Method for preparing triamcinolone acetonide and its intermediates

Abstract

The present disclosure provides a method for preparing triamcinolone acetonide, comprising the following steps: preparing triamcinolone acetonide acetate from tetraene acetate; and preparing triamcinolone acetonide from triamcinolone acetonide acetate. The disclosed method has the advantages of high reaction yield, safety, and controllable cost, and is suitable for large-scale industrial production.

Description

Technical Field

[0001] The present disclosure relates to the technical field of pharmaceutical intermediate synthesis, and in particular to a method for preparing triamcinolone acetonide and its intermediates. Background Art

[0002] Triamcinolone acetonide is widely used as a corticosteroid to treat various skin diseases or relieve the discomfort caused by mouth ulcers. For example, it is suitable for periarthritis of the shoulder, tenosynovitis, acute sprains, skin diseases (such as neurodermatitis, eczema, psoriasis, etc.), joint pain, bronchial asthma, periarthritis of the shoulder, and ophthalmological inflammation.

[0003] Triamcinolone acetonide acetate is a common skin disease drug with strong anti-inflammatory and anti-allergic effects. It is suitable for various skin diseases, acute sprains, rheumatoid arthritis, joint pain, bronchial asthma, allergic rhinitis, periarthritis of the shoulder, tenosynovitis, synovitis, etc.

[0004] The methods for preparing triamcinolone acetonide and triamcinolone acetonide acetate in the prior art have the disadvantages of complex process, low yield and poor safety, which need to be solved urgently. Summary of the Invention

[0005] In order to solve the above problems, the present disclosure provides a new method for synthesizing triamcinolone acetonide, which has the advantages of simple process, high yield, safety and reliability.

[0006] Specifically, the first aspect of the present disclosure provides a method for preparing triamcinolone acetonide, characterized in that it comprises the following steps: preparing triamcinolone acetonide acetate from tetraene acetate; and

[0007] Triamcinolone acetonide was prepared from triamcinolone acetonide acetate.

[0008] Preferably, the preparation of triamcinolone acetonide acetate from tetraene acetate comprises:

[0009] (1) oxidizing the tetraene acetate to an oxidation product;

[0010] (2) condensing the oxidation product of step (1) to form a condensed ring;

[0011] (3) deriving a crude triamcinolone acetonide acetate product from the ring-condensed product of step (2);

[0012] (4) Recrystallizing the crude triamcinolone acetonide acetate obtained in step (3) to obtain triamcinolone acetonide acetate.

[0013] Preferably, the step (1) comprises:

[0014] In the reactor, 40 g of tetraene acetate, 500 g of acetone, 500 g of dimethyl sulfoxide and 15 g of formic acid were added in sequence. After ice bathing for 10 minutes, 20 g of potassium permanganate was added within 1 hour (potassium permanganate was added in batches every 15 minutes, 5 g per batch), and then 250 mL of sodium sulfite aqueous solution (concentration of 75 g / L) was added. After heating to 50 ° C and reacting for 30 minutes, two-thirds of the solvent was removed by distillation under reduced pressure, and then after another ice bath, the mixture was filtered to obtain a filter cake, which was the oxidation product.

[0015] Preferably, the step (2) comprises:

[0016] In the reactor, 20 g of the oxidation product of step (1), 200 mL of acetone, 200 mL of dimethyl sulfoxide, 3.3 mL of perchloric acid, and 16 g of N-bromosuccinimide were added in sequence, and then stirred and reacted at 15° C. for 1 hour. Then, 150 mL of sodium sulfite aqueous solution (concentration of 75 g / L) was added to the reaction system. After stirring for 15 minutes, sodium hydroxide aqueous solution was added to the reaction system to adjust the pH of the reaction system to 9. The temperature was then raised to 65° C., reacted for 2 hours, and then cooled to 40° C. room temperature; dilute hydrochloric acid was added to the reaction system to adjust the pH value of the reaction system to 7, two-thirds of the solvent was removed by distillation under reduced pressure, 100 ml of deionized water was added and ice bathed, and after standing for 6 hours, crystals were precipitated, filtered and the solid was dried; the dried solid was dissolved in 200 mL of chloroform, and then 180 g of methanol was added, the temperature was raised to 50 ° C, and the reaction was carried out for 2 hours to obtain a concentrate; then 50 ml of methanol was added to the reaction system, followed by an ice bath, and the crystals were allowed to stand for 2 hours, filtered, and vacuum dried to obtain a ring-contracted product.

[0017] Preferably, the step (3) comprises:

[0018] In the reactor, 60 g of dimethylformamide and HF gas were added in sequence, the tail gas was absorbed with aqueous ammonia, and the temperature was lowered to below -10°C. 20 g of the ring-condensed product of step (2) was added to the reactor, and the temperature was raised to 0°C. After standing for 12 hours, the mixture was filtered, and the filter cake was washed with water and vacuum-dried to obtain a crude product of triamcinolone acetonide acetate.

[0019] Preferably, the step (4) comprises:

[0020] In the reactor, 20 g of the crude triamcinolone acetonide acetate obtained in step (3) above and 360 mL of the recrystallization solvent were added in sequence, and then the temperature was raised to 50° C. until completely dissolved, and then immediately ice-bathed. After standing in the ice bath for 6 hours, the mixture was filtered and vacuum-dried to obtain 18.8 g of white crystals, i.e., triamcinolone acetonide acetate.

[0021] More preferably, the recrystallization solvent is a mixture of 300 mL of dimethyl sulfoxide, 30 mL of acetone, and 30 mL of methanol.

[0022] Preferably, the preparation of triamcinolone acetonide from triamcinolone acetonide acetate comprises:

[0023] In a reactor, 30 g of triamcinolone acetonide acetate obtained in step 1 above, 300 ml of 10 wt % sodium hydroxide solution and 300 ml of dimethyl sulfoxide were added in sequence, and after stirring at room temperature for 3 hours to fully hydrolyze, dilute hydrochloric acid was added dropwise to a pH of 7-7.2, and then 200 ml of methanol was added and ice bathed to precipitate a large amount of solid, which was filtered and vacuum dried to obtain triamcinolone acetonide.

[0024] The second aspect of the present application provides triamcinolone acetonide prepared by the method described in the first aspect.

[0025] The above and other features, aspects and advantages of the present application will be more readily understood with reference to the following detailed description. Specific implementation plan

[0026] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. In the event of a conflict, the definitions in this specification shall prevail.

[0027] Unless otherwise indicated, all percentages, parts, ratios, etc. are by weight.

[0028] As used herein, the terms "comprises," "includes," "has," "having," "containing," or any other variations thereof, are intended to cover a non-exclusive inclusion. For example, a composition, process, method, article, or apparatus that comprises a list of elements is not necessarily limited to only those elements but may also include other elements not expressly listed or inherent to such composition, process, method, article, or apparatus.

[0029] When providing quantity, weight portion or other numerical value or parameter with scope, preferred range or a series of upper preferred value and lower preferred value, it should be understood that it specifically discloses all ranges formed by any pair of numerical values ​​of any larger range limit or preferred value and any smaller range limit or preferred value, and no matter whether scope is disclosed respectively.For example, when describing the scope of "1 to 5", described scope should be understood as including the scope of "1 to 4", "1 to 3", "1 to 2", "1 to 2 and 4 to 5", "1 to 3 and 5" etc.Unless otherwise stated, in describing numerical range herein, described scope is intended to include range end value and all integers and fractions within the scope.

[0030] In addition, the indefinite articles "a" and "an" before the elements or components of the present disclosure are intended to indicate that the number of occurrences (i.e., occurrences) of the elements or components is not limited. Therefore, "a" or "an" should be understood to include one or at least one, and unless it is clearly indicated that the number is singular, the elements or components in the singular also include plural cases.

[0031] Unless otherwise specified, the materials, methods, and examples described herein are illustrative only and not limiting. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described herein.

[0032] The present disclosure is described in detail below.

[0033] Example

[0034] Example 1

[0035] 1. Preparation of triamcinolone acetonide acetate from tetraene acetate

[0036] (1) In a reactor, 40 g of tetraene acetate, 500 g of acetone, 500 g of dimethyl sulfoxide, and 15 g of formic acid were added in sequence. After ice-bathing for 10 minutes, 20 g of potassium permanganate was added within 1 hour (potassium permanganate was added in batches every 15 minutes, 5 g per batch), and then 250 mL of sodium sulfite aqueous solution (concentration of 75 g / L) was added. The temperature was raised to 50° C. and reacted for 30 minutes. Two-thirds of the solvent was removed by distillation under reduced pressure, and then the mixture was ice-bathed again and filtered to obtain a filter cake, which was the oxidation product.

[0037] (2) In a reactor, 20 g of the oxidation product of step (1), 200 mL of acetone, 200 mL of dimethyl sulfoxide, 3.3 mL of perchloric acid, and 16 g of N-bromosuccinimide were added in sequence, and then stirred and reacted at 15° C. for 1 hour. Then, 150 mL of sodium sulfite aqueous solution (concentration of 75 g / L) was added to the reaction system. After stirring for 15 minutes, sodium hydroxide aqueous solution was added to the reaction system to adjust the pH of the reaction system to 9, and then the temperature was raised to 65° C., reacted for 2 hours, and then cooled to room temperature; dilute hydrochloric acid was added to the reaction system to adjust the pH of the reaction system to 7, and two-thirds of the solvent was removed by distillation under reduced pressure. 100 ml of deionized water was added and ice bathed. After standing for 6 hours, crystals were precipitated, filtered, and the solid was dried. The dried solid was dissolved in 200 mL of chloroform, and then 180 g of methanol was added. The temperature was raised to 50° C. and the reaction was carried out for 2 hours to obtain a concentrate. 50 ml of methanol was then added to the reaction system, followed by an ice bath. After standing for crystallization for 2 hours, the product was filtered and vacuum dried to obtain a ring-condensed product.

[0038] (3) In the reactor, 60 g of dimethylformamide was added and HF gas was introduced, and the tail gas was absorbed with ammonia water. The temperature was lowered to below -10 ° C., 20 g of the ring-condensed product of step (2) was added to the reactor, the temperature was raised to 0 ° C., and the mixture was allowed to stand for 12 hours. After filtration, the filter cake was washed with water and vacuum-dried to obtain 17.8 g of crude triamcinolone acetonide acetate, with a yield of 91.7%;

[0039] (4) In a reactor, 20 g of the crude triamcinolone acetonide acetate obtained in step (3), 300 mL of dimethyl sulfoxide, 30 mL of acetone, and 30 mL of methanol were added in sequence, and then the temperature was raised to 50° C. until completely dissolved, and then immediately ice-bathed. After standing in the ice bath for 6 hours, the mixture was filtered and vacuum-dried to obtain 18.8 g of white crystals, i.e., triamcinolone acetonide acetate, with a yield of 94%.

[0040] 2. Preparation of Triamcinolone Acetonide from Triamcinolone Acetonide Acetate

[0041] In a reactor, 30 g of triamcinolone acetonide acetate obtained in step 1 above, 300 ml of 10 wt % sodium hydroxide solution and 300 ml of dimethyl sulfoxide were added in sequence. After stirring at room temperature for 3 hours to fully hydrolyze, dilute hydrochloric acid was added dropwise to a pH of 7-7.2. 200 ml of methanol was then added and an ice bath was added to precipitate a large amount of solid. After suction filtration and vacuum drying, triamcinolone acetonide was obtained in a yield of 92%.

[0042] Example 2

[0043] 1. Preparation of triamcinolone acetonide acetate from tetraene acetate

[0044] (1) In a reactor, 40 g of tetraene acetate, 500 g of acetone, 500 g of dimethyl sulfoxide, and 15 g of formic acid were added in sequence. After ice-bathing for 10 minutes, 20 g of potassium permanganate was added within 1 hour (potassium permanganate was added in batches every 15 minutes, 5 g per batch), and then 250 mL of sodium sulfite aqueous solution (concentration of 75 g / L) was added. The temperature was raised to 50° C. and reacted for 30 minutes. Two-thirds of the solvent was removed by distillation under reduced pressure, and then the mixture was ice-bathed again and filtered to obtain a filter cake, which was the oxidation product.

[0045] (2) In a reactor, 20 g of the oxidation product of step (1), 200 mL of acetone, 200 mL of dimethyl sulfoxide, 3.3 mL of perchloric acid, and 16 g of N-bromosuccinimide were added in sequence, and then stirred and reacted at 15° C. for 1 hour. Then, 150 mL of sodium sulfite aqueous solution (concentration of 75 g / L) was added to the reaction system. After stirring for 15 minutes, sodium hydroxide aqueous solution was added to the reaction system to adjust the pH of the reaction system to 9, and then the temperature was raised to 65° C., reacted for 2 hours, and then cooled to room temperature; dilute hydrochloric acid was added to the reaction system to adjust the pH of the reaction system to 7, and two-thirds of the solvent was removed by distillation under reduced pressure. 100 ml of deionized water was added and ice bathed. After standing for 6 hours, crystals were precipitated, filtered, and the solid was dried. The dried solid was dissolved in 200 mL of chloroform, and then 180 g of methanol was added. The temperature was raised to 50° C. and the reaction was carried out for 2 hours to obtain a concentrate. 50 ml of methanol was then added to the reaction system, followed by an ice bath. After standing for crystallization for 2 hours, the product was filtered and vacuum dried to obtain a ring-condensed product.

[0046] (3) In the reactor, 60 g of dimethylformamide was added and HF gas was introduced, and the tail gas was absorbed with ammonia water. The temperature was lowered to below -10 ° C., 20 g of the ring-condensed product of step (2) was added to the reactor, the temperature was raised to 0 ° C., and the mixture was allowed to stand for 12 hours. After filtration, the filter cake was washed with water and vacuum-dried to obtain 17.8 g of crude triamcinolone acetonide acetate, with a yield of 91.7%;

[0047] (4) In a reactor, 20 g of the crude triamcinolone acetonide acetate obtained in step (3), 300 mL of dimethyl sulfoxide, 60 mL of acetone, and 60 mL of methanol were added in sequence, and then the temperature was raised to 50° C. until completely dissolved, and then immediately ice-bathed. After standing in the ice bath for 6 hours, the mixture was filtered and vacuum-dried to obtain 17 g of white crystals, i.e., triamcinolone acetonide acetate, with a yield of 85%.

[0048] 2. Preparation of Triamcinolone Acetonide from Triamcinolone Acetonide Acetate

[0049] In a reactor, 30 g of triamcinolone acetonide acetate obtained in step 1 above, 300 ml of 10 wt % sodium hydroxide solution and 300 ml of dimethyl sulfoxide were added in sequence. After stirring at room temperature for 3 hours to fully hydrolyze, dilute hydrochloric acid was added dropwise to a pH of 7-7.2. 200 ml of methanol was then added and an ice bath was added to precipitate a large amount of solid. After suction filtration and vacuum drying, triamcinolone acetonide was obtained in a yield of 92%.

[0050] Example 3

[0051] 1. Preparation of triamcinolone acetonide acetate from tetraene acetate

[0052] (1) In a reactor, 40 g of tetraene acetate, 500 g of acetone, 500 g of dimethyl sulfoxide, and 15 g of formic acid were added in sequence. After ice-bathing for 10 minutes, 20 g of potassium permanganate was added within 1 hour (potassium permanganate was added in batches every 15 minutes, 5 g per batch), and then 250 mL of sodium sulfite aqueous solution (concentration of 75 g / L) was added. The temperature was raised to 50° C. and reacted for 30 minutes. Two-thirds of the solvent was removed by distillation under reduced pressure, and then the mixture was ice-bathed again and filtered to obtain a filter cake, which was the oxidation product.

[0053] (2) In a reactor, 20 g of the oxidation product of step (1), 200 mL of acetone, 200 mL of dimethyl sulfoxide, 3.3 mL of perchloric acid, and 16 g of N-bromosuccinimide were added in sequence, and then stirred and reacted at 15° C. for 1 hour. Then, 150 mL of sodium sulfite aqueous solution (concentration of 75 g / L) was added to the reaction system. After stirring for 15 minutes, sodium hydroxide aqueous solution was added to the reaction system to adjust the pH of the reaction system to 9, and then the temperature was raised to 65° C., reacted for 2 hours, and then cooled to room temperature; dilute hydrochloric acid was added to the reaction system to adjust the pH of the reaction system to 7, and two-thirds of the solvent was removed by distillation under reduced pressure. 100 ml of deionized water was added and ice bathed. After standing for 6 hours, crystals were precipitated, filtered, and the solid was dried. The dried solid was dissolved in 200 mL of chloroform, and then 180 g of methanol was added. The temperature was raised to 50° C. and the reaction was carried out for 2 hours to obtain a concentrate. 50 ml of methanol was then added to the reaction system, followed by an ice bath. After standing for crystallization for 2 hours, the product was filtered and vacuum dried to obtain a ring-condensed product.

[0054] (3) In the reactor, 60 g of dimethylformamide was added and HF gas was introduced, and the tail gas was absorbed with ammonia water. The temperature was lowered to below -10 ° C., 20 g of the ring-condensed product of step (2) was added to the reactor, the temperature was raised to 0 ° C., and the mixture was allowed to stand for 12 hours. After filtration, the filter cake was washed with water and vacuum-dried to obtain 17.8 g of crude triamcinolone acetonide acetate, with a yield of 91.7%;

[0055] (4) In a reactor, 20 g of the crude triamcinolone acetonide acetate obtained in step (3), 300 mL of dimethyl sulfoxide, 10 mL of acetone, and 10 mL of methanol were added in sequence, and then the temperature was raised to 50° C. until completely dissolved, and then immediately ice-bathed. After standing in the ice bath for 6 hours, the mixture was filtered and vacuum-dried to obtain 16.2 g of white crystals, i.e., triamcinolone acetonide acetate, with a yield of 81%.

[0056] 2. Preparation of Triamcinolone Acetonide from Triamcinolone Acetonide Acetate

[0057] In a reactor, 30 g of triamcinolone acetonide acetate obtained in step 1 above, 300 ml of 10 wt % sodium hydroxide solution and 300 ml of dimethyl sulfoxide were added in sequence. After stirring at room temperature for 3 hours to fully hydrolyze, dilute hydrochloric acid was added dropwise to a pH of 7-7.2. 200 ml of methanol was then added and an ice bath was added to precipitate a large amount of solid. After suction filtration and vacuum drying, triamcinolone acetonide was obtained in a yield of 92%.

[0058] Comparative Example 1

[0059] 1. Preparation of triamcinolone acetonide acetate from tetraene acetate

[0060] (1) In a reactor, 40 g of tetraene acetate, 500 g of acetone, 500 g of dimethyl sulfoxide, and 15 g of formic acid were added in sequence. After ice-bathing for 10 minutes, 20 g of potassium permanganate was added within 1 hour (potassium permanganate was added in batches every 15 minutes, 5 g per batch), and then 250 mL of sodium sulfite aqueous solution (concentration of 75 g / L) was added. The temperature was raised to 50° C. and reacted for 30 minutes. Two-thirds of the solvent was removed by distillation under reduced pressure, and then the mixture was ice-bathed again and filtered to obtain a filter cake, which was the oxidation product.

[0061] (2) In a reactor, 20 g of the oxidation product of step (1), 200 mL of acetone, 200 mL of dimethyl sulfoxide, 3.3 mL of perchloric acid, and 16 g of N-bromosuccinimide were added in sequence, and then stirred and reacted at 15° C. for 1 hour. Then, 150 mL of sodium sulfite aqueous solution (concentration of 75 g / L) was added to the reaction system. After stirring for 15 minutes, sodium hydroxide aqueous solution was added to the reaction system to adjust the pH of the reaction system to 9, and then the temperature was raised to 65° C., reacted for 2 hours, and then cooled to room temperature; dilute hydrochloric acid was added to the reaction system to adjust the pH of the reaction system to 7, and two-thirds of the solvent was removed by distillation under reduced pressure. 100 ml of deionized water was added and ice bathed. After standing for 6 hours, crystals were precipitated, filtered, and the solid was dried. The dried solid was dissolved in 200 mL of chloroform, and then 180 g of methanol was added. The temperature was raised to 50° C. and the reaction was carried out for 2 hours to obtain a concentrate. 50 ml of methanol was then added to the reaction system, followed by an ice bath. After standing for crystallization for 2 hours, the product was filtered and vacuum dried to obtain a ring-condensed product.

[0062] (3) In the reactor, 60 g of dimethylformamide was added and HF gas was introduced, and the tail gas was absorbed with ammonia water. The temperature was lowered to below -10 ° C., 20 g of the ring-condensed product of step (2) was added to the reactor, the temperature was raised to 0 ° C., and the mixture was allowed to stand for 12 hours. After filtration, the filter cake was washed with water and vacuum-dried to obtain 17.8 g of crude triamcinolone acetonide acetate, with a yield of 91.7%;

[0063] (4) In a reactor, 20 g of the crude triamcinolone acetonide acetate obtained in step (3), 300 mL of dimethyl sulfoxide, and 30 mL of acetone were added in sequence, and then the temperature was raised to 50° C. until completely dissolved, and then immediately ice-bathed. After standing in the ice bath for 6 hours, the mixture was filtered and vacuum-dried to obtain 13.2 g of white crystals, i.e., triamcinolone acetonide acetate, with a yield of 65%.

[0064] 2. Preparation of Triamcinolone Acetonide from Triamcinolone Acetonide Acetate

[0065] In a reactor, 30 g of triamcinolone acetonide acetate obtained in step 1 above, 300 ml of 10 wt % sodium hydroxide solution and 300 ml of dimethyl sulfoxide were added in sequence. After stirring at room temperature for 3 hours to fully hydrolyze, dilute hydrochloric acid was added dropwise to a pH of 7-7.2. 200 ml of methanol was then added and an ice bath was added to precipitate a large amount of solid. After suction filtration and vacuum drying, triamcinolone acetonide was obtained in a yield of 92%.

[0066] Comparative Example 2

[0067] 1. Preparation of triamcinolone acetonide acetate from tetraene acetate

[0068] (1) In a reactor, 40 g of tetraene acetate, 500 g of acetone, 500 g of dimethyl sulfoxide, and 15 g of formic acid were added in sequence. After ice-bathing for 10 minutes, 20 g of potassium permanganate was added within 1 hour (potassium permanganate was added in batches every 15 minutes, 5 g per batch), and then 250 mL of sodium sulfite aqueous solution (concentration of 75 g / L) was added. The temperature was raised to 50° C. and reacted for 30 minutes. Two-thirds of the solvent was removed by distillation under reduced pressure, and then the mixture was ice-bathed again and filtered to obtain a filter cake, which was the oxidation product.

[0069] (2) In a reactor, 20 g of the oxidation product of step (1), 200 mL of acetone, 200 mL of dimethyl sulfoxide, 3.3 mL of perchloric acid, and 16 g of N-bromosuccinimide were added in sequence, and then stirred and reacted at 15° C. for 1 hour. Then, 150 mL of sodium sulfite aqueous solution (concentration of 75 g / L) was added to the reaction system. After stirring for 15 minutes, sodium hydroxide aqueous solution was added to the reaction system to adjust the pH of the reaction system to 9, and then the temperature was raised to 65° C., reacted for 2 hours, and then cooled to room temperature; dilute hydrochloric acid was added to the reaction system to adjust the pH of the reaction system to 7, and two-thirds of the solvent was removed by distillation under reduced pressure. 100 ml of deionized water was added and ice bathed. After standing for 6 hours, crystals were precipitated, filtered, and the solid was dried. The dried solid was dissolved in 200 mL of chloroform, and then 180 g of methanol was added. The temperature was raised to 50° C. and the reaction was carried out for 2 hours to obtain a concentrate. 50 ml of methanol was then added to the reaction system, followed by an ice bath. After standing for crystallization for 2 hours, the product was filtered and vacuum dried to obtain a ring-condensed product.

[0070] (3) In the reactor, 60 g of dimethylformamide was added and HF gas was introduced, and the tail gas was absorbed with ammonia water. The temperature was lowered to below -10 ° C., 20 g of the ring-condensed product of step (2) was added to the reactor, the temperature was raised to 0 ° C., and the mixture was allowed to stand for 12 hours. After filtration, the filter cake was washed with water and vacuum-dried to obtain 17.8 g of crude triamcinolone acetonide acetate, with a yield of 91.7%;

[0071] (4) In a reactor, 20 g of the crude triamcinolone acetonide acetate obtained in step (3), 300 mL of dimethyl sulfoxide, and 30 mL of methanol were added in sequence, and then the temperature was raised to 50° C. until completely dissolved, and then immediately ice-bathed. After standing in the ice bath for 6 hours, the mixture was filtered and vacuum-dried to obtain 12.0 g of white crystals, i.e., triamcinolone acetonide acetate, with a yield of 61%.

[0072] 2. Preparation of Triamcinolone Acetonide from Triamcinolone Acetonide Acetate

[0073] In a reactor, 30 g of triamcinolone acetonide acetate obtained in step 1 above, 300 ml of 10 wt % sodium hydroxide solution and 300 ml of dimethyl sulfoxide were added in sequence. After stirring at room temperature for 3 hours to fully hydrolyze, dilute hydrochloric acid was added dropwise to a pH of 7-7.2. 200 ml of methanol was then added and an ice bath was added to precipitate a large amount of solid. After suction filtration and vacuum drying, triamcinolone acetonide was obtained in a yield of 92%.

[0074] Although specific embodiments of the present disclosure have been described above, those skilled in the art will appreciate that these are merely illustrative and that the scope of protection of the present disclosure is defined by the appended claims. Those skilled in the art may make various changes or modifications to these embodiments without departing from the principles and essence of the present disclosure, and such changes and modifications are intended to fall within the scope of protection of the present disclosure.

Claims

1. A method for preparing triamcinolone acetonide, characterized in that It includes the following steps: Preparation of triamcinolone acetonide acetate from tetraene acetate; and Preparation of triamcinolone acetonide from triamcinolone acetonide acetate; The preparation of triamcinolone acetonide acetate from tetraene acetate comprises: (1) Oxidation of tetraene acetate to oxidation products; (2) condensing the oxidation product of step (1) to form a condensed ring; (3) deriving a crude triamcinolone acetonide acetate from the ring-condensed product of step (2); (4) recrystallizing the crude triamcinolone acetonide acetate obtained in step (3) to obtain triamcinolone acetonide acetate; The recrystallization in step (4) is carried out using a recrystallization solvent, which is a mixture of 300 mL of dimethyl sulfoxide, 30 mL of acetone, and 30 mL of methanol; The preparation of triamcinolone acetonide from triamcinolone acetonide acetate comprises: In a reactor, 30g of triamcinolone acetonide acetate obtained in step 1 above, 300ml of 10 wt% sodium hydroxide solution and 300ml of dimethyl sulfoxide were added in sequence, and after stirring at room temperature for 3 hours to fully hydrolyze, dilute hydrochloric acid was added dropwise to a pH of 7-7.2, and then 200ml of methanol was added and an ice bath was added to precipitate a large amount of solid, which was filtered and vacuum-dried to obtain triamcinolone acetonide.

2. The method according to claim 1, characterized in that The step (1) comprises: In the reactor, 40 g of tetraene acetate, 500 g of acetone, 500 g of dimethyl sulfoxide and 15 g of formic acid were added in sequence. After ice bathing for 10 minutes, 20 g of potassium permanganate was added within 1 hour (potassium permanganate was added in batches every 15 minutes, 5 g per batch), and then 250 mL of sodium sulfite aqueous solution (concentration of 75 g / L) was added. After heating to 50°C and reacting for 30 minutes, two-thirds of the solvent was removed by distillation under reduced pressure. After another ice bath, the mixture was filtered to obtain a filter cake, which was the oxidation product.

3. The method according to claim 1, characterized in that The step (2) includes: In the reactor, 20g of the oxidation product of step (1), 200mL of acetone, 200mL of dimethyl sulfoxide, 3.3mL of perchloric acid, 16g of N-bromosuccinimide is then stirred and reacted at 15°C for 1 hour, and then 150 mL of sodium sulfite aqueous solution (concentration of 75 g / L) is added to the reaction system. After stirring for 15 minutes, sodium hydroxide aqueous solution is added to the reaction system to adjust the pH of the reaction system to 9, and then the temperature is raised to 65°C, reacted for 2 hours, and then cooled to room temperature; dilute hydrochloric acid is added to the reaction system to adjust the pH of the reaction system to 7, two-thirds of the solvent is removed by vacuum distillation, 100 mL of deionized water is added, and an ice bath is added. After standing for 6 hours, crystals are precipitated, filtered, and the solid is dried; the dried solid is dissolved in 200 mL of chloroform, and then 180 g of methanol is added. The temperature is raised to 50°C and the reaction is carried out for 2 hours to obtain a concentrate; then 50 mL of methanol is added to the reaction system, followed by an ice bath, and the reaction is allowed to stand for 2 hours to crystallize, filtered, and vacuum dried to obtain a ring-condensed product.

4. The method according to claim 1, wherein The step (3) includes: In the reactor, 60 g of dimethylformamide and HF gas were added in sequence, the tail gas was absorbed with ammonia water, and the temperature was lowered to below -10°C. 20 g of the condensed product of step (2) was added to the reactor, and the temperature was raised to 0°C. After standing for 12 hours, the mixture was filtered, the filter cake was washed with water and vacuum dried to obtain crude triamcinolone acetonide acetate.

5. The method according to claim 1, characterized in that The step (4) includes: In the reactor, 20 g of the crude triamcinolone acetonide acetate obtained in step (3) above and 360 mL of the recrystallization solvent were added in sequence, and then the temperature was raised to 50°C until it was completely dissolved. The mixture was immediately placed in an ice bath and allowed to stand in the ice bath for 6 hours. The mixture was then filtered and dried in vacuo to obtain 18.8 g of white crystals, namely triamcinolone acetonide acetate.