GB2613137A

GB2613137A - Purification method for sertaconazole nitrate

Info

Publication number: GB2613137A
Application number: GB2113532.2A
Authority: GB
Inventors: Liu Yu; Wei Jiahua; Li Bofu
Original assignee: HAINAN HAISHEN TONGZHOU PHARMACEUTICAL CO Ltd
Current assignee: HAINAN HAISHEN TONGZHOU PHARMACEUTICAL CO Ltd
Priority date: 2021-07-30
Filing date: 2021-08-26
Publication date: 2023-05-31
Also published as: CN113501814A; WO2023004914A1

Abstract

A purification method for sertaconazole nitrate, which is used for preparing a sertaconazole nitrate crystal form with a melting point of 156-161°C. The purification method comprises: (1) mixing a crude product of sertaconazole nitrate with 95% ethanol, then raising the temperature to reflux; (2) adding activated carbon, then continuing to reflux; (3) after reflux finishes, filtering to remove the activated carbon so as to obtain a filtrate; (4) adding water dropwise to the obtained filtrate while stirring to precipitate a crystal; and (5) after dropwise addition is complete, filtering the crystal and then drying. After using 95% ethanol to heat and dissolve the crude product of sertaconazole nitrate, water is added dropwise to dissolve and crystallize same; it was unexpectedly found that a crystal form of sertaconazole nitrate with a melting point of 156-161°C can be obtained. The melting point of the crystal form meets requirements of the European Pharmacopoeia or the British Pharmacopoeia, which provides technical support for exporting the drug to these countries and regions.

Description

A PURIFICATION METHOD OF SERTACONAZOLE NITRATE TECHNICAL FIELD

This application relates to the technical field of the preparation of an active pharmaceutical ingredient (API), in particular to a purification method of sertaconazole nitrate.

BACKGROUND ART

Sertaconazole nitrate is a synthetic imidazole broad-spectrum antifungal drug.

For the purification of sertaconazole nitrate API, the prior art generally employed 95% ethanol to dissolve the crude sertaconazole nitrate under heating, and then recrystallized the crude sertaconazole nitrate by cooling and standing. The inventor found that the melting point of the sertaconazole nitrate obtained by this recrystallization method is 163-167°C, which meets the requirements of the National Drug Standards of the China Food and Drug Administration.

However, the melting point of sertaconazole nitrate recorded in the European Pharmacopoeia or the British Pharmacopoeia is 156-161°C, which is obviously different from the melting point recorded in the National Drug Standards In order to export sertaconazole nitrate API to the United Kingdom, the European Union and other countries and regions, it is necessary to develop a new purification method of sertaconazole nitrate, by which sertaconazole nitrate crystal form with a melting point of 156-161°C is obtained.

SUMMARY OF THE INVENTION

The application provides a novel purification method of sertaconazole nitrate, which is used to prepare sertaconazole nitrate crystal form with a melting point of 156-161°C.

The application provides a purification method of sertaconazole nitrate to obtain a sertaconazole nitrate crystal form with a melting point of 156-161°C, which comprises: (1) mixing crude sertaconazole nitrate with 95% ethanol, and raising temperature until reflux occurs; (2) adding activated carbon in the mixture and continuing the reflux; (3) removing the activated carbon by filtration after the reflux is completed to obtain filtrate; (4) dripping water to the filtrate obtained under stirring for crystalizing; and (5)obtaining crystals by filtration after completion of dripping and then drying the crystals.

In some embodiments, in step (1), the mass ratio of the crude sertaconazole nitrate to 95% ethanol is 1: (1-5).

In some embodiments, in step (1), the mass ratio of the crude sertaconazole nitrate to 95% ethanol is 1: (2-3).

In some embodiments, in step (1), the reflux lasts for 0.5-3 hours. In some embodiments, in step (1), the reflux lasts for 1-2 hours.

In some embodiments, in step (2), the reflux continues for 10-30 minutes after activated carbon being added.

In some embodiments, in step (4), the mass ratio of the dripped water to 95% ethanol is (0.5-2):1.

In some embodiments, in step (4), the mass ratio of the dripped water to 95% ethanol is 1:1.

In some embodiments, in step (5), after completion of dripping, crystals were obtained by filtration after stirring of another 10-50 minutes and then dried.

The present application also provides a purification method of sertaconazole nitrate, to obtain a sertaconazole nitrate crystal form with a inciting point of 156-161°C, which comprises: (1) mixing crude sertaconazole nitrate and 95% ethanol, and raising temperature until reflux occurs, and maintaining the reflux for 1 hour, wherein the mass ratio of the crude sertaconazole nitrate to 95% ethanol is 1: (2-3); (2) adding activated carbon and continuing the reflux for 30 min; (3) removing the activated carbon by filtration after the reflux to obtain filtrate; (4) dripping water to the filtrate obtained under stirring to crystalize, wherein the mass ratio of the dripped water to 95% ethanol is 1:1; and (5) keeping stirring for 30 minutes after completion of dripping, then obtaining crystals by filtration and then drying the crystals.

In this application, 95% ethanol refers to a mixture of ethanol and water with an ethanol mass percentage of 95%.

The purification method of sertaconazole nitrate provided in this application employs 95% ethanol to dissolve crude sertaconazole nitrate under heating, followed by solventing out crystallization through water dripping. 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, providing technical support for the export of drugs 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 (1) 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 completion of the reaction, an aqueous layer and an oil layer were obtained through standing and stratification. 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-methy1-7-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-bromomethy1-7-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-bromomethy1-7-chlorobenzo[b]thiophene, and 10.76 kg of 1-(2,4-dichlorobenzene)-2-(1-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.

Purification of Sertaconazole Nitrate Example 1 60.63g of 95% ethanol 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 to reflux temperature and the reflux state was kept for 1 hour. Activated carbon was added, and the reflux lasted for another 15 minutes. The activated carbon was filtered out when the mixture was hot to obtain filtrate. 60.63g of purified water was dripped to the filtrate under stirring to crystallize. After completion of dripping, the stir lasted for 30 minutes, and then crystals were obtained by filtration. The filtered crystals were dried in a vacuum drying oven to obtain 19.06g of sertaconazole nitrate crystals.

Example 2

Example 2 differs from Example 1 in that the amount of 95% ethanol was 100g. Example 3 Example 3 differs from Example 1 in that the amount of the dripped water was 100 g.

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 to reflux temperature and the reflux state was kept for 1 hour. Activated carbon was added, and the reflux lasted for another 15 minutes. The activated carbon was filtered out when the mixture 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.

Determination of melting point The melting point of sertaconazole nitrate crystals prepared in Examples 1-3 and Comparative Example 1 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 below.

Example/Comparative Example Melting point Example 1 158.2-159.0 °C Example 2 158.8-159.6 °C Example 3 159.0-159.8 °C Comparative Example 1 163.4-163.8 °C From the melting point data in the above table, it can be seen that in Examples 1-3, when sertaconazole nitrate was recrystallized by the solventing out crystallization method, the melting point of the crystal form was in the range of 156-161°C, which satisfies the requirements of exporting to the United Kingdom, the European Union and the other countries and regions. In Comparative Example 1, the sertaconazole nitrate crystal form prepared by the method of cooling crystallization using 95% ethanol has a melting point above 163°C.

The above-mentioned examples only present several embodiments of the present application, which are described in detail, but should not be constmed 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

CLAIMS1. A purification method of sertaconazole nitrate to obtain a sertaconazole nitrate crystal form with a melting point of 156-161°C, comprising: (1) mixing crude sertaconazole nitrate and 95% ethanol, and raising temperature until reflux occurs; (2) adding activated carbon and continuing the reflux; (3) removing the activated carbon by filtration after the reflux to obtain filtrate; (4) dripping water to the filtrate obtained under stirring for crystalizing; and (5) obtaining crystals by filtration after completion of dripping and then drying the crystals.
2. The purification method according to claim 1, wherein in step (1), the mass ratio of the crude sertaconazole nitrate to 95% ethanol is 1: (1-5).
3. The purification method according to claim 2, wherein in step (1), the mass ratio of the crude sertaconazole nitrate to 95% ethanol is 1: (2-3).
4. The purification method according to claim 1, wherein in step (1), the reflux lasts for 0.5-3 hours.
5. The purification method according to claim 4, wherein in step (1), the reflux lasts for 1-2 hours.
6. The purification method according to claim 1, wherein in step (2), the reflux continues for 10-30 minutes after activated carbon being added.
7. The purification method according to claim 1, wherein in step (4), the mass ratio of the dripped water to 95% ethanol is (0.5-2):1.
8. The purification method according to claim 7, wherein in step (4), the mass ratio of the dripped water to 95% ethanol is 1:1.
9. The purification method according to claim 1, wherein in step (5), crystals were obtained by filtration after stirring of another 10-50 minutes and then dried.
10. A purification method of sertaconazole nitrate to obtain a sertaconazole nitrate crystal form with a melting point of 156-161°C, comprising: (1) mixing crude sertaconazole nitrate and 95% ethanol, and raising temperature until reflux occurs, and maintaining the reflux for 1 hour, wherein the mass ratio of the crude sertaconazole nitrate to 95% ethanol is 1: (2-3); (2) adding activated carbon and continuing the reflux for 30 min; (3) removing the activated carbon by filtration after completion of the reflux to obtain filtrate; (4) dripping water to the filtrate obtained under stirring to crystalize, wherein the mass ratio of the dripped water to 95% ethanol is 1:1; and (5) keeping stirring for 30 minutes after completion of dripping, then obtaining crystals by filtration and then drying the crystals.