Preparation method of 1, 5-dihydropyrrolo [4, 3, 2-de] quinoline-4 (3H)-ketone derivative

Abstract

The invention provides a preparation method of a 1, 5-dihydropyrrolo [4, 3, 2-de] quinoline-4 (3H)-ketone derivative, and belongs to the technical field of heterocyclic compounds. The preparation method comprises the following steps: adding a palladium catalyst, a ligand, alkali, 1, 7-enyne, perfluoroiodobutane and di-tert-butyldiaziridone into an organic solvent, reacting at the temperature of 80-100 DEG C for 18-22 hours, and performing post-treatment to obtain the 1, 5-dihydropyrrolo [4, 3, 2-de] quinoline-4 (3H)-ketone derivative. The preparation method is simple and convenient to operate, the initial raw materials are cheap and easy to obtain, the reaction efficiency is high, the substrate compatibility is good, and the 1, 5-dihydropyrrolo [4, 3, 2-de] quinoline-4 (3H)-ketone derivative can be efficiently and rapidly synthesized in one step.

Description

Technical Field

[0001] The present application relates to a method for preparing a 1,5-dihydropyrrolo[4,3,2-de]quinoline-4(3H)-one derivative, belonging to the technical field of heterocyclic compounds. Background Art

[0002] Polycyclic quinolinone is an important structural skeleton, widely present in natural products and drug molecules, and has a variety of biological activities (Bioorg.Med.Chem.2007,15,6119-6125; J.Med.Chem.2014,57,1252-1275). For example: Euodenine A is a TLR4 antagonist. Yaequinolone J1 is an insecticidal antibiotic. Compound A is a potential antibacterial agent.

[0003]

[0004] Tandem reactions provide an important method for the direct and efficient synthesis of complex polycyclic systems (Med. Res. Rev. 2000, 20, 304-322). However, there are few reports on the synthesis of 1,5-dihydropyrrolo[4,3,2-de]quinolin-4(3H)-one derivatives containing polycyclic quinolinone skeletons based on tandem reactions, and their application is not widespread at present, but they have great application potential and need to be further studied. Summary of the invention

[0005] In view of this, the present application provides a method for preparing a 1,5-dihydropyrrolo[4,3,2-de]quinoline-4(3H)-one derivative. The preparation steps are simple, and the obtained product 1,5-dihydropyrrolo[4,3,2-de]quinoline-4(3H)-one derivative can be compatible with multiple functional groups at the same time, has good reaction substrate compatibility, and has good applicability.

[0006] Specifically, the present application is implemented through the following scheme:

[0007] A method for preparing a 1,5-dihydropyrrolo[4,3,2-de]quinolin-4(3H)-one derivative, characterized in that: a palladium catalyst, a ligand, a base, 1,7-enyne, perfluoroiodobutane and di-tert-butyldiaziridine ketone are added to an organic solvent, reacted at 80-100° C. for 18-22 hours, and after ensuring that the reaction is complete, post-processing is performed to obtain a 1,5-dihydropyrrolo[4,3,2-de]quinolin-4(3H)-one derivative.

[0008] The structural formula of the 1,7-enyne is:

[0009]

[0010] The structural formula of the 1,5-dihydropyrrolo[4,3,2-de]quinolin-4(3H)-one derivative is:

[0011]

[0012] R 1 is a substituent selected from C1-C6 alkyl, C1-C6 alkoxy or halogen; R 2 is a substituted phenyl group or an unsubstituted phenyl group, wherein the corresponding substituent on the substituted phenyl group is selected from C1-C6 alkyl, C1-C6 alkoxy or halogen; R 3 The substituent is selected from C1-C6 alkyl.

[0013] The reaction equation of the above process is as follows:

[0014]

[0015] The above scheme uses 1,7-enyne, di-tert-butyldiaziridine ketone and perfluoroiodobutane as starting materials. Fluorine free radicals add to the carbon-carbon double bond of 1,7-enyne to generate free radical intermediates, and intramolecular free radical addition and palladium (I) species generate alkenyl palladium (II) intermediates. Subsequently, intramolecular CH activation forms a five-membered cyclic palladium (II) intermediate. Di-tert-butyldiaziridine ketone and the five-membered cyclic palladium (II) intermediate undergo oxidative addition to obtain a palladium (IV) complex. Finally, the palladium (IV) complex undergoes reductive elimination to generate a 1,5-dihydropyrrolo [4,3,2-de] quinolin-4 (3H) -one derivative.

[0016] Further, as a preference:

[0017] The molar ratio of 1,7-enyne, di-tert-butyldiaziridine ketone, perfluoroiodobutane, palladium catalyst, ligand, and base is 1.0:2.0:6.0:0.1:0.2:3.0. In the process of material preparation, the amount of organic solvent used is sufficient to dissolve the raw materials well. Therefore, the amount of organic solvent used corresponding to 0.2 mmol of 1,7-enyne is preferably controlled to be around 2.0 mL.

[0018] The organic solvent is trifluorotoluene. At this time, various raw materials can be converted into products with a higher conversion rate.

[0019] The palladium catalyst is palladium acetate, which has a higher reaction efficiency among many palladium catalysts.

[0020] The ligand is bis(2-diphenylphosphinophenyl) ether.

[0021] When palladium acetate is selected as the palladium catalyst and bis(2-diphenylphosphinophenyl)ether is selected as the ligand, the molar ratio of palladium acetate to bis(2-diphenylphosphinophenyl)ether is 0.1:0.2.

[0022] The base is cesium carbonate.

[0023] The post-treatment process is as follows: the reaction product is filtered, the sample is mixed with silica gel, and finally the corresponding 1,5-dihydropyrrolo[4,3,2-de]quinoline-4(3H)-one derivative is obtained by column chromatography purification. The column chromatography purification parameters can be set conventionally.

[0024] The 1,5-dihydropyrrolo[4,3,2-de]quinolin-4(3H)-one derivative is any one of the following structural formulas:

[0025]

[0026] In the above preparation method, di-tert-butyldiaziridinone, perfluoroiodobutane, palladium acetate, bis(2-diphenylphosphinophenyl) ether and cesium carbonate are generally commercially available products and can be easily obtained from the market. 1,7-enyne can be quickly synthesized from corresponding o-iodoaniline, terminal alkyne, acyl chloride and other raw materials.

[0027] Compared with the prior art, the beneficial effects of the present invention are embodied in that: the preparation method is easy to operate and the post-treatment is simple; the reaction starting materials are cheap and easy to obtain, the substrate functional group tolerance range is wide, the reaction efficiency is high, and the 1,5-dihydropyrrolo[4,3,2-de]quinoline-4(3H)-one derivative is synthesized efficiently and quickly in one step, and the practicability is strong. DETAILED DESCRIPTION

[0028] In order to make the technical problems, technical solutions and beneficial effects to be solved by this application clearer, the technical solutions of this application will be further described in detail below in combination with the specific cases in the embodiments of this application. It should be understood that the specific embodiments described herein are only used to explain this application and are not used to limit the technical solutions of this application. Based on the embodiments in this application, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of this application.

[0029] According to the raw material ratio in Table 1, 1,7-enyne (II), perfluoroiodobutane, di-tert-butyldiaziridine ketone, palladium acetate, bis(2-diphenylphosphinophenyl) ether, cesium carbonate and 2.0 mL of an organic solvent were added to a 10 mL Schlenk tube, mixed and stirred evenly, and reacted at 90° C. for 20 hours, as shown in Table 1. After the reaction was complete, it was filtered, mixed with silica gel, and purified by column chromatography to obtain the corresponding 1,5-dihydropyrrolo[4,3,2-de]quinolin-4(3H)-one derivative (I).

[0030] The reaction equation of the above process is as follows:

[0031]

[0032] Table 1: Raw material addition amounts for different implementation schemes

[0033]

[0034] Table 2: Comparison of the effects of different implementation plans

[0035]

[0036]

[0037] In Table 1 and Table 2, T is the reaction temperature, t is the reaction time, Me is a methyl group, Et is an ethyl group, n Pr is n-propyl, OMe is methoxy, Ph is phenyl, and Bn is benzyl.

[0038] At the same time, the applicant also confirmed the structure of the product prepared by the above reaction, represented by Examples 1 to 5, and the test results are as follows:

[0039] The NMR ( 1 HNMR, 13 C NMR) and high resolution (HRMS) detection data are:

[0040]

[0041] 1 H NMR (400MHz, CDCl3) δ7.38(d,J=6.5Hz,1H),7.36-7.28(m,3H),7.28(dd,J=6.0,2.1Hz,2H),7.25(d,J=2.9Hz,1H),7.25-7.17(m,1H),7.02-6.98(m ,1H),6.96-6.91(m,2H),6.46(d,J=7.6Hz,1H),5.23(d,J=3.9Hz,2H),3.8 9(s,3H),3.11-2.95(m,1H),2.25-2.10(m,1H),1.54(s,9H),1.49(s,3H); 13C NMR (100MHz, CDCl3) δ173.8,160.1,137.4,135.3,134.1,133.1,132.6,128.7,127.9,127.1,127.0,122.3,115.2,1 13.2,113.1,112.4,110.2,102.3,59.9,55.4,46.3,42.8,39.7(t,J=18.2Hz),32.2,30.8; HRMS(ESI-TOF)m / z:[M+H] + Calcd.for C 34 H 32 F9N2O2 + :671.2315; found:671.2308.

[0042] The NMR ( 1 HNMR, 13 C NMR) and high resolution (HRMS) detection data are:

[0043]

[0044] 1 H NMR (400MHz, CDCl3) δ7.51-7.43(m,1H),7.40-7.27(m,6H),7.23(d,J=7.1Hz,1H),7.13(dt,J=8.6,6.1Hz,2H),7.03( t,J=8.1Hz,1H),6.49(d,J=7.6Hz,1H),5.24(s,2H),3.16-3.00(m,1H),2.19-2.02(m,1H),1.54(s,9H),1.49(s,3H); 13 C NMR (100MHz, CDCl3) δ173.6,163.1(d,J=249.6Hz),137.3,134.6(d,J=8.1Hz),134.2,134.0,133.72,133.68,132.7,132.0(d,J=3.8Hz),128.7 ,127.1,127.0,122.7,114.9(d,J=21.1Hz),112.7,110.3,102.5,60.0,46.3,42.7,39.7(t,J=18.3Hz).,32.2,30.9; HRMS(ESI-TOF)m / z:[M+H] + Calcd.for C 33 H29 F 10 N2O + :659.2115; found:659.2119.

[0045] Example 3 The NMR ( 1 HNMR, 13 C NMR) and high resolution (HRMS) detection data are:

[0046]

[0047] 1 H NMR (400MHz, CDCl3) δ7.49-7.40(m,4H),7.40-7.34(m,2H),7.33-7.30(m,4H),7.24(dd,J=6.3,2.8 Hz,1H),6.50(s,1H),5.19(s,2H),3.06-2.91(m,1H),2.20-2.04(m,1H),1.51(s,9H),1.46(s,3H); 13 C NMR (100MHz, CDCl3) δ173.8,136.7,135.9,135.6,134.0,133.2,132.8,131.9,129.2,128.8,128.2,127.9,127.8,12 7.3,127.0,113.6,112.4,110.0,103.6,60.3,46.3,42.7,39.7(t,J=18.1Hz),32.1,30.7; HRMS(ESI-TOF)m / z:[M+H] + Calcd.for C 33 H 28 ClF9N2ONa + :697.1639; found:697.1645.

[0048] The NMR ( 1 HNMR, 13 C NMR) and high resolution (HRMS) detection data are:

[0049]

[0050] 1H NMR (400MHz, CDCl3) δ7.45(d,J=7.1Hz,2H),7.44-7.35(m,3H),7.35(d,J=8.6Hz,1H),7.13(t,J=8.0Hz, 1H),6.54(d,J=7.5Hz,1H),3.44(s,3H),3.01-2.85(m,1H),2.17-2.01(m,1H),1.54(s,9H),1.42(s,3H); 13 C NMR (100MHz, CDCl3) δ173.4,136.2,135.3,134.0,133.4,132.9,131.9,128.9,127.8,127.6,122.5,11 5.1,112.4,110.3,101.3,60.0,42.4,39.9(t,J=17.9Hz),32.1,30.3,29.3; HRMS(ESI-TOF)m / z:[M+H] + Calcd.forC 27 H 26 F9N2O + :565.1896; found:565.1895.

[0051] The NMR of the 1,5-dihydropyrrolo[4,3,2-de]quinolin-4(3H)-one derivative (I-5) prepared in Example 5 is ( 1 HNMR, 13 C NMR) and high resolution (HRMS) detection data are:

[0052]

[0053] 1 H NMR (400MHz, CDCl3) δ7.44(td,J=6.0,2.0Hz,2H),7.41-7.35(m,3H),7.33(d,J=8.6Hz,1H),7.15-7.09(m,1H),6.55(d,J=7.6Hz, 1H),4.25-4.12(m,1H),3.96-3.83(m,1H),3.02-2.84(m,1H),2.17-1.99(m,1H),1.54(s,9H),1.41(s,3H),1.27(t,J=7.0Hz,3H); 13CNMR (100MHz, CDCl3) δ172.8,136.2,135.3,134.2,132.9,132.2,132.0,128.9,127.8,127.6,122.5,115. 3,112.4,110.0,101.2,60.0,42.3,39.9(t,J=18.4Hz),37.2,32.1,30.3,12.0; HRMS(ESI-TOF)m / z:[M+H] + Calcd.for C 28 H 28 F9N2O + :579.2052; found:579.2057.

[0054] The above-mentioned embodiments only express several feasible implementation methods of the present invention, and the description is relatively specific and detailed, but it cannot be understood as limiting the scope of the patent of the present invention, and the embodiments are not used to limit the scope of protection in the claims of the present invention. For ordinary technicians in this field, several modifications and improvements can be made without departing from the concept of the present invention, and all equivalent implementations or changes that do not depart from the present invention should be included in the technology of the present invention.

Claims

1. A method for preparing a 1,5-dihydropyrrolo[4,3,2-de]quinolin-4(3H)-one derivative, characterized in that: The palladium catalyst, ligand, base, 1,7-eneyne, perfluoroiodobutane and di-tert-butyldiaziridine ketone are added to an organic solvent, reacted at 80-100° C. for 18-22 hours, and then post-treated to obtain a 1,5-dihydropyrrolo[4,3,2-de]quinolin-4(3H)-one derivative. The structural formula of the 1,7-enyne is: The structural formula of the 1,5-dihydropyrrolo[4,3,2-de]quinolin-4(3H)-one derivative is: R 1 is a substituent selected from C1-C6 alkyl, C1-C6 alkoxy or halogen; R 2 is a substituted phenyl group or an unsubstituted phenyl group, wherein the corresponding substituent on the substituted phenyl group is selected from C1-C6 alkyl, C1-C6 alkoxy or halogen; R 3 The substituent is any one selected from C1 to C6 alkyl groups.

2. The method for preparing a 1,5-dihydropyrrolo[4,3,2-de]quinolin-4(3H)-one derivative according to claim 1, characterized in that: The molar ratio of 1,7-enyne, di-tert-butyldiaziridinone, perfluoroiodobutane, palladium catalyst, ligand and base is 1.0:2.0:6.0:0.1:0.2:3.

0.

3. The method for preparing a 1,5-dihydropyrrolo[4,3,2-de]quinolin-4(3H)-one derivative according to claim 1, characterized in that: The organic solvent is trifluorotoluene.

4. A 1,5-dihydropyrrolo[4,3,2-de]quinolin-4(3H)-one derivative according to claim 1, characterized in that: The palladium catalyst is palladium acetate.

5. The method for preparing a 1,5-dihydropyrrolo[4,3,2-de]quinolin-4(3H)-one derivative according to claim 1, characterized in that: The ligand is bis(2-diphenylphosphinophenyl) ether.

6. The method for preparing a 1,5-dihydropyrrolo[4,3,2-de]quinolin-4(3H)-one derivative according to claim 1, characterized in that: The base is cesium carbonate.

7. The method for preparing a 1,5-dihydropyrrolo[4,3,2-de]quinolin-4(3H)-one derivative according to claim 1, characterized in that: The post-treatment process is as follows: the reaction product is filtered, the sample is mixed with silica gel, and finally the corresponding 1,5-dihydropyrrolo[4,3,2-de]quinoline-4(3H)-one derivative is purified by column chromatography.

8. The method for preparing a 1,5-dihydropyrrolo[4,3,2-de]quinolin-4(3H)-one derivative according to any one of claims 1 to 7, characterized in that: The 1,5-dihydropyrrolo[4,3,2-de]quinolin-4(3H)-one derivative is any one of the following structural formulas:

Images