A method for synthesizing 1,2-disubstituted indoleazine derivatives by reacting a pyridine ring with propynyl ester.

Abstract

This invention develops a method for synthesizing 1,2-disubstituted indoleazine derivatives by reacting a pyridine ring with a propynyl ester. The method uses pyridine compounds and propynyl esters as raw materials, with calcium oxide as a base, and yields the 1,2-disubstituted indoleazine derivatives under a nitrogen atmosphere. This method has advantages such as low cost, mild reaction conditions, simple operation, and low pollution, and has potential for industrial application. This method provides a cheap and simple route for the preparation of 1,2-disubstituted indoleazine derivatives.

Description

Technical Field

[0001] This invention relates to a method for synthesizing 1,2-disubstituted indoleazine derivatives by reacting a pyridine ring with a propargyl ester, belonging to the field of organic synthesis. The reaction process is simple, utilizing activated alkynes to convert pyridine compounds into 1,2-disubstituted indoleazine derivatives. Background Technology

[0002] Indoleazine rings are essential core structural units in many drug molecules, and these substances possess potential biological activity. Furthermore, due to their large conjugated structures, indoleazine compounds are frequently used in the synthesis of dyes and as fluorescent probes. The synthesis of indoleazine skeletons primarily uses alkynyl or alkenylpyridine derivatives as starting materials, constructing them through reactions such as cyclocondensation, cycloaddition, cyclization / elimination, and cycloisomerization. However, these reactions have certain drawbacks: the required starting materials are relatively complex, requiring one or more steps, making the process cumbersome and expensive. Pyridine compounds and propynyl esters are commonly used chemicals, and using pyridine compounds and propynyl esters as starting materials for the synthesis of indoleazine skeletons offers advantages such as readily available starting materials, simple operation, and simple reaction conditions. Moreover, the formed indoleazine ring contains aliphatic ester groups at positions 1 and aromatic ester groups at positions 2, providing numerous reaction sites and a high potential for transformation. Summary of the Invention

[0003] To address the shortcomings of existing synthetic methods, we have developed a method for synthesizing 1,2-disubstituted indoleazine derivatives by reacting a pyridine ring with propargyl ester. This method uses pyridine compounds and propargyl ester as raw materials, with calcium oxide as a base, and yields the 1,2-disubstituted indoleazine derivative under a nitrogen atmosphere. This method has advantages such as low cost, mild reaction conditions, simple operation, and low pollution, making it feasible for industrial production. Its key feature is the use of calcium oxide as a base, pyridine compound I and propargyl ester II as reactants, and an effective reaction at 60-120℃ under a nitrogen atmosphere, yielding a high yield of 1,2-disubstituted indoleazine derivative III within 0.5-2 hours.

[0004]

[0005] Wherein R 1 R has functional groups such as hydrogen, methyl, methoxy, and phenyl. 2 It has functional groups such as methyl, ethyl, tert-butyl, and benzyl.

[0006] In the above synthesis method, the amount of alkali used is 1.0-1.4 equivalents, preferably calcium oxide; the reaction time is 0.5-2h, preferably 1h; and the reaction temperature is 60-120℃, preferably 60℃.

[0007] The present invention provides a new, low-cost, and simple method for synthesizing 1,2-disubstituted indoleazine derivatives by reacting a pyridine ring with a propynyl ester. Its advantages are: readily available raw materials, simple operation, and simple reaction conditions.

[0008] Reaction principle

[0009] Attached Figure Description

[0010] Appendix Figure 1 The diagram shown is a route for preparing 1,2-disubstituted indoleazine derivatives provided by this invention. Detailed Implementation

[0011] The present invention provides a novel and highly efficient method for synthesizing 1,2-disubstituted indoleazine derivatives. Please refer to the attached diagram: A pyridine compound, propargyl ester, and calcium oxide are placed in a reaction vessel and reacted at 60°C under nitrogen atmosphere for 1 hour. After the reaction is complete, the target product is obtained by column chromatography. The invention is further illustrated below with specific preparation examples:

[0012] Conditional Filtering

[0013]

[0014] Example 1:

[0015] Add pyridine compound I (R) to a 10 mL reaction tube 1 =H)2mL, propynate II (R 2 =methyl) 0.4 mmol, calcium oxide 0.24 mmol, the reaction was carried out at 60 °C with stirring for 1 h. After the reaction was completed, the target compound III (R) was obtained by column chromatography. 1 =H,R 2 =methyl), to give a brown solid, with a yield of 52%.

[0016] Characterization data: 1 H NMR (400MHz, CDCl3) δ7.79 (dd, J=7.2, 1.2Hz, 1H), 7.78 (s, 1H), 7.32 (dq, J=9.1, 1.0Hz, 1H), 6.67 (ddd,J=9.3,6.5,1.1Hz,1H),6.51(td,J=6.7,1.2Hz,1H),4.05(s,2H),3.85(s,3H),3.69(s,3H). 13C NMR (101MHz, CDCl3) δ172.43,165.48,131.55,125.30,118.10,117.87,117.60,116.13,112.38,106.63,51.87,51.18,29.98.HRMS(ESI)m / z:[M+Na] + calcd for C 13 H 13 NNaO4 + ,270.0742;Found,270.0746.

[0017] Example 2:

[0018] Add pyridine compound I (R) to a 10 mL reaction tube 1 =H)2mL, propynate II (R 2 =Ethyl) 0.4 mmol, calcium oxide 0.24 mmol, the reaction was carried out at 60 °C with stirring for 1 h. After the reaction was completed, the target compound III (R) was obtained by column chromatography. 1 =H,R 2 =ethyl), yielding a black solid in a yield of 49%. Example 3:

[0019] Add pyridine compound I (R) to a 10 mL reaction tube 1 =H)2mL, propynate II (R 2 =0.4 mmol of tert-butyl and 0.24 mmol of calcium oxide were added, and the reaction was carried out with stirring at 60 °C for 1 h. After the reaction was completed, the target compound III (R) was obtained by column chromatography. 1 =H,R 2 =tert-butyl), yielding a black solid with a yield of 52%.

[0020] Example 4:

[0021] Add pyridine compound I (R) to a 10 mL reaction tube 1 =H)2mL, propynate II (R 2 =Benzyl) 0.4 mmol, calcium oxide 0.24 mmol, the reaction was carried out at 60 °C with stirring for 1 h. After the reaction was completed, the target compound III (R) was obtained by column chromatography. 1 =H,R 2 =benzyl), yielding a black solid with a yield of 61%. Example 5:

[0022] Add pyridine compound I (R) to a 10 mL reaction tube 1 =4-methyl) 2 mL, propynate II (R 2=methyl) 0.4 mmol, calcium oxide 0.24 mmol, the reaction was carried out at 60 °C with stirring for 1 h. After the reaction was completed, the target compound III (R) was obtained by column chromatography. 1 =H,R 2 =ethyl), yielding a black solid in a yield of 27%. Example 6:

[0023] Add pyridine compound I (R) to a 10 mL reaction tube 1 =4-methoxy)2mL, propynate II (R 2 =Benzyl) 0.4 mmol, calcium oxide 0.24 mmol, the reaction was carried out at 60 °C with stirring for 1 h. After the reaction was completed, the target compound III (R) was obtained by column chromatography. 1 =4-methoxy, R 2 =benzyl), yielding a grayish-green solid with a yield of 21%.

[0024] Example 7:

[0025] Add quinoline I (R) to a 10 mL reaction tube 1 =Phenyl) 2mL, propynate II (R 2 =methyl) 0.4 mmol, calcium oxide 0.24 mmol, the reaction was carried out at 60 °C with stirring for 1 h. After the reaction was completed, the target compound III (R) was obtained by column chromatography. 1 =Phenyl, R 2 =methyl), to give a black solid, with a yield of 17%.

[0026] Example 8:

[0027] Add quinoline I (R) to a 10 mL reaction tube 1 =Phenyl) 2mL, propynate II (R 2 =Ethyl) 0.4 mmol, calcium oxide 0.24 mmol, the reaction was carried out at 60 °C with stirring for 1 h. After the reaction was completed, the target compound III (R) was obtained by column chromatography. 1 =Phenyl, R 2 =ethyl), yielding a dark red solid in 38% yield. Example 9:

[0028] Add isoquinoline I (R) to a 10 mL reaction tube 1 =Phenyl) 2mL, propynate II (R 2 =methyl) 0.4 mmol, calcium oxide 0.24 mmol, the reaction was carried out at 60 °C with stirring for 1 h. After the reaction was completed, the target compound III (R) was obtained by column chromatography. 1 =Phenyl, R 2 =methyl), yielding a brown solid in 74% yield. Example 10:

[0029] Add isoquinoline I (R) to a 10 mL reaction tube 1 =Phenyl) 2mL, propynate II (R 2 =Benzyl) 0.4 mmol, calcium oxide 0.24 mmol, the reaction was carried out at 60 °C with stirring for 1 h. After the reaction was completed, the target compound III (R) was obtained by column chromatography. 1 =Phenyl, R 2 =benzyl), to give a yellowish-brown solid in a yield of 69%.

[0030] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are specific and detailed, they should not be construed as limiting the scope of the present invention. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these modifications and improvements all fall within the scope of protection of the present invention. Therefore, the scope of protection of this patent should be defined by the appended claims.

Claims

1. A method for synthesizing 1,2-disubstituted indoleazine derivative III by reacting a pyridine ring with a propynyl ester, characterized in that... Using calcium oxide as a base, pyridine compound I and propargyl ester II as reactants, under nitrogen atmosphere, the reaction was carried out at 60-120℃ for 0.5-2 h to obtain 1,2-disubstituted indoleazine derivative III: Wherein R 1 R is a hydrogen, methyl, methoxy, or phenyl functional group. 2 It has methyl, ethyl, tert-butyl or benzyl functional groups.

2. The method according to claim 1, characterized in that, The amount of alkali used is 1.0-1.4 equivalents; the temperature is raised to 60℃ and the reaction is carried out for 1 h.

Images