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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.
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
Method used
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Embodiment 1
[0072] Example 1: Taking the preparation of 2-methyl-3-bromo-9H-pyridine[2,3-b]indole as an example
[0073] The synthetic process steps are: (1) Compound 2,5-dibromo-6-picoline (2.70g, 10.76mmol) and o-nitroaniline (1.78g, 12.91mmol) are dissolved in DMF (30mL), and t -BuOK (3.62 g, 32.28 mmol), 5% Pd / C (474.68 mg, 2.96 mmol), vented and protected with nitrogen, the mixture was stirred at 120 °C for 5 h, cooled, dissolved in 20 mL of water, extracted with EtOAc, The extract was washed with water and saturated brine successively, and 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-methylpyridine in a yield of 66%;
[0074] (2) 5-Bromo-o-nitroanilino-6-methylpyridine (2.41 g, 6.8 mmol) was dissolved in EtOAc (20 mL), and SnCl was added 2 (6.46 g, 34.08 mmol), the mixture was stirred and refluxed at 80 °C for 3 h, cooled, dissolved in 20 mL of water, and diss...
Embodiment 1-1
[0078] In the aforementioned step (1), the mass ratio of 2,5-dibromo-6 picoline and o-nitroaniline is selected to be 1:1, 2:1, 3:1; the volume mass of solvent DMF and o-nitroaniline The ratios are 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 was 2:1, 3:1, 4:1. The product 5-bromo-o-nitroaniline-6-methylpyridine was obtained, and the average yield was 64.8%; but the molar ratio of acid scavenger t-BuOK and o-nitroaniline was selected to be 1:1, and the average yield of the product was 1:1. The yield was 42.5%, which was not ideal.
Embodiment 1-2
[0080] In the aforementioned step (2), the volume (mL) molar ratio of EtOAc and 5-bromo-o-nitroanilino-6-picoline was selected as 20:1, 30:1, 40:1; iron powder-chlorinated The molar ratio of amine (1:3) to 5-bromo-o-nitroanilino-6-methylpyridine was 4.5:1, 5:1, 5.5:1, 6:1. The average yield of the product 5-bromo-o-aminoanilino-6-methylpyridine is over 90%.
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Abstract
The invention discloses a method for synthesizing carboline compounds, which uses pyridine derivatives to carry out coupling and reduction reactions with o-nitroaniline and its derivatives, or directly reacts with benzotriazole to convert them into heavy Nitriding the triazole intermediate, and finally reacting the obtained intermediate under the action of a reagent to obtain a substituted carbolin. Based on the improved Graebe-Ullmann method, the process optimizes the reaction raw materials, reaction reagents and conditions, and has the characteristics of enhancing the selectivity of the target product, shortening the reaction time, reducing the reaction temperature, less impurities and high yield. At the same time, the method is applicable to the synthesis of substituted α-carbolins and β-carbolins, and provides another simple and reliable selection scheme for the acquisition and utilization of such compounds.
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...
Claims
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