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Method for preparing aromatic heterocycle-containing methylene indolizine derivatives

A technology for methylene indolizine and derivatives, which is applied in the field of synthesizing pyrazine derivatives, can solve the problems of inability to meet large-scale production requirements, complicated and complicated operations, and high synthesis costs, and achieves that raw materials are readily available and economical, and the operation is simple. simple steps

Inactive Publication Date: 2018-06-08
赵艳阳
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The problem of this technical scheme is that the yield is low, the operation is cumbersome and complicated, the synthesis cost is high, and it cannot meet the requirements of large-scale production

Method used

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  • Method for preparing aromatic heterocycle-containing methylene indolizine derivatives
  • Method for preparing aromatic heterocycle-containing methylene indolizine derivatives
  • Method for preparing aromatic heterocycle-containing methylene indolizine derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] In a 50 mL round bottom flask, add 1 mmol 5-methyl-2-phenylindazine (207 mg), 1 mmol β-pyridinecarbaldehyde (107 mg), 1.3 mmol Hanstedil (330 mg), 94 mmol toluene (10 mL), stirred and dissolved, then added 0.1 mmol p-toluenesulfonic acid (17 mg), stirred at 60°C for 24 hours, cooled to room temperature, spin-dried the solvent under reduced pressure, and separated by column chromatography to obtain 277 mg of brown product with a yield of 93 %. Structural formula:

[0041]

[0042] Chinese name: 5-Methyl 2-phenyl-3-(pyridine-3-methylene) indazine

[0043] Appearance: brown solid

[0044] Melting point: 159-162 °C

[0045] H NMR spectrum (400MHz , CDCl 3 , internal standard: TMS); δ: 8.51 – 8.36 (m, 2H), 7.45(dt, J = 15.8, 7.8 Hz, 4H), 7.39 – 7.33 (m, 3H), 7.25 (d, J = 7.8 Hz, 1H),7.17 (dd, J = 7.7, 4.7 Hz, 1H), 6.66 (dd, J = 8.9, 6.6 Hz, 1H), 6.42 (t, J =6.7 Hz, 1H), 4.30 (s, 2H), 2.38 (s, 3H); see results in figure 1 .

[0046] C NMR spectrum (400MHz ...

Embodiment 2

[0048] Add 1 mmol 5-methyl-2-phenylindazine (207 mg), 1 mmol γ-pyridinecarbaldehyde (107 mg), 1.3 mmol Hanstedil (330 mg), 47 mmol toluene ( 5 mL), stirred and dissolved, then added 0.1 mmol p-toluenesulfonic acid (17 mg), stirred at 60°C for 18 h, cooled to room temperature, spin-dried the solvent, and separated by column chromatography to obtain 283 mg of a brown solid product with a yield of 95 %. Structural formula:

[0049]

[0050] Chinese name: 5-Methyl 2-phenyl-3-(pyridine-4-methylene) indazine

[0051] Appearance: brown solid

[0052] Melting point: 168-171 ℃

[0053] H NMR spectrum (400MHz , CDCl 3, internal standard: TMS); δ: 8.50 (d, J = 5.9 Hz, 2H), 7.51– 7.34 (m, 7H), 6.99 (d, J = 5.5 Hz, 2H), 6.68 (dd, J = 8.8, 6.5 Hz, 1H), 6.43 (t, J = 6.8 Hz, 1H), 4.28 (s, 2H), 2.39 (s, 3H); see results in image 3 .

[0054] C NMR spectrum (400MHz , CDCl 3 , internal standard: TMS); δ: 150.06, 147.89, 135.43, 130.12, 129.47, 128.40, 126.73, 123.19, 121.65, 1...

Embodiment 3

[0056] Add 1 mmol 5-methyl-2-phenylindazine (207 mg), 1 mmol α-pyridinecarbaldehyde (107 mg), 1.3 mmol Hanstedil (330 mg), 65.8 mmol toluene into a 50 mL round bottom flask (7 mL), stirred to dissolve, then added 0.05mmol p-toluenesulfonic acid (8.5mg,), stirred at 60°C for 12h, cooled to room temperature, spin-dried the solvent, separated by column chromatography to obtain 269 mg of brown solid product, produced The rate is 90%. structural formula

[0057]

[0058] Chinese name: 5-methyl 2-phenyl-3-(pyridine-2-methylene)indolizine

[0059] Appearance: brown solid

[0060] Melting point: 164-166 ℃

[0061] H NMR spectrum (400MHz , CDCl 3 , internal standard: TMS); δ: 8.59 (d, J = 4.2 Hz, 1H), 7.71(d, J = 7.0 Hz, 1H), 7.60 – 7.35 (m, 7H), 7.19 – 7.02 (m, 1H), 6.82 (d, J =7.8 Hz, 1H), 6.69 – 6.61 (m, 1H), 6.42 (t, J = 6.7 Hz, 1H), 4.49 (s, 2H), 2.40 (s, 3H); see results in Figure 5 .

[0062] C NMR spectrum (400MHz , CDCl 3 , Internal standard: TMS); Δ: 158.94...

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Abstract

The invention discloses a method for preparing aromatic heterocycle-containing methylene indolizine derivatives. The method comprises the following steps: (1) weighing raw materials according to a molar ratio: 1 part of 5-methyl-2-phenyl indolizine, 1 part of aromatic heterocyclic aldehyde, 1.3 parts of hantzsch ester, 47-94 parts of methylbenzene and 0.05-0.1 part of p-methylbenzene sulfonic acid; (2) sequentially dissolving the 5-methyl-2-phenyl indolizine, aromatic heterocyclic aldehyde and hantzsch ester into the methylbenzene, adding the catalyst p-methylbenzene sulfonic acid, and stirring at a temperature of 60 DEG C for 12-24 hours; (3) cooling a solution obtained in the (2) to a room temperature, and performing reduced pressure spin-drying on the solvent; and (4) performing columnchromatography isolation on the solid phase obtained in the (3), thereby obtaining the aromatic heterocycle-containing methylene indolizine derivatives. According to the method disclosed by the invention, the needed raw materials are readily available and economic, usage of a precious metal serving as the catalyst is saved, the synthesizing cost is further reduced, and possible heavy metal pollution is eliminated. The method disclosed by the invention is a three-component one-pot synthesis method, and is simple in step, easy to operate and high in yield.

Description

technical field [0001] The invention belongs to the technical field of organic medicine synthesis, in particular to a method for synthesizing pyrazine derivatives. Background technique [0002] In organic synthesis and drug synthesis, pyrazine and its derivatives are important raw materials for the synthesis of active natural products, and have important biological and pharmacological activities such as antibacterial, antihypertensive, antitumor, and antiarrhythmic, so they have received extensive attention. . However, how to synthesize pyrazine and its derivatives economically and effectively is a hotspot. At present, there are many preparation methods for pyrazine and its derivatives, the main method is to introduce a new group at the 3-position of indolizine, such as: (1) Org. Lett.,6(7), 1159- 1162,2004 [0003] [0004] Another example: (2) Org. Biomol. Chem., 13, 10986–10994, 2015 [0005] [0006] Also like: (3) Org. Biomol. Chem., 10, 7108–7119, 2012 ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 赵艳阳杨志刚张永坡
Owner 赵艳阳