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Synthesizing method of alpha-carboline compound

A synthesis method and compound technology, applied in the field of synthesis of α-carbolins, can solve the problems of difficult preparation or acquisition of starting materials, harsh reaction conditions, lack of flexibility, etc., to achieve increased yield and mild reaction conditions , the effect of shortening the reaction time

Inactive Publication Date: 2017-09-29
GUIZHOU MEDICAL UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] Therefore, although there are many schemes for the synthesis of α-carbolin, there are still some defects, such as low yield, expensive reagents, difficulty in preparing or obtaining starting materials, or lack of flexibility, harsh reaction conditions, etc.

Method used

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  • Synthesizing method of alpha-carboline compound
  • Synthesizing method of alpha-carboline compound
  • Synthesizing method of alpha-carboline compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] Example 1: Taking the preparation of 2-methyl-3-bromo-9H-pyridin[2,3-b]indole as an example

[0053] The synthesis process steps are: (1) Dissolve the compound 2,5-dibromo-6-picoline (2.70g, 10.76mmol) and o-nitroaniline (1.78g, 12.91mmol) in DMF (30mL), add t -BuOK (3.62g, 32.28mmol), 5%Pd / C (474.68mg, 2.96mmol), evacuate air and protect with nitrogen, stir the mixture at 120°C for 5h, cool, add 20mL water to dissolve, extract with EtOAc, The extract was washed successively with water and saturated brine, anhydrous Na 2 SO 4 Dry, concentrate under reduced pressure, and purify the residue by silica gel column chromatography to obtain the product 2-(2-nitroanilino)-5-bromo-6-methylpyridine with a yield of 65%;

[0054] (2) Dissolve the compound 2-(2-nitroanilino)-5-bromo-6-methylpyridine (2.41g, 6.8mmol) in EtOAc (20mL), add SnCl 2 (6.46g, 34.08mmol), the mixture was stirred and refluxed at 80°C for 1.5h, cooled, dissolved in 20mL of water, and dissolved in K 2 CO 3...

Embodiment 2

[0058] Step (1) The reaction temperature is 100°C, the reaction time is 10h, the reaction solvent is DMSO, CuI is the catalyst, and t-BuONa is the acid scavenger to obtain 2-(2-nitrophenylamino)-5-bromo-6-methyl The yield of pyridine was 64.7%.

[0059] Step (2) The reaction temperature is 100°C, the reaction time is 2h, the reaction solvent is tetrahydrofuran, iron powder-ammonium chloride is a reducing agent, and 2-(2-aminophenylamino)-5-bromo-6-picoline is obtained. The yield was 91%.

[0060] Step (3) The reaction temperature is -10°C, the reaction time is 3h, the solvent is propanol, and concentrated HCl is changed to hyposulfuric acid to obtain 1-(5-bromo-6-methyl-2-pyridyl)-1H-benzene The yield of triazole was 96.1%.

[0061] Step (4) The reaction temperature is 180°C, the reaction time is 0.5h, the polyphosphoric acid is changed to pyrophosphoric acid, and the yield of 2-methyl-3-bromo-9H-pyridine[2,3-b]indole is 53.7% .

[0062] Other steps are with embodiment 1. ...

Embodiment 3

[0064] Step (1) The reaction temperature is 140°C, the reaction time is 1h, the reaction solvent is toluene, Ni is the catalyst, and t-BuONa is the acid scavenger to obtain 2-(2-nitrophenylamino)-5-bromo-6-methyl The yield of pyridine was 62.8%.

[0065] Step (2) The reaction temperature is 100°C, the reaction time is 2h, the reaction solvent is tetrahydrofuran, iron powder-ammonium chloride is a reducing agent, and 2-(2-aminoanilino)-5-bromo-6-methylpyridine is obtained. The yield was 91%.

[0066] Step (3) The reaction temperature is -10°C, the reaction time is 3h, the solvent is propanol, and concentrated HCl is changed to hyposulfuric acid to obtain 1-(5-bromo-6-methyl-2-pyridyl)-1H-benzene The yield of triazole was 96.1%.

[0067] Step (4) The reaction temperature was 100°C, the reaction time was 1 h, and the polyphosphoric acid was changed to pyrophosphoric acid to obtain 2-methyl-3-bromo-9H-pyridin[2,3-b]indole in a yield of 64.8%.

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Abstract

The invention discloses a synthesizing method of an alpha-carboline compound. The synthesizing method comprises the following steps of firstly, enabling ortho-nitroaniline or a derivative thereof to perform typical Ullmann C-N coupling reaction under the action of a catalyst, and performing reduction reaction under the action of a reductant; reacting with nitrous acid under the existence of inorganic acid, and converting into a diazotized triazole intermediate; finally, treating the obtained intermediate after reaction under the action of pyrophosphoric acid or polyphosphoric acid, so as to obtain a target product, namely alpha-carboline or substituted alpha-carboline. The synthesizing method has the characteristics that on the basis of using the improved Graebe-Ullmann method to synthesize the alpha-carboline, the reaction raw materials, reaction reagents and reaction conditions are preferably selected, the selectivity of the target product is enhanced, the reaction time is shortened, the reaction temperature is reduced, the yield rate is increased, the amount of impurities in products is small, the yield rate is high, and the like; the method is conveniently suitable for synthesizing the alpha-carboline and the substituted alpha-carboline, so as to provide a simple and reliable selection solution for the obtaining and utilization of the compound.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a method for synthesizing α-carbolins. Background technique [0002] Carboline, also known as carboline and diazafluorene, is a heterocyclic compound in which the pyridine ring and the pyrrole ring of indole are fused. There are currently 4 isomers, of which 2-carboline is also known as α-carboline and α-carbolin, and its natural products have anti-inflammatory, bactericidal, cytotoxic, anti-cancer properties, activity, central nervous system and cardiovascular system activity and other biological activities. [0003] The synthetic route of α-carbolin has been reported in several cases. In 1924, Robinson et al first reported the improved Graebe-Ullmann method to synthesize α-carbolin, that is, o-phenylenediamine and 2-chloropyridine were heated to 140°C in ethanol and then coupled with nitrous acid in an acidic environment provided by hydrochloric acid. The reaction is ...

Claims

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Application Information

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IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 周孟廖祥明刘琴李芮张荣红张宝廖尚高徐国波何迅李靖李勇军王永林
Owner GUIZHOU MEDICAL UNIV
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