Preparation method for sertaconazole nitrate crystal form

Abstract

A preparation method for a sertaconazole nitrate crystal form, which is used for preparing a sertaconazole nitrate crystal form having a melting point of 156-161°C and which comprises the following st

Description

For this purpose, the application provides a method for preparing sertaconazole nitrate crystal form which is used to prepare sertaconazole nitrate crystal form with a melting point of 156-161 °C. The application provides a method for preparing sertaconazole nitrate crystal form with a melting point of 156-161°C, which comprises the following steps: A) mixing crude sertaconazole nitrate and ethanol aqueous solution with a concentration of 45-55% by mass, and then raising temperature until reflux occurs; B) adding activated carbon and continuing the reflux; C) removing the activated carbon by filtration, and then cooling and standing for crystallization; and D) obtaining crystals by filtration, and then drying the obtained crystals. In some embodiments of the application, in step A, the ethanol aqueous solution has a concentration of 50% by mass. In some embodiments of the application, in step A, the mass ratio of the crude sertaconazole nitrate to the ethanol aqueous solution is 1: (3-10). In some embodiments of the application, in step A, the mass ratio of the crude sertaconazole nitrate to the ethanol aqueous solution is 1: (4-6). In some embodiments of the application, in step A, reflux lasts for 0.5-3 hours. In some embodiments of the application, in step A, reflux lasts for 1-2 hours. In some embodiments of the application, in step B, reflux continues for 10-30 minutes after activated carbon being added. The application also provides a method for preparing sertaconazole nitrate crystal form with a melting point of 156-161 °C, which comprises the following steps: A) mixing crude sertaconazole nitrate and ethanol aqueous solution with a concentration of 50% by mass, raising temperature until reflux occurs and maintaining the reflux for 1 hour, wherein the mass ratio of the crude sertaconazole nitrate to the ethanol aqueous solution is 1: (4-6); B) adding activated carbon and continuing the reflux for 15 minutes; C) removing the activated carbon by filtration, and then cooling and standing for crystallization; and D) obtaining crystals by filtration, and then drying the crystals. In this application, when referring to the concentration of the ethanol aqueous solution, it all means the mass percentage of ethanol in the ethanol aqueous solution. For example, an ethanol aqueous solution with a concentration of 45-55% by mass means that in the ethanol aqueous solution, based on the total mass of the ethanol aqueous solution, the mass percentage of ethanol is 45-55%. In addition, in this application, when 95% ethanol, 80% ethanol, 70% ethanol, 60% ethanol, 40% ethanol, 30% ethanol or the like is mentioned, it all means that the mass percentage of ethanol is 95%, 80%, 70%, 60%, 40%, or 30% in the ethanol aqueous solution. The method for preparing sertaconazole nitrate crystal form provided in this application employs an ethanol aqueous solution with a concentration of 45-55% by mass to crystallize crude sertaconazole nitrate. It was unexpectedly found that the sertaconazole nitrate crystal form with a melting point of 156-161 °C can be obtained. The melting point of this crystal form meets the requirements of the European Pharmacopoeia or the British Pharmacopoeia, thus providing technical support for the export of sertaconazole nitrate to these countries and regions. DETAILED EMBODIMENTS In order to make the purpose, technical solutions, and advantages of the present application clearer, the technical solutions of the present application will be described specifically and completely through detailed examples below. It should be noted that, those specific conditions which are not indicated in the following examples are carried out in accordance with conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used without indicating the manufacturer are all conventional products that can be purchased on the market. Preparation examples of crude sertaconazole nitrate (I) 80kg of purified water was added to a reactor, and then 2.92kg of sodium hydroxide was added under stirring to make it completely dissolved, obtaining 3.6wt% sodium hydroxide solution. Then 10.4kg of o-chlorothiophenol was added and stirred for 30min at room temperature. Then 6.66kg of chloroacetone was added under stirring. The stir lasts for 60min after the addition to perform reaction. After the reaction was completed, it was allowed to stand and stratify into an aqueous layer and an oil layer. Then 21.36 kg of ether was added to the aqueous layer to perform extraction, obtaining an ether layer. The ether layer which was washed with water for 3 times was combined with the oil layer, and then distilled under reduced pressure, obtaining 12.14 kg of o-chlorophenylthioacetone. (2) 121.4 kg of polyphosphoric acid was added to reactor A and stirred, and then 12.14 kg of o-chlorophenylthioacetone was added. The reaction mixture was heated to 120°C and controlled to keep at 120~140°C for 5 hours. Water was added to another reactor B, and cooled for later use. The reaction liquid in reactor A was discharged and slowly added to reactor B for dilution. 86.20 kg of ether was added to the reactor B for extraction, and allowed to stand for stratification. The ether layer was collected, washed with water, concentrated, and distilled under reduced pressure. The 135 137°C / 10mmHg fraction was collected, obtaining 16.72 kg of 3 -methyl-7-chlorobenzo [b]thiophene. (3) 265.84 kg of carbon tetrachloride and 16.72 kg of 3-methyl-7-chlorobenzo [b]thiophene were added to a reactor, and irradiated with a 200W bulb. 1 kg of benzoyl peroxide was added under stirring, and the mixture was heated to boiling. 17.06 kg of N-bromosuccinimide was added in batches. After the addition, the stirring lasts for 5 hours while boiling. The reaction mixture then was cooled and filtered. The filtrate was concentrated to obtain a precipitate. After filtration, the filter cake was washed with 12.54 kg of petroleum ether and dried, obtaining 12.96 kg of yellow powder of 3 -bromomethy 1-7-chlorobenzo [b]thiophene. (4) 16.58 kg of water, 2.98 kg of sodium hydroxide, 43.28 kg of toluene, 3.36 kg of 50% by mass tetrabutylammonium chloride aqueous solution, 12.96 kg of 3-bromomethyl-7-chlorobenzo[b]thiophene, and 10.76 kg of l-(2,4-dichlorobenzene)-2-(l-imidazole)ethanol were added into a reactor, heated to 80°C, kept the temperature and stirred for 4 hours. Then the reaction mixture was cooled and allowed to stand for stratification. Then the toluene layer was collected. 36.42 kg of ether and 98.76 kg of water were added into the toluene layer, stirred, allowed to stand complete precipitation, and filtered. The filtrate is pumped back to the reactor for stratification. An organic layer was collected and 3.50 kg of concentrated nitric acid was added dropwise into it to precipitate solids. The solids were obtained by filtration, and then washed with water and ether successively. After drying, 23.04 kg of crude sertaconazole nitrate was obtained. Preparation of Sertaconazole Nitrate Crystal Form Example 1 115.2 g of 50% by mass ethanol aqueous solution was added to a reaction flask, and heated to 60 °C. 23.04 g of crude sertaconazole nitrate was added under stirring. The mixture was heated under reflux for 1 hour. Activated carbon was added, and the mixture continues the reflux for another 15 minutes. The activated carbon was filtered out when the mixture was hot. The filtrate was cooled to room temperature, allowed for standing to crystallize, and then filtered. The filtered crystals were dried in a vacuum drying oven, obtaining 19.24 g of sertaconazole nitrate crystals. In this example, the 50% by mass ethanol aqueous solution can be prepared by mixing 60.63 g of 95% ethanol and 54.57 g of purified water. Example 2 Example 2 differs from Example 1 in that the amount of crude sertaconazole nitrate added was 38.4g. Example 3 Example 3 differs from Example 1 in that the amount of crude sertaconazole nitrate added was 15 g. Example 4 Example 4 differs from Example 1 in that the reflux time was 0.5 hours. Comparative example 1 60.63g of 95% ethanol was added to a reaction flask and heated to 60°C. 23.04g of crude sertaconazole nitrate was added under stirring. The mixture was heated under reflux for 1 hour. Activated carbon was added, and the mixture continues the reflux for 15 minutes. The activated carbon filtered out when the mixture is was hot. The filtrate was cooled, allowed for standing to crystallize, and then filtered. The filtered crystals were dried in a vacuum drying oven to obtain 20.18 g of sertaconazole nitrate crystals. Comparative example 2 Comparative Example 2 differs from Comparative Example 1 in that the amount of 95% ethanol was 115.2 g. Comparative example 3 Comparative Example 3 differs from Comparative Example 1 in that 60.63 g of 95% ethanol was replaced with 115.2 g of 80% ethanol. Comparative example 4 Comparative Example 4 differs from Comparative Example 1 in that 60.63 g of 95% ethanol was replaced with 115.2 g of 70% ethanol. Comparative example 5 Comparative Example 5 differs from Comparative Example 1 in that 60.63 g of 95% ethanol was replaced with 115.2 g of 60% ethanol. Comparative example 6 Comparative Example 6 differs from Comparative Example 1 in that 60.63 g of 95% ethanol was replaced with 115.2 g of 40% ethanol. Comparative example 7 Comparative Example 7 differs from Comparative Example 1 was that 60.63 g of 95% ethanol was replaced with 115.2 g of 30% ethanol. Determination of melting point The melting point of sertaconazole nitrate crystals prepared in Examples 1-4 and Comparative Examples 1-7 was measured according to the first method of the General Rule 0612 Melting Point Determination Method (A temperature transfer liquid heating method) of the 2015 edition of the Chinese Pharmacopoeia. The results were shown in Table 1. Table 1 Example / Comparative example Melting point Example 1 158.4-159.7°C Example 2 156.2-157.1°C Example 3 156.8-157.7°C Example 4 156.5-157.2°C Comparative example 1 163.4-163.8°C Comparative example 2 163.6-164.3°C Comparative example 3 155.3-155.7°C Comparative example 4 155.4-156.8°C Comparative example 5 155.3-156.8°C Comparative example 6 155.5-157.0°C Comparative example 7 155.2-156.3°C From the melting point data in Table 1, it can be seen that in Examples 1-4, when the ethanol aqueous solution with a concentration of 50% by mass was used to prepare the sertaconazole nitrate crystal form, the melting point of the crystal form was in the range of 156-161 °C, which complies with the records in the Pharmacopoeia or the British Pharmacopoeia. Comparative Examples 1-2 employed 95% ethanol to prepare sertaconazole nitrate crystal form, and the melting point was above 163°C. In Comparative Examples 3-7, ethanol aqueous solutions of other concentrations were used to prepare sertaconazole nitrate crystal forms, and none of the melting points of the obtained crystal forms were in the range of 156-161°C. Further, the inventor of the present application found that the color of sertaconazole nitrate crystal form prepared in Examples 1-4 was from off-white to pure white, which was significantly lighter than that of the sertaconazole nitrate crystal form prepared in Comparative Example 1-2 (from light yellow to off-white). This result may be caused by a better decolorization effect of activated carbon rendered by a higher water content in the 50% by mass ethanol aqueous solution than in 95% ethanol, and thus the color of the product obtained is lighter after decolorization. The above-mentioned examples only present several embodiments of the present application, which are described in detail, but should not be construed as a limitation to the patent scope of the present application. It should be pointed out that without departing from the concept of this application, several modifications and improvements can be made by those of ordinary skill in the art, which all fall within the protection scope of this application.

Claims

1. A method for preparing sertaconazole nitrate crystal form with a melting point of 156-161°C, comprising:A) mixing crude sertaconazole nitrate and ethanol aqueous solution with a concentration of 45-55% by mass, and then raising temperature until reflux occurs;B) adding activated carbon and continuing the reflux;C) removing the activated carbon by filtration, and then cooling and standing for crystallization; andD) obtaining crystals by filtration, and then drying the crystals.

2. The method according to claim 1, wherein in step A), the ethanol aqueous solution has a concentration of 50% by mass.

3. The method according to claim 1, wherein in step A), the mass ratio of the crude sertaconazole nitrate to the ethanol aqueous solution is 1: (3-10).

4. The method according to claim 3, wherein in step A), the mass ratio of the crude sertaconazole nitrate to the ethanol aqueous solution is 1: (4-6).

5. The method according to claim 1, wherein in step A), the reflux lasts for 0.5-3 hours.

6. The method according to claim 5, wherein in step A), the reflux lasts for 1-2 hours.

7. The preparation method according to claim 1, wherein in step B), the reflux continues for 10-30 minutes after activated carbon is added.

8. A method for preparing sertaconazole nitrate crystal form, with a melting point of 156-161 °C, which comprises the following steps:A) mixing crude sertaconazole nitrate and ethanol aqueous solution with a concentration of 50% by mass, raising temperature until reflux occurs and maintaining the reflux for 1 hour, wherein the mass ratio of the crude sertaconazole nitrate to the ethanol aqueous solution is 1: (4-6);B) adding activated carbon and continuing to the reflux for 15 minutes;C) removing the activated carbon by filtration, and then cooling and standing for crystallization; andD) obtaining crystals by filtration, and then drying the crystals.