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Preparation method for Allisartan Isoproxil

A technology for allisartan medoxomil and trityl losac, which is applied in the field of drug synthesis, can solve problems such as being unfavorable for recovery, unsuitable for scale-up production and the like, and achieves the effects of simple operation, easy recovery and little environmental pollution

Inactive Publication Date: 2014-08-06
SHENZHEN SALUBRIS PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] CN201210020174.5 discloses a series of antihypertensive compounds and their preparation methods, the following route C, the temperature of the first step of the preparation is controlled at 0-5°C, oxidized with 5% sodium hypochlorite aqueous solution in a mixed solution of acetone and water, and the yield Yield of 70%, the second step uses potassium permanganate, also can produce manganese dioxide, and the yield is only 40%, the yield of the first two steps is 28%, very low, and the post-processing method is all column separation, Both the first two steps use organic and inorganic mixed solvents, which are not conducive to recycling and are not suitable for large-scale production

Method used

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  • Preparation method for Allisartan Isoproxil
  • Preparation method for Allisartan Isoproxil
  • Preparation method for Allisartan Isoproxil

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065] Example 1 2-butyl-4-chloro-1-[2`-(1-trityl-tetrazol-5-yl)-1,1`-biphenyl-methyl]-5-aldehyde Kiimidazole (IV)

[0066]

[0067] Add DMF6430mL into the 10L reaction kettle at room temperature, start stirring, and the speed of the stirrer is 300r / min. Trityl losartan (1170.4 g, 1.76 mol, 1.00 eq) was added, stirred for 15 min, and the temperature was controlled at 10-15°C. After complete dissolution, KBr (52.3g, 0.44mol, 0.25eq) and sodium bicarbonate (295.49g, 3.50mol, 2.00eq) were added to the reaction flask, and stirred for 10min. Tempo (27.84g, 0.18mol, 0.10eq) was added, and the reaction solution gradually turned reddish brown or orange red. Maintaining the reaction temperature at 13-16°C, calcium hypochlorite (209.2g, 1.40mol, 0.80eq) was added in batches. Maintain the reaction temperature at 13-18°C, keep it warm for 3 hours, take a sample after 3 hours of reaction, and send it to HPLC for detection. When the content of trityl losartan is ≤5.0%, add diatomaceou...

Embodiment 2

[0068] Example 2 2-butyl-4-chloro-1-[2`-(1-trityl-tetrazol-5-yl)-1,1`-biphenyl-methyl]-5-aldehyde Kiimidazole (IV)

[0069]

[0070] Add THF350mL into 1L reaction flask at room temperature, start stirring, and the speed of the stirrer is 300r / min. Trityl losartan (66.5 g, 0.1 mol, 1.00 eq) was added, stirred for 15 min, and the temperature was controlled at 10-15°C. After complete dissolution, KBr (4.1 g, 0.035 mol, 0.35 eq) and sodium bicarbonate (16.8 g, 0.2 mol, 2.00 eq) were added to the reaction flask, and stirred for 10 min. Tempo (1.1g, 7.5mmol, 0.075eq) was added, and the reaction solution gradually turned reddish brown or orange red. Maintaining the reaction temperature at 13-16°C, calcium hypochlorite (14.8g, 0.1mol, 1.0eq) was added in batches. Maintain the reaction temperature at 13-18°C, keep it warm for 3 hours, take a sample after 3 hours of reaction, and send it to HPLC for detection. When the content of trityl losartan is ≤5.0%, add diatomaceous earth an...

Embodiment 3

[0071] Example 3 2-butyl-4-chloro-1-[2`-(1-trityl-tetrazol-5-yl)-1,1`-biphenyl-methyl]-5-aldehyde Kiimidazole (IV)

[0072]

[0073] Add DMF6900mL into the 10L reactor at room temperature, start stirring, and the speed of the stirrer is 300r / min. Add trityl losartan (1064g, 1.6mol, 1.00eq), stir for 15min, and control the temperature at 10-15°C. After complete dissolution, KBr (95.2 g, 0.8 mol, 0.50 eq) and sodium bicarbonate (268.8 g, 3.2 mol, 2.00 eq) were added to the reaction flask, and stirred for 10 min. Tempo (12.16g, 0.08mol, 0.05eq) was added, and the reaction solution gradually turned reddish brown or orange red. Maintaining the reaction temperature at 13-16°C, calcium hypochlorite (213.9g, 1.44mol, 0.90eq) was added in batches. Maintain the reaction temperature at 13-18°C, keep it warm for 3 hours, take a sample after 3 hours of reaction, and send it to HPLC for detection. When the content of trityl losartan is ≤5.0%, add diatomaceous earth and continue stirri...

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Abstract

The invention relates to a preparation and refining method for Allisartan Isoproxil. The preparation method comprises the following steps: trityl chloride losartan is oxidized in a polarity organic solvent at the presence of a catalyst to obtain a compound expressed in formula IV; the compound expressed in the formula IV is further oxidized by oxidation reagent hydrogen peroxide / sodium chlorite, Resorcino / sodium chlorite, sulfamic acid / sodium chlorite or 2-methyl-2-butene / sodium chlorite to obtain Allisartan Isoproxil intermediate expressed in formula III; then the Allisartan Isoproxil intermediate is subjected to ester formation and deprotection to obtain an Allisartan Isoproxil crude product; finally, the Allisartan Isoproxil crude product is refined by ethanol / normal heptane to obtain purified Allisartan Isoproxil. According to the preparation method for Allisartan Isoproxil, the yield and efficiency are high, the by-product is few, the preparation method is environmental-friendly and suitable for industrialized production, the operation is simple and safe and the cost is low.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a method for preparing and refining alisartan medoxomil. Background technique [0002] Hypertension is a major disease that threatens human health. Finding high-efficiency and low-toxic antihypertensive drugs can help relieve social pressure and family burden, and has good social and economic benefits. [0003] Angiotensin II (Ang II), the major vasoconstrictor hormone of the renin-angiotensin-aldosterone system (RAAS), plays an important role in the pathobiology of a variety of chronic diseases, especially its effect on blood pressure regulation The role of the Ang II receptor is particularly prominent, so the Ang II receptor is considered to be a good target for the development of antihypertensive drugs. [0004] EP0253310 discloses a series of imidazole derivatives. Losartan Potassium, which was declared by DuPont in the United States and was listed on the market in ...

Claims

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Application Information

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IPC IPC(8): C07D403/10
CPCC07D403/10
Inventor 安东何建勋邓琼
Owner SHENZHEN SALUBRIS PHARMA CO LTD
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