CN103509002B - Purification decolorization method of fasudil hydrochloride - Google Patents

Abstract

The invention relates to a crude drug processing method, particularly relates to a purification decolorization method of a crude drug, and more particularly relates to a purification decolorization method of fasudil hydrochloride. Aiming at the problem that in the prior art a fasudil hydrochloride product is purified and decolored by organic solvent recrystallization, the new purification decolorization method of the fasudil hydrochloride is provided, through direct pH adjusting of a fasudil dichloromethane solution and matched filtering operation, the fasudil hydrochloride product is separated from pigments and water soluble impurities, a new idea that a crude drug hydrochloride can be crystallized in an aqueous solution is developed, so that the problem of organic compound recrystallion in an organic solution in the prior art is solved.

Description

A kind of purification and decolorization method of fasudil hydrochloride

technical field

The present invention relates to a kind of treatment method of crude drug, particularly relate to a kind of purification decolorization method of crude drug, more specifically relate to a kind of purification decolorization method of fasudil hydrochloride.

Background technique

Fasudil hydrochloride is a protein kinase inhibitor or intracellular calcium ion antagonist. Its pharmacological action is to dilate blood vessels by blocking the final stage of the vasoconstriction process, that is, the phosphorylation of globulin light chains. thereby inhibiting vasospasm. Its pharmaceutical products are clinically suitable for improving and preventing cerebral spasm after subarachnoid hemorrhage and the symptoms of cerebral ischemia caused by it.

The commonly used clinical dosage form of Fasudil hydrochloride is injection, so the requirements for its color and purity are extremely strict. How to decolorize and purify Fasudil hydrochloride is particularly important.

The purification method in the existing process can basically be divided into two steps. The first step adopts the organic solvent recrystallization method such as US5942505 to decolorize and purify the product, and the second step uses the free base of the compound to remove the organic phase and the aqueous phase. Such as EP1726306 and patent CN101723934A, etc., or decolorize and purify the product through silica gel chromatography column such as US5942505, EP187371 and patent CN101812051A. Inevitably, the first step of purifying and decolorizing the product by using the organic solvent recrystallization method and the two-phase elimination of the organic basic raw material drug, but the problem is that the result of doing so is often unsatisfactory, and it is repeated continuously These two processes not only make the operation more complicated and the loss greater, but the result is not satisfactory.

Contents of the invention

The present invention provides a new purification and decolorization method of fasudil hydrochloride for the problems existing in the current fasudil hydrochloride using organic solvent recrystallization to decolorize and purify the product, comprising the following steps:

(1) Prepare the dichloromethane solution of Fasudil;

(2) adjusting the pH value of the fasudil dichloromethane solution in step (1) to 4.5-5.5;

(3) Lower the temperature of the system to below 0°C, stir, and keep warm for half an hour;

(4) Filter the mixture obtained in step (3), collect the filter cake, and obtain the decolorized purified product of Fasudil hydrochloride.

As an improvement, dilute hydrochloric acid is used in the step (2) to adjust the pH value of the fasudil dichloromethane solution.

As another improvement, the preparation method of the fasudil dichloromethane solution in the step (1) is: adding the dichloromethane solution of 5-isoquinolinesulfonyl chloride dropwise to the dichloromethane solution of homopiperazine.

The present invention directly adjusts the pH of the fasudil dichloromethane solution and cooperates with the filtration operation to separate the pigment and water-soluble impurities from the fasudil hydrochloride product, and opens up the crystallization of the hydrochloride of the raw material drug in the aqueous solution The new idea has solved the problems that could not be solved by the recrystallization of organic compounds in organic solution in the past.

Detailed ways

Example 1

The purification and decolorization method of fasudil hydrochloride comprises the following steps:

(1) Prepare the dichloromethane solution of Fasudil;

(2) adjusting the pH value of the fasudil dichloromethane solution in step (1) to 4.5-5.5;

(3) Lower the temperature of the system to below 0°C, stir, and keep warm for half an hour;

(4) Filter the mixture obtained in step (3), collect the filter cake, and obtain the decolorized product of Fasudil hydrochloride.

Example 2

The purification and decolorization method of fasudil hydrochloride comprises the following steps:

(1) Add the dichloromethane solution of 5-isoquinolinesulfonyl chloride dropwise to the dichloromethane solution of homopiperazine to prepare the dichloromethane solution of fasudil;

(2) adjusting the pH value of the fasudil dichloromethane solution in step (1) to 4.5-5.5;

(3) Lower the temperature of the system to below 0°C, stir, and keep warm for half an hour;

(4) Filter the mixture obtained in step (3), collect the filter cake, and obtain the decolorized product of Fasudil hydrochloride.

Example 3

The purification and decolorization method of fasudil hydrochloride comprises the following steps:

(1) Prepare the dichloromethane solution of Fasudil;

(2) Gradually drop dilute hydrochloric acid into the solution system, and adjust the pH value of the fasudil dichloromethane solution in step (1) to 4.5-5.5;

(3) Lower the temperature of the system to below 0°C, stir, and keep warm for half an hour;

(4) Filter the mixture obtained in step (3), collect the filter cake, and obtain the decolorized product of Fasudil hydrochloride.

Example 4

Step 1: Add homopiperazine dichloromethane mixture to the reaction kettle, freeze and cool down to 0°C, add 5-isoquinolinesulfonyl chloride in dichloromethane dropwise, control the temperature of the reaction solution below 5°C, drop After the addition, the reaction solution was yellow-green.

Add 4 mol/L hydrochloric acid aqueous solution dropwise to the reaction system to adjust the pH to 5.

Cool down, when the temperature of the system is about 15°C, a white solid begins to precipitate, continue to cool down to below 0°C, keep warm for half an hour, filter, the filter cake is off-white solid, and the filtrate is yellow-green, which contains pigments and impurities soluble in acidic aqueous solution .

Second step: according to the method disclosed in EP1726306 and patent CN101723934A, the decolorized Fasudil hydrochloride is further purified. The specific process is as follows: Dissolve the off-white solid filter cake in water, add dichloromethane, wash, let it stand for stratification, discard the organic phase of dichloromethane (which contains some impurities soluble in dichloromethane), and take the water phase to wait use. Adjust the pH of the aqueous solution to above 10, add dichloromethane again, extract, let stand to separate layers, discard the aqueous solution (which contains some impurities soluble in alkaline aqueous solution), take the organic phase of dichloromethane, and pour the obtained dichloromethane A salt-forming reagent was added to the solution, and filtered to obtain the crude product of Fasudil hydrochloride. The crude product was recrystallized with about 90% ethanol aqueous solution to obtain pure Fasudil hydrochloride, HPLC content: 99.97%, single largest impurity 0.03%, color lower than yellow 0.5.

Compared with Fasudil hydrochloride obtained by the method in the literature (99.96% obtained by CN101812051A column chromatography method), not only the cost of obtaining the product is lower, the color is completely qualified, the content is higher, the operation is simple, and it is suitable for production.

The technical means disclosed in the solution of the present invention are not limited to the technical means disclosed in the above technical means, but also include technical solutions composed of any combination of the above technical features.

The above are specific implementations of the present invention. It should be pointed out that for those of ordinary skill in the art, without departing from the principle of the present invention, some improvements and modifications can also be made, and these improvements and modifications are also considered Be the protection scope of the present invention.

Claims (3)

1. a Purification decolorization method for Fasudil Hydrochloride, is characterized in that comprising the following steps:

(1) dichloromethane solution of obtained fasudil;

(2) pH value to 4.5 ~ 5.5 of the middle fasudil dichloromethane solution of regulating step (1);

(3) reduce below system temperature to 0 DEG C, stir, insulation half hour;

(4) mixture obtained in step (3) is filtered, collect filter cake, obtain Fasudil Hydrochloride decolouring purifying product.

2., according to the Purification decolorization method of the Fasudil Hydrochloride described in claim 1, it is characterized in that in described step (2), adopting dilute hydrochloric acid to regulate the pH value of fasudil dichloromethane solution.

3., according to the Purification decolorization method of the Fasudil Hydrochloride described in claim 1, it is characterized in that the preparation method of the dichloromethane solution of fasudil in described step (1) is: the dichloromethane solution dichloromethane solution of 5-isoquinoline sulfonyl chloride being dropped to homopiperazine.