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A preparation process and application of β-carboline compound for preparing anti-renal fibrosis drug and/or anti-chronic kidney disease drug

A technology for chronic kidney disease and preparation technology, which is applied in the field of preparation of β-carboline compounds, and can solve problems such as harsh reaction conditions, unsatisfactory preparation methods, and low yields

Active Publication Date: 2020-09-29
SHANGHAI TREEFUL PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Due to the complex structure of β-carboline compounds, the preparation method of β-carboline compounds in the above prior art is not ideal, for example, for CN106995440A, CN107163041A, CN107141285A, the corresponding product 1-pyridine-6-methoxy-9 -(2,3,4,5-tetrafluorobenzyl)β-carboline, 1-pyridine-6-methoxy-9-(4-methylbenzyl)β-carboline, 1-pyridine-6- The yield of methoxy-9-(3-methylbenzyl)β-carboline is not high, and the reaction conditions are very harsh due to the use of NaH, such as strict anhydrous treatment environment, etc.
This method is limited in industrial production

Method used

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  • A preparation process and application of β-carboline compound for preparing anti-renal fibrosis drug and/or anti-chronic kidney disease drug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Preparation of 1-pyridine-6-methoxy-9-(2-methylbenzyl)-β-carboline

[0027] 1) 2.75g (10mmol) of 1-pyridine-6-methoxy-β-carboline, 2.22g (13mmol) of 2-methylbromobenzene and 0.52g (3mmol) of p-toluenesulfonic acid were mixed and dissolved in N,N - in dimethylformamide, heated to 80°C and stirred for 0.5 to 1 hour to obtain mixture A;

[0028] 2) Keep at 80°C, add 1.2g (40mmol) of paraformaldehyde into the mixture A obtained in step 1) in 3 to 6 times, heat up to 110°C after addition, continue stirring and contacting for 8 hours, after the reaction is complete, let it stand for cooling to room temperature, poured into saturated sodium bicarbonate, extracted with ethyl acetate, washed with water, concentrated under reduced pressure, recrystallized from dichloromethane / n-hexane (1:10), and dried to obtain 1-pyridine-6-methoxy-9- (2-Methylbenzyl)-β-carboline 3.52g, yield 92.7%, purity 99.41% (HPLC area normalization method). 1 HNMR (300MHz, DMSO-d 6 ): δ8.66(d, 1H), 8.52...

Embodiment 2

[0030] Preparation of 1-pyridine-6-methoxy-9-(3-methylbenzyl)-β-carboline

[0031] 1) 2.75g (10mmol) of 1-pyridine-6-methoxy-β-carboline, 2.57g (15mmol) of 3-methylbromobenzene and 0.52g (3mmol) of p-toluenesulfonic acid were mixed and dissolved in N,N - in dimethylformamide, heated to 70°C and stirred for 0.5 to 1 hour to obtain mixture A;

[0032] 2) Keep at 70°C, add 0.9g (30mmol) of paraformaldehyde into the mixture A obtained in step 1) in 3 to 6 times, heat up to 120°C after addition, continue stirring and contacting for 10 hours, after the reaction is complete, let it stand for cooling to room temperature, poured into saturated sodium bicarbonate, extracted with ethyl acetate, washed with water, concentrated under reduced pressure, recrystallized from dichloromethane / n-hexane (1:10), and dried to obtain 1-pyridine-6-methoxy-9- (3-methylbenzyl)-β-carboline 3.48g, yield 91.8%, purity 99.22% (HPLC area normalization method). 1 HNMR (300MHz, DMSO-d 6 ): δ8.65(d, 1H), 8.5...

Embodiment 3

[0034] Preparation of 1-pyridine-6-methoxy-9-(4-methoxybenzyl)-β-carboline

[0035] 1) 2.75g (10mmol) of 1-pyridine-6-methoxy-β-carboline, 2.24g (12mmol) of 4-methoxybromobenzene and 0.69g (4mmol) of p-toluenesulfonic acid were mixed and dissolved in N, In N-dimethylformamide, heated to 70°C and stirred for 0.5-1 hour to obtain mixture A;

[0036] 2) Keep at 70°C, add 0.6g (20mmol) of paraformaldehyde into the mixture A obtained in step 1) in 3 to 6 times, heat up to 100°C after addition, continue stirring and contacting for 8 hours, after the reaction is complete, let it stand for cooling to room temperature, poured into saturated sodium bicarbonate, extracted with ethyl acetate, washed with water, concentrated under reduced pressure, recrystallized from dichloromethane / n-hexane (1:10), and dried to obtain 1-pyridine-6-methoxy-9- (4-Methoxybenzyl)-β-carboline 3.62g, yield 91.5%, purity 99.46% (HPLC area normalization method). 1 HNMR (300MHz, DMSO-d 6)δ8.74~8.69(m, 1H), 8.5...

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Abstract

The invention discloses a preparation technology of a beta-carboline compound for preparing drugs for preventing renal fibrosis and / or drugs for preventing chronic nephrosis and applications thereof.The preparation technology comprises the following steps: (1) dissolving 1-pyridine-6-methoxyl-beta-carboline, substituted bromobenzene, and p-toluene sulfonic acid in an organic solvent, and heatingand stirring to obtain a mixture A; and (2) contacting the mixture A with paraformaldehyde to carry out reactions to obtain 1-pyridine-6-methoxyl-9-(substituted benzyl)-beta-carboline. The preparationmethod can directly synthesize a N-benzyl-beta-carboline compound through a one-pot method, the reaction conditions are mild, the product yield is high, a novel synthesis route is provided, the production cost is reduced effectively, the raw materials are more stable, the sources of raw materials are wider, and the method is suitable for large scale production.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and specifically relates to a preparation process of a β-carboline compound used for preparing anti-renal fibrosis drugs and / or anti-chronic kidney disease drugs and the application of the compound. Background technique [0002] β-carboline alkaloids are active ingredients isolated from natural plants. They have attracted much attention due to their broad-spectrum pharmacological activities, such as anxiolytic, antidepressant, antispasmodic, and antitumor, Anti-malarial, anti-parasite, anti-AIDS, etc. [0003] Studies have shown that structurally modified β-carboline compounds have an obvious structure-activity relationship, and those skilled in the art have also conducted extensive research on structural modification. At present, β-carboline compounds are mainly obtained through organic synthesis methods in addition to the separation and purification of natural products. [0004] Due to the diffe...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 董媛媛
Owner SHANGHAI TREEFUL PHARMA
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