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A simple, low-cost and high-efficiency method for preparing valsartan

A low-cost, high-efficiency technology, applied in the direction of organic chemistry, can solve problems such as increased production costs, decreased chiral purity of raw materials and products, and difficult purification, achieving less side reactions, less environmental pollution, and high yields Effect

Active Publication Date: 2015-12-09
云南现代民族药工程技术研究中心 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Hydrolysis of the corresponding R group esters causes a decrease in the chiral purity of some raw materials and products, making the final purification very difficult and increasing production costs

Method used

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  • A simple, low-cost and high-efficiency method for preparing valsartan
  • A simple, low-cost and high-efficiency method for preparing valsartan
  • A simple, low-cost and high-efficiency method for preparing valsartan

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0072] Embodiment 1——the synthesis of compound (I)

[0073]

[0074] at 0 o Under nitrogen protection, 3g of 5-phenyltetrazolium (20.5mmol), 20mL of tetrahydrofuran, and 20mL of 2.5M n-butyllithium solution (50mmol) were sequentially added to the dry reaction flask. After warming up to room temperature, the mixture was stirred for 1 hour. Add 7.4 g of isopropyl pinnatyl borate (40 mmol), stir for 0.5 hour, and evaporate the reaction solution to dryness. Add 7.36g (20mmol) of compound VII, 175mg (1mmol) of palladium chloride, 8.2g (60mmol) of potassium carbonate, 20mL of toluene and 20mL of water. 100 o C was heated for 6 hours, acidified with 200 mL of 1M hydrochloric acid and purified twice with 20 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and recrystallized from ethyl acetate to obtain 4.3 g of the product, with a yield of 50%.

[0075] Its structural identification data are as follows: NMR 1...

Embodiment 2

[0076] Embodiment 2——the synthesis of compound (I)

[0077]

[0078] at 0 o Under nitrogen protection, 3g of 5-phenyltetrazolium (20.5mmol), 20mL of tetrahydrofuran, and 20mL of 2.5M n-butyllithium solution (50mmol) were sequentially added to the dry reaction flask. After warming up to room temperature, the mixture was stirred for 1 hour. Add 7.4 g of isopropyl pinnatyl borate (40 mmol), stir for 0.5 hour, and evaporate the reaction solution to dryness. Add 7.36g (20mmol) of compound VII, 233mg (1mmol) of palladium acetate, 2.4g (60mmol) of sodium hydroxide, and 40mL of ethylene glycol dimethyl ether. 80 o C was heated for 6 hours, acidified with 200 mL of 1M hydrochloric acid and purified twice with 20 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and recrystallized from ethyl acetate to obtain 4.7 g of the product, with a yield of 55%.

[0079] Its structural identification data are as follows: NM...

Embodiment 3

[0080] Embodiment 3 - the synthesis of compound (I)

[0081]

[0082] at 0 o Under nitrogen protection, 3g of 5-phenyltetrazolium (20.5mmol), 20mL of tetrahydrofuran, and 20mL of 2.5M n-butyllithium solution (50mmol) were sequentially added to the dry reaction flask. After warming to room temperature, the mixture was stirred for 1 hour. Add 9.2 g of tributyl borate (40 mmol), stir for 0.5 hour, and evaporate the reaction solution to dryness. Add 7.36 g (20 mmol) of compound VII, 30 mg (0.026 mmol) of tetrakis(triphenylphosphine) palladium (0), 6.3 g (60 mmol) of sodium carbonate, and 40 mL of dioxane. 110 o C was heated for 4 hours, concentrated under reduced pressure, acidified with 200 mL of 1M hydrochloric acid, and purified twice with 20 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and recrystallized from ethyl acetate to obtain 4.3 g of the product, with a yield of 50%.

[0083] Its structural...

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Abstract

The invention discloses a concise method of preparing valsartan at low cost and high efficiency. The method of preparing valsartan at low cost and high efficiency comprises the following step: in the presence of an alkali, carrying out a coupled reaction on a compound L-(N-4-bromo benzyl)-N-butyryl-valine VII and a borane derivative VIII of a compound 5-phenyl tetrazole in the presence of a palladium catalyst in an organic solvent and / or aqueous solution to obtain the target valsartan. The specific reaction equation is as shown in the specification. The method disclosed by the invention overcomes the defect that a synthetic method of valsartan in the prior art is severe in reaction condition, low in yield and greater in environmental pollution. Starting from low-price raw materials, the method disclosed by the invention is safe and reliable, short in synthetic line and easy to purify. The method disclosed by the invention is low in cost of raw materials and easy to get the raw materials, mild in reaction condition, fewer in side reactions, high in yield and less in environmental pollution, and is suitable for industrialized production.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and in particular relates to a simple, low-cost and high-efficiency method for preparing valsartan. Background technique [0002] Valsartan is one of the sartan antihypertensive drugs. Sartans are angiotensin II receptor antagonists. Angiotensin II is an oligopeptide hormone synthesized by the liver, which can activate angiotensin receptors, thereby causing physiological reactions such as vasoconstriction, increased blood pressure, and decreased renal blood flow. Sartan receptor antagonists block this process, thereby achieving a hypotensive effect. As a new drug for treating hypertension, valsartan has the characteristics of safety, long-acting, convenient administration and mild side effects. [0003] Valsartan was developed by the Swiss company Norvatis and was approved by the US FDA in 1998 for the treatment of hypertension. In 2005, the FDA expanded the drug's indications for the ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D257/04
CPCC07D257/04
Inventor 王喆应律丁悦
Owner 云南现代民族药工程技术研究中心
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