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A kind of preparation method for the β-carboline compound of anti-renal fibrosis drug and/or anti-chronic kidney disease drug

A technology for chronic kidney disease and renal fibrosis, which is applied in the field of preparation of β-carboline compounds, can solve the problems of low yield, difficulty, and harsh reaction conditions, and achieve the effects of high yield, simple operation, and mild reaction conditions

Active Publication Date: 2020-09-01
安徽和医天下医药科技有限公司
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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- Methoxy-9-(3-methylbenzyl)β-carboline etc. generally have the problem that the yield is not high, and due to the use of NaH, the reaction conditions are also very harsh, such as strict anhydrous treatment environment, but also give Handling increases the difficulty
This method is limited in industrial production

Method used

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  • A kind of preparation method for the β-carboline compound of anti-renal fibrosis drug and/or anti-chronic kidney disease drug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] Preparation of 1-pyridine-6-methoxy-9-(2-methylbenzyl)-β-carboline

[0023] Palladium acetate 0.2g (1mmol), silver oxide 0.93g (4mmol) and alkali 3.18g (sodium carbonate 30mmol), 1-pyridine-6-methoxy-β-carboline 2.75g (10mmol) were added to the In the reaction flask of acetonitrile, drop the acetonitrile solution of substituted benzyl bromide (containing 2.4g of 2-methylbenzyl bromide), raise the temperature to 45°C, stir and react for 1-2h, cool to room temperature after the reaction, extract with ethyl acetate, wash with water , concentrated, recrystallized from dichloromethane / n-hexane (1:10), dried to obtain 3.57g of 1-pyridine-6-methoxy-9-(2-methylbenzyl)-β-carboline, and the yield was 94.2%, purity 99.19% (HPLC area normalization method). 1 HNMR (300MHz, DMSO-d 6 ): δ8.66(d, 1H), 8.52(d, 1H), 8.04(d, 1H), 7.71~7.67(m, 1H), 7.59~7.54(m, 1H), 7.37(d, 1H), 7.33(d, 1H), 7.24(d, 1H), 6.98~6.84(m, 2H), 6.76~6.70(m, 1H), 6.46(d, 1H), 5.49(s, 2H), 4.04(s, 3H), 2.13(s,...

Embodiment 2

[0025] Preparation of 1-pyridine-6-methoxy-9-(3-methylbenzyl)-β-carboline

[0026] 2.2g (10mmol) of palladium acetate, 4.6g (20mmol) of silver oxide, 65.2g (cesium carbonate 200mmol) and 13.8g (50mmol) of 1-pyridine-6-methoxy-β-carboline were added to the Into a reaction flask of acetonitrile, drop the acetonitrile solution of substituted benzyl bromide (containing 13g of 3-methylbenzyl bromide), raise the temperature to 55°C, stir and react for 1-2h, after the reaction is completed, cool to room temperature, extract with ethyl acetate, concentrate, Washed with water, recrystallized from dichloromethane / n-hexane (1:10), and dried to obtain 18.25 g of 1-pyridine-6-methoxy-9-(3-methylbenzyl)-β-carboline with a yield of 96.2 %, purity 99.47% (HPLC area normalization method). 1 HNMR (300MHz, DMSO-d 6 ): δ8.65(d, 1H), 8.53(d, 1H), 8.05(d, 1H), 7.72~7.68(m, 1H), 7.59~7.54(m, 1H), 7.35(d, 1H), 7.32(d, 1H), 7.22(d, 1H), 6.98~6.85(m, 2H), 6.72(s, 1H), 6.46(d, 1H), 5.45(s, 2H), 3.98(...

Embodiment 3

[0028] Preparation of 1-pyridine-6-methoxy-9-(2,3,4,5-tetrafluorobenzyl)-β-carboline

[0029] Palladium acetate 3.4g (15mmol), silver oxide 6.95g (30mmol) and alkali 42.4g (sodium carbonate 400mmol), 1-pyridine-6-methoxy-β-carboline 27.5g (100mmol) were added to the Into the reaction flask of acetonitrile, then drip the acetonitrile solution of substituted benzyl bromide (containing 26.7g of 2,3,4,5-tetrafluorobenzyl bromide), raise the temperature to 50°C, stir for 1-2h, and cool to room temperature after the reaction is completed. Extracted with ethyl acetate, concentrated, washed with water, recrystallized from dichloromethane / n-hexane (1:10), and dried to obtain 1-pyridine-6-methoxy-9-(2,3,4,5-tetrafluorobenzyl )-β-carboline 41g, yield 93.7%, purity 99.33% (HPLC area normalization method). 1 HNMR (300MHz, DMSO-d 6 )δ9.56(d, J=5.1Hz, 1H), 9.51(dt, J=4.9, 1.2Hz, 1H), 9.04(d, J=5.1Hz, 1H), 7.79–7.75(m, 2H), 7.66(t, J=1.5Hz, 1H), 7.35–7.30(m, 1H), 7.23(d, J=1.5Hz, 2H), 6.09...

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Abstract

The invention discloses a preparation method of beta-carboline compound for preparing anti-renal fibrosis medicines and / or anti-chronic nephropathy medicines. The preparation method comprises contacting 1-pyridine-6-methoxy-beta-carboline with substituted benzyl bromide in the presence of palladium acetate, silver oxide and a base to obtain 1-pyridine-6-methoxy-9-(substituted benzyl)-beta-carboline. The preparation method of the beta-carboline compound provided by the invention has a mild condition and high yield of the target product, and is particularly suitable for the production of a largeamount of the beta-carboline compound.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a preparation method of a β-carboline compound used for preparing anti-renal fibrosis drugs and / or anti-chronic kidney disease drugs. Background technique [0002] β-carboline alkaloids are active ingredients isolated from natural plants, and have attracted much attention due to their broad-spectrum pharmacological activities, such as anxiolytic, antidepressant, antispasmodic, antitumor, anti Malaria, anti-parasites, 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 differences in the structure of β-carboline co...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04A61P13/12
CPCC07D471/04
Inventor 董媛媛任思冲
Owner 安徽和医天下医药科技有限公司