CN117402119A - Preparation method of trifluoromethyl substituted dihydroquinoxaline compound - Google Patents
Preparation method of trifluoromethyl substituted dihydroquinoxaline compound Download PDFInfo
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- CN117402119A CN117402119A CN202311166467.9A CN202311166467A CN117402119A CN 117402119 A CN117402119 A CN 117402119A CN 202311166467 A CN202311166467 A CN 202311166467A CN 117402119 A CN117402119 A CN 117402119A
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- dihydroquinoxaline
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- -1 dihydroquinoxaline compound Chemical class 0.000 title claims abstract description 42
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title abstract description 10
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims abstract description 26
- 238000006243 chemical reaction Methods 0.000 claims abstract description 23
- SYWIXHZXHQDFOO-UHFFFAOYSA-N methyl n-phenyliminocarbamate Chemical compound COC(=O)N=NC1=CC=CC=C1 SYWIXHZXHQDFOO-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000003960 organic solvent Substances 0.000 claims abstract description 10
- 238000000034 method Methods 0.000 claims abstract description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 claims description 9
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 8
- 150000002466 imines Chemical class 0.000 claims description 8
- 229910052717 sulfur Inorganic materials 0.000 claims description 8
- 239000011593 sulfur Substances 0.000 claims description 8
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 2
- HWCKGOZZJDHMNC-UHFFFAOYSA-M tetraethylammonium bromide Chemical compound [Br-].CC[N+](CC)(CC)CC HWCKGOZZJDHMNC-UHFFFAOYSA-M 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 5
- 239000002994 raw material Substances 0.000 abstract description 8
- 229910001385 heavy metal Inorganic materials 0.000 abstract description 3
- 239000003054 catalyst Substances 0.000 abstract description 2
- 231100000252 nontoxic Toxicity 0.000 abstract description 2
- 230000003000 nontoxic effect Effects 0.000 abstract description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 35
- XXBQLHATYQHJQC-UHFFFAOYSA-N 1,2-dihydroquinoxaline Chemical class C1=CC=C2N=CCNC2=C1 XXBQLHATYQHJQC-UHFFFAOYSA-N 0.000 description 7
- 238000001514 detection method Methods 0.000 description 5
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 150000001263 acyl chlorides Chemical class 0.000 description 2
- 150000004982 aromatic amines Chemical class 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- HMUNWXXNJPVALC-UHFFFAOYSA-N 1-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C(CN1CC2=C(CC1)NN=N2)=O HMUNWXXNJPVALC-UHFFFAOYSA-N 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- WZFUQSJFWNHZHM-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)CC(=O)N1CC2=C(CC1)NN=N2 WZFUQSJFWNHZHM-UHFFFAOYSA-N 0.000 description 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- CONKBQPVFMXDOV-QHCPKHFHSA-N 6-[(5S)-5-[[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]methyl]-2-oxo-1,3-oxazolidin-3-yl]-3H-1,3-benzoxazol-2-one Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C[C@H]1CN(C(O1)=O)C1=CC2=C(NC(O2)=O)C=C1 CONKBQPVFMXDOV-QHCPKHFHSA-N 0.000 description 1
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 1
- 208000031886 HIV Infections Diseases 0.000 description 1
- 208000037357 HIV infectious disease Diseases 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 150000001409 amidines Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 150000001448 anilines Chemical class 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- DIXBSCZRIZDQGC-UHFFFAOYSA-N diaziridine Chemical compound C1NN1 DIXBSCZRIZDQGC-UHFFFAOYSA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000010794 food waste Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 1
- MLRAALKFHIREQS-UHFFFAOYSA-N iodo(iodomethylsulfinyl)methane Chemical compound ICS(=O)CI MLRAALKFHIREQS-UHFFFAOYSA-N 0.000 description 1
- 150000002527 isonitriles Chemical class 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012434 nucleophilic reagent Substances 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 230000005588 protonation Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000001567 quinoxalinyl group Chemical class N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
- C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
- C07D241/40—Benzopyrazines
- C07D241/42—Benzopyrazines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of trifluoromethyl substituted dihydroquinoxaline compound, which comprises the following steps: in the air atmosphere, diisopropylethylamine, trifluoroacetyl imine thioylide and azo ester are added into an organic solvent to react for 20-30 hours at 60-100 ℃, and after the reaction is completed, the trifluoromethyl substituted dihydroquinoxaline compound is obtained by post-treatment. The preparation method is simple to operate, the initial raw materials are cheap and easy to obtain, the reaction can be carried out in an air atmosphere, the diisopropylethylamine is cheap and nontoxic, a heavy metal catalyst is not required to be used, the reaction can be expanded to gram level, and the method is convenient to operate and broadens the applicability.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a preparation method of trifluoromethyl substituted dihydroquinoxaline compounds.
Background
Dihydroquinoxaline compounds are an important class of benzonitrogenous heterocycles with excellent biological activity, such as anti-cancer, anti-fungal, anti-inflammatory, anti-tumor and anti-viral activity (j.med.chem.2007, 50,2301); dihydroquinoxaline molecules have been used as potential drugs for the treatment of HIV infection and allergic diseases (j.med. Chem.2002,45,2970); it can also be used to detect food residues to monitor food safety (chem.eur.j.2017, 23,14911). The introduction of trifluoromethyl groups in heterocyclic molecules can significantly improve the physicochemical properties and pharmacodynamics of the parent compound. Therefore, the development of a simple and efficient preparation method of the trifluoromethyl substituted dihydroquinoxaline compound has important research significance and application value.
Traditional methods of synthesizing dihydroquinoxaline compounds are multicomponent condensation reactions of ketones, amines and isocyanides, and asymmetric hydrogenation reactions of substituted quinoxaline compounds; there is also a copper-catalyzed coupling reaction of amino acids with substituted anilines and an aza-carbene-catalyzed polarity reversal reaction of amidines. However, the traditional method generally has the defects of low overall reaction efficiency, more severe reaction conditions, poor structural diversity of products and the like. Furthermore, for particularly functionalized trifluoromethyl-substituted dihydroquinoxaline compounds, efficient synthetic methods are not unusual.
Based on the method, a synthesis method of trifluoromethyl substituted dihydroquinoxaline compound which takes low-cost and easily available trifluoroacetyl imine sulfur ylide and azo ester as initial raw materials and diisopropylethylamine as an accelerator and has no heavy metal participation is developed.
Disclosure of Invention
The invention provides a preparation method of trifluoromethyl substituted dihydroquinoxaline compound, which has the advantages of simple steps, low cost and easy acquisition of initial raw materials, and the adoption of common organic base diisopropylethylamine as an accelerator, the use of heavy metal catalysts is avoided, and the reaction is carried out in an air atmosphere, so that the subsequent large-scale operation and application are facilitated.
A process for the preparation of trifluoromethyl substituted dihydroquinoxaline compounds comprising the steps of: adding diisopropylethylamine, trifluoroacetimidide ylide and azo ester into an organic solvent, reacting for 20-30 hours at 60-100 ℃, and after the reaction is completed, carrying out post-treatment to obtain the trifluoromethyl substituted dihydroquinoxaline compound;
the structure of the trifluoroacetyl imine sulfur ylide is shown as a formula (II):
the structure of the azo ester is shown as a formula (III):
the trifluoromethyl substituted dihydroquinoxaline compound has a structure shown in a formula (I):
in the formulae (I) to (III), R 1 H, C of a shape of H, C 1 ～C 4 Alkyl, C 1 ～C 4 Alkoxy, methylthio, halogen or trifluoromethyl; r is R 2 Is C 1 ～C 4 Alkyl, benzyl;
the reaction formula is as follows:
in the reaction, trifluoroacetyl imine sulfur ylide is taken as a nucleophilic reagent to attack azodiethyl ester to form hydrazine, the hydrazine takes place in the nucleophilic substitution reaction in the molecule to obtain a triad ring diazacyclopropane intermediate, then similar Friedel-crafts reaction in the molecule takes place, and simultaneously, nitrogen-nitrogen bond rupture and protonation process take place to obtain the final target dihydroquinoxaline product.
In the invention, the optional post-treatment process comprises: filtering, mixing with silica gel, and purifying by column chromatography to obtain corresponding trifluoromethyl substituted dihydroquinoxaline compound, wherein column chromatography purification is a common technical means in the field.
Preferably, R 1 Is H, methyl, isopropyl, tertiary butyl, methoxy, methylthio, F, cl, br or trifluoromethyl. At this time, the trifluoroacetyl iminosulfideYlide is readily available and the yield of the reaction is high.
Preferably, R 2 Is ethyl, isopropyl or benzyl. In this case, the azo ester compound is easily obtained.
The azo esters are relatively readily available and can be readily obtained by commercial purchase in an excess of the trifluoroacetyl imine thioylide, preferably on a molar basis: azo esters: diisopropylethylamine=1:2 to 4:1 to 3; as a further preferred, the trifluoroacetyl imine thioylide: azo esters: diisopropylethylamine=1:3:2.
In the invention, the organic solvent which can fully dissolve the raw materials can cause the reaction to occur, but the reaction efficiency is greatly different, preferably aprotic solvent which can effectively promote the reaction; preferably, the organic solvent is tetrahydrofuran, toluene or acetonitrile; as a further preference, the organic solvent is tetrahydrofuran, in which case the various starting materials can be converted into the product at a relatively high conversion.
The amount of the organic solvent can be used for better dissolution of the raw materials, and the amount of the organic solvent used by 1mmol of trifluoroacetyl imine sulfur ylide is about 5-10 mL.
Preferably, the accelerator is diisopropylethylamine, and the reaction efficiency is high when diisopropylethylamine is used as the accelerator.
As a further preference, the trifluoromethyl substituted dihydroquinoxaline compound is one of the compounds of formula (I-1) -formula (I-5):
in the preparation method, the aromatic amine, the trifluoroacetic acid, the iodomethyl sulfoxide, the triethylamine and the diisopropylethylamine are generally commercially available products and can be conveniently obtained from the market, and the azo ester can be directly purchased; the trifluoroacetyl imine sulfur ylide can be obtained by reacting trifluoro ethyl imine acyl chloride with methyl iodide sulfoxide; and the trifluoro ethylimide acyl chloride can be obtained by the rapid synthesis of corresponding aromatic amine, triphenylphosphine, carbon tetrachloride and trifluoroacetic acid.
Compared with the prior art, the invention has the advantages that: the preparation method is easy to operate and simple and convenient in post-treatment; the reaction is carried out in the air at room temperature without nitrogen protection; the reaction initial raw materials are easy to prepare, the diisopropylethylamine is cheap and nontoxic, the designability of the reaction substrate is strong, the range of the substrate functional groups is wide, different substituted dihydro quinoxaline compounds with trifluoromethyl can be designed and synthesized according to actual needs, and the practicability is strong.
Detailed Description
The invention is further described below in connection with specific embodiments.
According to the raw material ratio of Table 1, adding diisopropylethylamine, trifluoroacetyl imine sulfur ylide (II), azo ester (III) and 2mL of organic solvent into a 35mL Schlenk tube, mixing and stirring uniformly, reacting for 20-30 hours according to the reaction conditions of Table 2, filtering, stirring a sample on silica gel, and purifying by column chromatography to obtain a corresponding trifluoromethyl substituted dihydroquinoxaline compound (I), wherein the reaction process is shown in the following formula:
TABLE 1 amounts of raw materials to be added in examples 1 to 15
a：The whole is replaced by 2-naphthyl or 1-naphthyl respectively.
TABLE 2
In tables 1 and 2, T is the reaction temperature, T is the reaction time, ph is phenyl, me is methyl, et is ethyl, i-Pr is isopropyl, T-Bu is T-butyl, OMe is methoxy, bn is benzyl, and THF is tetrahydrofuran.
Structure confirmation data for the compounds prepared in examples 1 to 5:
nuclear magnetic resonance of trifluoromethyl-substituted dihydroquinoxaline Compound (I-1) obtained in example 1 1 H NMR、 13 C NMR 19 F NMR) detection data were:
1 H NMR(400MHz,CDCl 3 )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),6.92(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).
13 C NMR(101MHz,CDCl 3 )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.
19 F NMR(377MHz,CDCl 3 )δ-70.8.
HRMS(ESI):[M+H] + calcd.for C 15 H 17 F 3 N 3 O 4 + 360.1166,found 360.1180.
nuclear magnetic resonance of trifluoromethyl-substituted dihydroquinoxaline Compound (I-2) obtained in example 2 1 H NMR、 13 C NMR 19 F NMR) detection data were:
1 H NMR(400MHz,CDCl 3 )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).
13 C NMR(101MHz,CDCl 3 )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.
19 F NMR(377MHz,CDCl 3 )δ-71.0.
HRMS(ESI):[M+H] + calcd.for C 16 H 19 F 3 N 3 O 5 + 390.1271,found 390.1280.
nuclear magnetic resonance of trifluoromethyl-substituted dihydroquinoxaline Compound (I-3) obtained in example 3 1 H NMR、 13 C NMR 19 F NMR) detection data were:
1 H NMR(400MHz,CDCl 3 )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).
13 C NMR(101MHz,CDCl 3 )δ164.8,162.3,154.3,152.7,147.4(d,J＝38.6Hz),130.6(d,J＝10.2Hz),129.5,120.8(q,J＝276.6Hz),112.6(d,J＝23.2Hz),110.6(d,J＝28.6Hz),64.1,62.2,53.0,14.4.
19 F NMR(377MHz,CDCl 3 )δ-70.6,-106.6.
M.p.135.8.6-136.4℃.
HRMS(ESI):[M+H] + calcd.for C 15 H 16 F 4 N 3 O 4 + 378.1071,found 378.1079.
nuclear magnetic resonance of trifluoromethyl-substituted dihydroquinoxaline Compound (I-4) obtained in example 4 1 H NMR、 13 C NMR 19 F NMR) detection data were:
1 H NMR(400MHz,CDCl 3 )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).
13 C NMR(101MHz,CDCl 3 )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.
19 F NMR(377MHz,CDCl 3 )δ-70.9.
M.p.131.4-132.2℃.
HRMS(ESI):[M+H] + calcd.for C 20 H 27 F 3 N 3 O 4 + 430.1948,found 430.1956.
nuclear magnetic resonance of trifluoromethyl-substituted dihydroquinoxaline Compound (I-5) obtained in example 5 1 H NMR、 13 C NMR 19 F NMR) detection data were:
1 H NMR(400MHz,CDCl 3 )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).
13 C NMR(101MHz,CDCl 3 )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.
19 F NMR(377MHz,CDCl 3 )δ-70.7.
M.p.81.4-82.2℃.
HRMS(ESI):[M+H] + calcd.for C 26 H 23 F 3 N 3 O 4 + 498.1635,found 498.1640。
Claims (7)
1. a method for preparing a trifluoromethyl substituted dihydroquinoxaline compound, comprising the steps of: adding an accelerator, trifluoroacetyl imine sulfur ylide and azo ester into an organic solvent, reacting for 20-30 hours at 60-100 ℃, and after the reaction is completed, performing post-treatment to obtain the trifluoromethyl substituted dihydroquinoxaline compound;
the structure of the trifluoroacetyl imine sulfur ylide is shown as a formula (II):
the structure of the azo ester is shown as a formula (III):
the trifluoromethyl substituted dihydroquinoxaline compound has a structure shown in a formula (I):
in the formulae (I) to (III), R 1 H, C of a shape of H, C 1 ～C 4 Alkyl, C 1 ～C 4 Alkoxy, methylthio, halogen or trifluoromethyl; r is R 2 Is C 1 ～C 4 Alkyl or benzyl.
2. A process for producing a trifluoromethyl-substituted dihydroquinoxaline compound according to claim 1,R 1 is H, methyl, isopropyl, tertiary butyl, methoxy, methylthio, F, cl, br or trifluoromethyl.
3. The method for producing trifluoromethyl-substituted dihydroquinoxaline compound according to claim 1, wherein R 2 Is ethyl, isopropyl or benzyl.
4. The method for producing a trifluoromethyl-substituted dihydroquinoxaline compound according to claim 1, wherein said organic solvent is tetrahydrofuran.
5. The method for producing a trifluoromethyl-substituted dihydroquinoxaline compound according to claim 1, wherein said accelerator is diisopropylethylamine.
6. The method for producing a trifluoromethyl-substituted dihydroquinoxaline compound according to claim 1, wherein the trifluoroacetyl imine thioylide is calculated in terms of mole: azo esters: accelerator=1:2 to 4:1 to 3.
7. The method for producing a trifluoromethyl-substituted dihydroquinoxaline compound according to claim 1, wherein said trifluoromethyl-substituted dihydroquinoxaline compound is one of the compounds represented by the formula (I-1) -formula (I-5):
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