A process for the preparation of a trifluoromethyl substituted dihydroquinoxaline compound

Abstract

This invention discloses a method for preparing a trifluoromethyl-substituted dihydroquinoxaline compound, comprising the following steps: adding diisopropylethylamine, trifluoroacetylimine ylide, and azo ester to an organic solvent in an air atmosphere, reacting at 60–100°C for 20–30 hours, and after complete reaction, post-treatment to obtain the trifluoromethyl-substituted dihydroquinoxaline compound. This preparation method is simple to operate, uses inexpensive and readily available starting materials, can be carried out in an air atmosphere, utilizes inexpensive and non-toxic diisopropylethylamine, and eliminates the need for heavy metal catalysts. The reaction can also be scaled up to the gram level, facilitating operation and broadening the applicability of the method.

Description

Technical Field

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

[0002] Dihydroquinoxaline compounds are an important class of benzo[a] nitrogen-containing heterocyclic compounds with excellent biological activities, such as anticancer, antifungal, anti-inflammatory, antitumor, and antiviral activities (J.Med.Chem.2007,50,2301). Dihydroquinoxaline molecules have been used as potential drugs for treating HIV infection and allergic diseases (J.Med.Chem.2002,45,2970); they can also be used to detect food residues to monitor food safety (Chem.Eur.J.2017,23,14911). Introducing a trifluoromethyl group into the heterocyclic molecule can significantly improve the physicochemical properties and efficacy of the parent compound. Therefore, developing simple and efficient methods for preparing trifluoromethyl-substituted dihydroquinoxaline compounds has significant research and application value.

[0003]

[0004] Traditional methods for synthesizing dihydroquinoxaline compounds include multi-component condensation reactions of ketones, amines, and isocyanates, as well as asymmetric hydrogenation reactions of substituted quinoxaline compounds; copper-catalyzed coupling reactions of amino acids with substituted anilines; and polarity reversal reactions of amidines catalyzed by azacarbenes. However, these traditional methods generally suffer from low overall reaction efficiency, demanding reaction conditions, and poor product structural diversity. Moreover, efficient synthetic methods for specially functionalized trifluoromethyl-substituted dihydroquinoxaline compounds are rare.

[0005] Based on this, we have developed a simple, efficient and easy-to-operate method for synthesizing trifluoromethyl-substituted dihydroquinoxaline compounds using inexpensive and readily available trifluoroacetylimine thioylide and azo ester as starting materials, diisopropylethylamine as a promoter, and without the involvement of heavy metals. Summary of the Invention

[0006] This invention provides a method for preparing trifluoromethyl-substituted dihydroquinoxaline compounds. The preparation method is simple, the starting materials are inexpensive and readily available, and the common organic base diisopropylethylamine is used as a promoter. At the same time, the use of heavy metal catalysts is avoided, and the reaction is carried out in an air atmosphere, which facilitates subsequent large-scale operation and application.

[0007] A method for preparing a trifluoromethyl-substituted dihydroquinoxaline compound includes the following steps: adding diisopropylethylamine, trifluoroacetylimine thioylide and azo ester to an organic solvent, reacting at 60-100°C for 20-30 hours, and after the reaction is complete, post-treatment to obtain the trifluoromethyl-substituted dihydroquinoxaline compound.

[0008] The structure of the trifluoroacetylimine thioyl ylide is shown in formula (II):

[0009]

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

[0011]

[0012] The structure of the trifluoromethyl-substituted dihydroquinoxaline compound is shown in formula (Ⅰ):

[0013]

[0014] In equations (I) to (III), R 1 H, C1-C4 alkyl, C1-C4 alkoxy, methylthio, halogen, or trifluoromethyl; R 2 It is a C1-C4 alkyl group, benzyl group;

[0015] The reaction formula is as follows:

[0016]

[0017] The reaction may first involve trifluoroacetylimine thioylide attacking azodiethyl ester as a nucleophile to form hydrazine, which then undergoes an intramolecular nucleophilic substitution reaction to give a three-membered ring diazacyclopropane intermediate. Subsequently, an intramolecular Friedel-Crafts-like reaction occurs, along with nitrogen-nitrogen bond breaking and protonation processes, to give the final target product, dihydroquinoxaline.

[0018] In this invention, the optional post-processing steps include: filtration, silica gel mixing, and finally purification by column chromatography to obtain the corresponding trifluoromethyl-substituted dihydroquinoxaline compound. Column chromatography purification is a commonly used technique in this field.

[0019] As a preferred option, R 1 The solvent is H, methyl, isopropyl, tert-butyl, methoxy, methylthio, F, Cl, Br, or trifluoromethyl. In this case, the trifluoroacetylimine thioylide is readily available, and the reaction yield is high.

[0020] As a preferred option, R 2 It can be ethyl, isopropyl, or benzyl. In this case, the azo ester compound is readily available.

[0021] The azo ester is readily available and can be easily obtained through commercial purchase. It is used in excess of the trifluoroacetylimide ylide. Preferably, the molar ratio of trifluoroacetylimide ylide: azo ester: diisopropylethylamine is 1:2-4:1-3; more preferably, the molar ratio of trifluoroacetylimide ylide: azo ester: diisopropylethylamine is 1:3:2.

[0022] 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 tetrahydrofuran, toluene, or acetonitrile. More preferably, tetrahydrofuran is the most suitable organic solvent, in which case various raw materials can be converted into products with a high conversion rate.

[0023] 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 trifluoroacetylimine ylide is approximately 5 to 10 mL.

[0024] Preferably, the accelerator is diisopropylethylamine, as the reaction efficiency is high when diisopropylethylamine is used as the accelerator.

[0025] As a further preferred embodiment, the trifluoromethyl-substituted dihydroquinoxaline compound is one of the compounds shown in formulas (I-1) to (I-5):

[0026]

[0027] In the above preparation method, the aromatic amine, trifluoroacetic acid, iodomethyl sulfoxide, triethylamine, and diisopropylethylamine are generally commercially available products that can be easily obtained from the market. The azo ester can be purchased directly. The trifluoroacetylimine ylide can be obtained by reacting trifluoroethylimine acyl chloride with iodomethyl sulfoxide. The trifluoroethylimine acyl chloride can be rapidly synthesized from the corresponding aromatic amine, triphenylphosphine, carbon tetrachloride, and trifluoroacetic acid.

[0028] Compared with the prior art, the advantages of the present invention are: the preparation method is easy to operate and the post-processing is simple; the reaction is carried out in air at room temperature without the need for nitrogen protection; the starting materials are easy to prepare, diisopropylethylamine is cheap and non-toxic, the reaction substrate is highly designable, the substrate functional group range is wide, and different substituted dihydroquinoxaline compounds with trifluoromethyl groups can be designed and synthesized according to actual needs, which is highly practical. Detailed Implementation

[0029] The present invention will be further described below with reference to specific embodiments.

[0030] According to the raw material ratio in Table 1, add diisopropylethylamine, trifluoroacetylimine ylide (II), azo ester (III), and 2 mL of organic solvent to a 35 mL Schlenk tube, mix and stir thoroughly, and react for 20-30 hours according to the reaction conditions in Table 2. Filter, mix with silica gel, and purify by column chromatography to obtain the corresponding trifluoromethyl-substituted dihydroquinoxaline compound (I). The reaction process is shown in the following formula:

[0031]

[0032] Table 1. Raw material addition amounts for Examples 1-15

[0033]

[0034] a: The entire assembly is replaced with 2-naphthyl or 1-naphthyl.

[0035] Table 2

[0036]

[0037]

[0038] In Tables 1 and 2, T represents the reaction temperature, t represents the reaction time, Ph represents phenyl, Me represents methyl, Et represents ethyl, i-Pr represents isopropyl, t-Bu represents tert-butyl, OMe represents methoxy, Bn represents benzyl, and THF represents tetrahydrofuran.

[0039] Structural confirmation data of the compounds prepared in Examples 1-5:

[0040] Nuclear magnetic resonance (NMR) of the trifluoromethyl-substituted dihydroquinoxaline compound (I-1) prepared in Example 1 1 HNMR, 13 C NMR and 19 The F NMR detection data are as follows:

[0041]

[0042] 1 H NMR (400MHz, CDCl3) δ7.87(d,J=8.0Hz,1H),7.61(d,J=7.8Hz,1H),7.42(t,J=7.5Hz,1H),7.26(t,J=7.5Hz,1H),6.9 2(s,1H),5.29(s,1H),4.40-4.33(m,2H),4.10(dd,J=13.3,6.3Hz,2H),1.38(t,J=7.1Hz,3H),1.18(t,J=7.1Hz,3H).

[0043] 13 C NMR (101MHz, CDCl3) δ154.2, 152.7, 148.7 (t, J = 35.5Hz), 133.7, 130.7, 128.7, 127.6, 125.2, 123.5, 119.3 (d, J = 276.6Hz), 63.6, 62.0, 52.9, 14.3.

[0044] 19 F NMR (377MHz, CDCl3) δ-70.8.

[0045] HRMS(ESI):[M+H] + calcd.for C 15 H 17 F3N3O4 + 360.1166, found 360.1180.

[0046] Nuclear magnetic resonance (NMR) of the trifluoromethyl-substituted dihydroquinoxaline compound (I-2) prepared in Example 2 1 HNMR, 13 C NMR and 19 The F NMR detection data are as follows:

[0047]

[0048] 1 H NMR (400MHz, CDCl3) δ7.48(d,J=8.8Hz,1H),7.45(s,1H),6.86(s,1H),6.79-6.76(m,1H),5.42(d,J=9.2Hz ,1H),4.37-4.34(m,2H),4.10(q,J=7.1Hz,2H),3.84(s,3H),1.38(t,J=7.1Hz,3H),1.18(t,J=7.1Hz,3H).

[0049] 13 C NMR (101MHz, CDCl3) δ161.4, 154.4, 152.9, 145.4 (q, J = 35.4Hz), 130.0, 129. 1,127.9,119.6(q,J=276.2Hz),111.7,108.3,63.7,62.0,55.7,53.0,14.4.

[0050] 19 F NMR (377MHz, CDCl3) δ -71.0.

[0051] HRMS(ESI):[M+H]+ calcd.for C 16 H 19 F3N3O5 + 390.1271, found 390.1280.

[0052] Nuclear magnetic resonance (NMR) of the trifluoromethyl-substituted dihydroquinoxaline compound (I-3) prepared in Example 3 1 HNMR, 13 C NMR and 19 The F NMR detection data are as follows:

[0053]

[0054] 1 H NMR (400MHz, CDCl3) δ7.68(d,J=10.4Hz,1H),7.59(t,J=7.3Hz,1H),6.99-6.97(m,1H),6.83(s,1H),5.35( d,J=9.0Hz,1H),4.39(q,J=6.8Hz,2H),4.10(q,J=6.9Hz,2H),1.40(t,J=7.1Hz,3H),1.18(t,J=7.1Hz,3H).

[0055] 13 C NMR (101MHz, CDCl3) δ164.8,162.3,154.3,152.7,147.4(d,J=38.6Hz),130.6(d,J=10.2Hz),1 29.5, 120.8 (q, J = 276.6Hz), 112.6 (d, J = 23.2Hz), 110.6 (d, J = 28.6Hz), 64.1, 62.2, 53.0, 14.4.

[0056] 19 F NMR (377MHz, CDCl3) δ-70.6,-106.6.

[0057] MPa 135.8.6-136.4℃.

[0058] HRMS(ESI):[M+H] + calcd.for C 15 H 16 F4N3O4 + 378.1071, found 378.1079.

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

[0060]

[0061] 1 H NMR (400MHz, CDCl3) δ7.75(s,1H),7.41(d,J=8.0Hz,1H),7.00(d,J=7.9Hz,1H),6.86(s,1H),5.27(s,1H),2.39(s,3H),1.57(s,9H),1.39(s,9H).

[0062] 13 C NMR (101MHz, CDCl3) δ152.1, 150.4, 147.0 (q, J = 35.3Hz), 140.1, 130.7, 127. 4,127.0,124.7,122.8,118.6(d,J=276.4Hz),82.8,51.7,27.2,27.1,20.9.

[0063] 19 F NMR (377MHz, CDCl3) δ-70.9.

[0064] MPa 131.4-132.2℃.

[0065] HRMS(ESI):[M+H] + calcd.for C 20 H 27 F3N3O4 + 430.1948, found 430.1956.

[0066] Nuclear magnetic resonance (NMR) of the trifluoromethyl-substituted dihydroquinoxaline compound (I-5) prepared in Example 5 1 HNMR, 13 C NMR and 19 The F NMR detection data are as follows:

[0067]

[0068] 1H NMR(400MHz,CDCl3)δ7.66(s,1H),7.45(t,J=8.2Hz,2H),7.40-7.35(m,4H),7.33(d,J=6.2Hz,3H),7.29-7.26(m,2H),7.05(d,J=7.9Hz,1H),6.97(s,1H),5.40-5.31(m,3H),5.08(s,2H),2.37(s,3H).

[0069] 13 C NMR(101MHz,CDCl3)δ154.1,152.7,147.4(d,J=35.4Hz),141.6,135.6,135.2,131.8,128.8,128.7,128.5,128.4,127.2,126.5,124.0,119.5(q,J=276.4Hz).69.1,67.8,53.1,21.9.

[0070] 19 F NMR(377MHz,CDCl3)δ-70.7.

[0071] M.p.81.4-82.2℃.

[0072] HRMS(ESI):[M+H] + calcd.for C 26 H 23 F3N3O4 + 498.1635,found 498.1640。

Claims

1. A method for preparing a trifluoromethyl-substituted dihydroquinoxaline compound, characterized in that, The process includes the following steps: adding the accelerator, trifluoroacetylimine ylide and azo ester into an organic solvent, reacting at 60-100°C for 20-30 hours, and after the reaction is complete, post-treatment is performed to obtain the trifluoromethyl-substituted dihydroquinoxaline compound. The structure of the trifluoroacetylimine thioyl ylide is shown in formula (II): The structure of the azo ester is shown in formula (III): The structure of the trifluoromethyl-substituted dihydroquinoxaline compound is shown in formula (Ⅰ): In equations (I) to (III), R 1 H, C1-C4 alkyl, C1-C4 alkoxy, methylthio, halogen, or trifluoromethyl; R 2 It is a C1-C4 alkyl or benzyl group; The accelerator is diisopropylethylamine.

2. The method for preparing the trifluoromethyl-substituted dihydroquinoxaline compound according to claim 1, characterized in that, R 1 It can be H, methyl, isopropyl, tert-butyl, methoxy, methylthio, F, Cl, Br, or trifluoromethyl.

3. The method for preparing the trifluoromethyl-substituted dihydroquinoxaline compound according to claim 1, characterized in that, R 2 It can be ethyl, isopropyl, or benzyl.

4. The method for preparing the trifluoromethyl-substituted dihydroquinoxaline compound according to claim 1, characterized in that, The organic solvent is tetrahydrofuran.

5. The method for preparing the trifluoromethyl-substituted dihydroquinoxaline compound according to claim 1, characterized in that, In molar amounts, the ratio of trifluoroacetylimide ylide: azo ester: accelerator is 1:2-4:1-3.

6. The method for preparing the trifluoromethyl-substituted dihydroquinoxaline compound according to claim 1, characterized in that, The trifluoromethyl-substituted dihydroquinoxaline compound is one of the compounds shown in formulas (I-1) to (I-5):

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