A preparation method of 3-substituted indolizine derivatives

Abstract

The present application discloses a preparation method for synthesizing 3-substituted indolizine derivatives by electrochemical oxidation. The preparation method is obtained by reacting pyridine derivatives, acetophenone derivatives, maleic anhydride as reactants, nickel bromide as catalyst, 2,6-bis(4,5-dihydrooxazol-2-yl)pyridine as ligand, and N,N-dimethylacetamide (DMA) as solvent to obtain the target product. The reaction raw materials and solvents involved in the preparation method of the present application are all commercially available products with low prices; the reaction conditions are simple and mild, the yield is good, the atom utilization rate is high, it has the characteristics of green chemistry, and is in line with the concept of sustainable development.

Description

Technical Field

[0001] The present invention relates to the field of organic synthetic chemistry, and specifically relates to a method for preparing a 3-substituted indolizine derivative. Background Art

[0002] 3-Substituted indolizine derivatives are a class of compounds with excellent biological activity and are widely used in the biopharmaceutical field. Existing methods for the preparation of 3-substituted indolizine derivatives mainly fall into the following three categories:

[0003] Method 1: Using the ring-closure reaction of triazole and alkyne, the chemical reaction formula of this method is shown in formula (1).

[0004]

[0005] The disadvantages of this method are that such triazole derivatives are rarely available on the market and need to be prepared in advance. At the same time, two nitrogen atoms need to be removed during the reaction, resulting in poor atom economy and low economic benefits.

[0006] Method 2: Through the self-cyclization reaction of pyridine ylide, the chemical reaction formula of this method is shown in formula (2).

[0007]

[0008] The disadvantages of this method are that the pyridine ylide used in the reaction cannot be purchased directly and needs to be prepared in advance; the dimethyl sulfate used in the reaction is a highly toxic hazardous chemical; and the temperature needs to be changed during the reaction, making the operation cumbersome, which affects the synthetic value of the reaction.

[0009] Method 3: Using a three-component reaction of pyridine derivatives, bromide, and maleic anhydride. The chemical reaction formula of this method is shown in formula (3).

[0010]

[0011]

[0012] The disadvantages of this method are the use of excess oxidant, a long reaction time (12-24 h), and a high reaction temperature (60-120° C.). Summary of the Invention

[0013] Purpose of the invention: The purpose of this application is to provide a simple, easily available raw material 3-substituted indolizine derivative and its preparation method, which can greatly improve the atom economy and step economy of the reaction, is conducive to the study of the pharmacological activity of such compounds, and is beneficial to environmental protection.

[0014] Technical solution: This application provides a method for preparing 3-substituted indolizine derivatives, the preparation method is as shown in Reaction Formula 1.

[0015]

[0016] Wherein, R1 is selected from hydrogen, C1-C6 substituted or unsubstituted alkyl, ester group, benzophenone and a benzene ring fused to one side of the pyridine ring; R2 is selected from hydrogen, halogen, C1-C6 alkoxy, and a benzene ring fused to one side;

[0017] Step 1: Add a pyridine derivative structure such as Formula 1, an acetophenone derivative structure such as Formula 2, nickel bromide, maleic anhydride, 2,6-bis(4,5-dihydrooxazol-2-yl)pyridine and a reaction solvent into a reaction tube;

[0018] Step 2: Add N,N-dimethylacetamide to the reaction tube, seal the tube and react under a nitrogen atmosphere to obtain a product mixture in one step;

[0019] After the reaction in step 3 is completed, the product mixture obtained in step 2 is extracted and filtered, and the obtained filtrate is concentrated and separated to obtain a 3-substituted indolizine derivative having a structure as shown in Formula 3.

[0020] Beneficial effects:

[0021] Compared with the prior art, this application has the following beneficial effects:

[0022] One of the raw materials for the reaction of this application is an acetophenone derivative, which has always been a bromoacetophenone derivative. Considering the reaction principle, the C-H bond energy of acetophenone is greater than the C-Br bond energy of bromoacetophenone, which makes the reaction difficult. However, the price of acetophenone is cheaper than the corresponding bromoacetophenone and there are more varieties, such as: acetophenone: 30 yuan / 100ml, 2-bromoacetophenone: 190 / 100g; the preparation method provided by this application allows acetophenone derivatives to directly participate in the reaction, overcoming the reaction difficulty, and the reaction has more theoretical research value. In addition, from an economic perspective, this application greatly improves the atom economy and step economy of the reaction, is beneficial to environmental protection, and is in line with green chemistry and the "dual carbon" concept.

[0023] The 3-substituted indolizine derivatives prepared in the present application have excellent biological activity and can be used to treat inflammation and cardiovascular diseases. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 The hydrogen spectrum characterization spectrum of compound 3a prepared in Example 1 of the present application is shown;

[0025] Figure 2 The carbon spectrum characterization spectrum of compound 3a prepared in Example 1 of the present application is shown;

[0026] Figure 3 The hydrogen spectrum characterization spectrum of compound 3b prepared in Example 2 of the present application is shown;

[0027] Figure 4 The carbon spectrum characterization spectrum of compound 3b prepared in Example 2 of the present application is shown;

[0028] Figure 5 The hydrogen spectrum characterization spectrum of compound 3c prepared in Example 3 of the present application is shown;

[0029] Figure 6 The carbon spectrum characterization spectrum of compound 3c prepared in Example 3 of the present application is shown;

[0030] Figure 7 The hydrogen spectrum characterization spectrum of compound 3d prepared in Example 4 of the present application is shown;

[0031] Figure 8 The carbon spectrum characterization spectrum of compound 3d prepared in Example 4 of the present application is shown;

[0032] Figure 9 The hydrogen spectrum characterization spectrum of compound 3e prepared in Example 5 of the present application is shown;

[0033] Figure 10 The carbon spectrum characterization spectrum of compound 3e prepared in Example 5 of the present application is shown;

[0034] Figure 11 The hydrogen spectrum characterization spectrum of compound 3f prepared in Example 6 of the present application is shown;

[0035] Figure 12 The carbon spectrum characterization spectrum of compound 3f prepared in Example 6 of the present application is shown;

[0036] Figure 13 The hydrogen spectrum characterization spectrum of compound 3g prepared in Example 7 of the present application is shown;

[0037] Figure 14 The carbon spectrum characterization spectrum of compound 3g prepared in Example 7 of the present application is shown;

[0038] Figure 15 The hydrogen spectrum characterization spectrum of compound 3h prepared in Example 8 of the present application is shown;

[0039] Figure 16 The carbon spectrum characterization spectrum of compound 3h prepared in Example 8 of the present application is shown; DETAILED DESCRIPTION

[0040] The present application is further illustrated below with reference to specific embodiments. It should be understood that these embodiments are only used to illustrate the present application and are not used to limit the scope of the present application. After reading the present application, modifications of various equivalent forms of the present application made by those skilled in the art all fall within the scope defined by the claims attached to the present application.

[0041] One embodiment of the present application provides a method for preparing a 3-substituted indolizine derivative. The preparation method is as shown in Reaction Scheme 1.

[0042]

[0043] Wherein, R1 is selected from hydrogen, C1-C6 substituted or unsubstituted alkyl, ester group, benzophenone and a benzene ring fused to one side of the pyridine ring; R2 is selected from hydrogen, halogen, C1-C6 alkoxy, and a benzene ring fused to one side;

[0044] Step 1: Add a pyridine derivative structure such as Formula 1, an acetophenone derivative structure such as Formula 2, nickel bromide, maleic anhydride, 2,6-bis(4,5-dihydrooxazol-2-yl)pyridine and a reaction solvent into a reaction tube;

[0045] Step 2: Add N,N-dimethylacetamide to the reaction tube, seal the tube and react under a nitrogen atmosphere to obtain a product mixture in one step;

[0046] After the reaction in step 3 is completed, the product mixture obtained in step 2 is extracted and filtered, and the obtained filtrate is concentrated and separated to obtain a 3-substituted indolizine derivative having a structure as shown in Formula 3.

[0047] In one embodiment, the chemical structure of the pyridine derivative is selected from any one of the following structural formulas:

[0048]

[0049] In one embodiment, the chemical structure of the acetophenone derivative is selected from any one of the following structural formulas:

[0050]

[0051] In one embodiment, the structural formula of the 3-substituted indolizine derivative includes:

[0052]

[0053] In one embodiment, the reaction conditions shown in Reaction Formula 1 are reaction at room temperature for 4-8 hours, and the reaction solvent is N,N-dimethylacetamide.

[0054] In one embodiment, the molar ratio of the pyridine derivative, the acetophenone derivative, and maleic anhydride added in the reaction shown in Reaction Scheme 1 is 1:1:1.

[0055] In one embodiment, the molar ratio of the pyridine derivative to the nickel bromide added in the reaction shown in Reaction Formula 1 is 1:0.1.

[0056] In one embodiment, the molar ratio of the pyridine derivative to the 2,6-bis(4,5-dihydrooxazol-2-yl)pyridine added in the reaction shown in Reaction Scheme 1 is 1:0.12.

[0057] In one embodiment, the preparation method further includes a step of separating and purifying the product after the reaction is completed. The separation and purification step is to filter the obtained filtrate and vacuum concentrate it, and the obtained crude product is separated by column chromatography to obtain a yellow solid 3-substituted indolizine derivative.

[0058] In one embodiment, in step 3, the crude product obtained is separated by column chromatography to obtain a yellow solid 3-substituted indolizine derivative; wherein the yield of the 3-substituted indolizine derivative product is 62%-80%.

[0059] Example 1

[0060]

[0061] Synthesis of 3a: To a reaction tube, methyl isonicotinate (0.4 mmol), acetophenone (0.4 mmol), and maleic anhydride (0.4 mmol) were added, along with 4 mL of N,N-dimethylacetamide solvent. Then, 0.04 mmol of nickel bromide and 0.048 mmol of 2,6-bis(4,5-dihydrooxazol-2-yl)pyridine were added, respectively. After thorough mixing, the reaction apparatus was assembled (the reaction tube was filled with nitrogen and purged of air). The reaction was allowed to proceed for 6 hours. After the reaction was complete, the product was extracted and filtered. The filtrate was then concentrated by rotary evaporation and purified by silica gel column chromatography to afford a yellow solid. Yield: 83.7 mg, 75% yield. Mp: 132-133°C. 1 H NMR (400MHz, CDCl3) δ: 3.97 (s, 3H), 6.76 (d, J = 4.4Hz, 1H), 7.40 (d, J = 4.4Hz, 1H), 7.45 -.57(m,4H),7.81(dd,J=8.4,1.6Hz,2H),8.32(d,J=0.8Hz,1H),9.89(d,J=7.2Hz,1H). 13 CNMR (100MHz, CDCl3): δ185.4,165.7,140.3,137.8,131.4,129.1,128.3,127.9,126.9,124.9,124.1,121.6,112.5,106.0,52.5.

[0062] The hydrogen spectrum characterization results of the product 3a are shown in Figure 1 , carbon spectrum characterization results refer to Figure 2 .

[0063] Example 2

[0064]

[0065] Synthesis of 3b: To a reaction tube, add methyl isonicotinate (0.4 mmol), 4-methoxyacetophenone (0.4 mmol), and maleic anhydride (0.4 mmol). Add 4 mL of N,N-dimethylacetamide solvent, followed by 0.04 mmol of nickel bromide and 0.048 mmol of 2,6-bis(4,5-dihydrooxazol-2-yl)pyridine. After thorough mixing, assemble the reaction apparatus (fill the reaction tube with nitrogen and purge air). The reaction was allowed to proceed for 6 hours. After the reaction was complete, the product was extracted and filtered. The filtrate was then concentrated by rotary evaporation and purified by silica gel column chromatography to afford a yellow solid (yield: 98.9 mg, yield: 80%). Mp: 146-147°C. 1 H NMR (400MHz, CDCl3): δ3.80 (s, 3H), 3.97 (s, 3H), 6.74 (d, J = 4.4Hz, 1H), 7.00 (d, J = 8 .7Hz,2H),7.40-7.43(m,2H),7.83-7.85(m,2H),8.30(s,1H),9.82(d,J=7.6Hz,1H). 13 CNMR (100MHz, CDCl3): δ185.3,165.7,162.4,136.4,132.8,131.2,127.7,126.2,124.0,121.6,113.6,112.5,105.6,55.3,52.4.

[0066] The hydrogen spectrum characterization results of the product 3b are shown in Figure 3 , carbon spectrum characterization results refer to Figure 4 .

[0067] Example 3

[0068]

[0069] Synthesis of 3c: To a reaction tube, methyl isonicotinate (0.4 mmol), 2-acetonaphthone (0.4 mmol), and maleic anhydride (0.4 mmol) were added, along with 4 mL of N,N-dimethylacetamide solvent. Then, 0.04 mmol of nickel bromide and 0.048 mmol of 2,6-bis(4,5-dihydrooxazol-2-yl)pyridine were added. After thorough mixing, the reaction apparatus was assembled (the reaction tube was filled with nitrogen and purged of air). The reaction was allowed to proceed for 6 hours. After the reaction was complete, the product was extracted and filtered. The filtrate was then concentrated by rotary evaporation and purified by silica gel column chromatography to afford a yellow solid (yield: 92.1 mg, yield: 70%). Mp: 158-159°C. 1H NMR (400MHz, CDCl3): δ3.96 (s, 3H), 6.78 (d, J = 4.4Hz, 1H), 7.46-7.50 (m, 2H), 7. 56-7.63(m,2H),7.91-7.98(m,4H),8.32(d,J=9.2Hz,2H),9.92(d,J=7.2Hz,1H). 13 C NMR (100MHz, CDCl3): δ185.1,165.6,137.6,137.3,134.7,132.4,129.9,129.1,128.2 ,127.9,127.8,127.7,127.1,126.7,125.6,124.8,124.2,121.6,112.5,106.0,52.5.

[0070] The product 3c hydrogen spectrum characterization results of the reaction are shown in Figure 5 , carbon spectrum characterization results refer to Figure 6 .

[0071] Example 4

[0072]

[0073] Synthesis of 3d: 4-Benzoylpyridine (0.4 mmol), acetophenone (0.4 mmol), and maleic anhydride (0.4 mmol) were added to a reaction tube. 4 mL of N,N-dimethylacetamide was then added, followed by 0.04 mmol of nickel bromide and 0.048 mmol of 2,6-bis(4,5-dihydrooxazol-2-yl)pyridine. After thorough mixing, the reaction apparatus was assembled (the reaction tube was filled with nitrogen and the air was purged). The reaction was allowed to proceed for 6 hours. After the reaction was complete, the product was extracted and filtered. The filtrate was then concentrated by rotary evaporation and purified by silica gel column chromatography to afford a yellow solid (yield: 101.4 mg, yield: 78%). Mp: 143-144°C. 1 H NMR (400MHz, CDCl3): δ6.76 (d, J = 4.8Hz, 1H), 7.41 (dd, J = 7.2, 2.0Hz, 2H), 7.49-7.64 (m, 6H), 7.82-7.84 (m, 4H), 8.02 (s, 1H), 9.94 (d, J = 7.7Hz, 1H). 13 C NMR (100MHz, CDCl3): δ194.3,185.3,140.1,137.4,137.0,132.6,131.5,13 1.4,129.7,129.1,128.5,128.3,128.1,126.9,124.1,122.6,113.1,106.4.

[0074] The 3D hydrogen spectrum characterization results of the reaction products can be found in Figure 7 , carbon spectrum characterization results refer to Figure 8 .

[0075] Example 5

[0076]

[0077] Synthesis of 3e: Pyridine (0.4 mmol), 4-chloroacetophenone (0.4 mmol), and maleic anhydride (0.4 mmol) were added to a reaction tube. 4 mL of N,N-dimethylacetamide was then added, followed by 0.04 mmol of nickel bromide and 0.048 mmol of 2,6-bis(4,5-dihydrooxazol-2-yl)pyridine. After thorough mixing, the reaction apparatus was assembled (the reaction tube was filled with nitrogen and purged of air). The reaction was allowed to proceed for 6 hours. After the reaction was complete, the product was extracted and filtered. The filtrate was then concentrated by rotary evaporation and purified by silica gel column chromatography to afford a yellow solid. Yield: 69.4 mg, 68% yield. Mp: 121-122°C. 1 H NMR (400MHz, CDCl3): δ6.55 (d, J=4.8Hz, 1H), 6.98 (td, J=7.2, 0.8Hz, 1H), 7.22 (td, J=7.6, 1.2Hz, 1H), 7.30 (d,J=4.4Hz,1H),7.46(d,J=8.4Hz,2H),7.57(d,J=8.8Hz,1H),7.76(d,J=8.4Hz,2H),9.94(d,J=7.2Hz,1H). 13 C NMR (100MHz, CDCl3): δ182.9,139.7,139.1,137.0,130.3,128.9,128.4,126.6,124.5,122.3,118.8,114.0,102.8.

[0078] The product 3e hydrogen spectrum characterization results of the reaction are shown in Figure 9 , carbon spectrum characterization results refer to Figure 10 .

[0079] Example 6

[0080]

[0081] Synthesis of 3f: Isoquinoline (0.4 mmol), acetophenone (0.4 mmol), and maleic anhydride (0.4 mmol) were added to a reaction tube. 4 mL of N,N-dimethylacetamide was then added, followed by 0.04 mmol of nickel bromide and 0.048 mmol of 2,6-bis(4,5-dihydrooxazol-2-yl)pyridine. After thorough mixing, the reaction apparatus was assembled (the reaction tube was filled with nitrogen and purged of air). The reaction was allowed to proceed for 6 hours. After the reaction was complete, the product was extracted and filtered. The filtrate was then concentrated by rotary evaporation and purified by silica gel column chromatography to afford a yellow solid (yield: 67.2 mg, yield: 62%). Mp: 138-139°C. 1 H NMR (400MHz, CDCl3): δ7.06 (d, J = 4.4Hz, 1H), 7.11 (d, J = 7.6Hz, 1H), 7.32 (d, J = 4.4Hz, 1H), 7.48-7. 57(m,5H),7.73(dd,J=7.2,1.6Hz,1H),7.84-7.87(m,2H),8.16-8.20(m,1H),9.61(d,J=7.6Hz,1H). 13 C NMR (100MHz, CDCl3): δ185.4,140.6,136.9,131.0,129.1,128.9,128.2,128.0,127.6,126.9,126.0,125.8,124.6,123.6,113.4,101.9.

[0082] The 3f hydrogen spectrum characterization results of the reaction products can be found in Figure 11 , carbon spectrum characterization results refer to Figure 12 .

[0083] Example 7

[0084]

[0085] Synthesis of 3g: Add isoquinoline (0.4 mmol), 4-methoxyacetophenone (0.4 mmol), and maleic anhydride (0.4 mmol) to a reaction tube. Add 4 mL of N,N-dimethylacetamide solvent, then add 0.04 mmol of nickel bromide and 0.048 mmol of 2,6-bis(4,5-dihydrooxazol-2-yl)pyridine, respectively. After thorough mixing, assemble the reaction apparatus (fill the reaction tube with nitrogen and purge air). React for 6 hours. After the reaction is complete, extract and filter. The filtrate is concentrated by rotary evaporation and purified by silica gel column chromatography to obtain a yellow solid. Yield: 78.3 mg, yield: 65%. Mp: 182-183°C. 1H NMR (400MHz, CDCl3): δ3.89(s,3H),7.00(d,J=8.8Hz,2H),7.03(d,J=4.4Hz,1H),7.09(d,J=7.6Hz,1H),7.31(d,J=4.4Hz ,1H),7.53-7.57(m,2H),7.70(dd,J=8.4,1.6Hz,1H),7.85(d,J=8.4Hz,2H),8.16(d,J=7.2Hz,1H),9.53(d,J=7.6Hz,1H). 13 C NMR (100MHz, CDCl3): δ184.4,162.2,136.4,133.1,131.5,128.8,127.7,127.6,126.9,125.6,125.2,124.9,123.5,113.4,113.1,101.6,55.4.

[0086] The hydrogen spectrum characterization results of the product 3g are shown in Figure 13 , carbon spectrum characterization results refer to Figure 14 .

[0087] Example 8

[0088]

[0089] Synthesis of 3h: Quinoline (0.4 mmol), acetophenone (0.4 mmol), and maleic anhydride (0.4 mmol) were added to a reaction tube. 4 mL of N,N-dimethylacetamide was then added, followed by 0.04 mmol of nickel bromide and 0.048 mmol of 2,6-bis(4,5-dihydrooxazol-2-yl)pyridine. After thorough mixing, the reaction apparatus was assembled (the reaction tube was filled with nitrogen and the air was purged). The reaction was allowed to proceed for 6 hours. After the reaction was complete, the product was extracted and filtered. The filtrate was then concentrated by rotary evaporation and purified by silica gel column chromatography to afford a yellow solid. Yield: 75.7 mg, 70% yield. Mp: 92-93°C. 1 H NMR (400MHz, CDCl3): δ6.55(d,J=4.4Hz,1H),7.20(d,J=4.4Hz,1H),7.38-7.43(m,3H),7.48-7.54(m,3H ),7.61(t,J=7.6Hz,1H),7.71(dd,J=8.0,1.2Hz,1H),8.06(dd,J=8.0,1.2Hz,2H),8.17(d,J=8.4Hz,1H). 13C NMR (100MHz, CDCl3): δ184.3,139.5,139.5,133.7,132.1,130.1,128.9,128.5,128.5,128.1,128.1,125.7,125.0,124.6,120.1,117.8,104.1.

[0090] The 3h hydrogen spectrum characterization results of the reaction products can be found in Figure 15 , carbon spectrum characterization results refer to Figure 16 .

[0091] The above are only preferred embodiments of the present application. The scope of protection of the present application is not limited to the above embodiments. All technical solutions based on the principles of the present application are within the scope of protection of the present application. It should be noted that for those skilled in the art, various improvements and modifications that do not depart from the principles of the present application should be considered within the scope of protection of the present application.

Claims

1. A method for preparing a 3-substituted indolizine derivative, characterized in that: The preparation method is as shown in Reaction Formula 1. Wherein, R1 is selected from hydrogen, C1-C6 unsubstituted alkyl, ester group, benzophenone group and a benzene ring fused to one side of the pyridine ring; R2 is selected from hydrogen, halogen, C1-C6 alkoxy, and a benzene ring fused to one side; Step 1: Add a pyridine derivative structure such as Formula 1, an acetophenone derivative structure such as Formula 2, nickel bromide, maleic anhydride, 2,6-bis(4,5-dihydrooxazol-2-yl)pyridine and N,N-dimethylacetamide into a reaction tube; Step 2: Add N,N-dimethylacetamide to the reaction tube, seal the tube and react under a nitrogen atmosphere to obtain a product mixture in one step; After the reaction in step 3 is completed, the product mixture obtained in step 2 is extracted and filtered, and the obtained filtrate is concentrated and separated to obtain a 3-substituted indolizine derivative having a structure as shown in Formula 3.

2. The method for preparing a 3-substituted indolizine derivative according to claim 1, wherein The chemical structure of the pyridine derivative is selected from any one of the following structural formulas:

3. The method for preparing a 3-substituted indolizine derivative according to claim 1, wherein The chemical structure of the acetophenone derivative is selected from any one of the following structural formulas:

4. The method for preparing a 3-substituted indolizine derivative according to claim 1, wherein The structural formula of the 3-substituted indolizine derivative is:

5. The method for preparing a 3-substituted indolizine derivative according to claim 1, wherein The molar ratio of the pyridine derivative, the acetophenone derivative and maleic anhydride added in the reaction shown in Reaction Formula 1 is 1:1:

1.

6. The method for preparing 3-substituted indolizine derivatives according to claim 1, characterized in that: The molar ratio of the pyridine derivative to the nickel bromide added in the reaction shown in Reaction Formula 1 is 1:0.

1.

7. The method for preparing a 3-substituted indolizine derivative according to claim 1, wherein The molar ratio of the pyridine derivative to the 2,6-bis(4,5-dihydrooxazol-2-yl)pyridine added in the reaction shown in Reaction Formula 1 is 1:0.

12.

8. The method for preparing a 3-substituted indolizine derivative according to claim 1, wherein The preparation method further includes a step of separating and purifying the product after the reaction is completed. The separation and purification step is to filter the obtained filtrate and use vacuum concentration to obtain the crude product through column chromatography separation to obtain a yellow solid 3-substituted indolizine derivative.

9. The method for preparing a 3-substituted indolizine derivative according to claim 1, wherein: In step 3, the crude product is separated by column chromatography to obtain a yellow solid 3-substituted indolizine derivative; wherein the yield of the 3-substituted indolizine derivative product is 62%-80%.

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