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The preparation method of naftopidil

A technology of naftopidil and piperazine, which is applied in the field of preparation of antihypertensive drug naftopidil, can solve the problems of low product purity and yield, difficulty in complete reaction, uneven reaction, etc. Simple operation and high product purity

Active Publication Date: 2011-12-07
蚌埠丰原涂山制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The reaction mixture of this method is a viscous system that is extremely difficult to stir, the reaction is uneven, it is not easy to react completely, and the red solid generated by the reaction is extremely difficult to recrystallize with isopropanol
Therefore, the product purity and yield are not high

Method used

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  • The preparation method of naftopidil
  • The preparation method of naftopidil

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] In a 500ml round bottom flask, add 1-(2-methoxyphenyl)-4-(oxiranylmethyl)-piperazine (24.8g, 0.1mol), α-naphthol (17.3g, 0.12 mol), potassium hydroxide (8.4g, 0.15mol) were dissolved in 100ml ethanol, then added 50ml ethanol and heated to boiling point, reflux reaction under stirring for 6 hours, after the reaction was finished, cooled to room temperature, a large amount of crystals were precipitated, then filtered, After drying, 39.0 g of light yellow solid was obtained.

[0024] Take the above 39.0g naftopidil crude product, add 300ml of absolute ethanol, after heating to dissolve, add appropriate amount of activated carbon, continue to heat and reflux for 30min, filter while it is hot, cool and crystallize under stirring, suction filter, and vacuum dry at 50°C to obtain the finished product 35.0 g. The total yield is 89.3%, mp: 125-126°C (literature value mp: 125-126°C), MS m / z: 392 (M + ), the HPLC assay content is greater than 99%.

Embodiment 2

[0026] In a 500ml round bottom flask, add 1-(2-methoxyphenyl)-4-(oxiranylmethyl)-piperazine (24.8g, 0.1mol), α-naphthol (18.7g, 0.13 mol), sodium hydroxide (6.0g, 0.15mol) were dissolved in 100ml of ethanol, then added 50ml of ethanol, heated to the boiling point, reflux reaction under stirring for 7 hours, after the reaction was completed, cooled to room temperature, a large amount of crystals were precipitated, and then filtered , and dried to obtain 40.0 g of a yellowish solid.

[0027] Take the above 40.0 g naftopidil crude product, add 100 ml of acetone, heat to dissolve, add appropriate amount of activated carbon, continue to heat and reflux for 30 min, filter while hot, cool and crystallize under stirring, suction filter, and vacuum dry at 50 ° C to obtain 35.2 g of finished product. The total yield is 89.8%, mp: 126-127°C (literature value mp: 125-126°C), MS m / z: 392 (M + ), the HPLC assay content is greater than 99%.

Embodiment 3

[0029] In a 500ml round bottom flask, add 1-(2-methoxyphenyl)-4-(oxiranylmethyl)-piperazine (24.8g, 0.1mol), α-naphthol (18.7g, 0.13 mol), sodium hydroxide (8.0g, 0.2mol) were dissolved in 100ml of n-butanol, then added 50ml of n-butanol, heated to the boiling point, reflux reaction under stirring for 6 hours, after the reaction was completed, cooled to room temperature, a large amount of The crystals were then filtered and dried to obtain 38.5 g of a yellowish solid.

[0030] Take the above 38.5g naftopidil crude product, add 90ml of acetone, heat to dissolve, add appropriate amount of activated carbon, continue to heat and reflux for 20min, filter while it is hot, cool and crystallize under stirring, suction filter, and vacuum dry at 50°C to obtain 35.3g of finished product. The total yield is 90.1%, mp: 126-127°C (literature value mp: 125-126°C), MS m / z: 392 (M + ), the HPLC assay content is greater than 99%.

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Abstract

The present invention relates to the preparation method of naftopidil, comprising 1-(2-methoxyphenyl)-4-(oxiranylmethyl)-piperazine, α-naphthol and inorganic base in an organic solvent Heating to the boiling point of the solvent, reacting under the condition of reflux and stirring, and obtaining naftopidil through post-processing after the reaction is completed. The preparation method of the naftopidil of the present invention is novel, the product yield is high, the product is high in purity, and the operation is simple, and it is suitable for industrial production to produce excellent antihypertensive drugs.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, in particular to a preparation method of antihypertensive drug naftopidil. Background technique [0002] Naftopidil chemical name: (±)-1-[4-(2-methoxyphenyl)-1-piperazinyl]-3-(1-naphthyloxy)-2-propanol. Molecular formula: C 24 h 28 N 2 o 3 , molecular weight: 392.50. It is white or off-white crystalline powder. [0003] Naftopidil is a selective α1 receptor antagonist, which can inhibit the increase in blood pressure caused by α1 receptors, and also has calcium ion antagonism. Pharmacodynamic tests have shown that this product has antihypertensive effects on various animal models of hypertension , long duration of antihypertensive, does not cause reflex tachycardia during antihypertensive, no obvious first-dose effect and drug resistance after repeated oral administration. The results of cardiac hemodynamic tests show that this product can reduce the total peripheral resistance and dilat...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D295/096
Inventor 陈文明杜明松汪洪湖
Owner 蚌埠丰原涂山制药有限公司