Purification method of evocamide bulk drug

Abstract

The invention relates to a purification method of an Evocalpet bulk drug, and aims to improve the purity of the Evocalpet bulk drug. The method adopts a salifying extraction method to purify the evocamide, effectively overcomes the defects of traditional column chromatography and recrystallization methods in industrial production, significantly improves the purity of the evocamide bulk drug, and solves the problem of difficult purification of the evocamide bulk drug. The method has the advantages of excellent purification effect, high product quality, simplicity in operation and low production cost, and is of great significance to industrial production and quality control of the evocamide bulk drug.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of drug purification, and particularly relates to a purification method of Evocalcet raw material medicine. BACKGROUND

[0002] Evocalcet, also known as Ivan Calcet, is a second-generation calcimimetic agent developed by Kyowa Kirin Co., Ltd. of Japan, and its structural formula is as follows:

[0003]

[0004] It mainly inhibits the secretion of parathyroid hormone (PTH) by selectively activating the calcium-sensitive receptor (CaSR) on the surface of parathyroid cells to treat secondary hyperparathyroidism (SHPT) caused by calcium and phosphorus metabolic disorders in chronic kidney disease (CKD) dialysis patients. Compared with the first-generation calcimimetic agent Cinacalcet, Evocalcet has been optimized in molecular structure, significantly improving bioavailability and reducing gastrointestinal side effects and the risk of drug interactions. Clinical phase III trials show that 67.3% of patients have a decrease in iPTH levels of ≥30%, and the long-term use of blood calcium and phosphorus has a standard rate of up to 80%. Evocalcet was approved in Japan in 2018 and in China in July 2024, filling the market gap for new calcimimetic agents in China. It is suitable for SHPT and parathyroid cancer-related hypercalcemia in maintenance dialysis patients, especially for patients who are intolerant to traditional treatment or have drug metabolism risks.

[0005] At present, the synthesis method of Evocalcet has been disclosed, and the process involves multiple reaction steps, including nucleophilic substitution, amino protection and deprotection, Buchwald-Hartwig coupling and hydrolysis. Starting from (R / S)-1-Boc-3-hydroxypyrrolidine, Evocalcet can be synthesized by optimizing the reaction conditions or improving the reaction raw materials. However, these complex multi-step reactions inevitably produce various impurities, including many unknown impurities. According to the ICH guidelines, the content of unknown impurities in Evocalcet raw material medicine should be controlled below 0.10% to ensure that the needs of preparation production are met.

[0006] The common purification methods of the raw drug are column chromatography, recrystallization and the like. Among them, the column chromatography method has the problems of large solvent consumption, high production cost and low efficiency. In addition, the chemical structure of evocetrapib contains strong polar groups such as secondary amine, tertiary amine and carboxylic acid, and the polarity is strong, and at the same time, the base and acid root are contained, so it is not suitable for column chromatography purification. In addition, the existing recrystallization method has the problem of deficiency in removing impurities. The method depends on the selection of solvent, but the solubility of evocetrapib in common solvents is low, which leads to a large amount of solvent required in the recrystallization process, increases the production cost and limits the industrialization scale. Patent CN105517992A describes a process for purifying evocetrapib by recrystallization method. The method forms a salt by reacting the crude product with sodium hydroxide to improve its solubility, and then recrystallization and ethanol washing are performed. However, we found that part of the unknown impurities in the evocetrapib crude product are insoluble in alkali, which makes them precipitate with the main component at the same time in the above method, affecting the purity. Therefore, it is of great importance to develop a new and more efficient purification method of evocetrapib for its preparation production and clinical application. SUMMARY

[0007] In order to solve the technical problems of evocetrapib raw drug purification difficulties, the deficiencies of traditional column chromatography and recrystallization method in industrial production, and the difficulty in obtaining high-purity evocetrapib raw drug, and to achieve the technical effects of high purity, low cost, simple process and suitable for industrial production, the present application provides a purification method of evocetrapib raw drug. Specifically, the following technical solutions are adopted:

[0008] The present application provides a purification method of evocetrapib raw drug, which comprises salt extraction of evocetrapib crude product, followed by activated carbon decolorization treatment, and acidification crystallization and filtration drying to improve the purity of the drug.

[0009] According to the embodiment of the present application, the salt extraction step comprises mixing evocetrapib crude product with alkali solution, adding organic solvent for extraction, and then separating to remove impurities in the organic layer.

[0010] Further, the alkali solution in the salt extraction step is sodium hydroxide aqueous solution or potassium hydroxide aqueous solution.

[0011] Further, the organic solvent used in the salt extraction step is dichloromethane or ethyl acetate.

[0012] Further, the volume of the organic solvent per gram of crude product is 1 / 1 to 3 / 1, preferably 2 / 1.

[0013] According to the embodiment of the present application, the activated carbon decolorization step comprises heating the aqueous solution after salt extraction, adding activated carbon and stirring, cooling to 20-30℃, and then filtering to remove pigment impurities.

[0014] Further, the stirring time after adding the activated carbon is 30-60 minutes.

[0015] According to the embodiment of the present application, the acidification and crystallization step comprises heating the obtained filtrate and washing liquid to 50-60℃, dropping about 1 / 4 of the prepared acid solution, keeping warm for 30 minutes, dropping the remaining acid solution, keeping warm and stirring for 60 minutes, cooling to 20-30℃, adding ethanol, and stirring and crystallizing.

[0016] Further, the acid solution is selected from one or more of hydrochloric acid, phosphoric acid, acetic acid, citric acid, and trifluoroacetic acid solution.

[0017] Further, the purity of the purified evocacet raw material drug reaches more than 99.85%.

[0018] One of the preferred embodiments of the present application is:

[0019] A purification method of evocacet raw material drug, comprising the following steps:

[0020] Step one: preparation of alkali solution

[0021] 100g of sodium hydroxide is added to 1000ml of purified water in batches, stirred and dissolved, and cooled to room temperature with 0-10℃ ice water bath.

[0022] Step two: preparation of acid solution

[0023] 150g of phosphoric acid is added to 1000ml of purified water, stirred and dissolved at room temperature.

[0024] Step three: salt formation extraction

[0025] 100g of evocacet crude product is stirred and dissolved with the alkali solution prepared in step one, the temperature is controlled at 20-30℃, stirring is performed for 0.5-1 hour, 200ml of dichloromethane is added and stirred for 10-15 minutes, it is left to stand for 5-15 minutes, the lower organic layer is separated, and the water layer is retained. 200ml of dichloromethane is added to the upper water layer, stirred for 10-15 minutes, left to stand for 5-15 minutes, the lower organic layer is separated, and the water layer is retained.

[0026] Step four: activated carbon decolorization

[0027] The aqueous solution obtained in step three is heated to 40-50℃, kept warm and stirred for 10 minutes, 3g of activated carbon is added, and stirred for 30-60 minutes. The temperature is cooled to 20-30℃, filtered, the filter cake is washed with 100ml of purified water, filtered, and the filtrate and washing liquid are combined.

[0028] Step five: acidification and crystallization

[0029] The filtrate and washing solution from step four were transferred into a three-necked flask and heated to 50-60°C, and about 1 / 4 of the trifluoroacetic acid solution prepared in step two was added dropwise, and stirred for 30 minutes. The remaining trifluoroacetic acid solution was added dropwise, and stirred for 60 minutes. The temperature was lowered to 20-30°C, and 200 ml of ethanol was added, and stirred for 60 minutes to crystallize.

[0030] Step six filtration and drying

[0031] The material from step five was filtered through a Buchner funnel, and washed with 200 ml of 40% ethanol aqueous solution. The product was dried under vacuum at 50-60°C for 15-20 hours, and the ephedrine refined product was obtained as a white solid 82.6 g with a purity of 99.85%.

[0032] Second preferred embodiment of the present application:

[0033] Step one preparation of the base solution

[0034] Potassium hydroxide 100 g was added portionwise to 1000 ml of purified water, and stirred to dissolve. The solution was cooled to room temperature using an ice water bath.

[0035] Step two preparation of the acid solution

[0036] Trifluoroacetic acid 350 g was added to 1000 ml of purified water, and stirred to dissolve at room temperature.

[0037] Step three salt formation extraction

[0038] The ephedrine crude product 100 g was dissolved in the base solution prepared in step one, and stirred for 0.5-1 hour while controlling the temperature at 20-30°C. 200 ml of ethyl acetate was added, and stirred for 10-15 minutes. The mixture was allowed to stand for 5-15 minutes, and the lower organic layer was separated. 200 ml of ethyl acetate was added to the upper aqueous layer, and stirred for 10-15 minutes. The mixture was allowed to stand for 5-15 minutes, and the lower organic layer was separated.

[0039] Step four decolorization with activated carbon

[0040] The aqueous solution from step three was heated to 40-50°C, and stirred for 10 minutes. 3 g of activated carbon was added, and stirred for 30-60 minutes. The temperature was lowered to 20-30°C, and the mixture was filtered. The filter cake was washed with 100 ml of purified water, and filtered. The filtrate and washing solution were combined.

[0041] Step five acidification and crystallization

[0042] The filtrate and washing solution from step four were transferred into a three-necked flask and heated to 50-60°C, and about 1 / 4 of the trifluoroacetic acid solution prepared in step two was added dropwise, and stirred for 30 minutes. The remaining trifluoroacetic acid solution was added dropwise, and stirred for 60 minutes. The temperature was lowered to 20-30°C, and 200 ml of ethanol was added, and stirred for 60 minutes to crystallize.

[0043] Step six filtration and drying

[0044] The material obtained in step five was filtered with a Buchner funnel, eluted with 200 ml of 40% ethanol aqueous solution, and the obtained product was dried at 50-60°C under vacuum for 15-20 hours, and the material was collected to obtain the refined Evocabet product as a white solid 80.3 g with a purity of 99.86%.

[0045] Compared with the prior art, the present application has the following beneficial effects:

[0046] The Evocabet purification method provided by the present application effectively removes various impurities in the crude product through salting extraction and activated carbon decolorization, significantly improves the purity of Evocabet, and makes the purity of Evocabet reach more than 99.85%. Compared with the traditional purification method, the present application has the advantages of simple operation, low production cost, high solvent recovery rate, and further reduced production cost. Due to the simple and efficient production process, the present application is particularly suitable for large-scale industrial production, and can stably provide high-purity Evocabet raw material. Through the purification method of the present application, the obstacle of difficult purification of Evocabet is successfully overcome, which provides strong support for the preparation of Evocabet, and has important significance for quality control in industrial production. BRIEF DESCRIPTION OF DRAWINGS

[0047] Figure 1 is the HPLC graph of the Evocabet crude product.

[0048] Figure 2 is the HPLC graph of the refined Evocabet product. DETAILED DESCRIPTION

[0049] The present application will be further described below in combination with specific examples and drawings. The following examples are only descriptive and not limiting, and the protection scope of the present application cannot be limited by the following examples. If not otherwise specified, the raw materials used can be obtained by market purchase or self-preparation.

[0050] Comparative example 1: traditional column chromatography and recrystallization method

[0051] The common purification methods for raw materials are column chromatography, recrystallization and the like.

[0052] Among them, the column chromatography method has the problems of large solvent consumption, high production cost and low efficiency, and Evocabet is a carboxylic acid compound with strong polarity, so it is not suitable for column chromatography purification.

[0053] The most commonly used purification method in the production process of raw materials is recrystallization method, which has the advantages of simple production operation, large production scale and suitability for industrial production. The recrystallization method needs to select a suitable solvent, and the solubility of the solvent to the raw material should be moderate. If the solubility is too small, the solvent consumption will be large, and the production system will be too large to realize industrial production.

[0054] The solubility of evocetrapib in methanol, ethanol, propanol, isopropanol, acetone, ethyl acetate, ethyl formate, water, acetonitrile, toluene, tetrahydrofuran, methyl tert-butyl ether and other commonly used solvents in industry was studied, and the results are shown in Table 1:

[0055] Table 1

[0056]

[0057]

[0058] The data in Table 1 show that the solubility of evocetrapib in various solvents is less than 2.5 mg / ml, which leads to the need for a large amount of solvent in the recrystallization process, not only increasing the production cost, but also making it difficult to achieve industrial production. Therefore, the traditional method is inefficient in practical application and difficult to meet the needs of large-scale production. In order to solve these problems, the solubility of evocetrapib can be improved, and the impurities and target product can be more effectively separated.

[0059] Improved recrystallization method of Comparative Example 2

[0060] Reference the steps of patent CN105517992A:

[0061] Step one: preparation of lye

[0062] Add 1.63 g of sodium hydroxide to 33.6 g of water and stir until completely dissolved. Then add 28.1 g of ethanol and mix well.

[0063] Step two: compound dissolution

[0064] Add 10.0 g of evocetrapib crude product to the lye prepared in step one and stir at 60°C for 30 minutes to ensure complete dissolution.

[0065] Step three: filtration and washing

[0066] Filter the mixture obtained in step two. Wash the filter cake with a mixed solution (8.20 g of water, 0.18 g of sodium hydroxide and 7.00 g of ethanol).

[0067] Step four: acidification and crystallization

[0068] At 60°C, add 3.20 g of citric acid monohydrate in 29.8 g of water to the filtered solution dropwise until crystals precipitate. Continue stirring for 30 minutes, then add the remaining citric acid aqueous solution. After stirring for 1 hour, cool the mixture to 10°C within 1.5 hours.

[0069] Step five: crystallization, filtration and washing

[0070] The mixture obtained in step four was filtered. The obtained crystals were washed with 13.9 g of ethanol, 35.2 g of water and 13.9 g of ethanol in sequence.

[0071] Step six drying

[0072] The washed crystals were dried under suitable conditions.

[0073] The refined evocarnid product was obtained as a grayish-brown solid 9.1 g with a purity of 98.95% and a maximum unknown single impurity of 0.25%.

[0074] The purification method introduced two steps of alkaline treatment and acidification crystallization in an attempt to overcome the limitations of the traditional method, although it can reduce the content of some impurities, the purity of evocarnid is 98.95%, but the maximum unknown single impurity is 0.25%, which is greater than 0.10%. This may be due to the fact that some impurities are insoluble under alkaline conditions, and are crystallized and precipitated together with the main component during acidification crystallization, so they cannot be effectively removed by recrystallization. In addition, it was observed that the purified sample still had color during the purification process, which may be due to the incomplete removal of pigment impurities. These problems limit the application effect of the method in improving the purity of evocarnid, making it difficult to fully meet the strict requirements of production and quality control.

[0075] Example 1

[0076] Step one alkali preparation

[0077] 100 g of sodium hydroxide was added to 1000 ml of purified water in batches, stirred to dissolve, and cooled to room temperature with a 0-10 °C ice water bath.

[0078] Step two acid preparation

[0079] 150 g of phosphoric acid was added to 1000 ml of purified water, stirred to dissolve at room temperature.

[0080] Step three salting extraction

[0081] 100 g of evocarnid crude product was dissolved with the alkali prepared in step one, the temperature was controlled at 20-30 °C, stirred for 0.5-1 hour, 200 ml of dichloromethane was added and stirred for 10-15 minutes, and then the lower organic layer was separated after standing for 5-15 minutes. To the upper aqueous layer, 200 ml of dichloromethane was added and stirred for 10-15 minutes, and then the lower organic layer was separated after standing for 5-15 minutes.

[0082] Step four activated carbon decolorization

[0083] The aqueous solution obtained in step three was heated to 40-50°C, and stirred for 10 minutes. 3 g of activated carbon was added, and stirred for 30-60 minutes. The temperature was lowered to 20-30°C, and filtered. The filter cake was washed with 100 ml of purified water, and filtered. The filtrate and the washing liquid were combined.

[0084] Step five acidification and crystallization

[0085] The filtrate and the washing liquid obtained in step four were transferred into a three-necked flask, and heated to 50-60°C. About 1 / 4 of the phosphoric acid solution prepared in step two was added dropwise, and stirred for 30 minutes. The remaining phosphoric acid solution was added dropwise, and stirred for 60 minutes. The temperature was lowered to 20-30°C, and 200 ml of ethanol was added. The mixture was stirred for 60 minutes to crystallize.

[0086] Step six filtration and drying

[0087] The material obtained in step five was filtered through a Buchner funnel, and eluted with 200 ml of 40% ethanol aqueous solution. The product was dried under vacuum at 50-60°C for 15-20 hours. The refined product of Evocarn was obtained as a white solid, 82.6 g, with a purity of 99.85%.

[0088] The HPLC detection diagrams of the related substances of the crude product before purification and the refined product after purification of Evocarn are shown in Figure 1 、 Figure 2 The content of the unknown impurities in the pure product was less than 0.10%, which met the ICH guidelines.

[0089] Example 2

[0090] Step one preparation of alkali solution

[0091] 100 g of potassium hydroxide was added to 1000 ml of purified water in batches, and stirred to dissolve. The solution was cooled to room temperature using an ice water bath.

[0092] Step two preparation of acid solution

[0093] 350 g of trifluoroacetic acid was added to 1000 ml of purified water, and stirred to dissolve at room temperature.

[0094] Step three salt formation and extraction

[0095] 100 g of Evocarn crude product was dissolved in the alkali solution prepared in step one, and stirred for 0.5-1 hour while controlling the temperature at 20-30°C. 200 ml of ethyl acetate was added, and stirred for 10-15 minutes. The mixture was allowed to stand for 5-15 minutes, and the lower organic layer was separated. 200 ml of ethyl acetate was added to the upper aqueous layer, and stirred for 10-15 minutes. The mixture was allowed to stand for 5-15 minutes, and the lower organic layer was separated.

[0096] Step four decolorization with activated carbon

[0097] The aqueous solution obtained in step three was heated to 40-50°C and stirred for 10 minutes. 3 g of activated carbon was added and stirred for 30-60 minutes. The temperature was lowered to 20-30°C and filtered. The filter cake was washed with 100 ml of purified water and filtered. The filtrate and wash were combined.

[0098] Step five acidification and crystallization

[0099] The filtrate and wash obtained in step four were transferred to a three-necked flask and heated to 50-60°C. About 1 / 4 of the trifluoroacetic acid solution prepared in step two was added dropwise and stirred for 30 minutes. The remaining trifluoroacetic acid solution was added dropwise and stirred for 60 minutes. The temperature was lowered to 20-30°C and 200 ml of ethanol was added. The mixture was stirred for 60 minutes to crystallize.

[0100] Step six filtration and drying

[0101] The material obtained in step five was filtered using a Buchner funnel and eluted with 200 ml of 40% ethanol in water. The product was dried under vacuum at 50-60°C for 15-20 hours. The refined Evocet product was obtained as a white solid, 80.3 g, with a purity of 99.86%. The content of unknown impurities in the pure product was all below 0.10%, in accordance with the ICH guidelines.

[0102] Example 3

[0103] In step three, the organic solvent for salt formation extraction was n-hexane. The rest was the same as in example 1.

[0104] The refined Evocet product was obtained, 85.1 g, with a purity of 99.11%.

[0105] Example 4

[0106] In step three, the organic solvent for salt formation extraction was petroleum ether. The rest was the same as in example 1.

[0107] The refined Evocet product was obtained, 84.6 g, with a purity of 98.73%.

[0108] Example 5

[0109] In step three, the organic solvent for salt formation extraction was n-heptane. The rest was the same as in example 1.

[0110] The refined Evocet product was obtained, 90.2 g, with a purity of 98.86%.

[0111] Example 6

[0112] In step three, the organic solvent for salt formation extraction was cyclohexane. The rest was the same as in example 1.

[0113] The refined Evocet product was obtained, 88.6 g, with a purity of 98.68%.

[0114] According to the results of examples 1-6, by introducing the salting extraction and activated carbon decolorization steps, and optimizing the organic solvent, it is found that the effect of dichloromethane or ethyl acetate is more ideal. The possible reason is that among the commonly used extraction solvents, the dielectric constant of n-hexane, cyclohexane, n-heptane and the like is small, the polarity is weak, the solubility is poor, and the impurity removal capacity is not strong. When dichloromethane or ethyl acetate is selected, the dielectric constant is improved, the polarity is moderate, the solubility is good, the impurity removal capacity is obviously improved, the unknown single impurity can be reduced to below 0.10%, which meets the requirements of ICH guidelines. This improves the purity of evocet, and thus realizes the effective control of unknown impurities. In addition, the color of the purified product is clear, indicating that the pigment impurities have been effectively removed.

[0115] Finally, it should be noted that: the above examples are only used to illustrate the technical solutions of the present application, and not to limit it; although the present application has been described in detail with reference to the foregoing examples, those skilled in the art should understand that: it can still modify the technical solutions recorded in the foregoing examples, or make equivalent replacement for part of the technical features; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the embodiments of the present application.

Claims

1. A method for purifying an ivocet drug substance, characterized in that: The method includes salt extraction of crude ivocet, followed by activated carbon decolorization, acidification crystallization and filtration drying to improve the purity of the drug.

2. The method according to claim 1, characterized in that The salt-forming extraction step comprises mixing the crude evokase product with an alkaline solution, adding an organic solvent for extraction, and then separating the liquids to remove impurities in the organic layer.

3. The method according to claim 2, characterized in that The alkali solution in the salt-forming extraction step is a sodium hydroxide aqueous solution or a potassium hydroxide aqueous solution.

4. The method according to claim 2, characterized in that The organic solvent used in the salt-forming extraction step is dichloromethane or ethyl acetate.

5. The method according to claim 2, characterized in that The volume of the organic solvent in milliliters / weight of the crude product in grams is 1 / 1 to 3 / 1.

6. The method according to claim 5, characterized in that The volume of the organic solvent in milliliters / the weight of the crude product in grams is 2 / 1.

7. The method according to claim 1, characterized in that The activated carbon decolorization step includes heating the aqueous solution after salt extraction, adding activated carbon and stirring, cooling to 20-30° C., and then filtering to remove pigment impurities.

8. The method according to claim 1, characterized in that The acidification and crystallization step comprises heating the obtained filtrate and washing liquid to 50-60° C., dripping about 1 / 4 of the prepared acid solution, keeping the temperature for 30 minutes, dripping the remaining acid solution, keeping the temperature and stirring for 60 minutes, cooling to 20-30° C., adding ethanol, and stirring to crystallize.

9. The method according to claim 8, characterized in that The acid solution is selected from one or more of hydrochloric acid, phosphoric acid, acetic acid, citric acid, and trifluoroacetic acid solutions.

10. The method according to any one of claims 1 to 9, characterized in that: The purity of the purified ivocet raw material reaches more than 99.85%.

Images