Method for preparing isradipine impurities I

A technology for isradipine and impurities, which is applied in the field of preparation of isradipine impurity I, can solve the problems of difficulty in separation and affect the quality of the final product isradipine, and achieves the effects of easy availability of raw materials, high product purity and simple preparation process.

Inactive Publication Date: 2017-09-12
CHONGQING CONQUER PHARML
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Isradipine impurity I is produced during the preparation of compound 2, and may remain in the final product isradipine, affecting the quality of the final product isradipine, and the separation is difficult

Method used

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  • Method for preparing isradipine impurities I
  • Method for preparing isradipine impurities I
  • Method for preparing isradipine impurities I

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preparation example Construction

[0030] The invention provides a preparation method of isradipine impurity I, which is characterized in that: 2-acetyl-3-benzofurazan-4-yl-methyl acrylate is used as a raw material, and desorption occurs under alkaline organic conditions. Acetyl reaction, the isradipine impurity I is obtained after separation, the reaction formula is as follows:

[0031]

[0032] Further, the preparation method of the isradipine impurity I specifically includes the following steps:

[0033] S1. Add 5-10g of 2-acetyl-3-benzofurazan-4-yl-methyl acrylate into 120-250ml of organic solvent and stir. After fully dissolving, add 10-30ml of alkali solution to carry out temperature-raising reflux reaction;

[0034] S2, the reaction liquid obtained in step S1 is concentrated under reduced pressure, and the low boiling point components are removed;

[0035] S3. Adjust the concentrated solution of step S2 to PH=3 with concentrated hydrochloric acid, add 30-80 ml of ethyl acetate for extraction, separat...

Embodiment 1

[0048] Add 5g of compound 2 and 125mL of anhydrous methanol to the reaction bottle, stir and dissolve, add 10mL of 5% sodium hydroxide solution after fully dissolved, heat up and reflux for 10h, concentrate under reduced pressure to remove low boiling point components; adjust the concentrated solution to PH=3 with concentrated hydrochloric acid , add 30mL ethyl acetate for extraction, separate the layers to obtain the organic layer, add 5g of anhydrous sodium sulfate to dry, filter, and concentrate the filtrate; : n-hexane=2:1); Concentrate the purified solution, add 5 mL of ethyl acetate to heat up to dissolve, cool down to 5°C to crystallize, filter, and dry at 60°C to obtain impurity Ⅰ. Impurity I has a purity of 99.2%, a weight of 2.28 g, and a yield of 59.1%.

[0049] The mass spectrum data and NMR data detection of the product obtained in this embodiment are as follows: ESI-MS: 189.16 [M-H] -;1H-NMR: (δ-DMSO), δ7.076~7.102(1H,d), δ7.637~7.664(1H,dd), δ7.793~7.820(1H,d),...

Embodiment 2

[0051] Add 5g of compound 2, 150mLN, and N-dimethylformamide to the reaction flask, stir and dissolve, add 15mL of 5% potassium hydroxide solution after fully dissolving, heat up and reflux for 12h, concentrate under reduced pressure to remove low boiling point components; use concentrated hydrochloric acid to adjust the concentration solution to PH=3, add 30mL ethyl acetate for extraction, separate the layers to obtain an organic layer, add 10g of anhydrous sodium sulfate to dry, filter, and concentrate the filtrate; the concentrate is separated and purified by column (the eluent is a combination of ethyl acetate and n-hexane product, ethyl acetate: n-hexane = 2:1); concentrate the purified solution, add 5 mL of tetrahydrofuran to dissolve it at elevated temperature, cool down to 0°C to crystallize, filter, and dry at 60°C to obtain impurity Ⅰ. Impurity I has a purity of 99%, a weight of 2.56 g, and a yield of 66.3%.

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Abstract

The invention discloses a method for preparing isradipine impurities I. The method is characterized by comprising steps of carrying out deacetylation reaction on 2-acetyl-3-benzofuroxan-4-base-methyl acrylate under alkaline organic conditions; carrying out separation to obtain the isradipine impurities I. The 2-acetyl-3-benzofuroxan-4-base-methyl acrylate is used as a raw material. A reaction formula is shown. The method has the advantages that processes for preparing the isradipine impurities I are simple, the raw material is easily available, the isradipine impurities I which are products are high in purity [the HPLC (high-performance liquid chromatography) is higher than or equal to 98%], and the method can be directly used for quality research on isradipine key intermediates (compounds 2).

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, and relates to a preparation method of isradipine impurity I. Background technique [0002] Isradipine is a new type of dihydropyridine calcium channel blocker, developed by Sandoz in Switzerland, and first approved for marketing by Ciba-Geigy in February 1989. 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. 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 ischemic damage and improve the health of patients with angina pectoris and congestive hea...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D271/12
CPCC07D271/12
Inventor 陈用芳李斌徐刚
Owner CHONGQING CONQUER PHARML
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