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A synthetic method and compound technology, applied in the field of synthesis of carboline compounds, can solve the problems of expensive reagents, high toxicity, difficult preparation or acquisition of starting materials, etc.
Active Publication Date: 2018-07-13
GUIZHOU MEDICAL UNIV
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[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.
However, there are few synthetic methods for β-carbolin, mainly using 1-pyridylbenzotriazole intermediates to generate target compounds under the action of ultraviolet light or zinc chloride, which is difficult to operate and highly toxic, and is inconvenient for large-scale synthesis
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Embodiment 1
[0072] Example 1: Taking the preparation of 2-methyl-3-bromo-9H-pyridin[2,3-b]indole as an example
[0073] 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 5-bromo-o-nitroanilino-6-picoline with a yield of 66%;
[0074] (2) Dissolve 5-bromo-o-nitroanilino-6-picoline (2.41g, 6.8mmol) in EtOAc (20mL), add SnCl 2 (6.46g, 34.08mmol), the mixture was stirred and refluxed at 80°C for 3h, cooled, dissolved in 20mL of water, and dissolved in K 2 CO 3 Adjust PH=9, filter, and extract t...
Embodiment 1-1
[0078] In the aforementioned step (1), the mass ratio of 2,5-dibromo-6 picoline to o-nitroaniline is selected to be 1:1, 2:1, 3:1; the volumetric mass of solvent DMF and o-nitroaniline The ratio is 15:1, 16:1, 17:1, 18:1; the molar ratio of 5% Pd / C to o-nitroaniline is 0.2:1, 0.3:1, 0.4:1, 0.5:1; t- The molar ratio of BuOK to o-nitroaniline is 2:1, 3:1, 4:1. The product 5-bromo-o-nitroaniline-6-picoline was obtained, and the average yield was 64.8%. The yield was 42.5%, which was not ideal.
Embodiment 1-2
[0080] In the foregoing step (2), the volume (mL) molar ratio of EtOAc and 5-bromo-o-nitroanilino-6-picoline is selected to be 20:1, 30:1, 40:1; iron powder-chlorination The molar ratios of amine (1:3) to 5-bromo-o-nitroanilino-6-picoline are 4.5:1, 5:1, 5.5:1, 6:1. The average yield of the product 5-bromo-o-aminoanilino-6-picoline is more than 90%.
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Abstract
The invention discloses a synthesizing method of a carbolin compound. The synthesizing method comprises the following steps of enabling pyridine derivatives, o-nitroaniline and o-nitroaniline derivative thereof to generate coupling and reduction reaction, or directly generate coupling reaction with benzotriazole; converting into a diazotized triazole intermediate; finally, treating the obtained intermediate after reaction under the action of a reagent, so as to obtain substituted carbolin. The synthesizing method has the characteristics that on the basis of the improved Graebe-Ullmann method,the reaction raw materials, reaction reagents and conditions are preferably selected; the selectivity of target products is enhanced, the reaction time is shortened, the reaction temperature is reduced, the number of impurities is fewer, the yield rate is high, and the like; the method is suitable for synthesizing the substituted alpha-carbolin and beta-carbolin, so as to provide a simple and reliable selection plan 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 synthesis method of carboline compounds. 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 called α-carboline and α-carbolin, and 3-carboline is also called β-carbolin. Its natural products have anti-inflammatory, bactericidal, cytotoxic, A series of biological activities such as anticancer properties, activity of central nervous system and cardiovascular system. [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 provi...
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