reagent 1 is 1:0.

3.

10. The method for synthesizing a pyrazole tricyclic compound according to claim 1, characterized in that: The organic solvent 1 is one or more of dichloromethane, tetrahydrofuran (THF), 2-methyltetrahydrofuran, and methyl tert-butyl ether.

11. The method for synthesizing a pyrazole tricyclic compound according to claim 1, characterized in that: The alkaline reagent 1 is any one of methylamine (THF), ethylamine, and deuterated methylamine.

12. The method for synthesizing a pyrazole tricyclic compound according to claim 1, characterized in that: The organic solvent 2 is 1,4-dioxane.

13. The method for synthesizing a pyrazole tricyclic compound according to claim 1, characterized in that: The alkaline reagent 2 is potassium phosphate.

14. The method for synthesizing a pyrazole tricyclic compound according to claim 1, characterized in that: The mass ratio of the compound 3 to the palladium catalyst is 1:0.005-0.

05.

15. The method for synthesizing a pyrazole tricyclic compound according to claim 1, characterized in that: The mass ratio of the compound 3 to the palladium catalyst is 1:0.

01.

16. The method for synthesizing a pyrazole tricyclic compound according to claim 1, characterized in that: The palladium catalyst is Pd(dppf)Cl2 or tetrakistriphenylphosphine palladium.

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