Preparation method of triamcinolone acetonide with controllable crystal form

Abstract

The invention discloses a preparation method of triamcinolone acetonide with a controllable crystal form, and belongs to the technical field of organic synthesis. Triamcinolone acetonide has two crystal forms, namely a crystal form 1 and a crystal form 2. The preparation method comprises the following steps: adding ethanol into a triamcinolone acetonide crude product for reflux dissolution, cooling, stirring for crystallization, filtering to obtain a triamcinolone acetonide wet product, adding ethanol for reflux dissolution, adding water into reflux liquid, controlling the temperature of a system to be 70-80 DEG C, cooling after adding water, stirring for crystallization, and obtaining a triamcinolone acetonide single crystal form and the low-organic solvent content crystal form 1; and crystal form 2: adding ethanol into the triamcinolone acetonide crude product for reflux dissolution, cooling, stirring for crystallization, filtering to obtain a triamcinolone acetonide wet product, adding ethanol for reflux dissolution, cooling, stirring for crystallization to obtain the triamcinolone acetonide single crystal form and the low organic solvent content crystal form 2. The method for preparing triamcinolone acetonide is controllable in crystal form, high in purity, low in solvent residual quantity, high in controllability, easy to produce and high in process stability, and a product with a single crystal form can be prepared according to needs.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a method for preparing triamcinolone acetonide with controllable crystal form. Background Art

[0002] Triamcinolone acetonide, chemical formula: C 24 H 31 FO 6 , chemical name: 9-fluoro-11β,21-dihydroxy-16α,17[(1-methylethylidene)bis(oxy)]-pregnane-1,4-diene-3,20-dione. Triamcinolone acetonide is a long-acting adrenocortical hormone drug that has effects on glucose metabolism, anti-inflammatory, anti-toxic, anti-shock and anti-allergic effects. 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. Triamcinolone acetonide is used topically to treat skin diseases with excellent results.

[0003] At present, there are two main methods for preparing triamcinolone acetonide. One is to prepare triamcinolone acetonide from tetraene acetate through oxidation reaction, acetone forme reaction, bromohydroxy epoxidation reaction, fluorination reaction and hydrolysis reaction. Another method is to prepare triamcinolone acetonide from tetraene acetate through oxidation reaction, acetone forme reaction, bromohydroxy epoxidation reaction, hydrolysis reaction and fluorination reaction. At present, most of the research focuses on the preparation of triamcinolone acetonide, and there is almost no corresponding report on its impurity control, product solvent residue and crystal form.

[0004] Patent CN 106518952A discloses triamcinolone acetonide acetate crystal form B, its preparation method, pharmaceutical composition containing the crystal form B and its use, and discovers a crystal form B that is different from the existing triamcinolone acetonide acetate crystal form. Compared with the known crystal form A, the particles are smaller and will not undergo crystal transformation or agglomeration in aqueous solution, which is beneficial to the process treatment of its suspension injection and the storage of the product, thereby improving the quality of the product. It is shown that triamcinolone acetonide acetate will produce different crystal forms during the preparation process, and different crystal forms of triamcinolone acetonide acetate will have significant differences in the product quality and shelf life of the suspension injection.

[0005] Currently, the commercially available triamcinolone acetonide is in Form 1 (eg Figure 1As shown in the figure, its suspension injection has good stability, and other crystal forms of triamcinolone acetonide may affect its stability and shelf life. Patent CN101348516A discloses a process for refining triamcinolone acetonide raw materials. The finished product prepared by this method has the advantages of stable quality, high content, low impurities and high yield. However, it was further found that the two technical solutions of its embodiments have two different crystal forms: crystal form 1 (Example 2) and crystal form 2 (Example 1), and the refining method has the problem of high residual solvent, which will seriously affect the application of triamcinolone acetonide. Summary of the invention

[0006] In view of the problems that the existing method for preparing triamcinolone acetonide has non-unique crystal form and high residual organic solvent content, the present invention provides a method for preparing triamcinolone acetonide with controllable crystal form, clarifies the production process of crystal form 1 and crystal form 2 triamcinolone acetonide, and the prepared product has low organic solvent content, high purity, strong controllability, and is easy to scale up production.

[0007] The present invention is achieved through the following technical solutions: A method for preparing triamcinolone acetonide with controllable crystal form, wherein the triamcinolone acetonide has two crystal forms, namely, crystal form 1 and crystal form 2; The preparation method of the crystal form 1 is: (1) Add ethanol to the crude triamcinolone acetonide to dissolve it under reflux, cool it, stir it to crystallize it, and filter it to obtain the wet triamcinolone acetonide; (2) adding ethanol to the wet product of triamcinolone acetonide to reflux and dissolve, adding water to the reflux solution, controlling the system temperature to 70-80° C. during the water addition process, cooling after the water addition is completed, stirring to crystallize, filtering and drying to obtain triamcinolone acetonide single crystal form 1 with low organic solvent content; The preparation method of the crystal form 2 is: 1) Add ethanol to the crude triamcinolone acetonide to dissolve it under reflux, cool it, stir it to crystallize it, and filter it to obtain the wet triamcinolone acetonide; 2) Adding ethanol to the wet product of triamcinolone acetonide to dissolve under reflux, cooling, stirring to crystallize, filtering and drying to obtain triamcinolone acetonide monocrystalline form 2 with low organic solvent content; The preparation method of the crude triamcinolone acetonide is: ⅰ) Dissolve the tetraene acetate in a mixed solution of acetone and water, add formic acid, add potassium permanganate at -15~5°C, react for 0.5~2h after the addition is complete, add sodium sulfite aqueous solution to quench the reaction after the reaction is complete, 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°C, react for 1-1.5h after the addition is complete, add water and NBS after the reaction is complete, react at 10-40°C for 2-5h, add sodium sulfite aqueous solution after the reaction is complete to quench the reaction, then add sodium hydroxide aqueous solution at 10-40°C for 2-5h, add glacial acetic acid after the reaction is complete to adjust the pH to 6-7, filter, add ethanol to dissolve the solid, purify and dry to obtain intermediate II; iii) adding intermediate II to 70% pyridine hydrofluoride solution, reacting at -30~-10°C for 2~5h, quenching the reaction solution in ice water, filtering, dissolving the solid in ethanol, refining and drying to obtain intermediate III; iv) Add dichloromethane and methanol to dissolve the intermediate III, 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 value to 6-7 after the reaction is complete, add water and continue the reaction for 20-40 minutes, concentrate until there is no droplet after the reaction is complete, filter, and obtain a crude product of triamcinolone acetonide; .

[0008] Furthermore, in step (1), step (2), step 1) and step 2), the reflux dissolution time of ethanol is 0.5-2 h, and the reflux dissolution temperature is 70-80° C.

[0009] Furthermore, the cooling temperature in step (1), step (2), step 1) and step 2) is 0-10°C.

[0010] Furthermore, in step (2), the volume ratio of ethanol to water is 2:1.

[0011] Furthermore, in step i), the molar ratio of the tetraene acetate, 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 hydrofluoride 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.

[0012] Furthermore, 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 the sodium sulfite aqueous solution is 10-15wt%; in step ii), the concentration of the sodium sulfite aqueous solution is 10-15wt%; in step iii), the concentration of the hydrofluoric acid pyridine solution is 70wt%; and in step iv), the volume ratio of dichloromethane to methanol is 1:1.

[0013] Beneficial effects achieved by the present invention: The method for preparing triamcinolone acetonide provided by the invention has controllable crystal form, high purity of triamcinolone acetonide, low residual solvent content (compound pharmacopoeia standard), can prepare a single crystal product as required, has strong controllability, is easy to produce by the method, and has high process stability. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 This is the XRD pattern of commercially purchased triamcinolone acetonide (form 1); Figure 2 This is the XRD pattern of triamcinolone acetonide (crystal form 1) prepared in Example 2; Figure 3 HPLC chart of triamcinolone acetonide (crystal form 1) prepared in Example 2; Figure 4 This is the XRD pattern of triamcinolone acetonide (Crystal Form 2) prepared in Example 3; Figure 5 HPLC chart of triamcinolone acetonide (crystal form 2) prepared in Example 3; Figure 6 This is the XRD pattern of triamcinolone acetonide (crystal form 1) prepared in Comparative Example 1; Figure 7 HPLC chart of triamcinolone acetonide (crystal form 1) prepared in Comparative Example 1; Figure 8 This is the XRD pattern of triamcinolone acetonide (crystal form 1) prepared in Comparative Example 2; Fig. 9 This is the HPLC chart of triamcinolone acetonide (crystal form 1) prepared in Comparative Example 2. DETAILED DESCRIPTION

[0015] The above contents of the present invention are further described in detail below through examples, but this should not be understood as the scope of the above subject matter of the present invention being limited to the following examples, and all technologies implemented based on the above contents of the present invention belong to the scope of the present invention.

[0016] Commercialized triamcinolone acetonide was purchased from Tianjin Jinhui Pharmaceutical Group Co., Ltd. Its XRD pattern is shown in Figure 1 As shown, the crystal form is Form 1.

[0017] Example 1 Preparation of crude triamcinolone acetonide: (1) Add 4000 ml of acetone, 200 g of tetraene acetate, and 500 ml of water to a 10L three-necked flask and stir at room temperature until dissolved; add 45 ml of formic acid, cool to -10°C, control the temperature at -10±5°C, and slowly add KMnO 495.0 g of solid was added over 30 minutes, and the temperature was controlled to react for 1 hour; sodium sulfite solution (111 g / 800 ml) was added dropwise and stirred for 1 hour to quench the reaction; suction was taken to filter, and the filtrate was retained. The filter cake was transferred to a 5000 ml beaker, and 2000 ml of tetrahydrofuran was added. The mixture was stirred at room temperature for 30 minutes, suction was taken to filter, and the filtrate was combined. At 50°C, the mixture was concentrated under reduced pressure until no liquid flowed out, and the mixture was cooled to room temperature and suction was taken to obtain the intermediate I crude wet product; 600 ml of ethanol was added to the crude product and stirred at 75°C for 2 hours, and then the mixture was cooled to 15°C and stirred for 1 hour and suction was taken to filter. The solid was dried at 70±5°C for 12 hours to obtain intermediate I. The product purity was 98% and the molar yield was 75% as determined by HPLC.

[0018] (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 completed, 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 at 30 °C for 2.5 h; after the reaction is completed, adjust the pH to 6.5 with glacial acetic acid, and filter to obtain the intermediate II crude wet product; add 1500 ml of ethanol to the crude product, beat at 75 °C for 2 h, cool to 10-20 °C, stir for 1 h, filter, and dry the solid at 55 °C for 12 h to obtain intermediate II. The product purity is 95% and the molar yield is 70% as determined by HPLC.

[0019] (3) Add 350g of 70% pyridine hydrofluoride solution to a 500ml plastic reaction bottle (HDPE), cool to -20℃, slowly add 150g of intermediate II, react at 0℃ for 3h after addition, slowly add 2000ml of ice water, continue stirring for 1h to crystallize, filter, rinse with water until the mother liquor pH = 6.5, and obtain intermediate III crude wet product; add 1500ml of ethanol to the wet product, beat at 75℃ for 2h, cool to 20℃, continue stirring for 1h, filter, and dry the solid at 55℃ for 12h to obtain intermediate III. The product purity was 97% and the molar yield was 73% as determined by HPLC; (4) Add 1000ml of methanol and 1000ml of dichloromethane to a 3L three-necked flask, and add intermediate III at room temperature. 100g was stirred to dissolve, cooled to 15℃, and under nitrogen protection, a methanol solution of sodium hydroxide (1.6g / 100ml) was added dropwise, and the reaction was continued for 3h. After the reaction was completed, the pH was adjusted to 6.7 with glacial acetic acid, 300ml of water was added, and the stirring was continued for 30min. The mixture was concentrated at 50℃ until there was no droplet, cooled to 15℃, and filtered to obtain a crude product of triamcinolone acetonide. .

[0020] Example 2 Preparation of Form 1 Triamcinolone Acetonide: According to the method of Example 1, a crude triamcinolone acetonide was prepared. The crude triamcinolone acetonide was added to a 2L three-necked flask, and 1000 ml of ethanol was added to raise the temperature to 70-80° C. and refluxed, stirred for 2 h, cooled to 0-10° C., stirred for 1 h to crystallize, and filtered to obtain a wet triamcinolone acetonide product; The wet product of triamcinolone acetonide was added to a 5L three-necked flask, and 2000ml of ethanol was added and heated to 70-80℃ and refluxed. After 0.5h, it was completely dissolved, and 1000ml of water was added dropwise. After the addition was completed, the temperature was lowered to 0-10℃ and stirred for 1h. The solid was filtered and dried at 55℃ to obtain the finished product of triamcinolone acetonide (single crystal, low organic solvent content triamcinolone acetonide), with a molar yield of 65%. Its XRD pattern and HPLC pattern are shown as follows: Figure 2 and Figure 3 As shown, it is consistent with the existing commercial triamcinolone acetonide crystal form (crystal form 1). After testing, the product purity is 99.9%, the methanol solvent residue is not detected, and the ethanol solvent residue is 0.034%, which meets the standard.

[0021] Example 3 Preparation of Form 2 Triamcinolone Acetonide: According to the method of Example 1, a crude triamcinolone acetonide was prepared. The crude triamcinolone acetonide was added to a 2L three-necked flask, and 1000 ml of ethanol was added to raise the temperature to 70-80° C. and refluxed, stirred for 2 h, cooled to 0-10° C., stirred for 1 h to crystallize, and filtered to obtain a wet triamcinolone acetonide product; The wet product of triamcinolone acetonide was added to a 3L three-necked flask, and 2000ml of ethanol was added and heated to 70-80℃ and refluxed. After 0.5h, the mixture was completely dissolved, and the mixture was cooled to 0-10℃ and stirred for 1h, and then filtered. The solid was dried at 55℃ to obtain the finished product of triamcinolone acetonide (single crystal triamcinolone acetonide with low organic solvent content). The molar yield of the finished product was 60%. Its XRD and HPLC patterns are shown as follows: Figure 4 and Figure 5 As shown, it is different from the existing commercial triamcinolone acetonide crystal form (crystal form 1), which is crystal form 2. The detected product purity is 99.8%, the methanol solvent residue is 0.0032%, and the ethanol solvent residue is 0.17%.

[0022] Comparative Example 1 According to the method of Example 1, a crude triamcinolone acetonide was prepared. The crude triamcinolone acetonide was added to a 2L three-necked flask, and 1000 ml of ethanol was added to raise the temperature to 70-80° C. and refluxed, stirred for 2 h, cooled to 0-10° C., stirred for 1 h to crystallize, and filtered to obtain a wet triamcinolone acetonide product; The wet product of triamcinolone acetonide was added into a 500 ml three-necked flask, and 100 ml of methanol and 100 ml of chloroform were added. The temperature was raised to 50°C and refluxed for 2 h. The temperature was lowered to 0-10°C and stirred for 1 h. The solid was filtered and dried at 55°C for 12 h to obtain the finished product of triamcinolone acetonide. The molar yield of the finished product was 70±5%. The XRD pattern and HPLC pattern were shown as follows: Figure 6 and Figure 7 As shown, it is consistent with the existing commercial triamcinolone acetonide crystal form (crystal form 1), which is crystal form 1. The detected product purity is 99.9%, the methanol solvent residue is 2.68%, and the chloroform solvent residue is 0.03%. The solvent residue does not meet the standard.

[0023] Comparative Example 2 According to the method of Example 1, a crude triamcinolone acetonide was prepared. The crude product 1 was added to a 2L three-necked flask, and 1000ml of ethanol was added to raise the temperature to 70-80°C and reflux, stirred for 2h, cooled to 0-10°C, stirred for 1h to crystallize, filtered, and the solid was dried at 55°C for 8h to obtain a triamcinolone acetonide finished product. The molar yield of the finished product was 80±5%. Its XRD pattern and HPLC pattern are shown as follows: Figure 8 and Fig. 9 As shown, it is consistent with the existing commercial triamcinolone acetonide crystal form (crystal form 1), which is crystal form 1. The detected product purity is 99.9%, the methanol solvent residue is 0.52%, and the ethanol solvent residue is 0.23%. The solvent residue does not meet the standard.

Claims

1. A method for preparing triamcinolone acetonide with controllable crystal form, characterized in that: The triamcinolone acetonide has two crystal forms, namely, crystal form 1 and crystal form 2; The preparation method of the crystal form 1 is: (1) Add ethanol to the crude triamcinolone acetonide to dissolve it under reflux, cool it, stir it to crystallize it, and filter it to obtain the wet triamcinolone acetonide; (2) adding ethanol to the wet product of triamcinolone acetonide to reflux and dissolve, adding water to the reflux solution, controlling the system temperature to 70-80° C. during the water addition process, cooling after the water addition is completed, stirring to crystallize, filtering and drying to obtain triamcinolone acetonide single crystal form 1 with low organic solvent content; The preparation method of the crystal form 2 is: 1) Add ethanol to the crude triamcinolone acetonide to dissolve it under reflux, cool it, stir it to crystallize it, and filter it to obtain the wet triamcinolone acetonide; 2) Adding ethanol to the wet product of triamcinolone acetonide to dissolve under reflux, cooling, stirring to crystallize, filtering and drying to obtain triamcinolone acetonide monocrystalline form 2 with low organic solvent content; The preparation method of the crude triamcinolone acetonide is: ⅰ) Dissolve the tetraene acetate in a mixed solution of acetone and water, add formic acid, add potassium permanganate at -15~5°C, react for 0.5~2h after the addition is complete, add sodium sulfite aqueous solution to quench the reaction after the reaction is complete, 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°C, react for 1-1.5h after the addition is complete, add water and NBS after the reaction is complete, react at 10-40°C for 2-5h, add sodium sulfite aqueous solution after the reaction is complete to quench the reaction, then add sodium hydroxide aqueous solution at 10-40°C for 2-5h, add glacial acetic acid after the reaction is complete to adjust the pH to 6-7, filter, add ethanol to dissolve the solid, purify and dry to obtain intermediate II; iii) adding intermediate II to 70% pyridine hydrofluoride solution, reacting at -30~-10°C for 2~5h, quenching the reaction solution in ice water, filtering, dissolving the solid in ethanol, refining and drying to obtain intermediate III; iv) Add dichloromethane and methanol to dissolve the intermediate III, 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 value to 6-7 after the reaction is complete, add water and continue the reaction for 20-40 minutes, concentrate until there is no droplet after the reaction is complete, filter, and obtain a crude product of triamcinolone acetonide; 。 2. The method for preparing triamcinolone acetonide with controllable crystal form according to claim 1, characterized in that: In step (1), step (2), step 1) and step 2), the reflux dissolution time of ethanol is 0.5-2h, and the reflux dissolution temperature is 70-80°C.

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

4. The method for preparing triamcinolone acetonide with controllable crystal form according to claim 1, characterized in that: The volume ratio of ethanol to water in step (2) 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 hydrofluoride 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 the sodium sulfite aqueous solution is 10-15wt%; in step ii), the concentration of the sodium sulfite aqueous solution is 10-15wt%; in step iii), the concentration of the hydrofluoric acid pyridine solution is 70wt%; in step iv), the volume ratio of dichloromethane to methanol is 1:1.

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