A process for the preparation of trifluoromethyl and amino substituted 1,2,4-triazole compounds

Abstract

The application discloses a method for preparing trifluoromethyl and amino substituted 1,2,4-triazole compounds, which comprises the following steps: adding palladium acetate, lithium acetate, trifluoroethyl imine hydrazide and isocyanide into an organic solvent, and stirring at 90-110 o C for 8-16 hours, and after the reaction is completed, post-treatment is performed to obtain the trifluoromethyl and amino substituted 1,2,4-triazole compounds. The preparation method is simple in operation, the starting material is cheap and easy to obtain, the amount of the palladium acetate catalyst is small, the reaction is carried out in an air atmosphere, no anhydrous and anaerobic operation is needed, the reaction can be scaled up to a gram level, and the application 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 and amino-substituted 1,2,4-triazole compound. Background Technology

[0002] Trifluoromethyl-substituted 1,2,4-triazole molecules are an important class of nitrogen-containing five-membered heterocyclic compounds, widely found in various bioactive and pharmaceutical molecules (Bioorganic & Medicinal Chemistry Letters, 2004, 14, 2463; Journal of Medicinal Chemistry, 2011, 54, 387). Many bioactive molecules contain trifluoromethyl-substituted 1,2,4-triazole structures, such as sitagliptin for treating type II diabetes, anti-anxiety drugs, and various inhibitors. Introducing a trifluoromethyl group into a heterocyclic molecule can improve the physicochemical properties and pharmacodynamics of the heterocyclic parent compound, such as electronegativity, bioavailability, metabolic stability, and lipophilicity (Science 2007, 317, 1881).

[0003]

[0004] The methods reported in the literature for synthesizing trifluoromethyl-substituted 1,2,4-triazoles mainly focus on using trifluoromethyl synthetic building blocks with different structures to undergo tandem cyclization reactions with suitable substrates to generate the target heterocycle. The most commonly used trifluoromethyl synthetic block is trifluoroethylimine hydrazine, which undergoes a [4+1] cyclization reaction with one-carbon substrates such as aryl ethyl ketones, aryl keto acids, aliphatic amines, carbon monoxide, glucose, and DMF to construct trifluoromethyl-substituted 1,2,4-triazoles. For target products with more diverse structures, such as 1,2,4-triazoles containing both trifluoromethyl and amino substitutions, no reports have been published to date.

[0005] Based on this, we have developed a simple and efficient method for synthesizing trifluoromethyl and amino-substituted 1,2,4-triazoles using readily available trifluoroethylimine hydrazine and isocyanate as starting materials and palladium-catalyzed [4+1] cyclization reaction. Summary of the Invention

[0006] This invention provides a method for preparing trifluoromethyl and amino-substituted 1,2,4-triazole compounds. The preparation method is simple, uses inexpensive and readily available starting materials, employs a catalytic amount of palladium acetate as a catalyst and lithium acetate as a promoter, and reacts in an air atmosphere, which facilitates subsequent operations and applications.

[0007] A method for preparing a trifluoromethyl and amino-substituted 1,2,4-triazole compound includes the following steps: adding palladium acetate, lithium acetate, trifluoroethylimine hydrazine, and isocyanate to an organic solvent, and heating at 90-110 °C. o C reaction for 8-16 hours, after which the reaction is complete, post-treatment yields the trifluoromethyl and amino-substituted 1,2,4-triazole compounds.

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

[0009] (II)

[0010] The structure of the isocyanate is shown in formula (III):

[0011] (III)

[0012] The structures of the trifluoromethyl and amino-substituted 1,2,4-triazole compounds are shown in Formula (I):

[0013] (I)

[0014] In equations (I) to (III), R 1 For substituted or unsubstituted aryl groups; R 2 It can be alkyl, benzyl, substituted or unsubstituted aryl;

[0015] In R 1 and R 2 In this context, the substituents on the aryl group are independently selected from C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio, halogen, or trifluoromethyl.

[0016] R 1 and R 2 The substitution position of the aryl group can be ortho, para, or meta.

[0017] The reaction formula is as follows:

[0018]

[0019] The reaction may first involve a complexation reaction between palladium acetate and trifluoroacetylimine hydrazine, resulting in the loss of two molecules of acetic acid to form a five-membered-ring palladium intermediate. Subsequently, an isocyanate inserts into the nitrogen-palladium bond to form a six-membered-ring palladium intermediate. Following this, a reductive elimination reaction and a subsequent hydroisomerization reaction occur to yield the final trifluoromethyl and amino-substituted 1,2,4-triazole compound. The generated zero-valent palladium can be oxidized to divalent palladium by oxygen in the air, completing the catalytic cycle.

[0020] In this invention, the optional post-processing steps include: filtration, silica gel mixing, and finally purification by column chromatography to obtain the corresponding trifluoromethyl and amino-substituted 1,2,4-triazole compounds. Column chromatography purification is a commonly used technique in the field of organic synthesis.

[0021] As a preferred option, R 1 The phenyl group is naphthyl, substituted or unsubstituted, wherein the substituent on the phenyl group is selected from methyl, methoxy, methylthio, tert-butyl, chlorine, bromine or trifluoromethyl. In this case, the aromatic amine and trifluoroethylimine hydrazine are readily available and the reaction yield is high.

[0022] As a preferred option, R 2 The isocyanate is tert-butyl, adamantyl, substituted or unsubstituted phenyl or benzyl, wherein the substituent on the phenyl group is selected from methyl, methoxy or bromine, in which case the isocyanate is readily available and the reaction yield is high.

[0023] The isocyanate is relatively inexpensive and readily available, and its dosage is excessive relative to the amount of trifluoroethylimine hydrazine used. Preferably, the molar ratio of trifluoroethylimine hydrazine:isocyanate:palladium acetate:lithium acetate is 1:1~2:0.01~0.1:1~3; as a further preferred ratio, the molar ratio of trifluoroethylimine hydrazine:isocyanate:palladium acetate:lithium acetate is 1:1.5:0.05:2.

[0024] 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. Aprotic solvents are preferred, as they can effectively promote the reaction. Preferably, the organic solvent is toluene, acetonitrile, or dioxane. More preferably, toluene is the most suitable organic solvent, as it allows various raw materials to be converted into products with a high conversion rate.

[0025] 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 trifluoroethylimine hydrazine is approximately 5-10 mL.

[0026] Preferably, the catalyst is palladium acetate, as the reaction efficiency is high when palladium acetate is used as the catalyst.

[0027] Preferably, the additive is lithium acetate, as the reaction efficiency is high when lithium acetate is used as the additive.

[0028] As a further preferred embodiment, the trifluoromethyl and amino-substituted 1,2,4-triazole compound is one of the compounds shown in formulas (I-1) to (I-5):

[0029] (I-1)

[0030] (I-2)

[0031] (I-3)

[0032] (I-4)

[0033] (I-5)

[0034] In the above preparation method, the aromatic amine, isocyanate, palladium acetate, and lithium acetate are generally commercially available products that can be easily purchased from the market. The trifluoroethylimine hydrazine can be obtained from trifluoroethylimine chloride and hydrazine hydrate in almost quantitative yield, while the trifluoroethylimine chloride can be rapidly synthesized from the corresponding aromatic amine, triphenylphosphine, carbon tetrachloride, and trifluoroacetic acid.

[0035] Compared with the prior art, the advantages of the present invention are: the preparation method is easy to operate, can be carried out in an air atmosphere, and the post-processing is simple; the starting materials are inexpensive and readily available, the amount of palladium acetate catalyst used is small, the reaction substrates are extensive, the substrate functional groups have a wide tolerance range, and 1,2,4-triazole compounds with different substitutions at the 3 and 4 positions and containing trifluoromethyl and amino groups can be designed and synthesized according to actual needs, which has strong practicality. Detailed Implementation

[0036] The present invention will be further described below with reference to specific embodiments.

[0037] According to the raw material ratio in Table 1, palladium acetate, lithium acetate, trifluoroethylimine hydrazine (II), isocyanate (III), and 1 mL of organic solvent were added to a 35 mL Schlenk tube. The mixture was stirred until homogeneous and reacted for 8-16 hours under 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 and amino-substituted 1,2,4-triazole compounds (I). The reaction process is shown in the following formula:

[0038]

[0039] Table 1. Amounts of raw materials added in Examples 1-15

[0040]

[0041] Table 2

[0042]

[0043] In Tables 1 and 2, T represents the reaction temperature, t represents the reaction time, Ph represents phenyl, Me represents methyl, OMe represents methoxy, SMe represents methylthio, Bn represents benzyl, t-Bu represents tert-butyl, CF3 represents trifluoromethyl, and toluene represents toluene.

[0044] Structural confirmation data of the compounds prepared in Examples 1-5:

[0045] Nuclear magnetic resonance (NMR) of the trifluoromethyl and amino-substituted 1,2,4-triazole compound (I-1) prepared in Example 1 1 H NMR, 13 C NMR and 19 The F NMR detection data are as follows:

[0046] (I-1)

[0047] 1 H NMR (400 MHz, CDCl3) δ 7.40 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 8.2Hz, 2H), 3.57 (s, 1H), 2.50 (s, 3H), 1.45 (s, 9H).

[0048] 13 C NMR (101 MHz, CDCl3) δ 155.4, 141.4, 140.3 (CF, q, 2 J (C-F) = 38.6Hz), 131.2, 128.7, 127.4, 118.5 (CF, q, 2 J (C-F) = 269.8 Hz), 52.7, 29.1, 21.5.

[0049] 19 F NMR (376 MHz, CDCl3) δ -61.96.

[0050] MP 92.6 - 93.3 o C.

[0051] HRMS (ESI): [M+H] + calcd. for C 14 H 18 F3N4 + 299.1478, found 299.1497.

[0052] Nuclear magnetic resonance (NMR) of the trifluoromethyl and amino-substituted 1,2,4-triazole compound (I-2) prepared in Example 2 1 H NMR, 13 C NMR and 19 The F NMR detection data are as follows:

[0053] (I-2)

[0054] 1 H NMR (400 MHz, CDCl3) δ 7.75 – 7.72 (m, 2H), 7.21-7.19 (m, 2H), 3.56 (s, 1H), 1.43 (s, 9H).

[0055] 13 C NMR (101 MHz, CDCl3) δ 155.0, 139.9 (CF, q, 2 J (C-F) = 40.0 Hz),134.0, 130.4, 129.4, 125.3, 118.3 (CF, q, 1 J (C-F) = 270.2 Hz), 53.0, 29.0.

[0056] 19 F NMR (376 MHz, CDCl3) δ -61.79.

[0057] MP 151.1 - 151.8 o C.

[0058] HRMS (ESI): [M+H] + calcd. for C 13 H 15 BrF3N4 + 363.0427, found 363.0438.

[0059] Nuclear magnetic resonance (NMR) of the trifluoromethyl and amino-substituted 1,2,4-triazole compound (I-3) prepared in Example 3 1 H NMR, 13 C NMR and 19 The F NMR detection data are as follows:

[0060] (I-3)

[0061] 1H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 8.7 Hz, 1H), 7.99 – 7.96 (m,1H), 7.94 – 7.92 (m, 1H), 7.82 – 7.81 (m, 1H), 7.69 – 7.62 (m, 2H), 7.30 (dd,J = 8.7, 2.1 Hz, 1H), 3.64 (s, 1H), 1.41 (s, 9H).

[0062] 13 C NMR (101 MHz, CDCl3) δ 155.4, 140.2 (CF, q, 2 J (C-F) = 38.9 Hz),133.8, 133.4, 131.0, 128.6, 128.4, 128.3, 128.2, 127.8, 127.3, 124.1, 118.4(CF, q, 1 J (C-F) = 269.9 Hz), 52.8, 29.0.

[0063] 19 F NMR (376 MHz, CDCl3) δ -61.77.

[0064] MP 112.5 - 113.1 o C.

[0065] HRMS (ESI): [M+H] + calcd. for C 17 H 18 F3N4 + 335.1478, found 335.1492.

[0066] Nuclear magnetic resonance (NMR) of the trifluoromethyl and amino-substituted 1,2,4-triazole compound (I-4) prepared in Example 4 1 H NMR, 13 C NMR and 19 The F NMR detection data are as follows:

[0067] (I-4)

[0068] 1H NMR (400 MHz, CDCl3) δ 7.35 – 7.27 (m, 5H), 7.23 – 7.19 (m, 2H), 7.03 – 6.99 (m, 2H), 4.60 (d, J = 5.8 Hz, 2H), 4.05 – 4.02 (m, 1H), 3.85 (s,3H).

[0069] 13 C NMR (101 MHz, CDCl3) δ 161.3, 139.8 (CF, q, 2 J (C-F) = 41.6 Hz),138.0, 128.9, 128.1, 128.0, 123.3, 118.3 (CF, q, 1 J (C-F) = 270.0 Hz), 115.7,55.8, 47.7.

[0070] 19 F NMR (376 MHz, CDCl3) δ -62.07.

[0071] MP 119.2 - 120.1 o C.

[0072] HRMS (ESI): [M+H] + calcd. for C 17 H 16 F3N4O + 349.1276, found 349.1286.

[0073] Nuclear magnetic resonance (NMR) of the trifluoromethyl and amino-substituted 1,2,4-triazole compound (I-5) prepared in Example 5 1 H NMR, 13 C NMR and 19 The F NMR detection data are as follows:

[0074] (I-5)

[0075] 1H NMR (400 MHz, CDCl3) δ 7.41 (d, J = 9.0 Hz, 2H), 7.29 (d, J = 8.9Hz, 2H), 7.08 (d, J = 8.9 Hz, 2H), 6.84 (d, J = 9.0 Hz, 2H), 5.76 (s, 1H),3.90 (s, 3H), 3.77 (s, 3H).

[0076] 13 C NMR (101 MHz, CDCl3) δ 161.6, 155.9, 140.3 (C-F, q, 2 J (C-F) = 31.6Hz), 131.4, 129.3, 122.8, 120.5, 118.2 (C-F, q, 1 J (C-F) = 270.0 Hz), 115.9,114.6, 55.9, 55.7.

[0077] 19 F NMR (376 MHz, CDCl3) δ -62.11.

[0078] M.p. 204.6 - 205.2 o C.

[0079] HRMS (ESI): [M+H] + calcd. for C 17 H 16 F3N4O2 + 365.1220, found 365.1227。

Claims

1. A method for preparing a trifluoromethyl and amino-substituted 1,2,4-triazole compound, characterized in that, The steps include: adding palladium acetate, lithium acetate, trifluoroethylimine hydrazine, and isocyanate to an organic solvent, and heating at 90-110 °C. o The reaction was carried out for 8-16 hours. After the reaction was complete, the post-treatment yielded the trifluoromethyl and amino-substituted 1,2,4-triazole compounds. The structure of the trifluoroethylimine hydrazine is shown in formula (II): ； The structure of the isocyanate is shown in formula (III): ； The structures of the trifluoromethyl and amino-substituted 1,2,4-triazole compounds are shown in Formula (I): ； In equations (I) to (III), R 1 For substituted or unsubstituted aryl groups; R 2 It can be alkyl, benzyl, substituted or unsubstituted aryl; In R 1 and R 2 In this context, the substituents on the aryl group are independently selected from C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio, halogen, or trifluoromethyl.

2. The method for preparing the trifluoromethyl and amino-substituted 1,2,4-triazole compound according to claim 1, characterized in that, R 1 It is a naphthyl, substituted, or unsubstituted phenyl group; The substituents on the phenyl group are selected from methyl, tert-butyl, methoxy, methylthio, chlorine, bromine, or trifluoromethyl.

3. The method for preparing the trifluoromethyl and amino-substituted 1,2,4-triazole compound according to claim 1, characterized in that, R 2 It is tert-butyl, adamantyl, benzyl, substituted or unsubstituted phenyl; The substituents on the phenyl group are selected from methyl or methoxy groups.

4. The method for preparing the trifluoromethyl and amino-substituted 1,2,4-triazole compound according to claim 1, characterized in that, The organic solvent is toluene.

5. The method for preparing the trifluoromethyl and amino-substituted 1,2,4-triazole compound according to claim 1, characterized in that, In molar amounts, the ratio of trifluoroethylimine hydrazine: isocyanate: palladium acetate: lithium acetate is 1:1~2: 0.02~0.1: 1~3.

6. The method for preparing the trifluoromethyl and amino-substituted 1,2,4-triazole compound according to claim 1, characterized in that, The trifluoromethyl and amino-substituted 1,2,4-triazole compounds are one of the compounds shown in formulas (I-1) to (I-5): 。

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