Method for refining crude halobetasol propionate

Abstract

The invention discloses a method for refining a crude halobetasol propionate, and belongs to the technical field of drug purification. The method for refining a crude halobetasol propionate comprises the following steps: mixing the crude halobetasol propionate with a single organic solvent, then heating and stirring, then filtering while hot, and then cooling to precipitate crystals to obtain a fine halobetasol propionate. The content of a single impurity in the fine halobetasol propionate obtained by the method is less than 0.1%.

Description

Technical Field

[0001] The invention relates to the technical field of drug purification, and in particular to a method for refining a crude halobetasol propionate product. Background Art

[0002] Halobetasol Propionate, CAS No.: 66852-54-8, chemical name: 21-chloro-6α, 9α-difluoro-11β, 17α-dihydroxy-16β-methyl-1,4-pregnadiene-3,20-dione 17-propionate, Chinese alias: Halobetasol Propionate, molecular formula C25H31ClF2O5, molecular weight 484.96, structural formula is as follows:

[0003]

[0004] Halobetasol propionate is a topical corticosteroid developed by Ciba-Geigy of Switzerland. It was launched in 1991 and is used to relieve skin inflammation and itching symptoms that are sensitive to corticosteroids. At present, there are no imitation varieties of halobetasol propionate raw materials in China, and all rely on imports. The known synthesis route of halobetasol propionate is as follows: starting from NT-0 (betamethasone intermediate), the 17-hydroxyl group is esterified and the 21-hydroxyl sulfonyl group is esterified, and finally the sulfonate on the 20-methylene group is replaced by chlorine to form halobetasol propionate. The synthesis route is as follows:

[0005]

[0006] The second step of synthesizing halobetasol propionate uses methanesulfonyl chloride and the third step intermediate is a methanesulfonate compound. NT-02, as a raw material, is incompletely reacted and exists in the crude halobetasol propionate. This compound is a potential suspected genotoxic impurity and is very difficult to remove. Ordinary refining methods cannot reduce it to the pharmacopoeia standard, that is, all single impurities are ≤0.1%.

[0007] The existing method is to purify the crude halobetasol propionate using a mixed solvent system of dichloromethane and methanol, dichloromethane and acetone, chloroform and methanol, chloroform and acetone, etc., but all of them cannot effectively reduce all individual impurities in the crude halobetasol propionate to below 0.1%. Therefore, a new refining method for refining halobetasol propionate is needed in the art. Summary of the invention

[0008] The object of the present invention is to overcome the above technical deficiencies, provide a method for refining crude halobetasol propionate, and solve the technical problem that the prior art cannot effectively reduce all single impurities in crude halobetasol propionate to below 0.1%.

[0009] In order to achieve the above technical purpose, the technical solution of the present invention provides a method for refining a crude halobetasol propionate, comprising the following steps: mixing the crude halobetasol propionate with a single organic solvent, then heating and stirring, then filtering while hot, and then cooling to precipitate crystals to obtain a fine halobetasol propionate; the single organic solvent is ethanol or ethyl acetate.

[0010] In some embodiments, the heating temperature is 50-80°C.

[0011] In some embodiments, the stirring time is 1-2 hours.

[0012] In some embodiments, the temperature is lowered to 0-10°C to precipitate crystals.

[0013] In some embodiments, the ratio of the crude halobetasol propionate to a single organic solvent is 1 g: (2-40) mL.

[0014] In some embodiments, the purity of the crude halobetasol propionate is greater than 97%.

[0015] In some embodiments, the content of at least one single impurity in the crude halobetasol propionate is greater than 0.1%.

[0016] In some embodiments, the content of each individual impurity in the halobetasol propionate product is less than 0.1%.

[0017] Compared with the prior art, the beneficial effects of the present invention include: mixing a crude halobetasol propionate with a single organic solvent, then heating to dissolve, then filtering while hot, then cooling to precipitate crystals to obtain a fine halobetasol propionate product, and the content of a single impurity in the obtained fine halobetasol propionate product is less than 0.1%. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 It is a liquid chromatogram of the crude halobetasol propionate to be treated in Example 1-2 of the present invention and Comparative Example 1-2;

[0019] Figure 2 It is a liquid chromatogram of the crude halobetasol propionate treated in Example 1 of the present invention.

[0020] Figure 3 It is a liquid chromatogram of the crude product of halobetasol propionate after being treated in Comparative Example 1 of the present invention. DETAILED DESCRIPTION

[0021] The present specific embodiment provides a method for refining a crude halobetasol propionate, comprising the following steps: mixing the crude halobetasol propionate and a single organic solvent at a dosage ratio of 1 g: (2-40) mL, then heating and stirring at 50-80° C. for 1-2 hours, then filtering while hot, and then cooling to 0-10° C. to precipitate crystals to obtain a fine halobetasol propionate product; the single organic solvent is ethanol or ethyl acetate; the purity of the crude halobetasol propionate is above 99%, the content of at least one single impurity in the crude halobetasol propionate is greater than 0.1%, and the content of each single impurity in the obtained fine halobetasol propionate product is less than 0.1%.

[0022] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention.

[0023] In the present invention, reference is made to “some embodiments”, “this embodiment”, examples, etc., which describe a subset of all possible embodiments, but it can be understood that “some embodiments” may be the same subset or different subsets of all possible embodiments and may be combined with each other without conflict.

[0024] If similar descriptions of "first / second" appear in the application documents, the following instructions are added. In the following description, the terms "first\second\third" involved are merely used to distinguish similar objects and do not represent a specific ordering of the objects. It can be understood that "first\second\third" can be interchanged in a specific order or sequence where permitted, so that the embodiments described herein can be implemented in an order other than that illustrated or described herein.

[0025] In this embodiment, the term "and / or" is only a description of the association relationship of associated objects, indicating that there may be three relationships, for example, object A and / or object B can represent: object A exists alone, object A and object B exist at the same time, and object B exists alone. It should be noted that the ethanol in the following embodiments is anhydrous ethanol.

[0026] Example 1

[0027] This embodiment provides a method for refining a crude halobetasol propionate, comprising the following steps:

[0028] 20 g of crude halobetasol propionate with a purity of 99.20% and 60 ml of ethanol were mixed, heated to 60° C. and stirred for 1 hour, filtered while hot, and then the halobetasol propionate ethanol solution was cooled to 0° C., solids were gradually precipitated, stirred for 2 hours, filtered, and the filter cake was washed with 10 ml of ethanol and dried to obtain 15.6 g of halobetasol propionate fine product. The yield was 78% and the HPLC purity was 99.81%. The liquid chromatogram of the crude halobetasol propionate of this embodiment is as follows Figure 1 As shown, the liquid chromatogram of the fine product of halobetasol propionate in this embodiment is as follows Figure 2 The impurity content of the crude halobetasol propionate is shown in Table 1. It can be seen that there are 9 impurities, and there are three impurities with a content greater than 0.1%. As shown in Table 2, after being treated in Example 1, there are still three impurities, and the content of the impurities is less than 0.1%.

[0029] Table 1 Liquid chromatogram information of crude halobetasol propionate before treatment in Example 1

[0030]

[0031] Table 2 Liquid chromatogram information of halobetasol propionate fine product after treatment in Example 1

[0032]

[0033] Example 2

[0034] This embodiment provides a method for refining a crude halobetasol propionate, comprising the following steps:

[0035] 20g of 99.20% purity halobetasol propionate crude product and 50ml of ethyl acetate were mixed, heated to 80°C for reflux, stirred for 1 hour, then the halobetasol propionate ethyl acetate solution was cooled to 5°C, solids were gradually precipitated, stirred for 2 hours, filtered, the filter cake was washed with 20ml of ethanol, and dried to obtain 16.2g of halobetasol propionate fine product. The yield was 81% and the HPLC purity was 99.87%. The content of individual impurities in the obtained halobetasol propionate fine product was less than 0.1%.

[0036] Example 3

[0037] This embodiment provides a method for refining a crude halobetasol propionate, comprising the following steps:

[0038] 20g of crude halobetasol propionate with a purity of 97.58% was mixed with 50mL of ethanol, heated to 80°C for reflux, stirred for 1 hour, then the halobetasol propionate ethanol solution was cooled to 10°C, solids were gradually precipitated, stirred for 2 hours, filtered, the filter cake was washed with 15ml of ethanol, and dried to obtain 24.0g of halobetasol propionate fine product. The yield was 80%, and the HPLC purity was 99.8%. The content of individual impurities in the obtained halobetasol propionate fine product was less than 0.1%.

[0039] Example 4

[0040] This embodiment provides a method for refining a crude halobetasol propionate, comprising the following steps:

[0041] 3.3 kg of crude halobetasol propionate (purity 96.11%, containing 9 impurities with a content greater than 0.1%) and 113.2 L of ethyl acetate were mixed, heated to 80°C for dissolution, stirred for 1 hour, filtered while hot, and then the halobetasol propionate ethyl acetate solution was cooled to 0°C, solids were gradually precipitated, stirred for 2 hours, filtered, the filter cake was washed with 10 ml of ethyl acetate, and dried to obtain 2.5 kg of halobetasol propionate fine product. The yield was 75.7% and the HPLC purity was 99.82%. The content of individual impurities in the obtained halobetasol propionate fine product was all below 0.1%.

[0042] Example 5

[0043] This embodiment provides a method for refining a crude halobetasol propionate, comprising the following steps:

[0044] 2.5 kg of crude halobetasol propionate with a purity of 97.58% was mixed with 50 L of ethanol, heated to 80° C. and refluxed, stirred for 1 hour, then the halobetasol propionate ethanol solution was cooled to 10° C., solids were gradually precipitated, stirred for 2 hours, filtered, the filter cake was washed with 15 ml of ethanol, and dried to obtain 2 kg of halobetasol propionate fine product. The yield was 80%, and the HPLC purity was 99.81%. The content of individual impurities in the obtained halobetasol propionate fine product was less than 0.1%.

[0045] Example 6

[0046] This embodiment provides a method for refining a crude halobetasol propionate, comprising the following steps:

[0047] 2.5 kg of crude halobetasol propionate with a purity of 97.58% was mixed with 80 L of ethyl acetate, heated to 70° C. and refluxed, stirred for 1 hour, then the halobetasol propionate ethyl acetate solution was cooled to 5° C., solids were gradually precipitated, stirred for 2 hours, filtered, the filter cake was washed with 15 ml of ethyl acetate, and dried to obtain 2 kg of halobetasol propionate fine product. The yield was 80%, and the HPLC purity was 99.80%. The content of individual impurities in the obtained halobetasol propionate fine product was less than 0.1%.

[0048] Comparative Example 1

[0049] 20 g of crude halobetasol propionate with a purity of 99.20%, 100 mL of dichloromethane and 50 mL of methanol were mixed, heated to 60°C and dissolved, stirred for 1 hour, concentrated to a small volume under negative pressure, then cooled to 5°C, solids gradually precipitated, stirred for 2 hours, filtered, the filter cake was washed with 10 mL of methanol, and dried to obtain 17 g of halobetasol propionate. The yield was 85%, combined Figure 3 As shown in Table 3, the HPLC purity is 99.45%. (The impurities at RT: 0.62, 0.83 are both ≥ 0.1%).

[0050] Table 3 Liquid chromatogram information of halobetasol propionate after treatment in comparative example 1

[0051]

[0052] Comparative Example 2

[0053] Mix 20g of crude halobetasol propionate (purity 99.20%), 100mL of dichloromethane and 50ml of acetone, heat to 60°C to dissolve, stir for 1 hour, concentrate to a small volume under negative pressure, then cool to 5°C, gradually precipitate solid, stir for 2 hours, filter, wash the filter cake with 10ml of acetone, and dry to obtain 17.6g of halobetasol propionate. Yield 88%, HPLC purity 99.58%. (RT: 0.83, 0.86 impurities are ≥ 0.1%).

[0054] It should be noted that if the purity of the crude halobetasol propionate is less than 97%, it can be treated twice according to the refining method proposed in the present invention to obtain a fine halobetasol propionate with a single impurity content of less than 0.1%.

[0055] The present invention provides a novel method for refining halobetasol propionate, which comprises removing all single impurities greater than or equal to 0.1% of halobetasol propionate crude product by suction filtration or hot suction filtration and recrystallization under a single solvent condition, and reducing the impurities to less than 0.1%, thereby obtaining halobetasol fine product. The present invention provides a green, environmentally friendly, safe and simple method for removing unknown impurities greater than 0.1% in halobetasol, so that the content of all impurities in the halobetasol crude product is controlled to less than 0.1%, which meets the quality standards of European and American pharmacopoeias and is higher than the industry standards.

[0056] The specific implementation of the present invention described above does not constitute a limitation on the protection scope of the present invention. Any other corresponding changes and modifications made based on the technical concept of the present invention should be included in the protection scope of the claims of the present invention.

Claims

1. A method for refining a crude product of halobetasol propionate, characterized in that: The following steps are involved: A crude halobetasol propionate product and a single organic solvent are mixed, and then heated and stirred for 1-2 hours, the heating temperature is 50-80°C, and then filtered while hot, and then cooled to 0-10°C to precipitate crystals to obtain a fine halobetasol propionate product; the single organic solvent is ethyl acetate; the content of at least one single impurity in the crude halobetasol propionate product is greater than 0.1%; the content of each single impurity in the fine halobetasol propionate product is less than 0.1%.

2. The method for refining crude halobetasol propionate according to claim 1, characterized in that: The usage ratio of the crude halobetasol propionate to the single organic solvent is 1 g:(2-40) mL.

3. The method for refining crude halobetasol propionate according to claim 1, characterized in that: The purity of the crude halobetasol propionate is above 97%.

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