Synthesis method of polysubstituted cyclic amine compound

Abstract

The invention discloses a synthesis method of a polysubstituted cyclic amine compound, which comprises the following steps: by taking a cyclic amine compound, a disulfide compound and an amine compound as raw materials, selectively activating sp3-C-H bonds at alpha, beta and gamma sites of cyclic amine under the synergistic catalysis of transition metal and an organic small molecule catalyst to synthesize the polysubstituted cyclic amine compound in one step. The method has the advantages that synthesis steps are simple, operation is easy and convenient, raw materials are non-toxic, low in price and easy to obtain, the synthesis method is good in functional group compatibility, chemical selectivity, atom economy and the like, and compared with a traditional method, the method has obvious advantages in the aspect of achieving multi-site selective C-H bond functionalization. In a word, the complex problem that multi-step operation is needed in an existing method is effectively solved, meanwhile, the concept of step economy is better met, and efficient synthesis method reference and reliable technical support are provided for synthesis of the compounds with wide application value.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a method for synthesizing a polysubstituted cyclic amine compound. Background Art

[0002] Cyclic amines are a class of nitrogen-containing cyclic compounds. This structural unit is widely present in natural products and drug molecules, such as the anticoagulant Apixaban and the anticancer drug AM-8553. The main methods for synthesizing these structures include hydrogenation of unsaturated aromatic nitrogen heterocycles, multicomponent cyclization, and direct C–H functionalization of cyclic amines. Among them, direct C–H functionalization of cyclic amines is undoubtedly the simplest synthetic method. However, traditional synthetic methods are limited to relying on specific reactive sites, or relying on directing groups and functional group pre-activation, and are limited to single functionalization, and there are still many challenges in achieving multi-site selective C–H functionalization.

[0003] The continuous development of organic small molecule catalysis in the field of synthetic methodology provides a new solution for the synthesis and discovery of new compounds. Through the synergistic catalysis of organic small molecule catalysts and traditional metal catalysts, some reactions that cannot be achieved by a single catalyst can be achieved, which provides an effective method for the one-pot synthesis of complex organic molecules. Summary of the invention

[0004] The technical problem to be solved by the present invention is to provide a method for synthesizing polysubstituted cyclic amine compounds, which has the advantages of simple steps, simple operation, non-toxic and inexpensive raw materials, good compatibility of the synthesis method with functional groups, high chemical selectivity and atom economy, etc.

[0005] In order to solve the above technical problems, the present invention adopts the following technical solutions:

[0006] A method for synthesizing a polysubstituted cyclic amine compound, using a cyclic amine compound, a disulfide compound and an amine compound as raw materials, selectively activating the sp at the α, β and γ positions of the cyclic amine under the synergistic catalysis of a transition metal and an organic small molecule catalyst 3 -C–H bond to synthesize polysubstituted cyclic amines in one step.

[0007] The synthesis method of the above-mentioned polysubstituted cyclic amine compounds is carried out as follows: Compound 1, Compound 2, Compound 3, a metal catalyst, an organic catalyst, an oxidant, an additive and a solvent are added to a reactor, and the reaction is stirred at a certain temperature for a certain time. After the reaction is completed, it is cooled to room temperature, and the solvent is removed by vacuum rotary evaporation to obtain a crude product. The crude product is purified by column chromatography to obtain a polysubstituted cyclic amine compound product 4 or 5.

[0008] The synthesis method of the above-mentioned polysubstituted cyclic amine compounds conforms to the following reaction formula:

[0009]

[0010] In the formula, compound 1 is a cyclic amine compound; compound 2 is a disulfide compound; compound 3 is an amine compound; compounds 4 and 5 are multi-substituted cyclic amine products; wherein R 1 , R 2 , R 3 , R 4 It can be different substituents such as hydrogen, alkyl, alkenyl, aryl, etc.

[0011] Compound 1 is an N-phenylpiperidine compound, compound 2 is an aromatic disulfide compound, and compound 3 is a pyrazole or imidazole compound; the catalyst is a metal salt, elemental iodine, an organic small molecule catalyst or a combination thereof; the oxidant is oxygen, an inorganic oxide, an organic oxide or a combination thereof; the additive is an inorganic base, an organic base or a combination thereof; and the solvent is water, an organic solvent or a combination thereof.

[0012] The catalyst is a combination of copper acetate and diiodotri-(2,6-dimethoxyphenyl)phosphine; the oxidant is oxygen at 1 atmospheric pressure; the additive is sodium bicarbonate; and the solvent is water 1,4-dioxane.

[0013] The molar ratio of compound 1, compound 2 and compound 3 is 1:(1-10):(1-10); the reaction temperature is 0-200° C., and the reaction time is 1-48 h.

[0014] The molar ratio of compound 1, compound 2 and compound 3 is 1:1:3; the reaction temperature is 80°C and the reaction time is 18h.

[0015] The reactor is a Schlenk tube.

[0016] In view of the existing problems in the synthesis of cyclic amine compounds, the inventors have established a method for synthesizing polysubstituted cyclic amine compounds, using cyclic amine compounds, disulfide compounds and amine compounds as raw materials, and selectively activating the sp at the α, β and γ positions of the cyclic amine under the synergistic catalysis of transition metals and organic small molecule catalysts. 3 -C–H bond one-step synthesis of polysubstituted cyclic amine compounds. The method has the advantages of simple synthesis steps, simple operation, non-toxic and inexpensive raw materials, good compatibility of the synthesis method with functional groups, high chemical selectivity and atom economy. Compared with the traditional method, the present invention has obvious advantages in achieving multi-site selective C–H bond functionalization. In short, the present invention not only effectively solves the cumbersome problem of multi-step operation required in the existing method, but also conforms to the concept of step economy, providing an efficient synthesis method reference and reliable technical support for the synthesis of such compounds with wide application value. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 The hydrogen spectrum of the product obtained in Example 1 is shown in FIG.

[0018] Figure 2 This is the carbon spectrum of the product obtained in Example 1.

[0019] Figure 3 This is the hydrogen spectrum of the product obtained in Example 2.

[0020] Figure 4 This is the carbon spectrum of the product obtained in Example 2.

[0021] Figure 5 This is the hydrogen spectrum of the product obtained in Example 3.

[0022] Figure 6 This is the carbon spectrum of the product obtained in Example 3.

[0023] Figure 7 This is the hydrogen spectrum of the product obtained in Example 4.

[0024] Figure 8 This is the carbon spectrum of the product obtained in Example 4.

[0025] Fig. 9 This is the hydrogen spectrum of the product obtained in Example 5.

[0026] Fig.10 This is the carbon spectrum of the product obtained in Example 5. DETAILED DESCRIPTION

[0027] Example 1

[0028] In a Schlenk tube, 0.3 mmol N-phenylpiperidine, 0.3 mmol diphenyl disulfide, 0.9 mmol pyrazole, 0.3 mmol copper acetate, 0.6 mmol diiodotri-(2,6-dimethoxyphenyl)phosphine, 0.6 mmol sodium bicarbonate, and 3.0 mL 1,4-dioxane were added and heated at 80 °C under 1 atmosphere of O 2 After stirring the reaction for 18 hours under the same conditions, heating and stirring were stopped, and the mixture was cooled to room temperature. The solvent was removed by rotary evaporation under reduced pressure, and then the mixture was separated and purified by column chromatography using a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 5:1 as the eluent to obtain the target product.

[0029] The hydrogen spectrum and carbon spectrum of the obtained product are as follows: Figure 1 and Figure 2 The structural characterization data are as follows:

[0030] 1 H NMR (600 MHz, CDCl 3)δ8.44(d,J=2.5Hz,1H),7.53(d,J=1.7Hz,1H),7.39(t,J=7.8Hz,2H),7.34(t,J=7.4Hz,1H),7.28(d,J=7.4Hz,1H),7.26–7.21(m,4H),7.1 3(d,J=7.2Hz,2H),6.36(t,J=2.2Hz,1H),3.71(t,J=6.2Hz,2H),3.24(ddd,J=13.4,9.7,4.3Hz,1H),2.40–2.34(m,2H),2.05–1.99(m,1H).

[0031] 13 C NMR (151 MHz, CDCl 3 )δ166.16,142.93,139.58,136.35,132.73,130.01,129.61,129.23,127.64,126.42,106.81,74.83,52.16,32.09,20.24.

[0032] HRMS(ESI):Calcd.for C 20 H 19 N 3 SO[M+H + ]:350.1322; found:350.1317.

[0033] According to the above data, the structure of the obtained product is as follows:

[0034]

[0035] Example 2

[0036] In a Schlenk tube, 0.3 mmol N-phenylpiperidine, 0.3 mmol di-(4-methylphenyl) disulfide, 0.9 mmol pyrazole, 0.3 mmol copper acetate, 0.6 mmol triphenylphosphine, 0.3 mmol I 2 , 0.6mmol sodium bicarbonate, 3mL 1,4-dioxane, at 100℃, 1 atmosphere O 2 After stirring the reaction for 24 hours under the same conditions, heating and stirring were stopped, the mixture was cooled to room temperature, the solvent was removed by rotary evaporation under reduced pressure, and then the mixture was separated and purified by column chromatography using a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 5:1 as the eluent to obtain the target product.

[0037] The hydrogen spectrum and carbon spectrum of the obtained product are as follows: Figure 3 and Figure 4 The structural characterization data are as follows:

[0038] 1 H NMR (600 MHz, CDCl 3 )δ8.47(d,J=2.2Hz,1H),7.52(d,J=1.5Hz,1H),7.41–7.36(m,2H),7.29–7.26(m,1H),7.26–7.20(m,2H),7.06(d,J=8.0Hz, 2H),7.02(d,J=8.1Hz,2H),6.43–6.23(m,1H),3.78–3.54(m,2H),3.22–3.19(m,1H),2.44–2.24(m,5H),2.04–1.98(m,1H).

[0039] 13 C NMR (151 MHz, CDCl 3 )δ166.18,142.93,140.35,139.43,136.34,132.73,130.02,129.54,127.55,126.38,126.31,106.68,74.78,52.11,31.87,21.60,20.18.

[0040] HRMS(ESI):Calcd.for C 21 H 21 N 3 SO[M+H + ]:364.1478; found:364.1472.

[0041] According to the above data, the structure of the obtained product is as follows:

[0042]

[0043] Example 3

[0044] In a Schlenk tube, 0.3 mmol N-phenylpiperidine, 0.3 mmol diphenyl disulfide, 0.9 mmol pyrazole, 0.3 mmol copper acetate, 0.6 mmol diiodotri-(2,6-dimethoxyphenyl)phosphine, 0.6 mmol sodium bicarbonate, and 3.0 mL 1,3-dioxolane were added and heated at 60 °C under 1 atmosphere of oxygen. 2 After stirring the reaction for 12 hours under the same conditions, heating and stirring were stopped, and the mixture was cooled to room temperature. The solvent was removed by rotary evaporation under reduced pressure, and then the mixture was separated and purified by column chromatography using a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 10:1 as the eluent to obtain the target product.

[0045] The hydrogen spectrum and carbon spectrum of the obtained product are as follows: Figure 5 and Figure 6 The structural characterization data are as follows:

[0046] 1 H NMR (600 MHz, CDCl 3 )δ7.58(d,J=1.9Hz,1H),7.53(s,1H),7.48(d,J=2.3Hz,1H),7.37(dd,J=8.6,7 .2Hz,2H),7.30–7.22(m,4H),7.18–7.13(m,1H),7.11–7.04(m,3H),6.22(t,J=2 .1Hz,1H),4.92(dd,J=4.9,2.4Hz,1H),3.69(dt,J=12.1,3.7Hz,1H),3.58(td, J=12.6,3.1Hz,1H),2.54(dq,J=14.0,2.9Hz,1H),2.32(tt,J=13.6,4.6Hz,1H).

[0047] 13 C NMR (151 MHz, CDCl 3 )δ145.42,143.15,139.87,138.28,129.61,129.07,129.05,127.02,125.64,122.61,116.97,104.74,95.65,56.49,41.29,30.46.

[0048] HRMS(ESI):Calcd.for C 20 H 19 N 3 S[M+H + ]:334.1372; found:334.1366.

[0049] According to the above data, the structure of the obtained product is as follows:

[0050]

[0051] Example 4

[0052] In a Schlenk tube, 0.3 mmol N-(mesityl)piperidine, 0.3 mmol dibenzyl disulfide, 0.9 mmol pyrazole, 0.3 mmol copper chloride, 0.6 mmol diiodotri-(2,6-dimethoxyphenyl)phosphine, 0.6 mmol sodium bicarbonate, and 3.0 mL 1,3-dioxolane were added and heated at 80 °C under 1 atmosphere of oxygen. 2After stirring the reaction for 16 hours under the same conditions, heating and stirring were stopped, the mixture was cooled to room temperature, the solvent was removed by rotary evaporation under reduced pressure, and then the mixture was separated and purified by column chromatography using a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 10:1 to obtain the target product.

[0053] The hydrogen spectrum and carbon spectrum of the obtained product are as follows: Figure 7 and Figure 8 The structural characterization data are as follows:

[0054] 1 H NMR (600 MHz, CDCl 3 )δ7.61(d,J=1.4Hz,1H),7.57(d,J=1.9Hz,1H),7.28–7.25(m,2H),7.22–7.16(m,3H),6.8 4(dd,J=16.2,2.0Hz,2H),6.39(s,1H),6.26(t,J=2.1Hz,1H),4.93(d,J=3.7Hz,1H),3.64 (d,J=13.1Hz,1H),3.46(d,J=13.1Hz,1H),3.16(td,J=13.1,3.1Hz,1H),2.99–2.91(m,1H ),2.42(dq,J=13.7,2.8Hz,1H),2.25(s,3H),2.15–2.11(m,1H),2.09(s,3H),2.03(s,3H).

[0055] 13 C NMR (151 MHz, CDCl 3 )δ147.53,141.49,139.82,139.03,137.17,136.51,135.90,129.36,129.32,128.8 2,128.38,126.73,104.51,87.88,58.05,42.05,40.17,30.00,20.97,17.98,17.94.

[0056] HRMS(ESI):Calcd.for C 24 H 27 N 3 S[M+H + ]:390.1998;found:339.1991.

[0057] According to the above data, the structure of the obtained product is as follows:

[0058]

[0059] Example 5

[0060] In a Schlenk tube, 0.3 mmol N-(mesityl)piperidine, 0.3 mmol diphenyl disulfide, 0.9 mmol imidazole, 0.3 mmol copper acetate, 0.6 mmol diiodotri-(2,6-dimethoxyphenyl)phosphine, 0.6 mmol sodium bicarbonate, and 3.0 mL 1,3-dioxolane were added and heated at 80 °C and 1 atmosphere of oxygen. 2 After stirring the reaction for 18 hours under the same conditions, heating and stirring were stopped, the mixture was cooled to room temperature, the solvent was removed by rotary evaporation under reduced pressure, and then the mixture was separated and purified by column chromatography using a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 1:1 as the eluent to obtain the target product.

[0061] The hydrogen spectrum and carbon spectrum of the obtained product are as follows: Fig. 9 and Fig.10 The structural characterization data are as follows:

[0062] 1 H NMR (600 MHz, CDCl 3 )δ7.61(s,1H),7.26(dd,J=8.2,7.2Hz,2H),7.20–7.17(m,2H),7.15–7.11(m,1H),7.0 7(d,J=1.1Hz,1H),7.00(d,J=1.4Hz,1H),6.93(s,1H),6.91(s,1H),6.88(s,1H),4.74 (dt,J=3.8,1.8Hz,1H),3.33(td,J=13.2,3.1Hz,1H),3.17(dt,J=12.3,3.7Hz,1H),2. 40(dt,J=13.6,4.4Hz,1H),2.31(s,3H),2.29(s,3H),2.25(s,3H),2.24–2.20(m,1H).

[0063] 13 C NMR (151 MHz, CDCl 3 )δ148.19,141.28,139.36,137.65,136.71,136.30,135.60,129.70,129.58,129.30 ,129.07,126.50,125.42,118.26,87.48,52.73,41.97,31.93,21.01,18.28,18.24.

[0064] HRMS(ESI):Calcd.for C 23 H 25 N 3 S[M+H +]:376.1842; found:376.1838.

[0065] According to the above data, the structure of the obtained product is as follows:

[0066]

Claims

1. A method for synthesizing a polysubstituted cyclic amine compound, characterized in that: Using cyclic amine compounds, disulfide compounds and amine compounds as raw materials, the sp-2-terminal residues at the α, β and γ positions of cyclic amines are selectively activated under the synergistic catalysis of transition metals and organic small molecule catalysts. 3 -C–H bond to synthesize polysubstituted cyclic amines in one step.

2. The method for synthesizing a polysubstituted cyclic amine compound according to claim 1, characterized in that The operation is carried out as follows: Compound 1, Compound 2, Compound 3, a metal catalyst, an organic catalyst, an oxidant, an additive and a solvent are added to a reactor, and the reaction is stirred at a certain temperature for a certain time. After the reaction is completed, the reaction is cooled to room temperature, and the solvent is removed by rotary evaporation under reduced pressure to obtain a crude product. The crude product is purified by column chromatography to obtain a polysubstituted cyclic amine compound product 4 or 5.

3. The method for synthesizing a polysubstituted cyclic amine compound according to claim 2, characterized in that The following reaction formula is met: In the formula, compound 1 is a cyclic amine compound; compound 2 is a disulfide compound; compound 3 is an amine compound; compounds 4 and 5 are multi-substituted cyclic amine products; wherein R 1 , R 2 , R 3 , R 4 It is hydrogen, alkyl, alkenyl or aryl.

4. The method for synthesizing a polysubstituted cyclic amine compound according to claim 3, characterized in that: The compound 1 is an N-phenylpiperidine compound, the compound 2 is an aromatic disulfide compound, and the compound 3 is a pyrazole or imidazole compound; the catalyst is a metal salt such as copper, iodine, an organic small molecule catalyst or a combination thereof; the oxidant is oxygen, an inorganic oxide, an organic oxide or a combination thereof; the additive is an inorganic base, an organic base or a combination thereof; and the solvent is water, an organic solvent or a combination thereof.

5. The method for synthesizing a polysubstituted cyclic amine compound according to claim 4, characterized in that: The catalyst is a combination of copper acetate and diiodotri-(2,6-dimethoxyphenyl)phosphine; the oxidant is oxygen at 1 atmosphere; The additive is sodium bicarbonate; the solvent is water and 1,4-dioxane.

6. The method for synthesizing a polysubstituted cyclic amine compound according to claim 5, characterized in that: The molar ratio of the compound 1, the compound 2 and the compound 3 is 1:(1-10):(1-10); the reaction temperature is 0-200° C., and the reaction time is 1-48 hours.

7. The method for synthesizing a polysubstituted cyclic amine compound according to claim 6, characterized in that: The molar ratio of compound 1, compound 2 and compound 3 is 1:1:3; the reaction temperature is 80° C. and the reaction time is 18 h.

8. The method for synthesizing a polysubstituted cyclic amine compound according to claim 2, characterized in that: The reactor is a Schlenk tube.

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