A 4-(trifluoromethylsulfinyl)pyrazole compound and a preparation method thereof
Patent Information
- Application Number
- CN202610167686.6
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2026-02-05
- Publication Date
- 2026-06-23
Smart Images
Figure CN122255064A_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of organic synthesis and pharmaceutical synthesis technology, specifically relating to a 4-(trifluoromethylsulfinyl)pyrazole compound and its preparation method. Background Technology
[0002] Obesity is a chronic metabolic disease caused by multiple factors, characterized by excessive accumulation and abnormal distribution of body fat. It is a major risk factor for type 2 diabetes, hypertension, non-alcoholic fatty liver disease, and cardiovascular disease. Therefore, the development of safe and effective anti-obesity drugs has significant clinical and social implications.
[0003] Among numerous therapeutic targets, cannabinoid type 1 receptors have attracted significant attention due to their central role in regulating energy balance, food intake, and lipid metabolism. Rimonaban, developed by the French company Sanofi-Aventis, is the first highly selective CB1 receptor antagonist. Clinical trials have demonstrated its effectiveness in significantly reducing weight, improving insulin resistance, and alleviating dyslipidemia in obese patients, proving the efficacy of targeting the CB1 receptor for obesity treatment. However, further research and clinical application have revealed that rimonaban can cause serious central nervous system adverse reactions in some users, including depression, anxiety, and even suicidal tendencies.
[0004] Pyrazoles and their derivatives, as an important class of aromatic heterocyclic compounds, constitute the core framework of many marketed drugs, including rimonaban, celecoxib, and sildenafil, due to their excellent bioactivity spectrum and good drug-like properties. Their structures are highly modifiable, allowing for fine-tuning of bioactivity, selectivity, and physicochemical properties by introducing different substituents [Zhou Y, Lei SG, Abudureheman B, et al. Transforming an azaarene into the spine of fused bicyclics via cycloaddition-induced scaffold hopping of 5-Hydroxypyrazoles[J]. Nat. Commun. 2024 15(1) [1-10]. Therefore, while retaining the rimonaban core pyrazole skeleton to maintain its basic binding ability to the CB1 receptor, systematically modifying the key pharmacophore at position 4 is considered a reasonable strategy for developing a new generation of safer CB1 modulators. Summary of the Invention
[0005] The purpose of this section is to outline some aspects of embodiments of the present invention and to briefly describe some preferred embodiments. Simplifications or omissions may be made in this section, as well as in the abstract and title of this application, to avoid obscuring the purpose of these documents; however, such simplifications or omissions should not be construed as limiting the scope of the invention.
[0006] In view of the problems existing in the above and / or prior art, the present invention is proposed.
[0007] Therefore, the purpose of this invention is to overcome the shortcomings of the prior art and provide a method for preparing 4-(trifluoromethylsulfinyl)pyrazole compounds.
[0008] To solve the above-mentioned technical problems, the present invention provides the following technical solution: a 4-(trifluoromethylsulfinyl)pyrazole compound, characterized in that: the chemical structural formula of the 4-(trifluoromethylsulfinyl)pyrazole compound is shown in formula (a): Equation (a); Among them, R 1 Selected from phenyl, p-chlorophenyl, R 2 Selected from phenyl, methyl, R 3 Selected from phenyl, p-chlorophenyl, and 2,4-dimethylphenyl.
[0009] Another object of the present invention is to overcome the shortcomings of the prior art and provide a method for preparing 4-(trifluoromethylsulfinyl)pyrazole compounds, comprising, Under nitrogen atmosphere, terminal alkyne is dissolved in n-hexane, anhydrous zinc chloride is added, and trifluoromethyl sulfinyl chloride is reacted to give α-trifluoromethyl alkynyl sulfoxide. Benzoyl chloride was added dropwise to a CH2Cl2 solution of phenylhydrazine and triethylamine under a nitrogen atmosphere to obtain acylhydrazine; Carbon tetrachloride was added to a suspension of acetonitrile containing acylhydrazine and triphenylphosphine to obtain hydrazone chloride; α-Trifluoromethyl alkynyl sulfoxide, hydrazone chloride, potassium carbonate, and anhydrous ethanol are reacted at room temperature to give 4-(trifluoromethyl sulfinyl)pyrazole compounds.
[0010] As a preferred embodiment of the preparation method described in this invention, the molar ratio of terminal alkyne, n-hexane, anhydrous zinc chloride and trifluoromethylsulfinyl chloride is 1~2:1~2:1~2:1~2.
[0011] In a preferred embodiment of the preparation method described in this invention, the reaction temperature of terminal alkyne, n-hexane, anhydrous zinc chloride and trifluoromethyl sulfinyl chloride is -78 to -40°C, and the reaction time is 2 to 8 hours.
[0012] In a preferred embodiment of the preparation method described in this invention, the molar ratio of phenylhydrazine, benzoyl chloride and triethylamine is 1~2 : 1~2 : 2~3.
[0013] In a preferred embodiment of the preparation method described in this invention, the reaction temperature of phenylhydrazine, benzoyl chloride and triethylamine is 0~15℃ and the reaction time is 2~6h.
[0014] In a preferred embodiment of the preparation method described in this invention, the molar ratio of acylhydrazine, triphenylphosphine and carbon tetrachloride is 1~2:2~3:3~4.
[0015] In a preferred embodiment of the preparation method described in this invention, the reaction time of acylhydrazine, triphenylphosphine and carbon tetrachloride is 5-8 h, and the reaction temperature is 25-28 °C.
[0016] In a preferred embodiment of the preparation method described in this invention, the molar ratio of α-trifluoromethyl alkynyl sulfoxide, hydrazone chloride, and potassium carbonate is 1~2 : 1~2 : 1~2.
[0017] In a preferred embodiment of the preparation method described in this invention, the reaction temperature of α-trifluoromethyl alkynyl sulfoxide, hydrazone chloride, potassium carbonate and anhydrous ethanol is 25~28℃, and the reaction time is 10~24h.
[0018] Beneficial effects of this invention: This invention uses inexpensive and readily available raw materials, the entire reaction route is mild and simple to operate, does not require stringent reaction conditions, and most of the reaction process is carried out at room temperature. The product yield is high, and the prepared trifluoromethyl alkynyl sulfoxide has multiple derivatization sites in its pyrazole structure, which has good application prospects. Attached Figure Description
[0019] To more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings used in the description of the embodiments 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. Wherein: Figure 1 Compound 4a of the present invention 1 H NMR spectrum.
[0020] Figure 2 Compound 4a of the present invention 13 C10 NMR spectrum.
[0021] Figure 3 Compound 4a of the present invention 19FNMR spectrum.
[0022] Figure 4 Compound 4b of the present invention 1 H NMR spectrum.
[0023] Figure 5 Compound 4b of the present invention 13 C10 NMR spectrum.
[0024] Figure 6 Compound 4b of the present invention 19 FNMR spectrum.
[0025] Figure 7 Compound 4c of the present invention 1 H NMR spectrum.
[0026] Figure 8 Compound 4c of the present invention 13 C10 NMR spectrum.
[0027] Figure 9 Compound 4c of the present invention 19 FNMR spectrum.
[0028] Figure 10 This is a general formula diagram for the synthesis of compounds in embodiments of the present invention. Detailed Implementation
[0029] To make the above-mentioned objects, features and advantages of the present invention more apparent and understandable, the specific embodiments of the present invention will be described in detail below with reference to the examples in the specification.
[0030] Many specific details are set forth in the following description in order to provide a full understanding of the invention. However, the invention may also be practiced in other ways different from those described herein, and those skilled in the art can make similar extensions without departing from the spirit of the invention. Therefore, the invention is not limited to the specific embodiments disclosed below.
[0031] Secondly, the term "one embodiment" or "embodiment" as used herein refers to a specific feature, structure, or characteristic that may be included in at least one implementation of the present invention. The phrase "in one embodiment" appearing in different places in this specification does not necessarily refer to the same embodiment, nor is it a single or selective embodiment that is mutually exclusive with other embodiments.
[0032] Unless otherwise specified, all raw materials used in the embodiments of this invention are commercially available. See Table 1 for details.
[0033] Table 1
[0034] Example 1 1) Preparation of compound 1a: Under a nitrogen atmosphere, p-chlorophenylacetylene B1 (1.0 mmol) was dissolved in n-hexane (5 mL). Under cold conditions, n-butyllithium (1.0 mmol, 2.5 M in THF) was added dropwise to the reaction solution, followed by anhydrous zinc chloride (1.2 mmol) and then trifluoromethyl sulfinyl chloride (1.2 mmol). After stirring for 2-8 hours, the reaction was quenched with an aqueous solution of saturated ammonium chloride. The resulting mixture was extracted with ethyl acetate, the organic phases were combined and washed with water and saturated brine, and dried over anhydrous Na2SO4. After removing the solvent under reduced pressure, the final product 1a was purified by rapid column chromatography. Its reaction equation (1) is as follows: Equation (1) 2) Preparation of compound 2a: Under a nitrogen atmosphere, acetyl chloride S3 (1.0 mmol) was added dropwise to a CH2Cl2 (5 mL) solution of hydrazine S2 (1.2 mmol) and triethylamine (2.5 mmol). After stirring at 0-15 °C for 2-6 hours, the mixture was washed with water and extracted with DCM. The combined organic phase was dried with anhydrous Na2SO4, and the solvent was evaporated under reduced pressure to obtain the corresponding product 2a. The solid product was crystallized from ethanol. The reaction equation (2) is as follows: Equation (2) 3) Preparation of compound 3a: Carbon tetrachloride (3.0 mmol) was added to a suspension of acetonitrile (5 mL) containing acylhydrazine (1.0 mmol) and triphenylphosphine (2.0 mmol). The reaction was carried out at room temperature for 5-8 hours, and then the solvent was removed under reduced pressure. The crude product was subjected to flash column chromatography to obtain product 3a, and its reaction formula (3) is as follows: Equation (3) 4) Preparation of compound 4a: α-trifluoromethyl alkynyl sulfoxide 1a (1.2 mmol), hydrazone chloride 3a (1.0 mmol), potassium carbonate (1.0 mmol), and anhydrous ethanol (2 mL) were added to the reaction flask. The reaction was carried out at room temperature for 10-24 hours, and the reaction progress was monitored by TLC until the starting material disappeared. Saturated ammonium chloride solution was added, and the reaction solution was concentrated under vacuum to remove the solvent ethanol. The aqueous phase was extracted with ethyl acetate, the organic phases were combined, washed with brine, dried with Na2SO4, and the solvent was removed by rotary evaporation. The crude product was purified by silica gel rapid column chromatography to obtain the final product 4a (yield of 86%). Compound 4a was first processed using the LigPrep module in Schrödinger software (LigPrep, Schrödinger, LLC, New York, NY, 2021). The LogS was -5.46 and the LogP was 5.30. The reaction equation (4) is as follows: Equation (4) The NMR data are as follows: 1 H NMR (401 MHz, CDCl3) δ 7.45 – 7.41 (m, 2H), 7.32 (t, 1H), 7.16 –7.12 (m, 4H), 2.61 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 151.58, 145.86, 139.67, 137.33, 135.61,131.22, 129.66, 128.68, 125.75 (q, J = 341.9 Hz), 124.41, 123.34, 100.01,13.09. 19 F NMR (376 MHz, CDCl3) δ -71.53. HRMS (ESI) calcd for C 17 H 10 Cl3F3N2NaOS + [M+Na] + : 474.9424, found:474.9400. Figure 1 Compound 4a of the present invention 1 H NMR spectrum.
[0035] Figure 2 Compound 4a of the present invention 13 C10 NMR spectrum.
[0036] Figure 3 Compound 4a of the present invention 19 FNMR spectrum.
[0037] Example 2 1) Preparation of compound 1b: Under a nitrogen atmosphere, phenylacetylene S1 (1.0 mmol) was dissolved in n-hexane (5 mL). Under cold conditions, n-butyllithium (1.0 mmol, 2.5 M in THF) was added dropwise to the reaction solution, followed by anhydrous zinc chloride (1.2 mmol) and then trifluoromethyl sulfinyl chloride (1.2 mmol). After stirring for 2-8 hours, the reaction was quenched with an aqueous solution of saturated ammonium chloride. The resulting mixture was extracted with ethyl acetate, and the organic phases were combined and washed with water and saturated brine. The mixture was dried over anhydrous Na2SO4. After removing the solvent under reduced pressure, the product was purified by rapid column chromatography to obtain the final product α-trifluoromethyl alkynyl sulfoxide 1b. Its reaction equation (5) is as follows: Equation (5) 2) Preparation of compound 2b: Benzoyl chloride S (1.0 mmol) was added dropwise to a CH2Cl2 (5 mL) solution of hydrazine S2 (1.2 mmol) and triethylamine (2.5 mmol) under a nitrogen atmosphere. After stirring at 0-15 °C for 2-6 hours, the mixture was washed with water and extracted with DCM. The combined organic phase was dried with anhydrous Na2SO4, and the solvent was evaporated under reduced pressure to obtain the corresponding product 2b. The solid product was crystallized from ethanol. The reaction equation (6) is as follows: Equation (6) 3) Preparation of compound 3b: Carbon tetrachloride (3.0 mmol) was added to a suspension of acetonitrile (5 mL) containing acylhydrazine 2b (1.0 mmol) and triphenylphosphine (2.0 mmol). The reaction was carried out at room temperature for 5-8 hours, and then the solvent was removed under reduced pressure. The crude product was subjected to flash column chromatography to obtain product 3b, and its reaction formula (7) is as follows: Equation (7) 4) Preparation of compound 4b: α-trifluoromethyl alkynyl sulfoxide 1b (1.2 mmol), hydrazone chloride 3b (1 mmol), potassium carbonate (1.0 mmol), and anhydrous ethanol (2 mL) were added to the reaction flask. The reaction was carried out at room temperature for 10-24 hours, and the reaction progress was monitored by TLC until the starting material disappeared. Saturated ammonium chloride solution was added, and the reaction solution was concentrated under vacuum to remove the solvent ethanol. The aqueous phase was extracted with ethyl acetate, the organic phases were combined, washed with brine, dried with Na2SO4, and the solvent was removed by rotary evaporation. The crude product was purified by silica gel rapid column chromatography to obtain the final product 4b (yield of 90%). Compound 4b was first processed using the LigPrep module in Schrödinger software (LigPrep, Schrödinger, LLC, New York, NY, 2021). The LogS was -4.72 and the LogP was 5.12. The reaction equation (8) is as follows: Equation (8) The NMR data are as follows: 1 H NMR (400 MHz, CDCl3) : 1H NMR (400 MHz, CDCl3) δ 8.02 – 8.00 (m,2H), 7.48 – 7.44 (m, 3H), 7.44 – 7.37 (m, 2H), 7.33 – 7.29 (m, 8H). 13C NMR (101 MHz, CDCl3) δ 150.99, 147.58, 138.34, 133.24, 131.18,130.54, 130.32, 129.55, 129.11, 128.79, 128.68, 126.61, 126.59, 125.20,125.67 (q, J = 338.4 Hz), 114.03. 19 F NMR (376 MHz, CDCl3) δ -69.22 (s, 3F). HRMS (ESI) calcd for C 22 H 15 F3N2KOS + [M+K] + : 451.0489, found: 451.0484 Figure 4 Compound 4b of the present invention 1 H NMR spectrum.
[0038] Figure 5 Compound 4b of the present invention 13 C10 NMR spectrum.
[0039] Figure 6 Compound 4b of the present invention 19 FNMR spectrum.
[0040] Example 3 1) Preparation of compound 1a: Under a nitrogen atmosphere, p-chlorophenylacetylene B1 (1.0 mmol) was dissolved in n-hexane (5 mL). Under cold conditions, n-butyllithium (1.0 mmol, 2.5 M in THF) was added dropwise to the reaction solution, followed by anhydrous zinc chloride (1.2 mmol) and then trifluoromethyl sulfinyl chloride (1.2 mmol). After stirring for 2-8 hours, the reaction was quenched with an aqueous solution of saturated ammonium chloride. The resulting mixture was extracted with ethyl acetate, and the organic phases were combined and washed with water and saturated brine. The mixture was dried over anhydrous Na2SO4. After removing the solvent under reduced pressure, the product 1a was purified by rapid column chromatography. The reaction equation (9) is as follows: Equation (9) 2) Preparation of compound 2b: Benzoyl chloride S (1.0 mmol) was added dropwise to a CH2Cl2 (5 mL) solution of hydrazine S2 (1.2 mmol) and triethylamine (2.5 mmol) under a nitrogen atmosphere. After stirring at 0-15 °C for 2-6 hours, the mixture was washed with water and extracted with DCM. The combined organic phase was dried with anhydrous Na2SO4, and the solvent was evaporated under reduced pressure to obtain the corresponding product 2b. The solid product was crystallized from ethanol, and its reaction formula (10) is as follows: Equation (10) 3) Preparation of compound 3b: Carbon tetrachloride S7 (3.0 mmol) was added to a suspension of acetonitrile (5 mL) containing acylhydrazine 2b (1.0 mmol) and triphenylphosphine S6 (2.0 mmol). The reaction was carried out at room temperature for 5-8 hours, and then the solvent was removed under reduced pressure. The crude product was obtained by flash column chromatography. The reaction equation (11) is as follows: Equation (11) 4) Preparation of compound 4c: α-trifluoromethyl alkynyl sulfoxide 1a (1.2 mmol), hydrazone chloride 3b (1.0 mmol), potassium carbonate (1.0 mmol), and anhydrous ethanol (2 mL) were added to the reaction flask. The reaction was carried out at room temperature for 10-24 hours, and the reaction progress was monitored by TLC until the starting material disappeared. Saturated ammonium chloride solution was added, and the reaction solution was concentrated under vacuum to remove the solvent ethanol. The aqueous phase was extracted with ethyl acetate, the organic phases were combined, washed with brine, dried with Na2SO4, and the solvent was removed by rotary evaporation. The crude product was purified by silica gel rapid column chromatography to obtain the final product 4c (yield of 85%). Compound 4c was first processed using the LigPrep module in Schrödinger software (LigPrep, Schrödinger, LLC, New York, NY, 2021). The LogS was -5.44 and the LogP was 5.61. The reaction equation (12) is as follows: Equation (12) The NMR data are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.92 – 7.87 (m, 2H), 7.48 – 7.42 (m, 3H), 7.37 – 7.30 (m, 4H), 7.28 – 7.21 (m, 5H). 13C NMR (101 MHz, CDCl3) δ 154.32, 147.16, 138.25, 136.59, 131.96,130.71, 129.51, 129.42, 129.25, 129.03, 128.84, 128.53, 125.63 (q, J = 338.4Hz). 125.48, 125.40, 113.21. 19 F NMR (376 MHz, CDCl3) δ -69.40. HRMS (ESI) calcd for C 22 H 14 ClF3N2NaOS + [M+Na] + : 469.0360, found:469.0358. Figure 7 Compound 4c of the present invention 1 H NMR spectrum.
[0041] Figure 8 Compound 4c of the present invention 13 C10 NMR spectrum.
[0042] Figure 9 Compound 4c of the present invention 19 FNMR spectrum.
[0043] Example 4 The difference between this embodiment and Example 2 is that the alkali (1.0 mmol of potassium carbonate) in step (4) is replaced with potassium carbonate (1.5 mmol). The remaining steps are the same as in Example 2. The result was that the yield was 81% by column chromatography.
[0044] Figure 10 This is a general formula diagram for the synthesis of compounds in embodiments of the present invention.
[0045] The compounds in Examples 1-3 were processed using the LigPrep module in the Schrödinger software (LigPrep, Schrödinger, LLC, New York, NY, 2021), and the results are shown in Table 2.
[0046] Table 2
[0047] As shown in Table 2, LogS represents the logarithm of the compound's solubility in water. A higher value indicates better water solubility. The LogS of the examples is -5.46 to -4.72, compared to rimonaban's LogS of -6.0, indicating that our invention has better water solubility. LogP represents the logarithm of the partition coefficient of the compound in octanol (oil phase) and aqueous phase. Rimonaban is excessively lipophilic, with a LogP as high as 6.26, far exceeding the ideal range. This indicates that rimonaban is highly lipophilic and tends to accumulate in adipose tissue and cell membranes. The LogP of the examples is 5.30 to 5.61, which helps the compound achieve a better balance between the lipid and aqueous phases. The combination of high LogP and low LogS of rimonaban shows that it is both poorly soluble in water and extremely soluble in oils / lipids. This makes its absorption from the intestine into the bloodstream difficult, and once in the body, it easily accumulates in adipose tissue, resulting in a large volume of distribution and potentially a long elimination half-life. The embodiments, through structural optimization, significantly improved water solubility and reduced excessive lipophilicity while maintaining sufficient lipophilicity to penetrate cell membranes. By introducing the unique trifluoromethyl sulfinyl group, multiple optimizations of polarity and metabolic stability were achieved at the molecular level, aiming to solve problems such as solubility, permeability, or excessively rapid metabolism that may exist in traditional structures. This compound, like rimonaban, has its core skeleton, and the product has a certain weight-loss effect.
[0048] Comparative Example 1 The difference between this comparative example and Example 2 is that the base (potassium carbonate 1.0 mmol) in step (4) is replaced with N,N-diisopropylethylamine (1.0 mmol). The remaining steps are the same as in Example 2. The result is that the yield by column chromatography is only 65%, and the reaction effect is not as good as that in the example.
[0049] Comparative Example 2 The difference between this comparative example and Example 2 is that the base (potassium carbonate 1.0 mmol) in step (4) is replaced with triethylamine (1.0 mmol). The remaining steps are the same as in Example 2. The result is that the yield by column chromatography is only 58%, and the reaction effect is not as good as that in the example.
[0050] Comparative Example 3 The difference between this comparative example and Example 2 is that the base (1.0 mmol of potassium carbonate) in step (4) is replaced with pyridine (1.0 mmol). The remaining steps are the same as in Example 2. The result is that the yield by column chromatography is only 40%, and the reaction effect is not as good as that in the example.
[0051] Comparative Example 4 The difference between this comparative example and Example 2 is that the base (potassium carbonate 1.0 mmol) in step (4) is replaced with 1,8-diazabicyclo[5.4.0]undec-7-ene (1.0 mmol). The remaining steps are the same as in Example 2. The result is that the yield by column chromatography is only 49%, and the reaction effect is not as good as that in the example.
[0052] Comparative Example 5 The difference between this comparative example and Example 2 is that the base (potassium carbonate 1.0 mmol) in step (4) is replaced with 1,4-diazabicyclo[2.2.2]octane (1.0 mmol). The remaining steps are the same as in Example 2. The result is that the yield separated by column chromatography is only 58%, and the reaction effect is not as good as that in the example.
[0053] Comparative Example 6 The difference between this comparative example and Example 2 is that the alkali (potassium carbonate 1.0 mmol) in step (4) is replaced with cesium carbonate (1.0 mmol). The remaining steps are the same as in Example 2. The result is that the yield by column chromatography is only 48%, and the reaction effect is not as good as that in the example.
[0054] Comparative Example 7 The difference between this comparative example and Example 2 is that the alkali (potassium carbonate 1.0 mmol) in step (4) is replaced with sodium carbonate (1.0 mmol). The remaining steps are the same as in Example 2. The result is that the yield by column chromatography is only 48%, and the reaction effect is not as good as that in the example.
[0055] Comparative Example 8 The difference between this comparative example and Example 2 is that the alkali (1.0 mmol of potassium carbonate) in step (4) is replaced with potassium carbonate (2.0 mmol). The remaining steps are the same as in Example 2. The result is that the yield by column chromatography is only 69%, and the reaction effect is not as good as that in the example.
[0056] Comparative Example 9 The difference between this comparative example and Example 2 is that the temperature (room temperature) in step (4) is replaced with 50°C. All other steps are the same as in Example 2. The result is that the yield by column chromatography is only 74%, and the reaction effect is not as good as that in the example.
[0057] Comparative Example 10 The difference between this comparative example and Example 2 is that the temperature (room temperature) in step (4) is replaced with 0°C. All other steps are the same as in Example 2. The result is that the yield by column chromatography is only 67%, and the reaction effect is not as good as that in the example.
[0058] Comparative Example 11 The difference between this comparative example and Example 2 is that the solvent (ethanol) in step (4) is replaced with toluene. All other steps are the same as in Example 2. The result is that the yield by column chromatography is only 57%, and the reaction effect is not as good as that in the example.
[0059] Comparative Example 12 The difference between this comparative example and Example 2 is that the solvent (ethanol) in step (4) is replaced with dichloromethane. All other steps are the same as in Example 2. The result is that the yield by column chromatography is only 69%, and the reaction effect is not as good as that in the example.
[0060] Comparative Example 13 The difference between this comparative example and Example 2 is that the solvent (ethanol) in step (4) is replaced with 1,2-dichloroethane. All other steps are the same as in Example 2. The result is that the yield by column chromatography is only 72%, and the reaction effect is not as good as that in the example.
[0061] Comparative Example 14 The difference between this comparative example and Example 1 is that the solvent (ethanol) in step (4) is replaced with N,N-dimethylformamide. The remaining steps are the same as in Example 2. The result is that the yield by column chromatography is only 61%, and the reaction effect is not as good as that in the example.
[0062] Comparative Example 15 The difference between this comparative example and Example 2 is that the solvent (ethanol) in step (4) is replaced with water. The remaining steps are the same as in Example 2. The result is that the yield by column chromatography is only 48%, and the reaction effect is not as good as that in the example.
[0063] Comparative Example 16 The difference between this comparative example and Example 2 is that the solvent (ethanol) in step (4) is replaced with methanol. All other steps are the same as in Example 2. The result is that the yield by column chromatography is only 58%, and the reaction effect is not as good as that in the example.
[0064] It should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit it. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, and all such modifications or substitutions should be covered within the scope of the present invention.
Claims
1. A 4-(trifluoromethylsulfinyl)pyrazole compound, characterized in that: The chemical structural formula of the 4-(trifluoromethylsulfinyl)pyrazole compound is shown in formula (a): Equation (a); Among them, R 1 Selected from phenyl, p-chlorophenyl, R 2 Selected from phenyl, methyl, R 3 Selected from phenyl, p-chlorophenyl, and 2,4-dimethylphenyl.
2. The method for preparing 4-(trifluoromethylsulfinyl)pyrazole compounds as described in claim 1, characterized in that: include, Under nitrogen atmosphere, terminal alkyne is dissolved in n-hexane, anhydrous zinc chloride is added, and trifluoromethyl sulfinyl chloride is reacted to give α-trifluoromethyl alkynyl sulfoxide. Benzoyl chloride was added dropwise to a CH2Cl2 solution of phenylhydrazine and triethylamine under nitrogen atmosphere to obtain acylhydrazine; Carbon tetrachloride was added to a suspension of acetonitrile containing acylhydrazine and triphenylphosphine to obtain hydrazone chloride; α-Trifluoromethyl alkynyl sulfoxide, hydrazone chloride, potassium carbonate, and anhydrous ethanol are reacted at room temperature to give 4-(trifluoromethyl sulfinyl)pyrazole compounds.
3. The preparation method according to claim 2, characterized in that: The molar ratio of terminal alkyne, n-hexane, anhydrous zinc chloride and trifluoromethyl sulfinyl chloride is 1~2:1~2:1~2:1~2.
4. The preparation method according to claim 3, characterized in that: The reaction temperature of terminal alkyne, n-hexane, anhydrous zinc chloride and trifluoromethyl sulfinyl chloride is -78 to -40℃, and the reaction time is 2 to 8 hours.
5. The preparation method according to claim 2, characterized in that: The molar ratio of phenylhydrazine, benzoyl chloride and triethylamine is 1~2 : 1~2 : 2~3.
6. The preparation method according to claim 5, characterized in that: The reaction temperature of phenylhydrazine, benzoyl chloride and triethylamine is 0~15℃, and the reaction time is 2~6h.
7. The preparation method according to claim 2, characterized in that: The molar ratio of acylhydrazine, triphenylphosphine and carbon tetrachloride is 1~2:2~3:3~4.
8. The preparation method according to claim 7, characterized in that: The reaction time of acylhydrazine, triphenylphosphine and carbon tetrachloride is 5-8 hours, and the reaction temperature is 25-28℃.
9. The preparation method according to claim 2, characterized in that: The molar ratio of α-trifluoromethyl alkynyl sulfoxide, hydrazone chloride, and potassium carbonate is 1~2 : 1~2 : 1~2.
10. The preparation method according to claim 2, characterized in that: The reaction temperature of α-trifluoromethyl alkynyl sulfoxide, hydrazone chloride, potassium carbonate and anhydrous ethanol is 25~28℃, and the reaction time is 10~24h.