Preparation method of 2-methyl-3, 4-diphenyl-1-p-toluenesulfonyl-1, 2-dihydroquinoline derivative

Abstract

The invention provides a preparation method of a 2-methyl-3, 4-diphenyl-1-p-toluenesulfonyl-1, 2-dihydroquinoline derivative, and belongs to the technical field of heterocyclic compounds. The preparation method comprises the following steps: adding a palladium catalyst, alkali, N-(2-(cyclopropylphenylene methyl) phenyl)-4-methylbenzenesulfonamide and iodobenzene into an organic solvent, reacting at 80 DEG C for 12 hours, and performing post-treatment to obtain the 2-methyl-3, 4-diphenyl-1-p-toluenesulfonyl-1, 2-dihydroquinoline derivative. The preparation method has the advantages of simple operation, mild conditions, cheap and easily available initial raw materials, high reaction efficiency and wide application range of functional groups, and can realize one-step efficient and rapid synthesis of the 2-methyl-3, 4-diphenyl-1-tosyl-1, 2-dihydroquinoline derivative.

Description

Technical Field

[0001] The present application relates to a method for preparing a 2-methyl-3,4-diphenyl-1-toluenesulfonyl-1,2-dihydroquinoline derivative, and belongs to the technical field of heterocyclic compounds. Background Art

[0002] 1,2-Dihydroquinoline is an important nitrogen-containing hexameric structural framework, widely found in natural products and pharmaceutical molecules, and exhibits diverse biological activities. For example, compound A exhibits antitumor activity, EQ acts as an antioxidant, and compound B exhibits antibacterial activity. To date, the synthesis of fully substituted dihydroquinoline compounds requires further development of more efficient methods.

[0003] Summary of the Invention

[0004] In view of this, the present application provides a method for preparing 2-methyl-3,4-diphenyl-1-p-toluenesulfonyl-1,2-dihydroquinoline derivatives. The preparation steps are simple, and the resulting product, 2-methyl-3,4-diphenyl-1-p-toluenesulfonyl-1,2-dihydroquinoline derivatives, can be compatible with multiple functional groups at the same time, have good reaction substrate compatibility, and have good applicability.

[0005] Specifically, this application is implemented through the following solutions:

[0006] A method for preparing a 2-methyl-3,4-diphenyl-1-p-toluenesulfonyl-1,2-dihydroquinoline derivative, characterized by: adding a palladium catalyst, a base, N-(2-(cyclopropylphenylenemethyl)phenyl)-4-methylbenzenesulfonamide, and iodobenzene to an organic solvent, reacting at 80° C. for 12 hours to ensure the reaction is complete, and then post-processing to obtain a 2-methyl-3,4-diphenyl-1-p-toluenesulfonyl-1,2-dihydroquinoline derivative.

[0007] The structural formula of the N-(2-(cyclopropylphenylenemethyl)phenyl)-4-methylbenzenesulfonamide is:

[0008]

[0009] The structural formula of the 2-methyl-3,4-diphenyl-1-toluenesulfonyl-1,2-dihydroquinoline derivative is:

[0010]

[0011] R 1 is any one of an alkyl group, a phenyl group, a substituted phenyl group, and a heterocyclic group; R 2 is a substituted phenyl or heterocyclic group; R 3is a substituted phenyl group or a substituted phenyl group; R 4 is hydrogen or halogen.

[0012] The reaction equation of the above process is as follows:

[0013]

[0014] Furthermore, as a preference:

[0015] The molar ratio of N-(2-(cyclopropylphenylenemethyl)phenyl)-4-methylbenzenesulfonamide, iodobenzene, palladium catalyst, and base is 1.0:1.2:0.1:2.0. During the material preparation process, the amount of organic solvent used is sufficient to dissolve the raw materials. Therefore, the amount of organic solvent used for 0.2 mmol of N-(2-(cyclopropylphenylenemethyl)phenyl)-4-methylbenzenesulfonamide is preferably controlled at 2.0 mL.

[0016] The organic solvent is dimethyl sulfoxide. At this time, various raw materials can be converted into products with a higher conversion rate.

[0017] The palladium catalyst is bisacetonitrile palladium dichloride, which has a higher reaction efficiency among many palladium catalysts.

[0018] The base is N,N-diisopropylethylamine.

[0019] The post-treatment process is as follows: the reaction product is filtered, the sample is mixed with silica gel, and finally purified by column chromatography to obtain the corresponding 2-methyl-3,4-diphenyl-1-toluenesulfonyl-1,2-dihydroquinoline derivative. The column chromatography purification parameters can be set using conventional settings.

[0020] The 2-methyl-3,4-diphenyl-1-toluenesulfonyl-1,2-dihydroquinoline biological is any one of the following structural formulas:

[0021]

[0022] In the above preparation method, iodobenzene, bisacetonitrile palladium dichloride and N,N-diisopropylethylamine are generally commercially available products and can be easily obtained from the market. N-(2-(cyclopropylphenylenemethyl)phenyl)-4-methylbenzenesulfonamide can be quickly synthesized from the corresponding 2-(cyclopropylphenylenemethyl)aniline and sulfonyl chloride and other raw materials.

[0023] Compared with the prior art, the beneficial effects of the present invention are reflected in: the preparation method is easy to operate and the post-processing is simple; the reaction starting materials are cheap and easily available, the substrate functional group tolerance range is wide, the reaction efficiency is high, and the N-(2-(cyclopropylphenylenemethyl)phenyl)-4-methylbenzenesulfonamide derivative is synthesized efficiently and quickly in one step, which has strong practicality. DETAILED DESCRIPTION

[0024] In order to make the technical problems, technical solutions and beneficial effects to be solved by this application more clearly understood, the technical solutions of this application will be further described in detail below in conjunction with 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 making creative efforts are within the scope of protection of this application.

[0025] Example 1

[0026] According to the raw material ratios in Table 1, 0.2 mmol of N-(2-(cyclopropylphenylenemethyl)phenyl)-4-methylbenzenesulfonamide (I), 1.2 mmol of iodobenzene (II), 0.02 mmol of the palladium catalyst bisacetonitrile palladium dichloride, 0.4 mmol of the base cesium carbonate, and 2.0 mL of the organic solvent dimethyl sulfoxide were added to a 10 mL Schlenk tube. The mixture was stirred uniformly and reacted at 80°C for 12 hours, as shown in Table 1. After the reaction was complete, the mixture was filtered, the sample was washed with silica gel, and purified by column chromatography to obtain the corresponding 2-methyl-3,4-diphenyl-1-toluenesulfonyl-1,2-dihydroquinoline derivative (III).

[0027] The reaction equation of the above process is as follows:

[0028]

[0029] Table 1: Comparison of raw material composition and effects of different implementation plans

[0030]

[0031] In Table 1, OMe is methoxy, Me is methyl, OPh is phenoxy, thiophene is thiophene, Aceton is acetone, and Ts is p-toluenesulfonyl.

[0032] As can be seen from Table 1, this case can achieve high-yield preparation of multiple substrates. The above-mentioned compounds (I) and (II) with more than ten different substituent groups can basically achieve a high-yield synthesis of compound (III) of more than 85%.

[0033] At the same time, the applicant also confirmed the structure of the products prepared by the above reaction, with Examples 1 to 5 as representatives, and the test results are as follows:

[0034] The nuclear magnetic resonance (NMR) of the 2-methyl-3,4-diphenyl-1-toluenesulfonyl-1,2-dihydroquinoline derivative (III-1) prepared in Example 1 1 H NMR, 13C NMR) and high resolution (HRMS) detection data are:

[0035]

[0036] 1 H NMR (500MHz, CDCl3) δ7.87(dd,J=8.1,1.3Hz,1H),7.32(td,J=7.7,1.5Hz,1H),7.25(s,1H),7.16-7.09(m,5H),7.07(d,J=8.1Hz,2H),6.89(d,J= 7.9Hz,2H),6.76(dd,J=7.9,1.5Hz,1H),6.71-6.66(m,2H),6.45(s,2H) ,5.24(q,J=6.8Hz,1H),2.36(s,3H),2.24(s,3H),1.38(d,J=6.9Hz,3H).

[0037] 13 C NMR (101MHz, CDCl3) δ143.3,137.6,136.8,136.1,135.4,132.1,131.8,131.7,130.6,129.1,1 28.6,128.5,128.0,127.9,127.8,127.4,126.9,126.4,126.4,55.4,29.7,21.42,2.12,19.7.

[0038] HRMS(ESI)m / z:[M+H] + Calcd for C 30 H 28 NO2S + 466.6110; Found 466.6115.

[0039] The nuclear magnetic resonance (NMR) of the 2-methyl-3,4-diphenyl-1-toluenesulfonyl-1,2-dihydroquinoline derivative (III-2) prepared in Example 2 1 H NMR, 13 C NMR) and high resolution (HRMS) detection data are:

[0040]

[0041] 1H NMR(500MHz, CDCl3)δ7.86(dd,J=8.0,1.3Hz,1H),7.32(td,J=7.7,1.5Hz,1H),7.26-7.23(m,2H),7.17-7.09(m,4H),7.06(d,J=8.0 Hz,2H),6.77-6.70(m,3H),6.65-6.57(m,2H),6.45(s,2H),5.23(q,J=6.8Hz,1H),3.74(s,3H),2.36(s,3H),1.38(d,J=6.8Hz,3H).

[0042] 13 C NMR (101MHz, CDCl3) δ158.4,143.3,137.8,136.3,136.1,131.9,131.8,131.4,130.7,130.6,12 9.9,129.1,128.0,127.7,127.4,126.9,126.4,113.1,77.3,77.0,76.7,55.4,55.1,21.4,19.7.

[0043] HRMS(ESI)m / z:[M+H] + Calcd for C 30 H 28 NO3S + 482.1712; Found 482.1716.

[0044] Example 3 Preparation of 2-methyl-3,4-diphenyl-1-toluenesulfonyl-1,2-dihydroquinoline derivative (III-3) NMR ( 1 H NMR, 13 C NMR) and high resolution (HRMS) detection data are:

[0045]

[0046] 1 H NMR(400MHz, CDCl3)δ7.88(dd,J=8.0,1.3Hz,1H),7.34(tt,J=7.8,2.3Hz,3H),7.29-7.24(m,2H),7.17-7.05(m,7 H),7.01-6.94(m,2H),6.80-6.69(m,5H),6.47(s,2H),5.24(q,J=6.8Hz,1H),2.35(s,3H),1.41(d,J=6.8Hz,3H).

[0047] 13C NMR (101MHz, CDCl3) δ156.6,156.3,143.4,137.5,136.1,136.0,133.2,132.1,132.1,131.6,130.6,130. 1,129.8,129.1,128.0,127.9,127.4,127.1,126.5,126.4,123.6,119.3,117.6,55.3,26.9,21.4,19.7.

[0048] HRMS(ESI)m / z:[M+H] + Calcd for C 35 H 30 NO3S + 544.1941; Found 544.1937.

[0049] The nuclear magnetic resonance (NMR) of the 2-methyl-3,4-diphenyl-1-toluenesulfonyl-1,2-dihydroquinoline derivative (III-4) prepared in Example 4 1 H NMR, 13 C NMR) and high resolution (HRMS) detection data are:

[0050]

[0051] 1 H NMR (400MHz, CDCl3) δ7.87(d,J=8.0Hz,1H),7.34(td,J=7.7,1.5Hz,1H),7.28-7.23(m,2H),7.21-7.06(m,6H),6.91(t,J=8.0Hz,1H),6.77(dd,J= 7.9,1.5Hz,1H),6.61-6.38(m,3H),6.28(dd,J=11.4,1.8Hz,1H),5.17(q ,J=6.8Hz,1H),2.37(s,3H),2.16(d,J=1.8Hz,3H),1.39(d,J=6.8Hz,3H).

[0052] 13C NMR (101MHz, CDCl3) δ161.7,159.3,143.5,137.87(d,J=31.16Hz),137.2,136.1,135.43(d,J=27.84Hz),132.7,132.2,131.4,130.71( d,J=22.28Hz),130.4,129.2,128.2,128.09,128.06,127.3,127.2,126.7,126.5,123.93,(d,J=12.72Hz),123.7,123.6,115.5,115.24 55.3,21.4,19.7,14.3,14.25(d,J=21.84Hz)

[0053] 19 F NMR (377MHz, CDCl3) δ-117.68 (dd, J=11.2, 8.3Hz).

[0054] HRMS(ESI)m / z:[M+H] + Calcd for C 30 H 27 FNO2S + 484.1741; Found 484.1738.

[0055] The nuclear magnetic resonance (NMR) of the 2-methyl-3,4-diphenyl-1-toluenesulfonyl-1,2-dihydroquinoline derivative (III-5) prepared in Example 5 1 H NMR, 13 C NMR) and high resolution (HRMS) detection data are:

[0056]

[0057] 1 H NMR (400MHz, CDCl3) δ7.88 (dd, J=8.0, 1.3Hz, 1H), 7.35 (td, J=7.7, 1.5Hz, 1H), 7.28-7.23 (m, 2H), 7.18-7.03 (m, 8H), 6 .79(dd,J=7.8,1.5Hz,1H),6.73-6.68(m,2H),6.46(s,2H),5.19(q,J=6.8Hz,1H),2.37(s,3H),1.39(d,J=6.8Hz,3H).

[0058] 13C NMR (101MHz, CDCl3) δ143.5,137.2,136.9,136.1,135.5,132.9,132.8,132.2,131.2,130.4,130 .0,129.9,128.3,128.14,128.06,128.0,127.26,127.30,126.7,126.5,55.1,26.9,21.4,19.7.

[0059] HRMS(ESI)m / z:[M+H] + Calcd for C 29 H 24 ClNO2S + 487.1323; Found 487.1313.

[0060] The above-described embodiments merely represent several feasible implementation methods of the present invention. The description thereof is relatively specific and detailed, but it should not be understood as limiting the scope of the invention. The embodiments are not intended to limit the scope of protection in the claims of the present invention. For those skilled in the art, various modifications and improvements can be made without departing from the concept of the present invention. Any equivalent implementation or modification that does not depart from the scope of the present invention should be included in the technology of the present invention.

Claims

1. A method for preparing a 2-methyl-3,4-diphenyl-1-toluenesulfonyl-1,2-dihydroquinoline derivative, characterized in that: Palladium catalyst, base, N-(2-(cyclopropylphenylenemethyl)phenyl)-4-methylbenzenesulfonamide, and iodobenzene are added to an organic solvent, reacted at 80°C for 12 hours, and then post-treated to obtain 2-methyl-3,4-diphenyl-1-toluenesulfonyl-1,2-dihydroquinoline derivatives. The structural formula of the N-(2-(cyclopropylphenylenemethyl)phenyl)-4-methylbenzenesulfonamide is: The structural formula of the 2-methyl-3,4-diphenyl-1-toluenesulfonyl-1,2-dihydroquinoline derivative is: R 1 is any one of an alkyl group, a phenyl group, a substituted phenyl group, and a heterocyclic group; R 2 is a substituted phenyl group or a heterocyclic group; R 3 is a substituted phenyl group or a substituted phenyl group; R 4 is hydrogen or halogen.

2. The method for preparing a 2-methyl-3,4-diphenyl-1-toluenesulfonyl-1,2-dihydroquinoline derivative according to claim 1, characterized in that: The molar ratio of N-(2-(cyclopropylphenylenemethyl)phenyl)-4-methylbenzenesulfonamide, iodobenzene, palladium catalyst, and base is 1.0:1.2:0.1:2.

0.

3. The method for preparing a 2-methyl-3,4-diphenyl-1-toluenesulfonyl-1,2-dihydroquinoline derivative according to claim 1, characterized in that: The organic solvent is dimethyl sulfoxide.

4. A 2-methyl-3,4-diphenyl-1-toluenesulfonyl-1,2-dihydroquinoline derivative according to claim 1, characterized in that: The palladium catalyst is bisacetonitrile palladium dichloride.

5. The method for preparing a 2-methyl-3,4-diphenyl-1-toluenesulfonyl-1,2-dihydroquinoline derivative according to claim 1, characterized in that: The base is N,N-diisopropylethylamine.

6. The method for preparing a 2-methyl-3,4-diphenyl-1-toluenesulfonyl-1,2-dihydroquinoline 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 purified by column chromatography to obtain the corresponding 2-methyl-3,4-diphenyl-1-toluenesulfonyl-1,2-dihydroquinoline derivative.

7. The method for preparing a 2-methyl-3,4-diphenyl-1-toluenesulfonyl-1,2-dihydroquinoline derivative according to any one of claims 1 to 6, characterized in that: The 2-methyl-3,4-diphenyl-1-toluenesulfonyl-1,2-dihydroquinoline derivative is any one of the following structures:

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