Method for synthesizing phentolamine mesylate

The technology of phentolamine mesylate and phentolamine hydrochloride is applied in the field of synthesis of phentolamine mesylate, which can solve the problems of large stimulation to the human body, high boiling point, complicated process and the like, so as to reduce toxicity and reaction temperature, reducing the formation of impurities, removing irritating effects

Active Publication Date: 2009-06-24
TIANJIN CENT PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, due to the high toxicity of xylene and high boiling point, and the phentolamine hydrochloride needs to be refined before being used in the next step reaction, the mesylate needs to be concentrated in a solvent for crystallization, the process is complex, and the yield is low
[0006] In CN101104603A "A kind of production method of phentolamine", the method of dissolving phentolamine in water and passing through a silica gel chromatography column, and adjusting the pH value with ammonia water is relatively irritating to the human body, and the industrial production operation is difficult and uncomfortable. For large-scale industrial production needs

Method used

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  • Method for synthesizing phentolamine mesylate
  • Method for synthesizing phentolamine mesylate

Examples

Experimental program
Comparison scheme
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Embodiment 1

[0030] Preparation of Phentolamine Hydrochloride

[0031] Add 8g (0.04mol) of 3-hydroxy-4-methyldiphenylamine, 6.15g (0.04mol) of chloromethylimidazoline hydrochloride, and 64ml of toluene into the reaction flask, reflux to separate water, and react at 110°C for 15 hours, then cool down to 100°C, add 48ml of purified water and 48ml of ethyl acetate, heat up, reflux for 10 minutes, separate layers after cooling down, cool the water layer to 15-20°C for crystallization for 24 hours, filter, rinse with ethyl acetate and acetone to obtain hydrochloric acid Phentolamine 8.5g, properties: brown solid, HPLC 99%, melting point 244°C-249°C, yield 66.93%.

Embodiment 2

[0033] Preparation of Phentolamine

[0034] Add 8.5 g (0.027 mol) of phentolamine hydrochloride and 170 ml of purified water into the reaction flask in Example 1, heat up to 80° C. to completely dissolve, adjust the pH to 8 with aqueous sodium carbonate solution, add 0.7 g of activated carbon, and keep warm for 20 minutes for decolorization , filtered, the filtrate was cooled to 10°C, adjusted to pH = 9.5 with NaOH aqueous solution, kept at 5°C for crystallization for 4 hours, filtered, washed with purified water until neutral, and 6.5g of phentolamine was obtained. Properties: off-white solid, HPLC 98% , melting point 165°C-168°C, yield 85.56%.

Embodiment 3

[0036] Preparation of Phentolamine Mesylate:

[0037] Add 6.5g (0.023mol) of phentolamine and 52ml of isopropanol into the reaction flask in Example 2, slowly add methanesulfonic acid dropwise at 50-60°C to adjust the pH to 6, cool down to 10°C-15°C, and keep warm Crystallize for 4 hours, filter, rinse with ethyl acetate to obtain 7.4 g of crude phentolamine mesylate, properties: off-white solid, HPLC 98%, melting point 176°C-180°C, yield 85.24%.

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Abstract

The invention discloses a synthetic method of phentolamine mesylate. The method comprises the following steps: 3-hydroxy-4-methyldiphenylamine and chloromethylimidazoline hydrochloride are taken as raw materials, toluene is taken as a solvent, the raw materials and the solvent are condensed to obtain phentolamine hydrochloride solid in water, the solid is subject to pH regulation and alkalization to obtain phentolamine, finally the phentolamine is salified in isopropyl alcohol and refined in ethanol-ethyl acetate mixed solvent to obtain the phentolamine mesylate. In the method, the toluene is taken as the solvent for the condensation reaction, which avoids use of toxic xylene, lowers reaction temperature, enhances reaction yield; and inorganic alkali aqueous solution replaces ammonia water in the quaternization, which reduces irritation to human body. The prepared phentolamine mesylate has the advantages of stable property, higher content, better yield, simple and convenient industrial operation, thus the method is good for large-scale industrialized production.

Description

technical field [0001] The invention relates to a synthesis method of phentolamine mesylate, which belongs to the technical field of medicine and chemical industry. Background technique [0002] Phentolamine Mesylate (Phentolamine Mesylate) is also known as benzamidoline mesylate, Regitine, chemical name: 3-[[(4,5-dihydro-1H-imidazol-2-yl ) methyl] (4-tolyl) amino] phenol methanesulfonate, chemical structure: [0003] [0004] Phentolamine mesylate is an α-receptor blocking drug, which rapidly dilates peripheral blood vessels by blocking α-receptors and indirectly stimulating β-receptors, which can significantly reduce peripheral vascular resistance, increase peripheral blood volume, and improve microcirculation. Phentolamine mesylate has an excitatory effect on the heart, increasing myocardial contractility, heart rate, and cardiac output. It is mainly used clinically for the treatment of acute heart failure with pulmonary congestion or pulmonary edema, vasospasm dise...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D233/24
Inventor 孟庆礼杨冠宇宋风武
Owner TIANJIN CENT PHARM CO LTD
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