Preparation method of azilsartan impurity a and b

A technology of impurities and intermediates, applied in the field of preparation of Azilsartan impurities A and B, achieves the effects of high yield, avoiding the formation of impurities and improving product quality

Active Publication Date: 2018-09-25
SHANDONG XINHUA PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But at present, for the main impurity A of azilsartan (2-ethoxy-1-[[2'-(formamido)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid methyl ester) and the preparation of impurity B (2-ethoxy-1-[[2'-(formamido)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid) rarely reported

Method used

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  • Preparation method of azilsartan impurity a and b
  • Preparation method of azilsartan impurity a and b
  • Preparation method of azilsartan impurity a and b

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Add 10.0g (22.5mmol) of intermediate II to 100ml of 1,4-dioxane, heat to reflux, slowly add 3.84g (23.7mmol, 1.05eq) of carbonyldiimidazole in 50ml of 1,4-dioxane Oxycycline solution, after the dropwise addition, reflux reaction for 5 hours; stop the reaction, remove the solvent by distillation under reduced pressure; dissolve the residue in ethyl acetate, add water, under stirring, adjust the pH to 3 with HCl, let stand to separate, remove Aqueous phase; adding water to wash, separating and removing the water phase, washing the organic phase with saturated brine, removing the water phase, cooling and crystallizing the organic phase with an ice-water bath for 1 hour, filtering, and washing with a small amount of ethyl acetate to obtain impurity A, the product 85% rate

[0026] The product has passed the identification of mass spectrometry and NMR:

[0027] ESI-MS: 430.2 (M+1), 452.2 (M+Na).

[0028] 1H-NMR (600MHz, DMSO-d 6 )δ: 1.42(3H,t,J=6Hz),3.71(3H,s),4.62(2H,q,J...

Embodiment 2

[0031] Add 10.0g (22.5mmol) of intermediate II to 100ml of tetrahydrofuran, heat to reflux, slowly add dropwise 4.01g (24.7mmol, 1.1eq) carbonyldiimidazole in 50ml of tetrahydrofuran solution, after the dropwise addition is completed, reflux for 5 hours Stop the reaction, remove the solvent by distillation under reduced pressure; dissolve the residue in ethyl acetate, add water, under stirring, adjust the pH to 5 with HCl, leave to separate layers, and remove the water phase; add water to wash, separate the liquid to remove the water phase, organic The phase was washed with saturated brine, and the water phase was removed. The organic phase was cooled and crystallized in an ice-water bath for 1 hour, filtered, and washed with a small amount of ethyl acetate to obtain impurity A.

Embodiment 3

[0033] Add 4.3g of impurity A to 100mL of water, add dropwise 2N LiOH aqueous solution until the solid dissolves, then add 1mL, heat up to 75±3°C, and react for 1 hour;

[0034] Stop heating, add absolute ethanol, cool down to below 30°C, adjust the pH to 2.3±0.1 with 2M-HCl, and slowly precipitate a white insoluble solid; filter, wash with purified water, wash with water three times, each 10mL, dry to obtain impurity B , as a white powdery solid with a yield of 99%.

[0035] The product has passed the identification of mass spectrometry and NMR:

[0036] ESI-MS: 416.2 (M+1), 438.2 (M+Na).

[0037] 1H-NMR (600MHz, DMSO-d 6 )δ: 1.41 (3H, t, J = 6, 12Hz), 4.60 (2H, q, J = 6, 12, 6Hz), 5.68 (2H, s), 7.04 (2H, q, J = 6, 12, 12Hz), 7.18(1H,t,J=6,12Hz),7.26(1H,s),7.30-7.38(4H,m),7.41-7.47(2H,m),7.56(1H,d,J=6Hz ), 7.64 (1H, s), 7.68 (1H, d, J=6Hz), 13.13 (1H, br).

[0038] 13C-NMR (150MHz, DMSO-d 6 )δ: 14.5, 46.3, 66.6, 116.8, 120.7, 121.4, 123.5, 126.3, 127.0, 127.5, 128.6, 12...

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Abstract

The invention relates to a preparation method for an azilsartan impurity A and an azilsartan impurity B, belonging to the technical field of preparation of azilsartan impurities. The preparation method for the azilsartan impurity A provided by the invention comprises the following steps: subjecting an azilsartan intermediate II and carbonyldimidazole to refluxing reaction under heating in an organic solvent so as to prepare an impurity A, and subjecting the impurity A and an alkaline reagent to reaction under heating in water so as to obtain an impurity B, wherein the azilsartan intermediate II, the impurity A and the impurity B have chemical structural formulas as described in the specification. The preparation method for the azilsartan impurity A and the azilsartan impurity B provided by the invention has simple process and short period; and the prepared target products have high yield and are easy to purify.

Description

technical field [0001] The invention relates to a preparation method of azilsartan impurities A and B, belonging to the technical field of preparation of azilsartan impurities. Background technique [0002] Azilsartan (azilsartan, TAK-536) is a new generation of angiotensin Ⅱ receptor antagonist (ARB, sartan) developed by Takeda Corporation of Japan. It was approved for marketing in Japan in January 2012. Azilsartan medoxomil, as a prodrug of azilsartan medoxomil, was approved for marketing in the United States in 2011 and can achieve good therapeutic effects. It is also predicted to be the follow-up product of the blockbuster drug Blopress (candesartan medoxomil). [0003] The preparation method and therapeutic use of azilsartan have been disclosed in patent EP0520423. Its preparation method is as follows: [0004] [0005] Since drug impurities are very important in drug process research, optimization and quality control, the research on azilsartan impurities is also ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D235/26
CPCC07D235/26
Inventor 吴辉郑忠辉王军沈红徐玲
Owner SHANDONG XINHUA PHARMA CO LTD
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