Preparation method of pyrazole compound and pyrazole compound

Abstract

The invention relates to the field of compound preparation, in particular to a preparation method of a pyrazole compound and the pyrazole compound prepared by the method. According to the preparation method of the pyrazole compound, the pyrazole compound is obtained from phenyl alkyl nitrile with a structure as shown in a formula (1) in a tetrahydrofuran solution under the catalytic action of lithium bis (trimethylsilyl) amide, and the obtained pyrazole compound has a structure as shown in a formula (2). Compared with a common method, the synthesis method disclosed by the invention has the advantages that the required reaction raw materials are simple and easy to obtain, the reaction path is simple, the reaction condition is mild, and the obtained product is high in yield and easy to purify.

Description

Technical Field

[0001] The present invention relates to the field of compound preparation, and particularly to a method for preparing pyrazole compounds and pyrazole compounds manufactured thereby. Background Art

[0002] Pyrazole compounds are important intermediates in medicine and pesticides and have various functions. In medicine, they have functions such as analgesia, anti - inflammation, sedation, and antibacterial. In pesticides, they have functions such as insecticidal and herbicidal.

[0003] However, regarding the pyrazole compounds of the present invention, it is found that the theoretical synthesis reaction is to obtain them by a traditional pyrazole ring - closing reaction after the hydrogenation reaction of stilbene ether with palladium - carbon participation. However, this theoretical preparation method itself has high raw material costs, harsh reaction conditions, extremely low yields, and many by - products, is not suitable for process scale - up, and is difficult to apply to actual chemical production.

[0004] In addition, in Non - Patent Document 1, a synthetic route for a similar product 3 - tolyl - 4 - benzyl - 5 - methyl - 1H - pyrazole is reported. However, this preparation method also requires multiple reaction steps and gradual addition of new reaction raw materials, resulting in many by - products in the finally obtained product, difficult purification, and low product yields, and is also not suitable for process scale - up.

[0005] Based on the fact that the pyrazole compounds of this product have broad research and development prospects, there is an urgent need to find a preparation method with low synthesis route costs, simple purification processes, and capable of mass production.

[0006] Prior Art Documents:

[0007] Non - Patent Document 1: Advanced Synthesis and Catalysis, 2022, vol. 364, #21, p. 3657–3663. Summary of the Invention

[0008] In view of the problems existing in the above - mentioned prior art, the problem to be solved by the present invention is to provide a method for preparing pyrazole compounds and pyrazole compounds prepared by this method.

[0009] The inventors of the present invention studied the above - mentioned problems and tried to drop phenylalkyl nitriles such as 3 - phenylpropionitrile into a tetrahydrofuran solution of lithium bis(trimethylsilyl)amide. As a result, it was unexpectedly found that aromatic pyrazoles such as 4 - benzyl - 5 - phenylethyl - 1H - pyrazole can be obtained in high yields without additional reaction conditions, thus realizing the present invention.

[0010] Specifically, the main idea of the present invention is as follows.

[0011] [1] A method for preparing a pyrazole compound, characterized in that,

[0012] in a tetrahydrofuran solution containing lithium bis(trimethylsilyl)amide, a pyrazole compound is obtained from a phenylalkyl nitrile having the structure of formula (1),

[0013]

[0014] the pyrazole compound has the structure shown in formula (2),

[0015]

[0016] in the said formula (1) and (2), R1 represents an alkylene group having 1 to 3 carbon atoms.

[0017] [2] The method for preparing a pyrazole compound according to [1], which comprises the following steps:

[0018] (1) Dissolve the phenylalkyl nitrile having the structure of formula (1) in tetrahydrofuran to prepare a reactant solution;

[0019] (2) Dissolve lithium bis(trimethylsilyl)amide in a tetrahydrofuran solution to prepare a tetrahydrofuran solution of lithium bis(trimethylsilyl)amide;

[0020] (3) Dropwise add the reactant solution obtained in step (1) to the prepared tetrahydrofuran solution of lithium bis(trimethylsilyl)amide to make it react;

[0021] (4) Quench the reaction solution with a protic solvent and recover the reaction product.

[0022] [3] The method for preparing a pyrazole compound according to [1] or [2], wherein the molar ratio of the lithium bis(trimethylsilyl)amide to the phenylalkyl nitrile is 2 to 4.

[0023] [4] The method for preparing a pyrazole compound according to [1] or [2], wherein the dosage ratio of the tetrahydrofuran to the phenylalkyl nitrile is 5 - 10 mL / g.

[0024] [5] The method for preparing a pyrazole compound according to [1] or [2], wherein the reaction temperature is controlled at -30°C to 25°C.

[0025] [6] The method for preparing a pyrazole compound according to claim [5], wherein the reaction temperature is further controlled at 0°C to 25°C.

[0026] [7]The preparation method of the pyrazole compound according to [1] or [2], further comprising: evaporating the recovered reaction product to dryness with tetrahydrofuran using a rotary evaporator, extracting the resulting liquid phase with ethyl acetate, and further concentrating by rotary evaporation to obtain a purification step of the solid product.

[0027] [8]The preparation method of the pyrazole compound according to [1] or [2], wherein the phenylalkylnitrile is 3-phenylpropionitrile or 4-phenylbutyronitrile.

[0028] [9]A pyrazole compound obtained by the preparation method of the pyrazole compound according to [1] to [8], characterized in that it has the structure shown in formula (2),

[0029]

[0030] In the said formula (2), R1 is an alkylene group with 1 to 3 carbon atoms.

[0031] According to the present invention, a preparation method of a pyrazole compound that only requires a single raw material, has a simple reaction path, and mild reaction conditions can be obtained, and the target pyrazole compound can be obtained at a low cost and high yield. In addition, since this reaction only requires a single raw material and no by-products are generated, the purification of the reaction product is also simpler.

[0032] The pyrazole compounds obtained by the preparation method of the present invention are commonly used as building blocks of drug molecules in medicinal chemistry and have various pharmacological activities such as antibacterial, antiviral, antitumor, anti-inflammatory, and antidepressant. For example, they have potential application value in the treatment of cancer, cardiovascular diseases, dementia, diabetes, etc. In the agricultural field, pyrazole compounds and derivatives are widely used to control various crop diseases caused by fungi, such as powdery mildew and scab of wheat. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 1H NMR spectrum of the product obtained in Example 2;

[0034] Figure 2 1H NMR spectrum of the product obtained in Example 3. DETAILED DESCRIPTION OF THE INVENTION

[0035] Hereinafter, the embodiments of the present invention will be described in detail, but the present invention is not limited to the following embodiments and can be implemented with various modifications within the scope of its gist.

[0036] The preparation method of the pyrazole compound of the present invention is to obtain a pyrazole compound from a phenylalkylnitrile having the structure of formula (1) in tetrahydrofuran in the presence of lithium bis(trimethylsilyl)amide.

[0037]

[0038] The pyrazole compound has a structure shown in formula (2),

[0039]

[0040] In the above formulae (1) and (2), R1 represents an alkylene group having 1 to 3 carbon atoms.

[0041] Specifically, in tetrahydrofuran, phenylalkyl nitrile with a specific structure is catalyzed by lithium bis(trimethylsilyl)amide to prepare a pyrazole compound, and the specific reaction pathway is shown in the following formula (3).

[0042]

[0043] <Reaction mechanism>

[0044] Although the reaction mechanism of the above preparation method is not clear, the inventors speculate as follows: Lithium bis(trimethylsilyl)amide as a strong base will capture the hydrogen atom on the adjacent carbon of the α-cyano group of phenylalkyl nitrile in an aprotic solvent to form an α-cyano carbon anion (Phenyl-R1-HC - CN). The formed α-cyano carbon anion further attacks the cyano carbon of another nitrile molecule, and undergoes electron rearrangement and cyclization in the aprotic solvent environment of lithium bis(trimethylsilyl)amide to form an intermediate structure with a proton-deficient pyrazole ring (Phenyl-R1-C(CH)NN - C-CH2-R1-Phenyl), after adding water as a protic solvent for quenching, the reaction stops and a pyrazole compound is formed.

[0045] The preparation method of the pyrazole compound of the present invention is not particularly limited, but preferably comprises the following steps:

[0046] (1) dissolving a phenylalkylnitrile having a structure of formula (1) in tetrahydrofuran (which may be a polar aprotic solvent) to prepare a reactant solution;

[0047] (2) dissolving lithium bistrimethylsilylamide in a tetrahydrofuran solution to prepare a tetrahydrofuran solution of lithium bistrimethylsilylamide;

[0048] (3) adding dropwise the reactant solution obtained in step (1) to the prepared tetrahydrofuran solution of lithium bistrimethylsilylamide to allow the mixture to react;

[0049] (4) The reaction solution is quenched with a protic solvent and the reaction product is recovered.

[0050] There is no particular limitation on R1 in the phenylalkyl nitrile, and it is preferably an alkylene group having 1 to 3 carbon atoms, particularly preferably an alkylene group having 1 to 2 carbon atoms. That is, the phenylalkyl nitrile is particularly preferably 3-phenylpropionitrile or 4-phenylbutyronitrile.

[0051] There is no particular limitation on the solvent for the reaction as long as it is an aprotic solvent. However, in order to enable the reactants and the catalyst to be fully and uniformly mixed, a polar aprotic solvent is preferred, and from the perspectives of compatibility and easy availability, a tetrahydrofuran solvent is particularly preferred.

[0052] The dosage ratio of the catalyst to the reactants in the present invention, that is, the dosage ratio of lithium bis(trimethylsilyl)amide to the phenylalkyl nitrile, is preferably 2 to 4, and particularly preferably 2. When the ratio of the two is greater than 4, the reaction cost increases and the catalytic activity tends to decrease. On the other hand, when the ratio of the two is less than 2, the catalyst content in the reaction solution is too low and the catalytic activity tends to decrease.

[0053] There is no particular limitation on the dosage ratio of the solvent to the reactants in the reactant solution prepared in Step 1 of the present invention, that is, the dosage ratio of tetrahydrofuran to the phenylalkyl nitrile. However, from the perspective that the reactant molecules can be uniformly dispersed in the reaction solution at an appropriate concentration, the dosage ratio of the two is preferably 5 - 10 mL / g. By making the dosage of the solvent below 10 mL / g, the concentration of the reaction solution will not be too low, the frequency of contact between the reactants and the catalyst will not decrease, the tendency of the catalytic activity to decrease can be avoided, and unnecessary costs will not be increased. When the ratio of the two is above 5, the reaction cost will not increase. On the other hand, by making the ratio of the two above 2, the tendency of the catalytic activity to decrease can be avoided.

[0054] There is no particular limitation on the reaction temperature of the present invention, and it can be carried out in a relatively wide temperature range of -30°C to 25°C. From the perspective of obtaining a good yield, it is more preferably 0°C to 25°C.

[0055] This reaction is carried out only in an aprotic solvent environment, so a protic solvent can be selected as the quenching agent, preferably water.

[0056] There is no particular limitation on the purification step of the reactants as long as the target pyrazole compound can be separated from the reactant solution. Examples include rotary evaporation, extraction, recrystallization, column chromatography, etc. The purification step of the present invention specifically includes: evaporating the recovered reaction product to dryness of tetrahydrofuran using a rotary evaporator, extracting the resulting liquid phase with ethyl acetate, and further concentrating by rotary evaporation to obtain a solid product.

[0057] Examples

[0058] Hereinafter, the present invention will be further described in detail by way of examples, but the present invention is not limited to these examples.

[0059] <Product Analysis>

[0060] The composition and purity of the final product were analyzed using nuclear magnetic resonance hydrogen spectroscopy and mass spectrometry.

[0061] A nuclear magnetic resonance spectrometer (Braker400MHZ, Switzerland) was used with deuterated methanol-D4, (0.05% v / v TMS) as the deuterated solvent and TMS (0 ppm) as the reference standard. When multiple peaks appeared in the obtained spectrum, the following abbreviations were used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets). The coupling constant J was expressed in hertz (Hz).

[0062] Mass spectrometry analysis:

[0063] Equipment used: LC Agilent 1260Ⅱ, MS Agilent iQ;

[0064] LC set parameters

[0065] Chromatographic column: Poroshell 120EC-C18 3.0x50mm, 2.7μm

[0066] Mobile phase: A: H2O (0.1% Formic Acid); B: ACN (0.1% Formic Acid).

[0067] Gradient elution: Gradient from 5 to 95% of B in 3.5 min

[0068] Flow rate: 1.5 ml / min

[0069] MS set parameters

[0070] Scanning mode: UV (214, 254 nm) and MS (ESI, Pos mode, 50 to 500 amu)

[0071] Vaporization temperature: 426 °C

[0072] Carrier gas: N2

[0073] Carrier gas flow rate: 3.6 L / min,

[0074] <Specific Steps>

[0075] Example 1

[0076] Lithium bis(trimethylsilyl)amide (1M, 22.9 mL, 22.86 mmol, 2 eq) was added to a 1000 ml eggplant-shaped flask. The flask was purged with nitrogen three times and cooled to 0 °C in an ice bath. A solution of 3-phenylpropionitrile (1.5 g, 11.43 mmol) in tetrahydrofuran (15 mL) was slowly added dropwise. After the addition, the mixture was allowed to warm to room temperature naturally and reacted for 16 h. After sampling and detecting by TLC that the reaction was complete, ice water (50 mL) was added dropwise to the reaction solution in the ice bath to quench the reaction. The tetrahydrofuran was rotary evaporated to dryness. The aqueous phase was extracted with ethyl acetate (50 mL) three times. The organic phases were combined, dried over anhydrous sodium sulfate, and rotary evaporated to concentrate to obtain 1.10 g of a brown solid with a yield of 73.3%.

[0077] Example 2

[0078] The same operations as in Example 1 were carried out, except that the amounts of all raw materials, solvents, and catalysts in Example 1 were increased by 10 times.

[0079] The brown solid was analyzed using a nuclear magnetic resonance spectrometer (Braker 400 MHZ, Switzerland) and a mass spectrometer (LC Agilent 1260 Ⅱ MS Agilent 96160A). The results are as follows:

[0080] 1 H NMR (400 MHz, CD3OD) δ 7.28 - 7.11 (m, 11H), 3.29 (s, 2H), 2.85 (dd, J = 9.1, 6.8 Hz, 2H), 2.60 (dd, J = 9.2, 6.7 Hz, 2H).

[0081] LC-MS (UV = 254 nm): 263.10 M+H + ; 100% purity.

[0082] Example 3

[0083] Lithium bis(trimethylsilyl)amide (1M, 21.0 mL, 20.66 mmol, 2 eq) was added to a 100 ml eggplant-shaped flask. The flask was purged with nitrogen three times and cooled to 0 °C in an ice bath. A solution of 4-phenylbutyronitrile (1.5 g, 10.33 mmol) in tetrahydrofuran (15 mL) was slowly added dropwise. After the addition, the mixture was allowed to warm to room temperature naturally and reacted for 16 h. After sampling and detecting by TLC that the reaction was complete, ice water (50 mL) was added dropwise to the reaction solution in the ice bath to quench the reaction. The tetrahydrofuran was rotary evaporated to dryness. The aqueous phase was extracted with ethyl acetate (50 mL) three times. The organic phases were combined, dried over anhydrous sodium sulfate, and rotary evaporated to concentrate to obtain 1.06 g of a yellow oil with a yield of 70.60%.

[0084] The yellow oil was analyzed using a nuclear magnetic resonance spectrometer (Braker400MHZ, Switzerland) and a mass spectrometer (LC Agilent 1260Ⅱ MS Agilent 96160A), and the results are as follows:

[0085] 1 H NMR(400MHz,CD3OD)δ7.26-7.21(m,6H),7.20–7.09(m,5H),2.75(t,J=7.6Hz,2H),2.58(t,J=7.6Hz,2H),2.39–2.29(m,4H),1.83(dd,J=15.5,7.6Hz,2H).

[0086] LC-MS(UV=254nm): 291.30M+H + ; 100% purity.

[0087] Example 4

[0088] The same operation as in Example 1 was carried out except that the amount of 3-phenylpropionitrile was adjusted to 1.5 g (11.43 mmol) and the amount of lithium bis(trimethylsilyl)amide was adjusted to 34.0 ml.

[0089] Example 5

[0090] The same operation as in Example 1 was carried out except that the reaction temperature was adjusted to -30 °C, and the amount of 3-phenylpropionitrile was adjusted to 1.5 g (11.43 mmol) and the amount of lithium bis(trimethylsilyl)amide was adjusted to 23.0 ml.

[0091] Example 6

[0092] The same operation as in Example 1 was carried out except that the amount of 3-phenylpropionitrile was adjusted to 1.5 g (11.43 mmol) and the amount of lithium bis(trimethylsilyl)amide was adjusted to 46.0 ml.

[0093] Example 7

[0094] The same operation as in Example 1 was carried out except that the reaction temperature was adjusted to 25 °C, and the amount of 3-phenylpropionitrile was adjusted to 1.5 g (11.43 mmol) and the amount of lithium bis(trimethylsilyl)amide was adjusted to 23.0 ml.

[0095] The measurement results of Examples 1 to 6 are shown in Table 1.

[0096] [Table 1]

[0097]

[0098] According to the results in Table 1, according to the manufacturing method of the present invention, the synthesis route is simple and the yield of the reaction product is relatively high.

[0099] In particular, under the same conditions, when the ratio of phenylalkylnitrile to lithium bis(trimethylsilyl)amide is 1:2, the yield of the reaction product is the highest. In addition, when the ratio of phenylalkylnitrile to lithium bis(trimethylsilyl)amide is fixed, in the range of 0°C to 25°C, the yield of the reaction product is relatively high.

[0100] In addition, according to Examples 1 and 2, when the reaction process is scaled up by 10 times, there is almost no effect on the yield of the reactants.

[0101] Through the present invention, a preparation method of the pyrazole compound and the pyrazole compound obtained thereby can be provided. The preparation method of the present invention has a simple synthesis route and mild reaction conditions, and can obtain the pyrazole compound at a relatively low cost and with a relatively high yield.

Claims

1. A method for preparing a pyrazole compound, characterized in that, in a tetrahydrofuran solution containing lithium bis(trimethylsilyl)amide, a pyrazole compound is obtained from a phenylalkyl nitrile having the structure of formula (1), the pyrazole compound has the structure shown in formula (2), in the said formula (1) and (2), R1 represents an alkylene group with 1 to 3 carbon atoms.

2. The method for preparing a pyrazole compound according to claim 1, which comprises the following steps: (1) Dissolve the phenylalkyl nitrile having the structure of formula (1) in tetrahydrofuran to prepare a reactant solution; (2) Dissolve lithium bis(trimethylsilyl)amide in a tetrahydrofuran solution to prepare a tetrahydrofuran solution of lithium bis(trimethylsilyl)amide; (3) Dropwise add the reactant solution obtained in step (1) to the prepared tetrahydrofuran solution of lithium bis(trimethylsilyl)amide to make them react; (4) Quench the reaction solution with a protic solvent and recover the reaction product.

3. The preparation method of the pyrazole compound according to claim 1 or 2, wherein, The molar ratio of lithium bis(trimethylsilyl)amide to the phenylalkyl nitrile is 2 to 4.

4. The preparation method of the pyrazole compound according to claim 1 or 2, wherein, The dosage ratio of tetrahydrofuran to the phenylalkyl nitrile is 5 - 10 mL / g.

5. The preparation method of the pyrazole compound according to claim 1 or 2, wherein, The reaction temperature is controlled at -30°C to 25°C.

6. The preparation method of the pyrazole compound according to claim 5, wherein, The reaction temperature is further controlled at 0°C to 25°C.

7. The preparation method of the pyrazole compound according to claim 1 or 2, wherein It further includes: A purification step of evaporating tetrahydrofuran from the recovered reaction product using a rotary evaporator, extracting the obtained liquid phase with ethyl acetate, and further rotary evaporating and concentrating to obtain a solid product.

8. The method for preparing a pyrazole compound according to claim 1 or 2, wherein, The phenylalkyl nitrile is 3-phenylpropionitrile or 4-phenylbutyronitrile.

9. A pyrazole compound obtained by the preparation method of the pyrazole compounds described in claims 1 to 8, characterized in that, Having the structure shown in formula (2), in the said formula (2), R1 is an alkylene group with 1 to 3 carbon atoms.

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