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Solid-phase preparation method of avanafil

A solid-phase preparation, Avanafil technology, applied in the direction of organic chemistry, etc., to achieve the effect of easy post-processing, good application prospects, and easy to achieve purification

Inactive Publication Date: 2013-12-11
NANJING UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The main purpose of the present invention is to provide a new method for the solid-phase preparation of avanafil that is easy to operate, simple in the separation process, and easy to realize purification in view of the defects in the current liquid synthesis

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Embodiment 1: the synthesis of compound (II):

[0047] The high load Merrifiled resin (2.15mmol / g, 5g) was put into the reactor, and thiourea (4g, 53.75mmol) was dissolved in 200mL of dioxane-ethanol solution with a volume ratio of 4:1, and added into the reactor, stirred at 85°C for 15h, washed four times with ethanol at 70°C, washed twice each with dioxane and pentane at room temperature, and dried the obtained solid in vacuum at 60°C to obtain compound (II )6g.

Embodiment 2

[0048] Embodiment 2: the synthesis of compound (III):

[0049] The product (II) (3 g, 5.375 mmol) was put into a solid phase reactor, 10 mL of DMF was added, shaken at room temperature for 5 min, and N,N-diisopropylethylamine (2.3 mL, 13.438 mmol) was added slowly. Then diethyl ethoxymethylene malonate (5.8 g, 26.875 mmol) was dissolved in 5 mL of DMF, slowly added into the reactor, and shaken overnight at room temperature. After the reaction was completed, filter and wash with DMF, ethanol, and dichloromethane in sequence, and the obtained solid was vacuum-dried at 60° C. to obtain compound (III).

Embodiment 3

[0050] Embodiment 3: the synthesis of compound (IV):

[0051] POCl 3 (20mL, 21.8mmol) was cooled to 10°C and added to the reactor, and compound (III) (2.82g, 4.36mmol) was added to the reactor in batches, keeping the temperature not exceeding 25°C, and then heated to 65-80 ℃ for 3 to 5 hours, after the reaction is completed, filter off excess POCl 3 , the obtained solid was washed successively with ice water, ethanol and dichloromethane, and dried under vacuum at 60° C. to obtain compound (IV).

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PUM

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Abstract

The invention discloses a solid-phase preparation method of avanafil. The chemical name of the avanafil is (S)-4-(3-chloro-4-methoxy benzyl amino)-2-(2-hydroxymethyl-1-pyrrolidyl)-N-(2-pyrimidylmethyl)-5-pyrimidinecarboxamide; the avanafil has the following structural formula (IX). Compared with the liquid-phase synthetic method, the method provided by the invention has the advantages that shortcomings in liquid phase synthesis are overcome, the operation steps are simplified, the separation process is simple and purification is easy to realize.

Description

technical field [0001] The invention relates to the fields of medicinal chemistry and organic chemistry, in particular to a new method for preparing avanafil, and the compound can be used for treating male erectile dysfunction. Background technique [0002] The chemical name of Avanafil is (S)-4-(3-chloro-4-methoxybenzylamino)-2-(2-hydroxymethyl-1-pyrrolidinyl)-N-( 2-Pyrimidinemethyl)-5-pyrimidinecarboxamide is a drug developed by Vivus Company of the United States authorized by Mitsubishi Tanabe Pharmaceutical Co., Ltd. of Japan for the treatment of male erectile dysfunction. It was approved by the FDA in April 2012 and listed in the United States. The trade name is Stendra. This product has the same mechanism of action as other phosphodiesterase-5 inhibitors (PDE-5 inhibitors), but has unique pharmacokinetic and pharmacodynamic properties, and its advantage is faster oral absorption, which means that large Most patients with erectile dysfunction can obtain satisfactory e...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/14
Inventor 苏贤斌郭加赛金凯军董海军
Owner NANJING UNIV OF TECH
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