Method for removing chloride ions in phentolamine

Abstract

The invention discloses a method for removing chloride ions in phentolamine, and belongs to the technical field of pharmaceutical chemicals. The method comprises the following steps: mixing and dissolving phentolamine hydrochloride and a solvent, filtering, carrying out non-concentration or vacuum concentration, cooling, adding free alkali to adjust pH, and crystallizing to obtain phentolamine; wherein the temperature during dissolution is 0-50 DEG C. According to the method, the phentolamine hydrochloride is dissolved in the solvent, then acid radical is removed through lye dissociation and crystallization is carried out to obtain phentolamine, dissociation dechlorination is carried out according to the low-temperature solvent ratio, chloride ions in phentolamine are efficiently removed, the dissociated phentolamine has high purity, the subsequent refining process is reduced, and the yield of the phentolamine is improved. New reaction aids and adsorption materials are not introduced, so that the method is suitable for large-scale production of methanesulfonic acid bulk drugs.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical chemical industry, and particularly relates to a method for removing chloride ions in phentolamine. Background Art

[0002] Phentolamine, as an α-receptor blocker, is widely used to solve peripheral vascular problems. It is a vasodilator that can directly act on vascular smooth muscle to reduce cardiac preload and postload, and indirectly enhance myocardial contraction by activating norepinephrine and inducing β-receptor effects.

[0003] Phentolamine mesylate, also known as phentolamine methanesulfonate, has a chemical name of 2-[N-(m-hydroxy)-p-toluidine methyl]-2-imidazoline mesylate. It is a non-selective adrenergic α receptor blocker that can reduce peripheral vascular resistance and increase peripheral vascular blood flow. Because it has an excitatory effect on the heart and can promote vasodilation, its application field has become increasingly wide in recent years. There are also many production processes and methods for preparing phentolamine mesylate, but in large-scale industrial production processes, it is difficult to control the generation of chloride. At present, the chloride in phentolamine mesylate is removed by first adjusting the pH by dilute ammonia water, then purifying by column chromatography, and finally adjusting the pH by dilute ammonia water to obtain high-purity phentolamine. However, the product prepared by this method can be repeatedly loaded on the column, but the column chromatography process restricts industrial production capacity and cost control. Chinese patent CN103408495A eliminates column chromatography and replaces it with silica gel H adsorption. Chloride ions are removed by adjusting the pH by dilute ammonia water many times, and the effect is obvious. However, the operation is too complicated, and silica gel adsorption cannot meet the requirements of industrial sustainable operation. The pH adjustment times are too high, and the pH control range is too narrow each time, which makes it difficult to adapt to industrial production.

[0004] Therefore, it is necessary to provide a method for removing chloride ions in phentolamine. Summary of the invention

[0005] In view of the above problems existing in the prior art, the first technical problem to be solved by the present invention is to provide a method for removing chloride ions in phentolamine, which adopts a low temperature solvent ratio for free dechlorination, efficiently removes chloride ions in phentolamine, and the freed phentolamine has a higher purity, which reduces the subsequent refining process, does not introduce new reaction aids and adsorption materials, and is suitable for large-scale production of mesylate bulk drugs. The second technical problem to be solved by the present invention is to provide phentolamine, which has no chloride ions and is suitable for large-scale production of mesylate bulk drugs. The third technical problem to be solved by the present invention is to provide the application of phentolamine in the preparation of phentolamine mesylate, which is used to deal with the problem of containing chloride in the preparation of phentolamine mesylate.

[0006] In order to solve the above problems, the technical solution adopted by the present invention is as follows:

[0007] A method for removing chloride ions from phentolamine comprises the steps of mixing phentolamine hydrochloride and a solvent to dissolve the mixture, filtering the mixture without concentration or concentrating the mixture under reduced pressure, cooling the mixture, adding a free alkali to adjust the pH value, and crystallizing the mixture to obtain phentolamine; wherein the temperature during the dissolution is 0-50°C.

[0008] Furthermore, the solvent is one or more of purified water, ethanol and methanol.

[0009] Furthermore, the mass volume ratio of the phentolamine hydrochloride and the solvent is 1g:50-200mL.

[0010] Furthermore, the dissolving temperature is 0-25°C.

[0011] Furthermore, the dissolving temperature is 5 to 15°C.

[0012] Furthermore, after the filtration, if the filtrate contains alcohol solvent, it is concentrated under reduced pressure; if it does not contain alcohol solvent, it is not concentrated; wherein the temperature of the reduced pressure concentration is 15 to 35°C.

[0013] Furthermore, the free alkali is one or more of sodium carbonate, sodium bicarbonate, potassium carbonate and ammonia water.

[0014] Furthermore, the free alkali is a 10-20% sodium carbonate solution or a 10-20% potassium carbonate solution.

[0015] Furthermore, the free alkali is a 15% sodium carbonate solution.

[0016] Furthermore, the filter cloth used for filtration is 400-1000 mesh; preferably, the filter cloth is 600-800 mesh; more preferably, the filter cloth is 800 mesh.

[0017] Further, the crystallization temperature is 0-20°C, and the crystallization time is 2-14h; preferably, the crystallization temperature is 5-10°C, and the crystallization time is 8-18h; more preferably, the crystallization temperature is 5-10°C, and the crystallization time is 8-12h.

[0018] Further, adjust the pH ≥ 10.

[0019] The phentolamine prepared by the method.

[0020] The application of the phentolamine in the preparation of phentolamine mesylate.

[0021] Beneficial effects: Compared with the prior art, the advantages of the present invention are:

[0022] (1) The present invention dissolves phentolamine hydrochloride in a solvent, and then utilizes an alkali solution to free and remove acid radicals to crystallize phentolamine. A low-temperature solvent ratio is used for free dechlorination, and chloride ions in phentolamine are efficiently removed. The free phentolamine has a high purity, which reduces the subsequent refining process, does not introduce new reaction aids and adsorption materials, and is suitable for large-scale production of methanesulfonic acid raw materials.

[0023] (2) The present invention removes chloride ions in phentolamine, eliminates the degree of column chromatography in the existing process, and improves the equipment capacity utilization rate.

[0024] (3) The neutralization process of the present invention is completed in one step, eliminating the operation of adjusting pH twice or more, dissolving and neutralizing in the existing process, thus simplifying the production operation process.

[0025] (4) The present invention uses phentolamine hydrochloride to remove chloride ions through neutralization, and the obtained phentolamine yield can be above 80%, the purity is above 98.5%, most of the impurities are removed, and the subsequent phentolamine salt formation and refining pressure is reduced. The quality of the refined phentolamine mesylate finished product meets the standards of mainstream pharmacopoeias such as the Chinese Pharmacopoeia, the European Pharmacopoeia, and the United States Pharmacopoeia. The product requirements of phentolamine mesylate injection, tablets, capsules, and other preparations are fully met. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 The present invention is a process flow chart for removing chloride ions from phentolamine mesylate;

[0027] Figure 2 The HPLC spectrum of phentolamine hydrochloride used as the raw material of the present invention;

[0028] Figure 3 The HPLC spectrum of phentolamine prepared in Example 1 of the present invention. DETAILED DESCRIPTION

[0029] The present invention is further described below in conjunction with specific embodiments.

[0030] The phentolamine hydrochloride used in the following examples was homemade in the laboratory. The preparation method was as follows: 0.1 mol of 2-(p-methylaminomethyl)imidazoline hydrochloride, 0.12 mol of 3-chlorophenol and 200 mL of xylene were mixed, reacted at 10-20° C. for 24 h, the organic phase was washed and quenched twice, the aqueous phase was cooled to below 10° C., allowed to stand overnight, and filtered to obtain a brown phentolamine hydrochloride crude product. The crude product was refined by reflux with chloroform-ethanol, cooled to below 10° C., filtered, and dried to obtain an off-white phentolamine hydrochloride. The HPLC spectrum of phentolamine hydrochloride is shown in FIG. Figure 2 shown.

[0031] The following example uses phentolamine to prepare phentolamine mesylate as follows: 0.1 mol of phentolamine is dissolved in 50 mL of methanol, the mixture is kept warm to 0-10° C., methanesulfonic acid is added dropwise and stirred to form a salt until the solution pH is 3-4, the mixture is stirred at room temperature for 3 h, filtered, and the filter cake is refined and dried with a mixed solution of 20 mL of ethanol and 40 mL of ethyl acetate to obtain a white powdery solid phentolamine mesylate.

[0032] The following examples are used to detect chloride ions in phentolamine using the chloride ion detection method of the Chinese Pharmacopoeia, using a silver nitrate solution for titration. If white turbidity appears, it indicates the presence of chloride ions; if clear, it indicates the absence of chloride ions.

[0033] Example 1

[0034] The method for removing chloride ions from phentolamine is as follows:

[0035] Add 5L purified water and 200mL ethanol to the reaction flask, cool to 0-10°C, add 100g phentolamine hydrochloride, stir for 2h, wait for the solid to dissolve, filter through 800 mesh filter cloth, and remove insoluble matter. The filtrate is concentrated under reduced pressure at 35°C to remove ethanol. After concentration, the filtrate is cooled to below 25°C, and 10% sodium carbonate solution is slowly added dropwise to adjust the pH ≥ 10. Solids precipitate, stir and crystallize at 5-15°C for 16h, and filter. The solid is vacuum dried at 40-50°C for 12h to obtain white phentolamine with an HPLC purity of 98.8% and a molar yield of 85.6%. The filter cake is washed 4 times with 1L purified water, and the last filtrate is taken and tested according to the chloride ion detection method of the "Chinese Pharmacopoeia". No chloride ion remains. The process flow is as follows Figure 1 As shown, the HPLC spectrum of phentolamine is as shown Figure 3 shown.

[0036] Figure 3 The HPLC spectrum of phentolamine prepared in Example 1 of the present invention shows that the present embodiment not only avoids the operation process of limiting industrial production such as column chromatography and silica gel adsorption used in the existing process; the chloride ion detection method of the Chinese Pharmacopoeia is used for detection, and chloride ion is not detected, while the free phentolamine has a higher purity, which reduces the pressure of subsequent refining and ensures the yield and purity of the production process of phentolamine mesylate.

[0037] Example 2

[0038] The method for removing chloride ions from phentolamine is as follows:

[0039] Add 10L of purified water to the reaction flask, cool to 0-10°C, add 100g of phentolamine hydrochloride, stir for 2h, wait for the solid to dissolve, filter through 800-mesh filter cloth, and remove insoluble matter. Cool the filtrate to below 15°C, slowly add 15% sodium carbonate solution, adjust the pH ≥ 10, solid precipitates, stir and crystallize at 5-10°C for 12h, and filter. The solid is vacuum dried at 40-50°C for 12h to obtain off-white phentolamine with HPLC purity of 99.0% and molar yield of 89.6%. Wash the filter cake 4 times with 1L of purified water, take the last filtrate, and test it according to the chloride ion detection method of the "Chinese Pharmacopoeia". No chloride ion remains. The process flow is as follows Figure 1 shown.

[0040] Example 3

[0041] The method for removing chloride ions from phentolamine is as follows:

[0042] Add 5L purified water and 100mL methanol to the reaction flask, cool to 0-20°C, add 100g phentolamine hydrochloride, stir for 2h, wait for the solid to dissolve, filter through a 600-mesh filter cloth to remove insoluble matter. The filtrate is concentrated under reduced pressure at 35°C to remove methanol. After concentration, the filtrate is cooled to below 20°C, 20% sodium carbonate solution is slowly added dropwise, and the pH is adjusted to ≥10. Solids precipitate, stir at 5-15°C for crystallization for 8h, and filter. The solid is vacuum dried at 40-50°C for 12h to obtain off-white phentolamine with an HPLC purity of 98.6% and a molar yield of 80.9%. Wash the filter cake 4 times with 1L purified water, take the last filtrate, and test it according to the chloride ion detection method of the "Chinese Pharmacopoeia". No chloride ion remains. The process flow is as follows Figure 1 shown.

[0043] Example 4

[0044] The method for removing chloride ions from phentolamine is as follows:

[0045] Add 10L of purified water to the reaction flask, cool to 0-10°C, add 100g of phentolamine hydrochloride, stir for 2h, wait until most of the solids are dissolved, filter through 800 mesh filter cloth, and remove insoluble matter. Cool the filtrate to below 10°C, slowly add 15% sodium carbonate solution, adjust the pH ≥ 10, a large amount of solid precipitates, stir at 5-10°C for crystallization for 12h, and filter. The solid is vacuum dried at 40-50°C for 12h to obtain off-white phentolamine with HPLC purity of 99.1% and molar yield of 89.7%. Wash the filter cake 4 times with 1L of purified water, take the last filtrate, and test it according to the chloride ion detection method of the "Chinese Pharmacopoeia". No chloride ion remains. The process flow is as follows Figure 1 shown.

[0046] Comparative Example 1

[0047] (1) Add 35 kg of water to a container, heat it to 60°C, start stirring, slowly add 0.6 kg of phentolamine hydrochloride, and adjust the pH to 7-8 with ammonia water after dissolution.

[0048] (2) Column packing: The size of the column is selected according to the production volume. Qingdao silica gel (100-200 mesh) (Qingdao Ocean Chemical Plant) is used for dry column packing. The column diameter is 15 cm and the column height is 20 cm.

[0049] (3) The above solution is loaded onto the column, and the filtrate is cooled to room temperature. Ammonia water is added dropwise with stirring until the white precipitate is completely precipitated. Then, the mixture is controlled and filtered.

[0050] (4) The precipitate was washed with purified water until neutral, then washed with ethanol, drained, moved to an oven, and dried at 70° C. to obtain light yellow phentolamine with a molar yield of 69.7% and an HPLC purity of 89.1%. After impurity separation and determination, the major impurity was 7.5% of impurity A listed in the European Pharmacopoeia.

[0051] Comparative Example 2

[0052] (1) Add 2500 mmL of distilled water heated to 65°C into a 4000 mmL beaker, add 50 g of phentolamine hydrochloride into the beaker under stirring, add 25 g of silica gel H for the first time after stirring until it is completely dissolved, adjust the pH to 7.5 with dilute ammonia water, and then filter to obtain filtrate I;

[0053] (2) Add 20 g of silica gel H to filtrate I for the second time, adjust the pH to 8 with dilute ammonia water, and filter to obtain filtrate II;

[0054] (3) Add 15 g of silica gel H to filtrate II for the third time, adjust the pH to 8.5 with dilute ammonia water, and filter to obtain filtrate III;

[0055] (4) The temperature of filtrate III was lowered to below 30°C, and dilute ammonia water was slowly added dropwise under stirring until all crystals were precipitated. After waiting for 1 hour, the mixture was filtered and washed with distilled water for several times. The chloride tracking test of the filtrate was qualified. The phentolamine crystals in the liquid funnel were washed with anhydrous ethanol for 2 to 3 times until the ethanol solution dripped out was colorless, and dried at 80°C for 6 hours to obtain about 34 g of refined phentolamine. The molar yield was 67.7%, and the HPLC purity was 99.0%.

[0056] In summary, the quality index of the method for removing chloride ions provided by the present invention is better than that of the existing method, and the yield is much higher than the technical effects of Comparative Examples 1 to 2. In addition, the present invention does not require column chromatography, is simple to operate, and is suitable for industrial scale-up production.

Claims

1. A method for removing chloride ions from phentolamine, characterized in that: Phentolamine hydrochloride and a solvent are mixed and dissolved, filtered, not concentrated or concentrated under reduced pressure, cooled, and free alkali is added to adjust the pH value, and crystallized to obtain phentolamine; wherein the temperature during the dissolution is 0-50°C.

2. The method for removing chloride ions from phentolamine according to claim 1, wherein: The solvent is one or more of purified water, ethanol and methanol.

3. The method for removing chloride ions from phentolamine according to claim 1, characterized in that: The mass volume ratio of the phentolamine hydrochloride and the solvent is 1g:50-200mL.

4. The method for removing chloride ions from phentolamine according to claim 3, wherein: The temperature during the dissolution is 5-15°C.

5. The method for removing chloride ions from phentolamine according to claim 1, characterized in that: After the filtration, if the filtrate contains alcohol solvent, it is concentrated under reduced pressure; if it does not contain alcohol solvent, it is not concentrated; wherein the temperature of the reduced pressure concentration is 15-35°C.

6. The method for removing chloride ions from phentolamine according to claim 1, characterized in that: The free alkali is one or more of sodium carbonate, sodium bicarbonate, potassium carbonate and ammonia water.

7. The method for removing chloride ions from phentolamine according to claim 6, characterized in that: The free alkali is a 10-20% sodium carbonate solution or a 10-20% potassium carbonate solution.

8. The method for removing chloride ions from phentolamine according to claim 7, characterized in that: The free base is a 15% sodium carbonate solution.

9. Phentolamine prepared by the method according to any one of claims 1 to 8.

10. Use of the phentolamine according to claim 9 in the preparation of phentolamine mesylate.

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