A process for the preparation of 5-trifluoromethyl substituted 1,2,4-triazole compounds involving a fatty amine

Abstract

The application discloses a method for preparing 5-trifluoromethyl-substituted 1,2,4-triazole compounds with the participation of aliphatic amines, which comprises the following steps: adding elemental sulfur, trifluoroethyl imine hydrazide and aliphatic amines into an organic solvent, and reacting at 110-130 DEG C for 16-24 hours; and after the reaction is completed, post-treatment is carried out to obtain the 5-trifluoromethyl-substituted 1,2,4-triazole compounds. The preparation method is simple in operation, the starting materials are cheap and easy to obtain, the elemental sulfur is odorless and nontoxic, the reaction does not need to use heavy metal catalysts, the reaction can be enlarged to a gram level, and the method can be directly used to synthesize GlyT1 inhibitor molecules with biological activity, so that the operation is facilitated and the application of the method is widened.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of organic synthesis, and particularly relates to a preparation method of a 5-trifluoromethyl-substituted 1,2,4-triazole compound participated by a fatty amine. BACKGROUND

[0002] The 5-trifluoromethyl-substituted 1,2,4-triazole compound is an important nitrogen-containing five-membered heterocyclic derivative, and widely exists in various active molecules and drug molecules (Org. Process Res. Dev., 2005, 9, 634). Many bioactive molecules contain the 5-trifluoromethyl-substituted 1,2,4-triazole structure, such as sitagliptin drugs, anxiolytic drugs, and various inhibitors, etc. The introduction of the trifluoromethyl group into the heterocyclic molecule can significantly improve the physical and chemical properties of the parent compound, such as electronegativity, biological effectiveness, metabolic stability, and lipophilicity, etc. (Science 2007, 317, 1881).

[0003]

[0004] The elemental sulfur-promoted oxidative cyclization reaction is one of the common methods for synthesizing azole compounds, and a o-aminophenyl / mercapto / hydroxyphenylamine is used as a starting material to undergo a tandem cyclization reaction with a suitable substrate. Commonly used carbon donor substrates include acids, aldehydes, benzyl chlorides, alcohols, nitriles, amines, phenylethanones, phenylethylene, phenylacetylene, and methyl-substituted heterocycles, etc. Among them, the fatty amine compound widely exists in nature, is cheap and easy to obtain, and can be used as a good carbon donor to participate in the reaction, and one molecule of ammonia gas is released in the reaction process.

[0005] Nowadays, the methods for synthesizing the 5-trifluoromethyl-substituted 1,2,4-triazole reported in the literature are not extensive, and most of them use trifluoromethyl synthon which is not easy to obtain, or have the disadvantages of harsh reaction conditions, complicated synthesis steps, low reaction efficiency, and narrow substrate range. Recently developed several synthesis methods based on trifluoroacetyl imine chloride as a raw material, and the reaction substrates are aldehydes or hydrazides, which are far less expensive than the amine compounds widely existing in nature.

[0006] Based on this, a simple and efficient synthesis method for the 5-trifluoromethyl-substituted 1,2,4-triazole is developed, which uses the easily available trifluoroethyl imine hydrazide and fatty amine as starting materials, and elemental sulfur as a promoter, and is free of metal participation. SUMMARY

[0007] The present application provides a preparation method of a 5-trifluoromethyl-substituted 1,2,4-triazole compound, which has simple steps, cheap and easy-to-obtain starting materials, uses odorless solid elemental sulfur as a promoter, avoids the use of heavy metal catalysts, and is convenient for subsequent operation and application.

[0008] A method for preparing a 5-trifluoromethyl substituted 1,2,4-triazole compound, comprising the following steps: adding elemental sulfur, trifluoroethyl imine hydrazide and aliphatic amine into an organic solvent, reacting at 90-110 DEG C for 16-24 hours, and after the reaction is completed, post-treating to obtain the 5-trifluoromethyl substituted 1,2,4-triazole compound;

[0009] The structure of the trifluoroethyl imine hydrazide is shown in formula (II):

[0010]

[0011] The structure of the aliphatic amine is shown in formula (III):

[0012]

[0013] The structure of the 5-trifluoromethyl substituted 1,2,4-triazole compound is shown in formula (I):

[0014]

[0015] In formulae (I)-(III), R 1 is a substituted or unsubstituted aryl group; R 2 is an alkyl group, a substituted or unsubstituted aryl group, or a heteroaryl group;

[0016] In R 1 and R 2 , the substituents on the aryl group are independently selected from C1-C4 alkyl, C1-C4 alkoxy, halogen or cyano.

[0017] R 1 and R 2 The substitution position of the aryl group can be ortho, para or meta.

[0018] The reaction formula is as follows:

[0019]

[0020] In the reaction, two molecules of benzylamine and elemental sulfur can first react to generate a thioamide, which then reacts with trifluoroacetimidic hydrazine to generate an amidine compound, while releasing one molecule of benzylamine, and then under the combined promotion of elemental sulfur and heating, an intramolecular cyclization and dehydrogen sulfide reaction occurs to generate the final 5-trifluoromethyl substituted 1,2,4-triazole compound; the released hydrogen sulfide can be successfully detected by lead acetate test paper.

[0021] In the present application, the optional post-treatment process includes: filtration, silica gel mixing, and finally column chromatography purification to obtain the corresponding 5-trifluoromethyl-substituted 1,2,4-triazole compound. The column chromatography purification is a common technical means in the art.

[0022] As preferred, R 1 is a substituted or unsubstituted phenyl, and the substituent on the phenyl is selected from methyl, methoxy, tert-butyl, fluorine, bromine, chlorine or cyano. In this case, the aromatic amine and the trifluoroethyl imine hydrazide are easy to obtain, and the reaction yield is high.

[0023] As preferred, R 2 is n-pentyl, n-heptyl, a substituted or unsubstituted phenyl, naphthyl, furanyl or thienyl, and the substituent on the phenyl is selected from methyl, methoxy or bromine. In this case, the aliphatic amine is easy to obtain, and the reaction yield is high.

[0024] The aliphatic amine is relatively cheap and easy to obtain. The amount of the trifluoroethyl imine hydrazide is in excess relative to the amount of the aliphatic amine. As preferred, the molar ratio of trifluoroethyl imine hydrazide: aliphatic amine:sulfur is 1:2-3:2-4. As further preferred, the molar ratio of trifluoroethyl imine hydrazide: aliphatic amine:sulfur is 1:2.5:3.

[0025] In the present application, any organic solvent that can fully dissolve the raw materials can cause the reaction to occur, but the reaction efficiency differs greatly. As preferred, the organic solvent is an aprotic solvent, which can effectively promote the reaction. As preferred, the organic solvent is dimethyl sulfoxide, acetonitrile or dioxane. As further preferred, the organic solvent is dimethyl sulfoxide, which is the most suitable solvent. In this case, various raw materials can be converted into products at a high conversion rate. Dimethyl sulfoxide is also commonly used as an activator for elemental sulfur.

[0026] The amount of the organic solvent can be used to better dissolve the raw materials. For 1 mmol of trifluoroethyl imine hydrazide, the amount of the organic solvent used is about 2-5 mL.

[0027] As preferred, the promoter is elemental sulfur, and the reaction efficiency is higher when elemental sulfur is used as an additive.

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

[0029]

[0030] In the above preparation method, the aromatic amine, the aliphatic amine, the palladium trifluoroacetate and the triethylamine are generally commercially available products, which can be conveniently obtained from the market, the trifluoroethyl imine hydrazide can be obtained from trifluoroethyl imine chloride and hydrazine hydrate in almost quantitative yield, and the trifluoroethyl imine chloride can be quickly synthesized from the corresponding aromatic amine, triphenylphosphine, carbon tetrachloride and trifluoroacetic acid.

[0031] Compared with the prior art, the preparation method has the advantages that the preparation method is easy to operate and the post-treatment is simple; the reaction starting materials are cheap and easy to obtain; elemental sulfur is odorless and non-toxic; the reaction substrate has strong designability; the functional group tolerance range of the substrate is wide; 1,2,4-triazole compounds with different 3,4-position substitutions, trifluoromethyl groups and various aryl groups or alkyl groups can be designed and synthesized according to actual needs, and the practicability is relatively strong. DETAILED DESCRIPTION

[0032] The application will be further described below in combination with specific examples.

[0033] According to the raw material ratio in Table 1, elemental sulfur, trifluoroethyl imine hydrazide (II), aliphatic amine (III) and 1 mL of organic solvent are added in a 35 mL Schlenk tube, uniformly mixed and stirred, reacted for 16-24 hours according to the reaction conditions in Table 2, filtered, silica gel sample is mixed, and the corresponding 5-trifluoromethyl-substituted 1,2,4-triazole compound (I) is obtained by column chromatography purification. The reaction process is as shown in the following formula:

[0034]

[0035] Table 1: Raw material addition amount of examples 1-15

[0036]

[0037] Table 2

[0038]

[0039]

[0040] In Table 1 and Table 2, T is the reaction temperature, t is the reaction time, Ph is phenyl, Me is methyl, OMe is methoxy, t-Bu is tert-butyl, CN is cyano, and DMSO is dimethyl sulfoxide.

[0041] The structure confirmation data of the compounds prepared in examples 1-5 are as follows:

[0042] The nuclear magnetic resonance (NMR) data of the 5-trifluoromethyl-substituted 1,2,4-triazole compound (I-1) prepared from example 1 are as follows: 1 H NMR, 13 C NMR and 19F NMR) detection data are:

[0043]

[0044] 1 H NMR (400 MHz, CDC13) δ 7.46 - 7.41 (m, 2H), 7.37 (d, J = 2.6 Hz, 1H), 7.33 - 7.27 (m, 4H), 7.15 (d, J = 8.3 Hz, 2H), 2.44 (s, 3H).

[0045] 13 C NMR (101 MHz, CDC13) δ 156.8, 145.9 (C-F, q, 2 J (C-F) 38.8 Hz), 141.1, 130.6, 130.4, 128.7, 128.7, 127.1, 125.4, 122.3, 118.2 (C-F, q, 1 J (C-F) = 271.2 Hz), 21.4.

[0046] 19 F NMR (377 MHz, CDC13) δ -61.0.

[0047] M.p. 161.5 - 162.6 °C

[0048] The 5-trifluoromethyl substituted 1,2,4-triazole compound (1-2) prepared from Example 2 was subjected to NMR (1H NMR, 1 H NMR, 13 C NMR and 19 F NMR) detection data are:

[0049]

[0050] 1 H NMR (400 MHz, CDC13) δ 7.65 (d, J = 8.6 Hz, 2H), 7.42 (d, J = 7.5 Hz, 3H), 7.35 (d, J = 7.1 Hz, 2H), 7.17 (d, J = 8.5 Hz, 2H).

[0051] 13 C NMR (101 MHz, CDC13) δ 156.7, 145.7 (C-F, q, 2 J (C-F)= 40.7 Hz), 133.4, 132.05, 130.9, 128.9, 128.9, 128.8, 125.2, 124.9, 122.1, 119.4, 116.8.

[0052] 19 F NMR (377 MHz, CDC13) δ -60.5.

[0053] M.p. 175.6-177.8 °C

[0054] The 5-trifluoromethyl substituted 1,2,4-triazole compound (I-3) prepared from Example 3 was tested for NMR (1H,13C and19F) data: 1 H NMR, 13 C NMR and 19 F NMR) detection data:

[0055]

[0056] 1 H NMR (400 MHz, CDC13) δ 7.39 (d, J = 8.7 Hz, 2H), 7.28 (d, J = 8.7 Hz, 2H), 7.19 (d, J = 8.9 Hz, 2H), 7.00 (d, J = 8.9 Hz, 2H), 3.88 (s, 3H).

[0057] 13 C NMR (101 MHz, CDC13) δ 161.1, 155.9, 146.2 (C-F, q, J = 38.9 Hz), 137.0, 129.9, 129.1, 128.5, 125.1, 123.9, 118.1 (C-F, q, J = 271.3 Hz), 115.2, 55.7. 2 J (C-F) = 38.9 Hz), 137.0, 129.9, 129.1, 128.5, 125.1, 123.9, 118.1 (C-F, q, J = 271.3 Hz), 115.2, 55.7. 1 J (C-F) = 271.3 Hz), 115.2, 55.7.

[0058] 19 F NMR (377 MHz, CDC13) δ -61.2.

[0059] M.p. 145.5-147.2 °C.

[0060] The 5-trifluoromethyl substituted 1,2,4-triazole compound (I-4) prepared from Example 4 was tested for NMR (1H,13C and19F) data: 1 H NMR, 13 C NMR and 19 F NMR) detection data:

[0061]

[0062] 1 H NMR (400 MHz, CDC13) δ 7.35 - 7.23 (m, 4H), 7.14 (s, 1H), 7.06 (d, J = 8.8 Hz, 2H), 3.92 (s, 3H).

[0063] 13 C NMR (101 MHz, CDC13) δ 161.3, 153.4, 145.4 (C-F, q, J = 38.7 Hz), 128.8, 127.1, 126.7, 126.4, 126.2, 125.2, 118.2 (C-F, q, J = 271.1 Hz), 115.3, 55.7. 2 J (C-F) = 38.7 Hz), 128.8, 127.1, 126.7, 126.4, 126.2, 125.2, 118.2 (C-F, q, J = 271.1 Hz), 115.3, 55.7. 1 J (C-F) = 271.1 Hz), 115.3, 55.7.

[0064] 19 F NMR (377 MHz, CDC13) δ -61.3.

[0065] M.p. 129.5 - 132.6 °C.

[0066] HRMS (ESI): [M+H] + calcd. for C 14 H 11 F3N3OS + 326.0569, found 326.0574.

[0067] The 5-trifluoromethyl substituted 1,2,4-triazole compound (1-5) prepared from Example 5 had the following NMR (1H,13C and19F) test data: 1 H NMR, 13 C NMR and 19 F NMR) detection data:

[0068]

[0069] 1 H NMR (400 MHz, CDC13) δ 7.15 (d, J = 8.9 Hz, 2H), 7.01 (d, J = 8.9 Hz, 2H), 3.86 (s, 3H), 2.57 - 2.49 (m, 2H), 1.69 - 1.57 (m, 2H), 1.25 - 1.18 (m, 4H), 0.79 (t, J = 6.9 Hz, 3H).

[0070] 13C NMR (101 MHz, CDC13) δ 161.0, 158.8, 145.0 (C-F, q, J = 37.0 Hz), 128.3, 124.5, 118.2 (C-F, q, J = 38.6 Hz), 115.0, 55.6, 31.2, 26.8, 24.6, 22.1, 13.7. 2 J (C-F) = 270.9 Hz), 115.0, 55.6, 31.2, 26.8, 24.6, 22.1, 13.7. 1 J (C-F) = 270.9 Hz), 115.0, 55.6, 31.2, 26.8, 24.6, 22.1, 13.7.

[0071] 19 F NMR (377 MHz, CDC13) δ -61.6.

[0072] HRMS (ESI): [M + H] calculated for C + calcd. for C 10 H9F3N3 314.1488, found 314.1480.

Claims

1. A process for the preparation of a 5-trifluoromethyl substituted 1,2,4-triazole compound involving a fatty amine, characterized in that, comprising the steps of: adding elemental sulfur, trifluoroethyl imine hydrazide and aliphatic amine into an organic solvent, and reacting at 110-130 o C reacts for 16-24 hours, after the reaction is complete, the post-processing obtains the 5-trifluoromethyl substituted 1,2,4-triazole compound; The structure of the trifluoroethyl imine hydrazide is shown in formula (II): (I) The structure of the fatty amine is shown in formula (III): (III) The structure of the 5-trifluoromethyl substituted 1,2,4-triazole compound is shown in formula (I): （Ⅰ） In formulae (I) to (III), R 1 is a substituted or unsubstituted phenyl group; The substituent on the phenyl group is selected from methyl, tert-butyl, methoxy, fluorine, bromine, chlorine or cyano; R 2 is n-pentyl, n-heptyl, substituted or unsubstituted phenyl, naphthyl, furanyl or thienyl; The substituent on the phenyl group is selected from methyl, methoxy, chlorine or bromine; The organic solvent is dimethyl sulfoxide; The molar ratio of trifluoroethyl imine hydrazide, fatty amine and elemental sulfur is 1:2~3: 2~4.

2. The process for preparing a 5-trifluoromethyl substituted 1,2,4-triazole compound according to claim 1, characterized by, The 5-trifluoromethyl substituted 1,2,4-triazole compound is one of the compounds shown in formula (I-1) to formula (I-5): 。

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