A method for preparing trifluoromethyl-functionalized pyrazole fused ring compounds

Abstract

The application discloses a preparation method of a trifluoromethyl functionalized pyrazole fused ring compound, which comprises the following steps: adding a catalyst, a silver salt, an additive, an amino pyrazole and a trifluoroacetylimine sulfoxide ylide into an organic solvent, and reacting for 12-20 hours at 70-90 o C, and after the reaction is completed, post-treatment is performed to obtain the trifluoromethyl functionalized pyrazole fused ring compound. The preparation method is relatively simple in operation, starting materials are easy to obtain, functional group tolerance is high, the reaction can be scaled up to a gram level, and a trifluoromethyl functionalized pyrazole fused ring compound with diversified structures can be synthesized through substrate design, the latter can be used for design and development of drugs with different structures in later stage, and the practicability of the method is widened.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, and particularly relates to a method for preparing a trifluoromethyl-functionalized pyrazole fused-ring compound. Background Technology

[0002] Pyrazole fused-ring compounds are a common class of organic molecular skeletons, widely found in various drug molecules, natural products, and clinical therapeutics (J. Med. Chem., 2013, 56, 7458). They possess a range of biological activities, including antitumor, anti-inflammatory, antituberculosis, and antifungal activity (J. Med. Chem., 2018, 61, 8670; Bioorg. Med. Chem. Lett., 2009, 19, 4196). Meanwhile, due to the unique properties of fluorine atoms, the presence of trifluoromethyl groups can significantly improve the physicochemical properties of heterocyclic parent molecules, thereby affecting their pharmacological efficacy (J. Med. Chem., 2018, 61, 5822). Therefore, developing direct and efficient methods to construct trifluoromethyl-functionalized pyrazole fused-ring compounds has significant theoretical research value and practical application value.

[0003]

[0004] Traditional methods for synthesizing pyrazole fused-ring compounds mainly involve transition metal-catalyzed coupling cyclization reactions, condensation cyclization reactions, or direct hydrocarbon-activated cyclization strategies. In recent years, transition metal-catalyzed directed hydrocarbon activation reactions of 1-aryl-5-aminopyrazole compounds have become one of the mainstream methods for synthesizing pyrazole fused-ring derivatives. Common active coupling reaction substrates include acetylacetic acid esters, functionalized alkenes, iodine ylides, diazo compounds, and thioylides. However, for certain specifically functionalized pyrazole fused-ring compounds, such as trifluoromethyl-functionalized pyrazole fused-ring compounds, conventional and universal synthetic methods are almost non-existent.

[0005] Trifluoroacetylimine sulfoxide ylide is a highly efficient building block and active carbene precursor for the synthesis of trifluoromethyl compounds, which can be directly applied to transition metal-catalyzed directed hydrocarbon activation reactions to synthesize trifluoromethyl-substituted heterocyclic compounds. Based on this, we developed a method for synthesizing trifluoromethyl-functionalized pyrazole fused-ring compounds using readily available aminopyrazole and trifluoroacetylimine sulfoxide ylide as starting materials via a hydrocarbon activation-tandem oxidative cyclization reaction catalyzed by dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer. Summary of the Invention

[0006] This invention provides a method for preparing trifluoromethyl-functionalized pyrazole fused-ring compounds. The synthetic method has simple operation steps, inexpensive and easy-to-prepare reaction raw materials, good applicability, and a wide range of functional groups. The method can also be scaled up to gram-scale reaction and can be used for various derivatizations, providing potential possibilities for large-scale industrial application and the development and synthesis of related drugs.

[0007] A method for preparing a trifluoromethyl-functionalized pyrazole fused-ring compound includes the following steps: adding a catalyst, silver salt, additive, aminopyrazole, and trifluoroacetylimine sulfoxide ylide to an organic solvent, and heating at 70-90°C. o C is reacted for 12-20 hours. After the reaction is complete, post-treatment is performed to obtain the trifluoromethyl-functionalized pyrazole fused-ring compound.

[0008] The structure of the aminopyrazole is shown in formula (II):

[0009] (II);

[0010] The structure of the trifluoroacetylimine sulfoxide ylide is shown in formula (III):

[0011] (III);

[0012] The structure of the trifluoromethyl-functionalized pyrazole fused-ring compound is shown in formula (I):

[0013] (I);

[0014] In equations (I) to (III), R 1 and R 2 Independently selected from H, halogen, C1-C5 alkyl, C1-C5 alkoxy, phenyl, or trifluoromethyl; R 3 Selected from C1-C5 alkyl, phenethyl, substituted or unsubstituted C6-C 20 Aryl;

[0015] The C6~C mentioned 20 The substituents on the aryl group are selected from C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkylthio, halogen, methoxycarbonyl or trifluoromethyl.

[0016] The molar ratio of the catalyst, silver salt, and additives is 0.025:0.2:1.0.

[0017] The substitution position on the aryl group can be ortho, para, or meta.

[0018] The reaction formula is as follows:

[0019]

[0020] The reaction may first involve rhodium-catalyzed nitrogen-atom-directed aryl sp group formation on the pyrazole group. 2 Hydrogen activation and trifluoroacetylimine sulfoxide ylide reaction form carbon-carbon bonds, yielding an imine-alkylated coupling product. The imine bonds can be isomerized to enamine bonds. Then, the amino group on the pyrazole undergoes a silver-catalyzed intramolecular carbon-nitrogen bond formation reaction and oxidative aromatization to generate a trifluoromethyl-functionalized pyrazole fused-ring compound.

[0021] In this invention, the optional post-processing steps include: filtration, vacuum rotary evaporation, silica gel mixing, and finally purification by column chromatography to obtain the corresponding trifluoromethyl-functionalized pyrazole fused-ring compound. Column chromatography purification is a commonly used technique in the field of organic synthesis.

[0022] As a preferred option, R 1 Selected from H, F, Cl, Br, methyl, trifluoromethyl; R 2 Selected from H, methyl, substituted or unsubstituted phenyl, R 3 The derivative is selected from phenethyl, substituted or unsubstituted phenyl or naphthyl groups, wherein the substituent on the phenyl group is selected from methyl, methoxy, tert-butyl, chlorine, bromine, methoxycarbonyl or trifluoromethyl. In this case, the trifluoroacetylimine sulfoxide ylide and aminopyrazole are readily available and the reaction yield is high.

[0023] The aromatic amines and trifluoroacetic acid used to prepare trifluoroacetylimine sulfoxide ylide are relatively inexpensive and widely available in nature. The amount of trifluoroacetylimine sulfoxide ylide used is excessive compared to the aminopyrazole used. Preferably, the molar ratio is: aminopyrazole: trifluoroacetylimine sulfoxide ylide: dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer: bis(trifluoromethanesulfonylimide) silver: sodium acetate = 1:1~2:0.01~0.1: 0.1~0.3:0.5~2; a further preferred molar ratio is: aminopyrazole: trifluoroacetylimine sulfoxide ylide: dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer: bis(trifluoromethanesulfonylimide) silver: sodium acetate = 1:1.5:0.025:0.2:1.0.

[0024] Preferably, the reaction time is 12 to 20 hours. If the reaction time is too long, it will increase the reaction cost or generate by-products. Conversely, it will be difficult to ensure the completeness of the reaction.

[0025] In this invention, any organic solvent that can fully dissolve the raw materials can enable the reaction to occur, but the reaction efficiency varies greatly. Halogenated solvents are preferred, as they can effectively promote the reaction. Preferably, the organic solvent is chlorobenzene, dichloromethane, or dichloroethane. More preferably, the organic solvent is chlorobenzene, in which case various raw materials can be converted into products with a high conversion rate.

[0026] The amount of organic solvent used should be sufficient to dissolve the raw material well; the amount of organic solvent used for 1 mmol of aminopyrazole is approximately 5-10 mL.

[0027] Preferably, the catalyst is dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer. Among many transition metal catalysts, the highly catalytically active dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer is most widely used in the field of directed hydrocarbon activation, and the reaction efficiency is high when dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer is used as the catalyst.

[0028] Preferably, the silver salt is silver bis(trifluoromethanesulfonyl)imide, and the additive is sodium acetate.

[0029] As a further preferred embodiment, the trifluoromethyl-functionalized pyrazole fused-ring compound is one of the compounds shown in formulas (I-1) to (I-5):

[0030] (I-1)

[0031] (I-2)

[0032] (I-3)

[0033] (I-4)

[0034] (I-5)

[0035] In the above preparation method, the aromatic amine, dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer, bis(trifluoromethanesulfonyl)imide silver, and sodium acetate are generally commercially available products that can be easily obtained from the market. The aminopyrazole can be synthesized from arylhydrazine and alkenyl nitrile. The trifluoroacetylimide sulfoxide ylide can be rapidly synthesized from the corresponding aromatic amine, triphenylphosphine, carbon tetrachloride, trifluoroacetic acid, and trimethylthioiodide.

[0036] Compared with the prior art, the beneficial effects of the present invention are as follows: the preparation method is relatively easy to operate and the post-processing is relatively simple; the starting materials are inexpensive and readily available, the substrate range is wide, the substrate functional group tolerance is high, and trifluoromethyl-containing pyrazole fused-ring compounds with different functional groups can be designed and synthesized according to actual needs. The substrate structure is highly designable, the product structure is diverse, the reaction can be scaled up to the gram scale, and the obtained trifluoromethyl-functionalized pyrazole fused-ring compounds can be further used in the design and development of drug molecules, making it highly practical. Detailed Implementation

[0037] The present invention will be further described below with reference to specific embodiments.

[0038] According to the raw material ratio in Table 1, dichlorocyclopentyl rhodium dimer, bis(trifluoromethanesulfonyl)imide silver, sodium acetate, aminopyrazole (II), trifluoroacetylimide sulfoxide ylide (III), and 2 mL of organic solvent were added to a 35 mL Schlenk tube. The mixture was stirred evenly and reacted for 12-20 hours according to the reaction conditions in Table 2. After filtration, the sample was mixed with silica gel and purified by column chromatography to obtain the corresponding trifluoromethyl-containing pyrazoloquinazoline compound (I). The reaction process is shown in the following formula:

[0039]

[0040] Table 1. Amounts of raw materials added in Examples 1-14

[0041]

[0042] Table 2

[0043]

[0044] In Tables 1 and 2, T represents the reaction temperature, t represents the reaction time, Ph represents phenyl, Me represents methyl, OMe represents methoxy, CO2Me represents methoxycarbonyl, CF3 represents trifluoromethyl, NaOAc represents sodium acetate, and PhCl represents chlorobenzene.

[0045] Structural confirmation data of the compounds prepared in Examples 1-5:

[0046] Nuclear magnetic resonance (NMR) of the trifluoromethyl-functionalized pyrazole fused-ring compound (I-1) prepared in Example 1 1 HNMR, 13 C NMR and 19 The F NMR detection data are as follows:

[0047] (I-1)

[0048] 1 H NMR (400 MHz, CDCl3) δ 8.39 (d, J = 8.3 Hz, 1H), 7.79 – 7.74 (m,1H), 7.46 (dd, J = 8.2, 1.3 Hz, 1H), 7.33 – 7.29 (m, 1H), 6.94 – 6.90 (m,2H), 6.74 (s, 1H), 6.61 – 6.57 (m, 2H), 3.62 (s, 3H), 2.59 (s, 3H).

[0049] 13C NMR (101 MHz, CDCl3) δ 159.0, 153.6, 151.4, 150.7 (CF, q, 2 J (C-F) =35.3 Hz), 145.0, 138.9, 136.3, 134.8, 126.6, 125.2, 124.0, 119.8 (CF, q, 1 J (C-F) = 279.2 Hz), 115.1, 114.8, 114.3, 100.8, 55.3, 14.7.

[0050] 19 F NMR (377 MHz, CDCl3) δ -68.91.

[0051] MP 85.1-85.8 o C

[0052] HRMS (ESI): [M+H] + calcd. for C 20 H 16 F3N4O + 385.1271, found 385.1281.

[0053] Nuclear magnetic resonance (NMR) of the trifluoromethyl-functionalized pyrazole fused-ring compound (I-2) prepared in Example 2 1 HNMR, 13 C NMR and 19 The F NMR detection data are as follows:

[0054] (I-2)

[0055] 1 H NMR (400 MHz, CDCl3) δ 8.39 (d, J = 8.8 Hz, 1H), 7.82 – 7.77 (m,1H), 7.49 (d, J = 8.3 Hz, 1H), 7.39 – 7.34 (m, 1H), 7.07 – 7.03 (m, 2H), 6.88– 6.85 (m, 2H), 6.73 (s, 1H), 2.58 (s, 3H).

[0056] 13 C NMR (101 MHz, CDCl3) δ 154.2 (CF, q, 2 J(C-F) = 35.7 Hz), 153.8,150.0, 144.7, 144.6, 136.2, 135.0, 132.6, 129.2, 126.3, 125.3, 122.2, 119.4(CF, q, 1 J (C-F) = 279.6 Hz), 115.3, 114.9, 100.9, 14.7.

[0057] 19 F NMR (377 MHz, CDCl3) δ -69.33.

[0058] MP 139.3-139.9 o C

[0059] HRMS (ESI): [M+H] + calcd. for C 19 H 13 ClF3N4 + 389.0775, found 389.0774.

[0060] Nuclear magnetic resonance (NMR) of the trifluoromethyl-functionalized pyrazole fused-ring compound (I-3) prepared in Example 3 1 HNMR, 13 C NMR and 19 The F NMR detection data are as follows:

[0061] (I-3)

[0062] 1 H NMR (400 MHz, CDCl3) δ 8.39 (d, J = 8.4 Hz, 1H), 7.83 – 7.78 (m,1H), 7.55 (d, J = 8.0 Hz, 1H), 7.42 – 7.38 (m, 1H), 7.35 (d, J = 8.4 Hz, 2H), 7.00 (d, J = 8.1 Hz, 2H), 6.73 (s, 1H), 2.57 (s, 3H).

[0063] 13 C NMR (101 MHz, CDCl3) δ 155.4 (CF, q, 2 J (C-F)= 35.6 Hz), 153.9,149.4, 149.1, 144.6, 136.2, 135.1, 128.5 (CF, q, 2 J (C-F) = 32.9 Hz), 126.3 (CF, q, 3 J (C-F) = 3.8 Hz), 126.2, 125.3, 123.8 (CF, q, 1 J (C-F) = 272.1 Hz), 120.4,119.2 (CF, q, 1 J (C-F) = 280.0 Hz), 115.4, 115.0, 101.0, 14.7.

[0064] 19 F NMR (377 MHz, CDCl3) δ -62.57, -69.48.

[0065] MP 133.5-133.9 o C

[0066] HRMS (ESI): [M+H] + calcd. for C 20 H 13 F6N4 + 423.1039, found 423.1045.

[0067] Nuclear magnetic resonance (NMR) of the trifluoromethyl-functionalized pyrazole fused-ring compound (I-4) prepared in Example 4 1 HNMR, 13 C NMR and 19 The F NMR detection data are as follows:

[0068] (I-4)

[0069] 1 H NMR (400 MHz, CDCl3) δ 8.26 (d, J = 8.9 Hz, 1H), 7.82 (dd, J = 8.9,2.0 Hz, 1H), 7.52 (d, J = 2.0 Hz, 1H), 6.92 – 6.88 (m, 2H), 6.76 (s, 1H), 6.65 – 6.61 (m, 2H), 3.65 (s, 3H), 2.58 (s, 3H).

[0070] 13 C NMR (101 MHz, CDCl3) δ 159.2, 154.1, 150.2 (CF, q, 2 J (C-F) = 35.6Hz), 150.1, 144.8, 138.9, 137.7, 135.1, 128.9, 123.7, 119.6 (CF, q, 1 J (C-F) =279.3 Hz), 118.3, 117.0, 115.9, 114.4, 101.3, 55.4, 14.8.

[0071] 19 F NMR (377 MHz, CDCl3) δ -68.84.

[0072] MPa 65.3-65.9 o C

[0073] HRMS (ESI): [M+H] + calcd. for C 20 H 15 BrF3N4O + 463.0376, found 463.0385.

[0074] Nuclear magnetic resonance (NMR) of the trifluoromethyl-functionalized pyrazole fused-ring compound (I-5) prepared in Example 5 1 HNMR, 13 C NMR and 19 The F NMR detection data are as follows:

[0075] (I-5)

[0076] 1 H NMR (400 MHz, CDCl3) δ 8.46 (d, J = 8.4 Hz, 1H), 8.16 (d, J = 2.2Hz, 1H), 7.82 – 7.78 (m, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.39 – 7.35 (m, 1H), 6.97 (d, J = 2.2 Hz, 1H), 6.95 – 6.91 (m, 2H), 6.62 – 6.58 (m, 2H), 3.62 (s, 3H).

[0077] 13C NMR (101 MHz, CDCl3) δ 159.1, 151.7, 150.6 (C-F, q, 2 J (C-F) = 35.0Hz), 144.3, 143.4, 138.8, 136.6, 134.9, 126.6, 125.8, 124.0, 119.7 (C-F, q, 1 J (C-F) = 279.1 Hz), 115.5, 115.1, 114.3, 101.4, 55.3.

[0078] 19 F NMR (377 MHz, CDCl3) δ -68.86.

[0079] M.p. 124.5-125.3 o C

[0080] HRMS (ESI): [M+H] + calcd. for C 19 H 14 F3N4O + 371.1114, found 371.1116。

Claims

1. A method for preparing a trifluoromethyl-functionalized pyrazole fused-ring compound, characterized in that, The process includes the following steps: adding the catalyst, silver salt, additives, aminopyrazole, and trifluoroacetylimine sulfoxide ylide to an organic solvent, and heating at 70-90°C. o C is reacted for 12-20 hours. After the reaction is complete, post-treatment is performed to obtain the trifluoromethyl-functionalized pyrazole fused-ring compound. The structure of the aminopyrazole is shown in formula (II): ； The structure of the trifluoroacetylimine sulfoxide ylide is shown in formula (III): ； The structure of the trifluoromethyl-functionalized pyrazole fused-ring compound is shown in formula (I): ； In equations (I) to (III), R 1 and R 2 Independently selected from H, halogen, C1-C5 alkyl, C1-C5 alkoxy, phenyl, or trifluoromethyl; R 3 Selected from C1-C5 alkyl, phenethyl, substituted or unsubstituted C6-C 20 Aryl; The C6~C mentioned 20 The substituents on the aryl group are selected from C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkylthio, halogen, methoxycarbonyl or trifluoromethyl.

2. The method for preparing the trifluoromethyl-functionalized pyrazole fused-ring compound according to claim 1, characterized in that, R 1 Selected from H, Cl, Br, methyl, methoxy, or trifluoromethyl.

3. The method for preparing the trifluoromethyl-functionalized pyrazole fused-ring compound according to claim 1, characterized in that, R 2 Selected from H, methyl, and phenyl.

4. The method for preparing the trifluoromethyl-functionalized pyrazole fused-ring compound according to claim 1, characterized in that, R 3 The phenyl group is selected from methyl, phenethyl, substituted or unsubstituted phenyl or naphthyl groups; the substituents on the phenyl group are selected from methyl, methoxy, methylthio, tert-butyl, chlorine, bromine, methoxycarbonyl or trifluoromethyl.

5. The method for preparing the trifluoromethyl-functionalized pyrazole fused-ring compound according to claim 1, characterized in that, In molar amounts, aminopyrazole: trifluoroacetylimine sulfoxide ylide: catalyst: silver salt: additive = 1:1~2:0.01~0.1:0.1~0.3:0.5~2.

6. The method for preparing the trifluoromethyl-functionalized pyrazole fused-ring compound according to claim 1, characterized in that, The organic solvent is chlorobenzene.

7. The method for preparing the trifluoromethyl-functionalized pyrazole fused-ring compound according to claim 1, characterized in that, The catalyst is a dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer.

8. The method for preparing the trifluoromethyl-functionalized pyrazole fused-ring compound according to claim 1, characterized in that, The silver salt is bis(trifluoromethanesulfonyl)imide silver.

9. The method for preparing the trifluoromethyl-functionalized pyrazole fused-ring compound according to claim 1, characterized in that, The additive mentioned is sodium acetate.

10. The method for preparing the trifluoromethyl-functionalized pyrazole fused-ring compound according to claim 1, characterized in that, The trifluoromethyl-functionalized pyrazole fused-ring compound is one of the compounds shown in formulas (I-1) to (I-5): 。

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