A method for synthesizing pyrazoloisoindole derivatives

Abstract

The invention discloses a method for synthesizing a pyrazoloisoindole derivative, comprising: carrying out a cyclization reaction of a 5-arylpyrazole compound and a cyclopropanol derivative in an organic solvent under the action of a rhodium catalyst, a co-catalyst, an oxidant and an additive, and obtaining the pyrazoloisoindole derivative by post-treatment after the reaction. The synthesis method can synthesize a novel polycyclic structure containing pyrazoloisoindole, and the reaction conditions are mild and the reaction yield is high.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and particularly relates to a method for synthesizing pyrazoloisoindole derivatives. Background Art

[0002] Pyrazole compounds have a wide range of applications and are important structural units for many medicines, pesticides, and dyes. They can also be used as side chains of monomers for certain photosensitive materials. In pharmaceutical applications, pyrazole compounds are effective for many diseases and exhibit high efficiency, low toxicity, and structural diversity. In pesticide applications, pyrazole compounds have insecticidal, bactericidal, and herbicidal activities, with a broad spectrum of action and strong efficacy. Therefore, pyrazole drugs have broad research and development prospects. Arylpyrazole compounds can be used to kill insects and mites, such as Fipronil (5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethyl-sulfinylpyrazole-3-carbonitrile) jointly developed by Bayer and BASF, which is the first phenylpyrazole pesticide used for pest control. It induces Cl- flow by blocking the nerve membrane Cl- channel controlled by γ-aminobutyric acid receptors, causing extreme excitement of the nervous system and leading to insect death (Dominik Hainzl, Loretta M. Cole, and John E. Casida, Mechanisms for selective toxicity of fipronil insecticide and its sulfonemetabolite and desulfinyl photoproduct. Chem. Res. Toxicol. 1998, 11, 1529). Since its discovery in 1987, it has been widely used in many fields such as agriculture and veterinary medicine, becoming an important insecticide variety. Compared with traditional insecticides (organophosphorus, pyrethroids, carbamates), this drug has the advantages of broad spectrum and high efficiency, and has been widely used in many agricultural fields. It is a common insecticide for pest control. In addition, there are Ethiprole (Santos Fustero, Raquel Román, Juan F. Sanz-Cervera, Antonio Simón-Fuentes, Jorge Bueno, and Salvador Villanova, Synthesis of new fluorinatedtebufenpyrad analogs with acaricidal activity through regioselective pyrazole formation. J. Org. Chem. 2008, 73, 21, 8545) developed by Aventis and Flufiprole (Flufiprole) developed by Dalian Ruize Pesticide Chemical Company, all of which have good insecticidal effects.

[0003] On the other hand, isoindole is also widely present in natural products and drug molecules. For example, WO2016169421 discloses a novel structure of highly efficient and low-toxic selective indoleamine-pyrrole-2,3-dioxygenase (IDO) inhibitor compounds, which have excellent effects and functions, especially excellent pharmacokinetic absorption activity, and its chemical name is (S)-2-(4-(4-(4-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)piperidin-1-yl)phenyl)-1H-pyrazol-1-yl)ethanol. Therefore, it is of great significance to develop new potential drug structures of pyrazoloisoindole ring structural units. The present invention utilizes 5-arylpyrazoles to react with cyclopropanol derivatives to obtain novel polycyclic structures containing pyrazoloisoindole, and provides a method for synthesizing potential drugs. Summary of the invention

[0004] The invention provides a method for synthesizing pyrazoloisoindole derivatives. The method can synthesize novel polycyclic structures containing pyrazoloisoindole with high yield.

[0005] A method for synthesizing a pyrazoloisoindole derivative, comprising:

[0006] Under the action of rhodium catalyst, co-catalyst, oxidant and additive, 5-aryl pyrazole compound and cyclopropanol derivative undergo cyclization reaction in organic solvent, and after the reaction, post-treatment is performed to obtain the pyrazoloisoindole derivative;

[0007]

[0008] Among them, R 1 is H, methyl, methoxy, F, Cl, Br, I, cyano, trifluoromethyl or trifluoromethoxy;

[0009] R 2 is H, methyl, ethyl or allyl;

[0010] R 3 is methyl, phenyl or trifluoromethyl;

[0011] R 4 is a substituted or unsubstituted phenyl group, wherein the substituent on the phenyl group is selected from methyl, methoxy, F, Cl, Br, I or trifluoromethyl.

[0012] Preferably, the rhodium catalyst is [Cp*RhCl2]2.

[0013] Preferably, the co-catalyst is AgNTf2.

[0014] Preferably, the oxidant is AgOAc.

[0015] Preferably, the additive is Na2HPO4.

[0016] Preferably, the reaction temperature is 70-90° C. and the reaction time is 10-20 h.

[0017] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0018] The synthesis method of the invention can synthesize novel polycyclic structures containing pyrazoloisoindole, and the reaction conditions are mild and the reaction yield is high. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 The H NMR spectrum and C NMR spectrum of the obtained compound 3a;

[0020] Figure 2 The H NMR spectrum and C NMR spectrum of the obtained compound 3b;

[0021] Figure 3 The H NMR spectrum and C NMR spectrum of the obtained compound 3c;

[0022] Figure 4 are the hydrogen and carbon nuclear magnetic resonance spectra of the obtained compound 3d;

[0023] Figure 5 The H NMR spectrum and C NMR spectrum of the obtained compound 3e;

[0024] Figure 6 The hydrogen and carbon nuclear magnetic resonance spectra of the obtained compound 4n are shown in FIG. DETAILED DESCRIPTION

[0025] The general reaction formula of the preparation method of the present invention is as follows:

[0026]

[0027] The present invention will be further described below in conjunction with specific embodiments:

[0028] Example 1

[0029] 5-Arylpyrazole compound 1a (0.1mmol, 1.0equiv.), cyclopropanol derivative 2a (0.15mmol, 1.5equiv.), [Cp*RhCl2]2 (5mol%), AgNTf2 (25mol%), AgOAc (0.2mmol, 2.0equiv.), Na2HPO4 (0.1mmol, 1.0equiv.) and CH3OH (1.0mL) were added to a 25mL sealed tube equipped with a magnetic stirrer. The sealed tube was protected with nitrogen and stirred in an oil bath at 80°C for 12h. Then it was cooled to room temperature and diluted with ethyl acetate. The obtained mixture was filtered and washed with ethyl acetate. The organic phases were combined, concentrated under reduced pressure, and then column chromatography was used to obtain the target product pyrazoloisoindole derivative 3a in a yield of 71%.

[0030] The structural formula of the pyrazoloisoindole derivative 3a is as follows:

[0031]

[0032] The NMR spectrum of pyrazoloisoindole derivative 3a is shown in Figure 1 .

[0033] Example 2

[0034] 5-Arylpyrazole compound 1b (0.1mmol, 1.0equiv.), cyclopropanol derivative 2a (0.15mmol, 1.5equiv.), [Cp*RhCl2]2 (5mol%), AgNTf2 (25mol%), AgOAc (0.2mmol, 2.0equiv.), Na2HPO4 (0.1mmol, 1.0equiv.) and CH3OH (1.0mL) were added to a 25mL sealed tube equipped with a magnetic stirrer. The sealed tube was protected with nitrogen and stirred in an oil bath at 80°C for 12h. Then it was cooled to room temperature and diluted with ethyl acetate. The obtained mixture was filtered and washed with ethyl acetate. The organic phases were combined, concentrated under reduced pressure, and then column chromatography was used to obtain the target product pyrazoloisoindole derivative 3b in a yield of 57%.

[0035] The structural formula of the pyrazoloisoindole derivative 3b is as follows:

[0036]

[0037] The NMR spectrum of pyrazoloisoindole derivative 3b is shown in Figure 2 .

[0038] Example 3

[0039] To a 25 mL sealed tube equipped with a magnetic stirrer, 5-arylpyrazole compound 1c (0.1 mmol, 1.0 equiv.), cyclopropanol derivative 2a (0.15 mmol, 1.5 equiv.), [Cp*RhCl2]2 (5 mol%), AgNTf2 (25 mol%), AgOAc (0.2 mmol, 2.0 equiv.), Na2HPO4 (0.1 mmol, 1.0 equiv.) and CH3OH (1.0 mL) were added. The sealed tube was protected with nitrogen and stirred in an oil bath at 80°C for 12 h. Then cooled to room temperature, diluted with ethyl acetate, the resulting mixture was filtered and washed with ethyl acetate, the organic phases were combined, concentrated under reduced pressure, and then column chromatography was used to obtain the target product pyrazoloisoindole derivative 3c in a yield of 66%.

[0040] The structural formula of the pyrazoloisoindole derivative 3c is as follows:

[0041]

[0042] The NMR spectrum of pyrazoloisoindole derivative 3c is shown in Figure 3 .

[0043] Example 4

[0044] To a 25 mL sealed tube equipped with a magnetic stirrer, 5-arylpyrazole compound 1d (0.1 mmol, 1.0 equiv.), cyclopropanol derivative 2a (0.15 mmol, 1.5 equiv.), [Cp*RhCl2]2 (5 mol%), AgNTf2 (25 mol%), AgOAc (0.2 mmol, 2.0 equiv.), Na2HPO4 (0.1 mmol, 1.0 equiv.) and CH3OH (1.0 mL) were added. The sealed tube was protected with nitrogen and stirred in an oil bath at 80°C for 12 h. Then cooled to room temperature, diluted with ethyl acetate, the resulting mixture was filtered and washed with ethyl acetate, the organic phases were combined, concentrated under reduced pressure, and then column chromatography was used to obtain the target product pyrazoloisoindole derivative 3d in a yield of 65%.

[0045] The structural formula of the pyrazoloisoindole derivative 3d is as follows:

[0046]

[0047] The NMR spectrum of pyrazoloisoindole derivative 3d is shown in Figure 4 .

[0048] Example 5

[0049] A 25 mL sealed tube equipped with a magnetic stirrer was added with 5-arylpyrazole compound 1e (0.1 mmol, 1.0 equiv.), cyclopropanol derivative 2a (0.15 mmol, 1.5 equiv.), [Cp*RhCl2]2 (5 mol%), AgNTf2 (25 mol%), AgOAc (0.2 mmol, 2.0 equiv.), Na2HPO4 (0.1 mmol, 1.0 equiv.) and CH3OH (1.0 mL). The sealed tube was protected with nitrogen and stirred in an oil bath at 80 °C for 12 h. Then it was cooled to room temperature and diluted with ethyl acetate. The resulting mixture was filtered and washed with ethyl acetate. The organic phases were combined, concentrated under reduced pressure, and then column chromatography was used to obtain the target product pyrazoloisoindole derivative 3e in a yield of 43%.

[0050] The structural formula of the pyrazoloisoindole derivative 3e is as follows:

[0051]

[0052] The NMR spectrum of pyrazoloisoindole derivative 3e is shown in Figure 5 .

[0053] Example 6

[0054] 5-Arylpyrazole compound 1a (0.1mmol, 1.0equiv.), cyclopropanol derivative 2b (0.15mmol, 1.5equiv.), [Cp*RhCl2]2 (5mol%), AgNTf2 (25mol%), AgOAc (0.2mmol, 2.0equiv.), Na2HPO4 (0.1mmol, 1.0equiv.) and CH3OH (1.0mL) were added to a 25mL sealed tube equipped with a magnetic stirrer. The sealed tube was protected with nitrogen and stirred in an oil bath at 80°C for 12h. Then it was cooled to room temperature and diluted with ethyl acetate. The resulting mixture was filtered and washed with ethyl acetate. The organic phases were combined, concentrated under reduced pressure, and then column chromatography was used to obtain the target product pyrazoloisoindole derivative 4b in a yield of 56%.

[0055] The structural formula of the pyrazoloisoindole derivative 4b is as follows:

[0056]

[0057] Example 7

[0058] 5-Arylpyrazole compound 1a (0.1mmol, 1.0equiv.), cyclopropanol derivative 2c (0.15mmol, 1.5equiv.), [Cp*RhCl2]2 (5mol%), AgNTf2 (25mol%), AgOAc (0.2mmol, 2.0equiv.), Na2HPO4 (0.1mmol, 1.0equiv.) and CH3OH (1.0mL) were added to a 25mL sealed tube equipped with a magnetic stirrer. The sealed tube was protected with nitrogen and stirred in an oil bath at 80°C for 12h. Then it was cooled to room temperature and diluted with ethyl acetate. The resulting mixture was filtered and washed with ethyl acetate. The organic phases were combined, concentrated under reduced pressure, and then column chromatography was used to obtain the target product pyrazoloisoindole derivative 4c in a yield of 53%.

[0059] The structural formula of the pyrazoloisoindole derivative 4c is as follows:

[0060]

[0061] Example 8

[0062] To a 25 mL sealed tube equipped with a magnetic stirrer, 5-arylpyrazole compound 1a (0.1 mmol, 1.0 equiv.), cyclopropanol derivative 2d (0.15 mmol, 1.5 equiv.), [Cp*RhCl2]2 (5 mol%), AgNTf2 (25 mol%), AgOAc (0.2 mmol, 2.0 equiv.), Na2HPO4 (0.1 mmol, 1.0 equiv.) and CH3OH (1.0 mL) were added. The sealed tube was protected with nitrogen and stirred in an oil bath at 80°C for 12 h. Then cooled to room temperature, diluted with ethyl acetate, the resulting mixture was filtered and washed with ethyl acetate, the organic phases were combined, concentrated under reduced pressure, and then column chromatography was used to obtain the target product pyrazoloisoindole derivative 4d in a yield of 53%.

[0063] The structural formula of the pyrazoloisoindole derivative 4d is as follows:

[0064]

[0065] Example 9

[0066] 5-Arylpyrazole compound 1a (0.1 mmol, 1.0 equiv.), cyclopropanol derivative 2l (0.15 mmol, 1.5 equiv.), [Cp*RhCl2]2 (5 mol%), AgNTf2 (25 mol%), AgOAc (0.2 mmol, 2.0 equiv.), Na2HPO4 (0.1 mmol, 1.0 equiv.) and CH3OH (1.0 mL) were added to a 25 mL sealed tube equipped with a magnetic stirrer. The sealed tube was protected with nitrogen and stirred in an oil bath at 80 °C for 12 h. Then cooled to room temperature, diluted with ethyl acetate, the obtained mixture was filtered and washed with ethyl acetate, the organic phases were combined, concentrated under reduced pressure, and then column chromatography was used to obtain the target product pyrazoloisoindole derivative 4l in a yield of 84%.

[0067] The structural formula of pyrazoloisoindole derivative 41 is as follows:

[0068]

[0069] Example 10

[0070] 5-Arylpyrazole compound 1a (0.1mmol, 1.0equiv.), cyclopropanol derivative 2n (0.15mmol, 1.5equiv.), [Cp*RhCl2]2 (5mol%), AgNTf2 (25mol%), AgOAc (0.2mmol, 2.0equiv.), Na2HPO4 (0.1mmol, 1.0equiv.) and CH3OH (1.0mL) were added to a 25mL sealed tube equipped with a magnetic stirrer. The sealed tube was protected with nitrogen and stirred in an oil bath at 80°C for 12h. Then it was cooled to room temperature and diluted with ethyl acetate. The resulting mixture was filtered and washed with ethyl acetate. The organic phases were combined, concentrated under reduced pressure, and then column chromatography was used to obtain the target product pyrazoloisoindole derivative 4n in a yield of 84%.

[0071] The structural formula of the pyrazoloisoindole derivative 4n is as follows:

[0072]

[0073] The NMR spectrum of pyrazoloisoindole derivative 4n is shown in Figure 6 .

Claims

1. A method for synthesizing a pyrazoloisoindole derivative, characterized in that: include: Under the action of rhodium catalyst, co-catalyst, oxidant and additive, 5-aryl pyrazole compound and cyclopropanol derivative undergo cyclization reaction in organic solvent, and after the reaction, post-treatment is performed to obtain the pyrazoloisoindole derivative; Among them, R 1 is H, methyl, methoxy, F, Cl, Br, I, cyano, trifluoromethyl or trifluoromethoxy; R 2 is H, methyl, ethyl or allyl; R 3 is methyl; R 4 is a substituted or unsubstituted phenyl group, wherein the substituent on the phenyl group is selected from methyl, methoxy, F, Cl, Br, I or trifluoromethyl; The rhodium catalyst is [Cp*RhCl2]2; The co-catalyst is AgNTf2; The oxidant is AgOAc; The additive is Na2HPO4; The organic solvent is methanol; The reaction temperature is 70-90°C and the reaction time is 10-20h.

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