Refining method of fasudil hydrochloride

Abstract

The invention discloses a refining method of fasudil hydrochloride. The method comprises the following steps: reacting homopiperazine with 5-isoquinoline sulfonyl chloride to obtain Fasudil free alkali, dissolving the Fasudil free alkali in a solvent A, uniformly mixing, dropwise adding hydrochloric acid into the solution at a constant temperature to adjust the pH value, stirring the solution at alow temperature to crystallize, filtering, drying a filter cake to constant weight to obtain Fasudil dihydrochloride, dissolving fasudil dihydrochloride in a solvent B, mixing, adding sodium hydroxide to adjust the pH value, separating the liquid, filtering the organic phase to obtain a filtrate, adding hydrochloric acid into the filtrate at constant temperature, stirring to crystallize, filtering, and drying the filter cake to obtain the fasudil hydrochloride refined product. According to the method, impurities in the fasudil hydrochloride can be effectively removed, the total impurity content is controlled to be 0.1% or below, the single impurity content is controlled to be 0.05% or below, the content is 99% or above, the pH value of the fasudil hydrochloride is effectively controlled to be 4.5-6.0, traditional column chromatography operation is avoided, and industrial production is facilitated.

Description

technical field [0001] The invention relates to the field of pharmaceutical chemical synthesis, in particular to a method for refining fasudil hydrochloride. Background technique [0002] Fasudil hydrochloride is a sulfonyl isoquinoline derivative, its chemical name is: hexahydro-1-(5-isoquinolinesulfonyl)-1H-1,4-diazepine hydrochloride, The molecular formula is: C 14 h 17 N 3 o 2 S·HCl, the molecular weight is 327.83. [0003] Fasudil hydrochloride, as a vasodilator drug, can effectively relieve cerebral vasospasm, improve the prognosis of patients with subarachnoid hemorrhage (SAH), and has great potential in the prevention and treatment of cardiovascular and cerebrovascular diseases. [0004] At present, there are many refining methods disclosed by Fasudil hydrochloride. Including the use of resin adsorption, followed by adsorption and decolorization with activated carbon, crystallization of water-n-butanol system; adsorption of impurities through silica gel; decolo...

AI Technical Summary

Problems solved by technology

[0006] Chinese patent CN101723934B uses resin-adsorbed fasudil and activated carbon to adsorb and decolorize, then acidify into salt, and recrystallize with water / n-butanol under reduced pressure and azeotropic recrystallization. It is necessary to add n-butanol to maintain the concentration of the material, the operation is complicated, and N-butanol has a high boiling point and is easy to remain, with a special smell

[0009] Chinese patent CN102002036B adopts the method of ethyl acetate and n-hexane recrystallization to refine, but it is actually found that the requirements for the crude product are relatively high, and it is difficult to achieve the patent effect

[0010] Chinese patent CN102775387B added hydrochloric acid gas to adjust the pH when forming salt, and the control of the amount of gas entering is not as accurate as that of liquid

[0011] Chinese patent CN103509002B combines the purification and decolorization of fasudil, but when the dichloromethane solution of 5-isoquinolinesulfonyl chloride and the dichloromethane solution of homopiperazine prepare the fasudil dichloromethane solution, it is difficult to react Complete, and the patent does not specify the purity and content of the product

[0012] Chinese patent CN104098547B also uses recrystallization for refining, but the solvent ether and acetone are easy-to-toxic solvents

[0013] Chinese patent CN109705096A converts fasudil hydrochloride into fasudil dihydrogen phosphate to remove homopiperazine, pigments and other water-soluble impurities, but uses phosphate and then converts it into hydrochloride, which requires additional Control Phosphate Content

[0014] These patents can remove some impurities, but there is no control that fasudil can form a salt with two molecules of hydrogen chloride. The product may contain both fasudil hydrochloride and part of fasudil dihydrochloride, so that the content is low and the pH value low