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High-yield purification method for preparation of high-purity sildenafil freebases

A technology of sildenafil and purification method, which is applied in the purification field of removing new impurities from sildenafil free base, and can solve problems such as undetectable impurities and the like

Active Publication Date: 2013-03-27
CHINA RESOURCES SAIKE PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0025] At the same time, the existing USP and EP quality standards all adopt isocratic analytical methods, which cannot detect the impurity. It is very necessary to determine a purification method on the quality control of sildenafil free base to ensure that the impurity content is not greater than 0.1%

Method used

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  • High-yield purification method for preparation of high-purity sildenafil freebases
  • High-yield purification method for preparation of high-purity sildenafil freebases
  • High-yield purification method for preparation of high-purity sildenafil freebases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0068] Example 1 Preparation of Sildenafil Free Base (II) Crude Product

[0069] Among them, 4-amino-1-methyl-3-n-propylpyrazole-5-carboxamide (VII) comes from Quzhou Yongchuang Chemical Technology Co., Ltd., and o-ethoxybenzoyl chloride (VI) comes from Zibo Yi New Chemical Co., Ltd., and other reagents were from Sinopharm Chemical Reagent Beijing Co., Ltd.

[0070] 1) Synthesis of 1-methyl-3-propyl-4-(2-ethoxybenzamido)pyrazole-5-carboxamide (V)

[0071] Add 500ml of dichloromethane into a 2L reaction flask, then add 100g of (VII), start stirring, then add 83g of triethylamine, then cool in a low-temperature bath to 0°C, add 110g of (VI) dropwise, and keep it warm at room temperature for 4 hours after dropping , and then add water to wash once, let stand for liquid separation, and directly divide the obtained dichloromethane layer into two equal parts, concentrate and evaporate to dryness.

[0072] Method A: Refined with 100ml ethyl acetate, filtered and dried to obtain 75g...

Embodiment 2

[0086] Example 2 Preparation of Sildenafil Free Base (II) Essence

[0087] Add 15ml of toluene and 2ml of methanol to a 100ml reaction flask, add 5g of crude sildenafil free base (II), stir well, heat up to 45~50°C, keep stirring for 2h, then cool to room temperature, filter, and dry to obtain Product (II).

[0088] Method A: Yield 92.8%, wherein the content of impurity I08 is 0.058%

[0089] Method B: Yield 93.4%, wherein the content of impurity I08 is 0.028%

Embodiment 3

[0090] Example 3 Preparation of Sildenafil Free Base (II) Essence

[0091] Add 15ml of toluene and 4ml of methanol to a 100ml reaction flask, add 5g of crude sildenafil free base (II), stir well, heat up to 45~50°C, keep stirring for 2h, then cool to room temperature, filter, and dry to obtain Product (II).

[0092] Method A: Yield 90.6%, wherein the content of impurity I08 is 0.054%

[0093] Method B: Yield 91.2%, wherein the content of impurity I08 is 0.025%

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Abstract

The invention belongs to the technical field of medicinal chemistry, relates to a purification method for high-purity sildenafil freebases, particularly to a purification method for removing new impurities from the sildenafil freebases. The method includes adding 1-6 times (v / w) of organic solvents to sildenafil freebase (II) crude products, stirring fully, warming to 40-60DEG C, stirring for 1-6h with temperature preservation, then cooling to the room temperature, filtering and drying to obtain sildenafil freebase (II) fine products.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry and relates to a method for purifying sildenafil free base, in particular to a purification method for removing new impurities from sildenafil free base. Background technique [0002] Sildenafil citrate, whose trade name is viagra, is a new phosphodiesterase type 5 (PDE5) inhibitor developed and marketed by Pfizer in 1997. The chemical name is 5-[-2-ethoxy-5 ( - 4-Methylpiperazine-1-sulfonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidine-7 - Ketones are mainly used clinically to treat sexual dysfunction. Its mechanism of action is to inhibit the activity of phosphodiesterase V, prevent the hydrolysis of cGMP and cAMP to generate corresponding 5-monophosphate nucleotides, increase the concentration of cGMP in tissues, inhibit the relaxation of smooth muscle, and achieve the purpose of treatment. [0003] So far, the compound patent of sildenafil citrate has expir...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04G01N30/02
Inventor 刘沫毅刘清梁李继斌李志强祈伟
Owner CHINA RESOURCES SAIKE PHARMA
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