Method for treating azide ions, non-genotoxic impurity Sartan raw material medicine and immediate thereof

A genotoxic, sartan-like technology, applied in organic chemistry and other directions, can solve problems such as the generation of genotoxic impurities

Active Publication Date: 2019-05-14
珠海润都制药股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] Aiming at the problem of generating genotoxic impurities when dealing with azide ions in the prior art, t

Method used

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  • Method for treating azide ions, non-genotoxic impurity Sartan raw material medicine and immediate thereof
  • Method for treating azide ions, non-genotoxic impurity Sartan raw material medicine and immediate thereof
  • Method for treating azide ions, non-genotoxic impurity Sartan raw material medicine and immediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0125] Example 1 Preparation of Compound I-1

[0126] In the three-neck flask, add about 50g of compound II-1, 36g of triethylamine hydrochloride, 17g of sodium azide and 100g of toluene, stir and heat up to 100~110°C for reaction. After the reaction is completed, cool down and use 10% NaOH solution After washing, extract with 180g of water and separate liquids to obtain a water layer, add 72g of ethanol and 50% hydrogen peroxide to the water layer, slowly add hydrochloric acid dropwise, adjust the pH to 4~4.5 (the residual azide ion of the ferric chloride indicator detection system , hydrogen peroxide can be added when insufficient). Filter, wash, and dry to obtain compound I-1, yield: 86.5%, HPCL purity: 99.10%, azide: not detected, NDEA content: not detected.

Embodiment 2

[0127] Example 2 Preparation of Compound I-1

[0128] In the there-necked flask, add about 50g of compound II-1, 21g of diethylamine hydrochloride, 12g of sodium azide and 55g of toluene, stir and raise the temperature to 130°C for reaction. After the reaction, cool down and wash with 10% KOH solution , extracted with 250g of water, and separated to obtain the water layer, adjust the pH to 8~9, add 15% hydrogen peroxide to the water layer (the azide ion remains in the ferric chloride indicator detection system, hydrogen peroxide can be added when it is insufficient) After the quenching is complete, slowly add dilute hydrochloric acid dropwise to adjust the pH to 3~4. Filter, wash, and dry to obtain compound I-1, yield: 84.5%, HPCL purity: 99.12%, azide: not detected, NDEA content: not detected.

Embodiment 3

[0129] Example 3 Preparation of Compound I-1

[0130] In the three-neck flask, add about 50g of compound II-1, 62g of dimethylamine hydrochloride, 33g of sodium azide and 400g of toluene, stir and raise the temperature to 130°C for reaction. After the reaction, cool down and wash with saturated sodium bicarbonate solution Finally, extract with 300g of water, separate the liquid to obtain the water layer, adjust the pH to 5, add 70% hydrogen peroxide in the water layer, slowly add dilute hydrochloric acid, adjust the pH to be 3 ~ 4 (ferric chloride indicator detection system azide Ions remain, hydrogen peroxide can be added if insufficient), crystallization, filtration, washing, drying to obtain compound I-1, yield: 83.3%, HPCL purity 99.27%, azide: not detected, NDEA content: not Check out.

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Abstract

The invention discloses a method for treating azide ions in a system and application thereof to the preparation of a compound with a tetrazolium group and without genotoxic impurities. The method is that the azide ions contained in the hydrogen peroxide treatment system are used. The method is used for preparing the compound with the tetrazolium group and comprises the following preparation steps:enabling a compound containing a cyano group to react with an azide, adding hydrogen peroxide after the reaction to quench and remove excessive sodium azide and further obtaining the compound with the tetrazolium group. The compound prepared by the method does not contain the genotoxic impurities. The method is simple in operation, mild in reaction conditions and suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of organic synthesis, and relates to a method for treating azide ions in a system and the application of the method to sartan compounds containing tetrazole groups and their intermediates. Specifically, the method does not produce genotoxic substances And the product obtained by applying the treatment method does not contain genotoxic impurities. Background technique [0002] In inorganic chemistry, azide compounds refer to compounds containing azide ions, such as sodium azide, lithium azide, etc. Azide ion reacts with acid to produce azido acid, which is a colorless liquid with a low boiling point (37°C), is freely miscible with water, has an unpleasant odor, and is highly toxic and explosive. In the reaction, the azide ion is usually excessive, and quenching is required after the reaction to prevent the production of azide. The usual quenching reagent is sodium nitrite or sodium hypochlorite, and the presence of so...

Claims

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Application Information

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IPC IPC(8): C07D403/10C07D257/04
Inventor 范志雄刘联康陈冬文焦慎超罗伟苑刘杰陈新民
Owner 珠海润都制药股份有限公司
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