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Method for preparing israbipine medicament for treating hypertension

A technology of isradipine and compounds, applied in the field of compound preparation, can solve the problems of long steps, poor controllability, pollution, etc.

Inactive Publication Date: 2010-07-07
SHANGHAI SUN SAIL PHARMA SCI & TECH CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] Obviously, the above method has long steps, dangerous operation, poor controllability, and causes a lot of pollution

Method used

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  • Method for preparing israbipine medicament for treating hypertension
  • Method for preparing israbipine medicament for treating hypertension
  • Method for preparing israbipine medicament for treating hypertension

Examples

Experimental program
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preparation example Construction

[0052] The preparation method of the present invention is described more specifically below. However, it should be understood that the present invention is not limited to the specific reaction conditions (eg, solvent, amount of compound used, reaction temperature, time required for reaction, etc.) given below.

[0053] In the process of the present invention, each reaction is usually carried out in an inert solvent at room temperature to reflux temperature (such as 0°C to 100°C, preferably 0°C to 80°C). The reaction time is usually 0.1-60 hours, preferably 0.5-48 hours.

[0054] The preparation method of the present invention can be represented by the following flow process:

[0055]

[0056] The following is a more specific description of process 1:

[0057] (a). 2-Amino-3-methylnitrobenzene is oxidized and ring-closed to form 4-methylbenzofurazan oxide (compound 2)

[0058] In this step, usable inert solvents include methanol, ethanol, isopropanol, water, or any combin...

Embodiment 1

[0106] Example 1 4-methylbenzofurazan oxide (compound 2)

[0107] Add compound 1 (22.8g, 0.15mol) to a 1L three-neck round bottom flask, then add KOH (10g) ethanol solution (200ml), add NaClO solution (100ml) dropwise under ice-cooling, and continue the reaction under ice-water bath . After the reaction is complete, CH is added to the system 2 Cl 2 (150ml) was stirred, and the insoluble matter was filtered off, and the filtrate was separated into an organic phase, anhydrous Na 2 SO 4 Dry and concentrate. 20.77 g of crude product were obtained. Ethyl acetate was added for recrystallization to obtain 15.5 g of yellow needle-like crystals, with a yield of 68.9%.

Embodiment 2

[0108] Example 2 4-methylbenzofurazan oxide (compound 2)

[0109] (a) Compound 1 (30.4g, 0.2mol), water (80mL) and concentrated hydrochloric acid (45mL) were added to a 500mL three-neck round bottom flask, and after cooling in an ice bath, an aqueous solution of sodium nitrite (14.5g, 0.21mol) was added dropwise (50 mL), after the dropwise addition, keep stirring for 1 hour.

[0110] (b) Suction filtration, pour the filtrate into a 1L beaker, add sodium azide (13g, 0.2mol) in batches under ice bath conditions, after adding, keep stirring for 1 hour, suction filtration, wash the filter cake with water (100mL, 2 times ).

[0111] (c) The filter cake obtained in the (b) process is dropped into a three-necked round-bottomed flask equipped with toluene (60mL), slowly warming up to reflux, reflux reaction for 5 hours, the system is cooled to room temperature, and the insolubles are removed by suction filtration, and the filtrate is concentrated. The residue was cooled and crystall...

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Abstract

The invention relates to a method for preparing an israbipine medicament for treating hypertension. Particularly the method of the invention comprises the following steps: (a) carrying out oxidative cyclization on 2-amino-3-methyl nitrobenzene to form 4-methyl benzofuroxan oxide; (b) reducing the 4-methyl benzofuroxan oxide to form 4-methyl benzofuroxan; (c) carrying out substitution bromination on the 4-methyl benzofuroxan to form 4-bromomethyl benzofuroxan; (d) carrying out hydrolyzation on the 4-bromomethyl benzofuroxan to form 4-hydroxymethyl benzofuroxan; (e) carrying out oxidation on the 4-hydroxymethyl benzofuroxan to form 4-formaldehyde benzofuroxan; and (f) performing a reaction of the 4-formaldehyde benzofuroxan amd alpha-aminocrotonic acid isopropyl ester to form israbipine. The method of the invention has high yield and simple and convenient operation and can prepare high-purity israbipine.

Description

technical field [0001] The present invention relates to the preparation method of the compound, more specifically to the preparation method of the drug isradipine (Isradipine). Background technique [0002] Isradipine is a new type of dihydropyridine calcium channel blocker. Isradipine was developed by the Swiss company Sandoz and was first introduced to the market by the British company Ciba-Geigy in February 1989. [0003] Isradipine achieves the purpose of lowering blood pressure by dilating blood vessels, reducing peripheral vascular resistance, increasing coronary blood flow, and improving myocardial oxygen supply. [0004] Isradipine has a strong vasodilator effect, but no heart inhibitory effect, and almost does not cause reflex tachycardia. Clinical and animal experiments have proved that the drug has obvious antihypertensive and anti-atherosclerotic effects. By maintaining or restoring the blood flow under the left ventricular endothelium, it can prevent local isc...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/04A61K31/4439A61P9/12
Inventor 陈义朗韩硕徐自奥李晓祥
Owner SHANGHAI SUN SAIL PHARMA SCI & TECH CO LTD
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