Crystal-form-controllable triamcinolone acetonide preparation method

Abstract

The present invention relates to the technical field of organic synthesis. Disclosed is a crystal-form-controllable triamcinolone acetonide preparation method. Triamcinolone acetonide has two crystal forms, i.e. crystal form 1 and crystal form 2, respectively. The method comprises: for crystal form 1, adding ethanol to a crude product of triamcinolone acetonide for dissolution under reflux, cooling and stirring the mixture for crystallization, and performing filtering to obtain a wet product of triamcinolone acetonide; adding ethanol for dissolution under reflux, adding water to a reflux solution and controlling the temperature of the system to be 70-80ºC; and after the addition of water is complete, cooling and stirring for crystallization to obtain single crystal form 1 of triamcinolone acetonide having a low organic solvent content; and for crystal form 2, adding ethanol to a crude product of triamcinolone acetonide for dissolution under reflux, cooling and stirring the mixture for crystallization, and performing filtering to obtain a wet product of triamcinolone acetonide; adding ethanol for dissolution under reflux, cooling and stirring the mixture for crystallization to obtain single crystal form 2 of triamcinolone acetonide having a low organic solvent content. The triamcinolone acetonide preparation method of the present invention achieves crystal form controllability, high purity, and low solvent residual amount, and can prepare a product of a single crystal form according to requirements, with strong controllability, easy method production, and high process stability.

Description

A method for preparing triamcinolone acetonide with controllable crystal form Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for preparing triamcinolone acetonide with controllable crystal form. Background Technology

[0002] Triamcinolone acetonide, chemical formula C 24 H 31 FO6, chemical name: 9-fluoro-11β,21-dihydroxy-16α,17[(1-methylethylidene)bis(oxy)]-pregn-1,4-diene-3,20-dione. Triamcinolone is a long-acting corticosteroid with effects on glucose metabolism, anti-inflammation, antitoxicity, anti-shock, and anti-allergy. It is mainly used to treat active rheumatism, rheumatoid arthritis, allergic dermatitis, and psoriasis, as well as perennial and allergic rhinitis. It can also be used for eczema, neurodermatitis, seborrheic dermatitis, and pruritus. Topical application of triamcinolone for treating skin diseases is highly effective.

[0003] Currently, there are two main methods for preparing triamcinolone acetonide. One method involves the oxidation of acetate tetraene, acetone esterification, bromohydroxyepoxidation, fluorination, and hydrolysis. The other method involves the oxidation of acetate tetraene, acetone esterification, bromohydroxyepoxidation, hydrolysis, and fluorination. Most current research focuses on the preparation of triamcinolone acetonide, with almost no reports on impurity control, solvent residues, or crystal form.

[0004] Patent CN 106518952A discloses triamcinolone acetonide crystal form B, its preparation method, pharmaceutical compositions containing said crystal form B, and its uses. It discovers a crystal form B that differs from existing triamcinolone acetonide crystal forms. Compared to the known crystal form A, crystal form B has smaller particles and does not undergo crystallization or agglomeration in aqueous solution. This is beneficial for the processing and storage of its suspension injection, thus improving product quality. This indicates that triamcinolone acetonide can produce different crystal forms during preparation, and different crystal forms of triamcinolone acetonide can significantly affect the product quality and shelf life of the suspension injection.

[0005] Currently, commercially available triamcinolone acetonide is in crystal form 1 (as shown in Figure 1), and its suspension for injection exhibits good stability. Other crystal forms of triamcinolone acetonide may affect its stability and shelf life. Patent CN101348516A discloses a process for refining triamcinolone acetonide active pharmaceutical ingredient. The finished product prepared using this method has the advantages of stable quality, high content, low impurities, and high yield. However, further investigation revealed that the two technical solutions in the examples contain two different crystal forms: crystal form 1 (Example 2) and crystal form 2 (Example 1), and this refining method suffers from high solvent residue, which will seriously affect the application of triamcinolone acetonide. Summary of the Invention

[0006] To address the problems of non-unique crystal forms and high organic solvent residues in existing methods for preparing triamcinolone acetonide, this invention provides a method for preparing triamcinolone acetonide with controllable crystal forms. The production processes for triamcinolone acetonide with crystal forms 1 and 2 are clearly defined, and the prepared product has low organic solvent content, high purity, strong controllability, and is easy to scale up for production.

[0007] This invention is achieved through the following technical solution:

[0008] A method for preparing triamcinolone acetonide with controllable crystal form, wherein the triamcinolone acetonide exists in two crystal forms, namely crystal form 1 and crystal form 2;

[0009] The preparation method of crystal form 1 is as follows:

[0010] (1) Dissolve crude triamcinolone acetonide under reflux with ethanol, cool, stir to precipitate crystals, and filter to obtain wet triamcinolone acetonide;

[0011] (2) Dissolve the wet product of triamcinolone acetonide by reflux with ethanol, add water to the reflux solution, and control the system temperature at 70~80℃ during the water addition process. After the water addition is completed, cool down, stir to precipitate crystals, filter and dry to obtain triamcinolone acetonide single crystal form and crystal form 1 with low organic solvent content.

[0012] The preparation method of the crystal form 2 is as follows:

[0013] 1) Dissolve crude triamcinolone acetonide under reflux with ethanol, cool, stir to precipitate crystals, and filter to obtain wet triamcinolone acetonide;

[0014] 2) Dissolve wet triamcinolone acetonide under reflux with ethanol, cool, stir to crystallize, filter and dry to obtain triamcinolone acetonide single crystal form and crystal form 2 with low organic solvent content;

[0015] The method for preparing the crude triamcinolone acetonide is as follows:

[0016] i) Dissolve the acetate tetraene in a mixed solution of acetone and water, add formic acid, add potassium permanganate at -15~5℃, react for 0.5~2h after the addition is complete, add sodium sulfite aqueous solution to quench the reaction, filter, concentrate the filtrate until no droplets flow out, cool and filter, dissolve the solid in ethanol, purify and dry to obtain intermediate I.

[0017] ii) Add acetone to intermediate I, add perchloric acid at 10~20℃, react for 1~1.5h after the addition is complete, add water and NBS, react for 2~5h at 10~40℃, add sodium sulfite aqueous solution to quench the reaction after the reaction is complete, then add sodium hydroxide aqueous solution and react for 2~5h at 10~40℃, add glacial acetic acid to adjust the pH to 6~7 after the reaction is complete, filter, dissolve the solid in ethanol, purify and dry to obtain intermediate II;

[0018] iii) Add intermediate II to a 70% pyridine hydrofluoric acid solution and react at -30 to -10°C for 2 to 5 hours. Quench the reaction solution in ice water, filter, dissolve the solid in ethanol, purify and dry to obtain intermediate III.

[0019] iv) Dissolve intermediate III in dichloromethane and methanol, cool to 10-30°C, add a methanol solution of sodium hydroxide dropwise under nitrogen protection, react for 2-5 hours after the addition is complete, adjust the pH to 6-7 after the reaction is complete, add water and continue the reaction for 20-40 minutes, concentrate until no droplets remain after the reaction is complete, filter to obtain crude triamcinolone acetonide.

[0020] .

[0021] Furthermore, in steps (1), (2), (1) and (2), the reflux dissolution time of ethanol is 0.5 to 2 hours, and the reflux dissolution temperature is 70 to 80°C.

[0022] Furthermore, the cooling temperature in steps (1), (2), (1), and (2) is 0~10℃.

[0023] Furthermore, in step (2), the volume ratio of ethanol to water is 2:1.

[0024] Further, in step i), the molar ratio of acetate tetraene, formic acid, and potassium permanganate is 1:2~2.5:1.1~1.4; in step ii), the molar ratio of intermediate I:perchloric acid:NBS:sodium sulfite:sodium hydroxide is 1:1.05~1.27:1.75~2.0:1.48:4.0; in step iii), the molar ratio of intermediate II to hydrofluoric acid pyridine solution is 1:2~2.5; and in step iv), the molar ratio of intermediate III to sodium hydroxide is 1:0.2~0.3.

[0025] Further, in step i), the volume ratio of acetone to water in the mixed solution of acetone and water is 8:1, and the concentration of sodium sulfite aqueous solution is 10~15wt%; in step ii), the concentration of sodium sulfite aqueous solution is 10~15wt%; in step iii), the concentration of hydrofluoric acid pyridine solution is 70wt%; and in step iv), the volume ratio of dichloromethane to methanol is 1:1.

[0026] The beneficial effects achieved by this invention are as follows:

[0027] The method for preparing triamcinolone acetonide according to this invention has controllable crystal form, high purity of triamcinolone acetonide, low solvent residue (combined pharmacopoeia standards), and can prepare products with a single crystal form as needed. It has strong controllability, is easy to produce, and has high process stability. Attached Figure Description

[0028] Figure 1 shows the XRD pattern of commercially purchased triamcinolone acetonide (crystal form 1);

[0029] Figure 2 shows the XRD pattern of triamcinolone acetonide (crystal form 1) prepared in Example 2;

[0030] Figure 3 is the HPLC chromatogram of triamcinolone acetonide (crystal form 1) prepared in Example 2;

[0031] Figure 4 shows the XRD pattern of triamcinolone acetonide (crystal form 2) prepared in Example 3;

[0032] Figure 5 is the HPLC chromatogram of triamcinolone acetonide (crystal form 2) prepared in Example 3;

[0033] Figure 6 shows the XRD pattern of triamcinolone acetonide (crystal form 1) prepared in Comparative Example 1;

[0034] Figure 7 shows the HPLC chromatogram of triamcinolone acetonide (crystal form 1) prepared in Comparative Example 1;

[0035] Figure 8 shows the XRD pattern of triamcinolone acetonide (crystal form 1) prepared in Comparative Example 2;

[0036] Figure 9 shows the HPLC chromatogram of triamcinolone acetonide (crystal form 1) prepared in Comparative Example 2. Detailed Implementation

[0037] The following examples further illustrate the above-described content of the present invention, but it should not be construed as limiting the scope of the subject matter of the present invention to the following examples. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention.

[0038] The commercially available triamcinolone acetonide was purchased from Tianjin Jinhui Pharmaceutical Group Co., Ltd., and its XRD pattern is shown in Figure 1. The crystal form is crystal form 1.

[0039] Example 1

[0040] Preparation of crude triamcinolone acetonide:

[0041] (1) Add 4000 ml of acetone to a 10L three-necked flask Mix 200g of acetate tetraene and 500ml of water at room temperature until dissolved; add 45ml of formic acid, cool to -10℃, control the temperature at -10±5℃, slowly add 95.0g of KMnO4 solid over 30min, and react for 1h under controlled temperature; add sodium sulfite solution (111g / 800ml) dropwise and stir for 1h to quench the reaction; filter, retain the filtrate, transfer the filter cake to a 5000ml beaker, add 2000ml of tetrahydrofuran, stir at room temperature for 30min, filter, combine the filtrates, concentrate under reduced pressure at 50℃ until no droplets flow out, cool to room temperature and filter to obtain intermediate I crude wet product; add 600ml of ethanol to the crude product and stir at 75℃ for 2h, cool to 15℃ and stir for 1h, filter, dry the solid at 70±5℃ for 12h to obtain intermediate I, the purity of which is 98% and the molar yield is 75% as determined by HPLC.

[0042] (2) Add 900 ml of acetone and 150 g of intermediate I solid to a 3 L three-necked flask, stir for 10 min, add 41.4 g of perchloric acid at 10-20 °C, stir and react for 1 h, add 375 ml of water after the reaction, slowly add 124.4 g of NBS at 30 °C, and react for 2.5 h after the addition is complete; after the reaction is complete, add sodium sulfite solution (70 g sodium sulfite / 600 ml water) dropwise at 30 °C, add 10% sodium hydroxide solution (60.7 g sodium hydroxide / 540 ml water), and react for 2.5 h at 30 °C; after the reaction is complete, adjust the pH to 6.5 with glacial acetic acid, filter to obtain crude wet intermediate II; add 1500 ml of ethanol to the crude product and beat at 75 °C for 2 h, cool to 10-20 °C and stir for 1 h, filter, and dry the solid at 55 °C for 12 h to obtain intermediate II. The purity of the product was 95% and the molar yield was 70% as determined by HPLC.

[0043] (3) Add 350g of 70% pyridine hydrofluoric acid solution to a 500ml plastic reaction flask (HDPE), cool to -20℃, slowly add 150g of intermediate II, react at 0℃ for 3h after addition, slowly add the reaction solution to 2000ml of ice water, continue stirring for 1h to crystallize, filter, wash with water until the pH of the mother liquor is 6.5, to obtain crude wet intermediate III; add 1500ml of ethanol to the wet product, slurry at 75℃ for 2h, cool to 20℃ and continue stirring for 1h, filter, dry the solid at 55℃ for 12h to obtain intermediate III, the purity of the product is 97% and the molar yield is 73% by HPLC; (4) Add 1000ml of methanol and 1000ml of dichloromethane to a 3L three-necked flask, add intermediate III at room temperature. 100g of sodium hydroxide solution was stirred until dissolved, cooled to 15℃, and under nitrogen protection, a methanol solution of sodium hydroxide (1.6g / 100ml) was added dropwise. The reaction was allowed to proceed for 3 hours. After the reaction was completed, the pH was adjusted to 6.7 with glacial acetic acid, 300ml of water was added, and stirring was continued for 30 minutes. The solution was concentrated at 50℃ until no droplets remained, cooled to 15℃, and filtered to obtain crude triamcinolone acetonide.

[0044] .

[0045] Example 2

[0046] Preparation of Triamcinolone Acetonide Crystal Form 1:

[0047] Crude triamcinolone was prepared according to the method in Example 1 above. Crude triamcinolone was added to a 2L three-necked flask, 1000ml of ethanol was added, the temperature was raised to 70~80℃ and refluxed, stirred for 2h, cooled to 0~10℃ and stirred for 1h to precipitate crystals, and filtered to obtain wet triamcinolone.

[0048] The wet triamcinolone acetonide was added to a 5L three-necked flask, and 2000ml of ethanol was added. The mixture was heated to 70-80℃ and refluxed for 0.5 hours until completely dissolved. Then, 1000ml of water was added dropwise. After the addition was complete, the mixture was cooled to 0-10℃ and stirred for 1 hour. The mixture was then filtered, and the solid was dried at 55℃ to obtain the finished triamcinolone acetonide product (single crystal form with low organic solvent content) with a molar yield of 65%. Its XRD and HPLC chromatograms are shown in Figures 2 and 3, respectively, which are consistent with the existing commercial triamcinolone acetonide crystal form (crystal form 1). The purity of the product was tested to be 99.9%, with no detectable methanol solvent residue and 0.034% ethanol solvent residue, which meets the standards.

[0049] Example 3

[0050] Preparation of crystalline form 2-triamcinolone:

[0051] Crude triamcinolone was prepared according to the method in Example 1 above. Crude triamcinolone was added to a 2L three-necked flask, 1000ml of ethanol was added, the temperature was raised to 70~80℃ and refluxed, stirred for 2h, cooled to 0~10℃ and stirred for 1h to precipitate crystals, and filtered to obtain wet triamcinolone.

[0052] The wet triamcinolone acetonide was added to a 3L three-necked flask, and 2000ml of ethanol was added. The mixture was heated to 70-80℃ and refluxed for 0.5h until completely dissolved. The solution was then cooled to 0-10℃ and stirred for 1h. The mixture was filtered, and the solid was dried at 55℃ to obtain the finished triamcinolone acetonide product (single crystal form, low organic solvent content). The molar yield of the product was 60%. Its XRD and HPLC chromatograms are shown in Figures 4 and 5, respectively. Unlike the existing commercial triamcinolone acetonide crystal form (crystal form 1), it is crystal form 2. The purity of the product was 99.8%, with methanol solvent residue of 0.0032% and ethanol solvent residue of 0.17%.

[0053] Comparative Example 1

[0054] Crude triamcinolone was prepared according to the method in Example 1 above. Crude triamcinolone was added to a 2L three-necked flask, 1000ml of ethanol was added, the temperature was raised to 70~80℃ and refluxed, stirred for 2h, cooled to 0~10℃ and stirred for 1h to precipitate crystals, and filtered to obtain wet triamcinolone.

[0055] The wet product of triamcinolone acetonide was added to a 500ml three-necked flask, along with 100ml of methanol and 100ml of chloroform. The mixture was heated to 50℃ and refluxed for 2 hours, then cooled to 0-10℃ and stirred for 1 hour. The mixture was filtered, and the solid was dried at 55℃ for 12 hours to obtain the finished triamcinolone acetonide product. The molar yield of the product was 70±5%. Its XRD and HPLC chromatograms are shown in Figures 6 and 7, respectively. It is consistent with the existing commercial triamcinolone acetonide crystal form (crystal form 1), and is crystal form 1. The purity of the product was tested to be 99.9%, with methanol solvent residue of 2.68% and chloroform solvent residue of 0.03%. The solvent residue did not meet the standard.

[0056] Comparative Example 2

[0057] Crude triamcinolone acetonide was prepared according to the method described in Example 1 above. Crude product 1 was added to a 2L three-necked flask, followed by 1000ml of ethanol. The mixture was heated to 70-80℃ and refluxed, stirred for 2 hours, then cooled to 0-10℃ and stirred for 1 hour to induce crystallization. The crystals were filtered, and the solid was dried at 55℃ for 8 hours to obtain the finished triamcinolone acetonide product. The molar yield of the product was 80±5%. Its XRD and HPLC chromatograms are shown in Figures 8 and 9, respectively. It is consistent with the existing commercial triamcinolone acetonide crystal form (crystal form 1), indicating crystal form 1. The product purity was 99.9%, with methanol solvent residue of 0.52% and ethanol solvent residue of 0.23%, which did not meet the standard for solvent residue.

Claims

1. A method for preparing triamcinolone acetonide with controllable crystal form, characterized in that, The triamcinolone acetonide exists in two crystal forms, namely crystal form 1 and crystal form 2; The preparation method of crystal form 1 is as follows: (1) Dissolve crude triamcinolone acetonide under reflux with ethanol, cool, stir to precipitate crystals, and filter to obtain wet triamcinolone acetonide; (2) Dissolve the wet product of triamcinolone acetonide by reflux with ethanol, add water to the reflux solution, and control the system temperature at 70~80℃ during the water addition process. After the water addition is completed, cool down, stir to precipitate crystals, filter and dry to obtain triamcinolone acetonide single crystal form and crystal form 1 with low organic solvent content. The preparation method of the crystal form 2 is as follows: 1) Dissolve crude triamcinolone acetonide under reflux with ethanol, cool, stir to precipitate crystals, and filter to obtain wet triamcinolone acetonide; 2) Dissolve wet triamcinolone acetonide under reflux with ethanol, cool, stir to crystallize, filter and dry to obtain triamcinolone acetonide single crystal form and crystal form 2 with low organic solvent content; The method for preparing the crude triamcinolone acetonide is as follows: i) Dissolve the acetate tetraene in a mixed solution of acetone and water, add formic acid, add potassium permanganate at -15~5℃, react for 0.5~2h after the addition is complete, add sodium sulfite aqueous solution to quench the reaction, filter, concentrate the filtrate until no droplets flow out, cool and filter, dissolve the solid in ethanol, purify and dry to obtain intermediate I. ii) Add acetone to intermediate I, add perchloric acid at 10~20℃, react for 1~1.5h after the addition is complete, add water and NBS, react for 2~5h at 10~40℃, add sodium sulfite aqueous solution to quench the reaction after the reaction is complete, then add sodium hydroxide aqueous solution and react for 2~5h at 10~40℃, add glacial acetic acid to adjust the pH to 6~7 after the reaction is complete, filter, dissolve the solid in ethanol, purify and dry to obtain intermediate II; iii) Add intermediate II to a 70% pyridine hydrofluoric acid solution and react at -30 to -10°C for 2 to 5 hours. Quench the reaction solution in ice water, filter, dissolve the solid in ethanol, purify and dry to obtain intermediate III. iv) Dissolve intermediate III in dichloromethane and methanol, cool to 10-30°C, add a methanol solution of sodium hydroxide dropwise under nitrogen protection, react for 2-5 hours after the addition is complete, adjust the pH to 6-7 after the reaction is complete, add water and continue the reaction for 20-40 minutes, concentrate until no droplets remain after the reaction is complete, filter to obtain crude triamcinolone acetonide. 。 2. The method for preparing triamcinolone acetonide with controllable crystal form according to claim 1, characterized in that, In steps (1), (2), (1) and (2), the reflux dissolution time of ethanol is 0.5-2h, and the reflux dissolution temperature is 70-80℃.

3. The method for preparing triamcinolone acetonide with controllable crystal form according to claim 1, characterized in that, The cooling temperature in steps (1), (2), (1) and (2) is 0~10℃.

4. The method for preparing triamcinolone acetonide with controllable crystal form according to claim 1, characterized in that, In step (2), the volume ratio of ethanol to water is 2:

1.

5. The method for preparing triamcinolone acetonide with controllable crystal form according to claim 1, characterized in that, In step i), the molar ratio of acetate tetraene, formic acid, and potassium permanganate is 1:2~2.5:1.1~1.4; in step ii), the molar ratio of intermediate I:perchloric acid:NBS:sodium sulfite:sodium hydroxide is 1:1.05~1.27:1.75~2.0:1.48:4.0; in step iii), the molar ratio of intermediate II to hydrofluoric acid pyridine solution is 1:2~2.5; in step iv), the molar ratio of intermediate III to sodium hydroxide is 1:0.2~0.

3.

6. The method for preparing triamcinolone acetonide with controllable crystal form according to claim 1, characterized in that, In step i), the volume ratio of acetone to water in the mixed solution of acetone and water is 8:1, and the concentration of sodium sulfite aqueous solution is 10~15wt%; in step ii), the concentration of sodium sulfite aqueous solution is 10~15wt%; in step iii), the concentration of hydrofluoric acid pyridine solution is 70wt%; and in step iv), the volume ratio of dichloromethane to methanol is 1:1.

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