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Azilsartan medoxomil intermediates and synthetic methods thereof, as well as synthetic method of azilsartan medoxomil

A technology of azilsartan medoxomil and synthetic method, which is applied in the field of chemical synthesis, can solve the problems of low reaction yield, destruction, difficulty in large-scale production, etc., and achieve the effect of high yield and reduced production cost

Inactive Publication Date: 2014-09-03
ZHEJIANG TIANYU PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0024] Wherein, method a) will leave acyl chloride and its corresponding hydrolysis product carboxylic acid in the product after the reaction; method b) easily destroys the ethoxy structure substituted on the benzimidazole when azilsartan acid is prepared into acyl chloride; method c) The reaction lacks selectivity, and it is easy to generate N, O double-substituted impurities, and the reaction yield is low; method d) the corresponding product generated by the condensing agent absorbing water in the reaction will remain in azilsartan medoxomil, which is difficult to remove
Moreover, the 4-hydroxymethyl-5-methyl-1,3-dioxol-2-one needed for method a), method b), and method d) is difficult to produce on a large scale, and the price is relatively high

Method used

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  • Azilsartan medoxomil intermediates and synthetic methods thereof, as well as synthetic method of azilsartan medoxomil
  • Azilsartan medoxomil intermediates and synthetic methods thereof, as well as synthetic method of azilsartan medoxomil
  • Azilsartan medoxomil intermediates and synthetic methods thereof, as well as synthetic method of azilsartan medoxomil

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0133] Embodiment 1: preparation formula 5 compound

[0134] The chemical name of the compound of formula 5: N'-hydroxyl-4'-methylbiphenyl-2-amidine hydrochloride

[0135]

[0136] 38.6g (0.20mol) 2'-cyano-4-methylbiphenyl (compound of formula 4) was added to 200mL ethanol, 40mL water, 83.4g (1.20mol) hydroxylamine hydrochloride, 68.9g (0.65mol) sodium carbonate, and reflux reaction After 12 hours, filter, remove ethanol from the filtrate under reduced pressure, add 150mL ethyl acetate and 100mL water to the residue, stir and separate layers, add 50mL ethyl acetate to the water layer for extraction, combine the organic layers, cool to 0-5°C, add dropwise 15 % hydrochloric acid to adjust the pH to 1, a white solid was precipitated, stirred for 1 hour, filtered, and the filter cake was vacuum-dried to obtain 46.6 g of a white solid, with a yield of 88.7%.

[0137] The white solid is identified as a compound of formula 5, and the identification data are as follows:

[0138] ...

Embodiment 2

[0142] Embodiment 2: preparation formula 6 compound

[0143] The chemical name of the compound of formula 6: N'-(ethoxycarbonyl)oxygen-4'-methylbiphenyl-2-amidine

[0144]

[0145] Add 78.8g (0.30mol) of the compound of formula 5 into 500mL of dichloromethane, cool to 0-5°C, add 65.8g (0.65mol) of triethylamine, dropwise add 35.8g (0.33mol) of ethyl chloroformate at 0-5°C A solution of the ester in 120 mL of dichloromethane. After the dropwise addition, stir at room temperature for 1 hour, add 250 mL of water and stir, add 15% hydrochloric acid dropwise to adjust the pH to 6-7, separate layers, wash the organic layer with 2×250 mL of water, and remove the solvent under reduced pressure to obtain an off-white solid 89.3 g, yield 99.8%.

[0146] This type of white solid is identified as a compound of formula 6, and the identification data are as follows:

[0147] Mp125℃

[0148] 1 H-NMR (400MHz, CDCl 3 )δ: 7.632 (dd, J 1 =7.6Hz,J 2 =1.2Hz, 1H, ArH), 7.480(td, J 1 =7....

Embodiment 3

[0151] Embodiment 3: preparation formula 7 compound

[0152] The chemical name of the compound of formula 7: 3-(4'-methylbiphenyl-2-yl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole

[0153]

[0154] 89.5g (0.30mol) of the compound of formula 6 was dissolved in 450mL of ethanol, and refluxed for 20 hours. The solvent was removed under reduced pressure to obtain an orange-red oil, which was dissolved by adding 100 mL of dichloromethane, then added 250 mL of water, cooled to below 20°C, added dropwise 15% sodium hydroxide solution to pH = 10, separated into layers, and added 5 ×50mL of dichloromethane after extraction, cool the water layer to below 20°C, add 15% hydrochloric acid dropwise until pH≤7, a white solid precipitates, continue to add 15% hydrochloric acid dropwise until pH=2, cool to 0-5°C, stir for 1 hours, filtered, and the filter cake was vacuum-dried to obtain 65.9 g of a white solid, with a yield of 87.1%.

[0155] The white solid is identified as a compound of formula ...

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PUM

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Abstract

The invention provides three kinds of azilsartan medoxomil intermediates and synthetic methods thereof. The azilsartan medoxomil intermediates are as shown in formulae 8, 9 and 11, and prepared according to the scheme as shown in the specification. The invention also provides a synthetic method of azilsartan medoxomil, wherein the synthetic method is as shown in the specification. The invention provides three types of azilsartan medoxomil intermediates, and expands the research field of important azilsartan medoxomil intermediates; a compound shown in the formula 11 is adopted and subjected to hydrolysis, condensation and deprotection so as to obtain a final product azilsartan medoxomil; compared with the prior art, the synthetic method has the advantages that the utilization of expensive 4-hydroxymethyl-5-methyl-1,3-dioxo hetercyclopentene-2-ketone is avoided, so that the production cost can be greatly reduced; in the production process of the azilsartan medoxomil intermediates disclosed by the invention, the purity of the intermediates can achieve over 98%, and can meet market demands, and the yields of the compound as shown in the formula 11 to a final product azilsartan medoxomil are high, and is up to 68-75%; the purity of obtained final products azilsartan medoxomil reaches 99.0-99.5%.

Description

technical field [0001] The invention relates to the field of chemical synthesis, in particular to an azilsartan medoxomil intermediate, a synthesis method thereof, and azilsartan medoxomil intermediates. Background technique [0002] Azilsartan medoxomil, its English name is Azilsartan medoxomil (trade name: EDARBI), its chemical name is 2-ethoxy-1-{[2'-(5-oxo-4,5-dihydro-1 ,2,4-Oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylic acid (5-methyl-2-oxo-1,3-di Oxol-4-yl) methyl ester, CAS863031-21-4, its chemical structural formula is as follows: [0003] [0004] Azilsartan medoxomil is a prodrug. It is an angiotensin II receptor antagonist developed by Japan's Takeda Pharmaceutical Company for the treatment of hypertension (approved by the FDA for listing in the United States on February 25, 2011). The drug can be used alone or in combination with other blood pressure-lowering drugs and is considered the next generation of candesartan. The antihypertensi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/10C07D413/14C07D271/06
CPCC07D413/10C07D271/07C07D413/14
Inventor 程荣德李美君王波杨会林
Owner ZHEJIANG TIANYU PHARMA
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