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Preparation method of olmesartan medoxomil intermediate and synthesis method of olmesartan medoxomil

A technology of olmesartan medoxomil and synthesis method, which is applied in the field of olmesartan medoxomil synthesis, can solve problems such as high price, and achieve the effect of simple process

Inactive Publication Date: 2013-09-25
LINHAI TIANYU PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the price of 2-(trimethylsilyl)ethoxymethyl is relatively expensive, and this method is rarely used in the current industrial synthesis

Method used

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  • Preparation method of olmesartan medoxomil intermediate and synthesis method of olmesartan medoxomil
  • Preparation method of olmesartan medoxomil intermediate and synthesis method of olmesartan medoxomil
  • Preparation method of olmesartan medoxomil intermediate and synthesis method of olmesartan medoxomil

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Embodiment 1: the preparation of formula (2) compound

[0054] Step 1: Preparation of the compound of formula (2-1)

[0055] Chemical name of compound of formula (2-1): 5-(4'-methylbiphenyl-2-yl)tetrazole.

[0056] The structural formula of the compound of formula (2-1) is as follows:

[0057]

[0058] Its preparation process: 19.3g (about 0.1mol) of 2-cyano-4'-methylbiphenyl (that is, the compound of formula (2-0)), 9.8g (about 0.15mol) of sodium azide dissolved in 100g of dimethyl Add 4.5 g of sodium bisulfate silica gel to base formamide, and react at 120° C. for 10 hours. The reaction mixture was cooled to room temperature, filtered, and the filter cake was washed with 100 mL×2 ethyl acetate. Add 600mL ethyl acetate and 400mL 4mol / L hydrochloric acid to the filtrate, and stir vigorously. The organic layer was separated, and the aqueous layer was extracted with 200 mL×2 ethyl acetate. The organic layers were combined, washed with 200 mL×2 water, and concentra...

Embodiment 2

[0083] Embodiment 2: the preparation of formula (3) compound

[0084] Step 1: Preparation of the compound of formula (3-1)

[0085] Chemical name of compound of formula (3-1): 2-propyl-4,6-dihydrofuro[3,4-d]imidazole-4,6-dione.

[0086] The structural formula of the compound of formula (3-1) is as follows:

[0087]

[0088] Its preparation process: 106.0g (about 1.0mol) of powdered sodium carbonate and 119.0g (about 1.0mol) of newly distilled thionyl chloride and 500ml of anhydrous dichloromethane are stirred and mixed at room temperature, and 200.2 g (about 1.0mol) 2-propylimidazole-4,5-dicarboxylic acid (i.e. the compound of formula (3-0)) in 1000mL dichloromethane and dioxane (1:1 volume ratio) solution, add Reflux reaction for 3h. After cooling to room temperature, the mixture was filtered, the filter cake was washed with 200 mL of dichloromethane, the filtrates were combined, and the solvent was evaporated under reduced pressure to obtain 155.0 g of the compound of ...

Embodiment 3

[0100] Embodiment 3: the preparation of formula (4) compound

[0101] The chemical name of the compound of formula (4): 4,4-dimethyl-2-propyl-1-[[2'-[2-(1-methyl-1-phenylethyl)tetrazole-5- Base]biphenyl-4-yl]methyl]-4,6-dihydrofuro[3,4-d]imidazol-6-one

[0102] The structural formula of the compound of formula (4) is as follows:

[0103]

[0104] Its preparation process: add 19.4g (about 0.10mol) of the compound of formula (3) to 200mL of acetone, stir, add 43.3g (about 0.10mol) of the compound of formula (2), 48.3g (about 0.35mol) of potassium carbonate, 1.6g (about 0.005mol) tetrabutylammonium bromide, heated to 50-55°C for 20 hours. Filter, wash the filter cake with 50 mL of acetone, evaporate the filtrate to remove the solvent under reduced pressure to obtain an oil, add 185 g of dichloromethane and 240 g of water, stir for 10 minutes, separate layers, and extract the water layer with 30 g of dichloromethane×2. The organic layers were combined, dried with anhydrous m...

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Abstract

The invention relates to a preparation method of an olmesartan medoxomil intermediate 4-(1-hydroxyl-1-methylethyl)-2-propyl-1-[[2'-[2-(1-methyl-1-phenylethyl)tetrazole-5-yl]biphenyl-4-yl]methyl]imidazole-5-carboxylic acid, and a preparation method of another olmesartan medoxomil intermediate 4-(1-hydroxyl-1-methylethyl)-2-propyl-1-[[2'-[2-(1-methyl-1-phenylethyl)tetrazole-5-yl]biphenyl-4-yl]methyl]imidazole-5-methyl(5-methyl-2-oxo-1,3-dioxol-4-yl)carboxylate, and a synthesis method of olmesartan medoxomil. Compared with the prior art, the method provided by the invention is simpler, more convenient and more economical.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a preparation method of two intermediates of olmesartan medoxomil and a synthesis method of olmesartan medoxomil comprising the preparation methods of the two intermediates. Background technique [0002] Olmesartan medoxomil, its English name is Olmesartan Medoxomil, its chemical name is 4-(1-hydroxyl-1-methylethyl)-2-propyl-1-[[2'-(tetrazol-5-yl ) biphenyl-4-yl] methyl] imidazole-5-carboxylic acid (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl ester, its chemical structure as follows: [0003] [0004] It is an angiotensin Ⅱ receptor antagonist developed by Sankyo Pharmaceutical in Japan for the treatment of hypertension (approved by the FDA in 2002 and marketed in the United States, trade name: Benicar), which can be used alone or in combination with other antihypertensive drugs. Due to its long half-life, it can be taken once a day. Compared with other sartan drugs, the drug h...

Claims

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Application Information

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IPC IPC(8): C07D403/10C07D405/14
Inventor 张毅徐少军章波徐贤光
Owner LINHAI TIANYU PHARMA
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