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Preparation method of cinnarizine impurity and impurity

A technology of cinnarizine and impurities, which is applied to the preparation method of cinnarizine impurities and the field of impurities, and can solve the problems of less research on the preparation of impurities

Pending Publication Date: 2022-02-18
湖南增达生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] At present, there are many domestic studies on the synthesis method of cinnarizine, but less research on the preparation of its impurities, and the current drug declaration has higher requirements for impurity research, and its impurity research is conducive to improving the research and improvement of drug quality.

Method used

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  • Preparation method of cinnarizine impurity and impurity
  • Preparation method of cinnarizine impurity and impurity
  • Preparation method of cinnarizine impurity and impurity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Cinnarizine impurity preparation method comprises the steps:

[0043] step one:

[0044] Weigh 30g of cinnamyl alcohol, 200ml of dichloromethane, add dropwise 60g of phosphorus tribromide at 0°C, keep the temperature at 0°C for 12 hours, and the reaction is completed;

[0045] Step two:

[0046] Step 1 After the reaction, add 200ml of anhydrous tetrahydrofuran, 20g of zinc powder, and 200mg of iodine, heat to reflux, then remove the heat source, stir at room temperature for 30min, cool down to 0°C, add 6g of cinnamaldehyde dropwise, stir for 30min, and the reaction is complete;

[0047] Step three:

[0048] After the reaction in step 2, add 200ml of dichloromethane, add dropwise 8g of phosphorus tribromide at 0°C, keep the temperature at 0°C for 12 hours, and the reaction is completed;

[0049] Step four:

[0050] After the reaction in step 2, add 6.3g of compound 1, 2.5g of potassium carbonate, 50ml of 1,4-dioxane, and heat to reflux for 12 hours. After the reactio...

Embodiment 2

[0052] step one:

[0053] Weigh 30g of cinnamyl alcohol, 100ml of dichloromethane, add dropwise 50g of phosphorus tribromide at 0°C, keep the temperature at 0°C for 12 hours, and the reaction is completed;

[0054] Step two:

[0055] Step 1 After the reaction, add 100ml of anhydrous tetrahydrofuran, 25g of zinc powder, and 200mg of iodine, heat to reflux, then remove the heat source, stir at room temperature for 30min, cool down to 0°C, add 8g of cinnamaldehyde dropwise, stir for 30min, and the reaction is complete;

[0056] Step three:

[0057] Step 3 After the reaction, add 100ml of dichloromethane, add 12g of phosphorus tribromide dropwise at 0°C, keep the temperature at 0°C for 12 hours, and the reaction is completed;

[0058] Step four:

[0059]After the reaction in Step 3, add 6.8g of compound 1, 3.5g of potassium carbonate, 50ml of 1,4-dioxane, and heat to reflux for 12 hours. After the reaction is complete, filter and concentrate the filtrate under reduced pressure....

Embodiment 3

[0061] step one:

[0062] Weigh 30g of cinnamyl alcohol, 200ml of dichloromethane, add dropwise 40g of phosphorus tribromide at 0°C, keep the temperature at 0°C for 12 hours, and the reaction is completed;

[0063] Step two:

[0064] Step 1 After the reaction, add 200ml of anhydrous tetrahydrofuran, 30g of zinc powder, and 500mg of iodine, heat to reflux, then remove the heat source, stir at room temperature for 30min, cool down to 0°C, add 9g of cinnamaldehyde dropwise, stir for 30min, and the reaction is complete;

[0065] Step three:

[0066] After the reaction in step 2, add 200ml of dichloromethane, add 15g of phosphorus tribromide dropwise at 0°C, keep the temperature at 0°C for 12 hours, and the reaction is completed;

[0067] Step four:

[0068] After the reaction in Step 3, add 7.3g of compound 1, 4.5g of potassium carbonate, 50ml of 1,4-dioxane, and heat to reflux for 12 hours. After the reaction is complete, filter and concentrate the filtrate under reduced press...

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Abstract

The invention discloses a preparation method of a cinnarizine impurity. The preparation method comprises the following steps: (1) reacting cinnamyl alcohol with a halogenating reagent in a solvent at -10 to 30 DEG C; (2) reacting the reaction product in the step (1) with metal in a solvent under the catalysis of iodine to form an organic metal reagent intermediate, and reacting with cinnamyl aldehyde; (3) reacting a reaction product in the step (2) with a halogenating reagent in a solvent at -10 DEG C to 30 DEG C; and (4) reacting the reaction product in the step (3) with benzhydryl piperazine under the action of the halogenating reagent to obtain a crude product. The invention further provides the cinnarizine impurity prepared by the method, and the cinnarizine impurity prepared by the method is high in yield and good in purity.

Description

technical field [0001] The invention relates to the field of medicine, in particular to a preparation method of cinnarizine impurity and the impurity. Background technique [0002] Cinnarizine, molecular formula: C 26 h 28 N 2 , Molecular weight: 368.52, is a cardiovascular system drug. It is white or off-white crystalline powder, odorless and tasteless. Cinnarizine directly acts on vascular smooth muscle to dilate blood vessels, which can significantly improve circulation. At the same time, cinnarizine is a calcium ion channel antagonist, which can directly act on vascular smooth muscle and reduce the permeability of cell membrane to calcium ions, thereby selectively inhibiting cerebral vasospasm, inhibiting platelet aggregation, improving microcirculation and blood oxygen supply, and improving blood circulation. The tolerance of brain tissue to hypoxia; and against the vasospasm caused by vasoconstrictor substances 5-HT, histamine, norepinephrine, etc., and has an ant...

Claims

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Application Information

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IPC IPC(8): C07D295/03C07D295/023
CPCC07D295/03C07D295/023
Inventor 毛雨刘凯请刘桂英
Owner 湖南增达生物科技有限公司
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