Preparation method of high-purity triamcinolone acetonide acetate

Abstract

The invention discloses a preparation method of high-purity triamcinolone acetonide acetate, which comprises the following steps: acetylating triamcinolone acetonide serving as a raw material, crystallizing and pulping to obtain the triamcinolone acetonide acetate. According to the method, triamcinolone acetonide acetate can be obtained at a relatively high yield by replacing alkali, temperature and a crystallization solvent, the purity of triamcinolone acetonide acetate is obviously improved, meanwhile, the solution is stable, the cost is reduced, a high-risk solvent is avoided, and the method is environment-friendly.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical chemistry synthesis, and particularly relates to a preparation method of high-purity triamcinolone acetonide. BACKGROUND

[0002] Triamcinolone acetonide is an important corticosteroid drug, has anti-inflammatory, anti-allergic and immunosuppressive effects, and is widely used in the treatment of skin diseases, arthritis and the like. Its chemical name is: 16α, 17-[(1-methylethylidene) bis (oxy)]-11β, 21-dihydroxy-9-fluoropregna-1, 4-diene-3, 20-dione-21-acetate. The molecular formula is C 26 H 33 FO7, the molecular weight is 476.54, and the chemical structure is as follows:

[0003]

[0004] Triamcinolone acetonide is a long-acting glucocorticoid, mainly used for anti-inflammatory, anti-allergic and immunosuppression, commonly used in local injection or external preparation (such as cream, spray), for treating arthritis, skin diseases and the like. At present, the synthesis method of triamcinolone acetonide has problems of complex reaction condition, low yield and low product purity. Therefore, it is of great significance to develop an efficient, economical and suitable for industrial production preparation method.

[0005] At present, there are many synthesis methods of triamcinolone acetonide. Chinese patent CN 101735237 B discloses a synthesis method of triamcinolone acetonide, which removes by-products by using crystallization-re-crystallization technology, but the process still has the problems of complexity and high cost. Chinese patent application CN 103319451 A also proposes a synthesis method of triamcinolone acetonide, which improves the ketalization reaction and reduces the use of toxic reagents. However, the overall process involves multiple steps, increasing the operation difficulty and equipment requirements.

[0006] The problems of complex process, high cost and low yield in the production process of triamcinolone acetonide have not been solved, so it is urgent to develop a method which is easy to operate and can obtain triamcinolone acetonide with high yield. SUMMARY

[0007] To solve the above technical problems, the purpose of the present application is to provide a preparation method of triamcinolone acetonide, which can effectively reduce the operation difficulty and production cost, and improve the production efficiency.

[0008] The technical scheme adopted by the present application to solve the technical problems is:

[0009] A preparation method of triamcinolone acetonide, comprising the following steps:

[0010] (1) taking triamcinolone as a starting material, dissolving the triamcinolone in tetrahydrofuran, adding acetic anhydride, an organic base and 4-dimethylaminopyridine (DMAP) and then performing reaction by incubation and stirring, wherein the molar ratio of triamcinolone, tetrahydrofuran, acetic anhydride, the organic base and 4-dimethylaminopyridine is 1:(100-110):1:1:(0.05-0.3);

[0011] (2) adding purified water to perform crystallization, filtering and drying;

[0012] (3) adding an organic solvent to the filtered filter cake, then performing crystallization by incubation and stirring, and then performing centrifugation and drying to obtain triamcinolone acetonide.

[0013] Preferably, the molar ratio of triamcinolone, tetrahydrofuran, acetic anhydride, the organic base and 4-dimethylaminopyridine in step (1) is 1:108:1:1:0.2.

[0014] Preferably, the reaction temperature in step (1) is 35-45℃, and the stirring reaction is performed for 4-6 hours.

[0015] Preferably, the organic base in step (1) includes pyridine, triethylamine and bicyclo amidine (DBU); and preferably, the organic base is triethylamine.

[0016] Preferably, the stirring crystallization in step (2) is performed for 2-3 hours, and the filtering material is one of polypropylene, titanium microporous membrane and non-woven filter cloth; and preferably, the filtering material is non-woven filter cloth.

[0017] Preferably, the organic solvent in step (3) includes methanol, acetone, methyl tert-butyl ether, dichloromethane and chloroform; and preferably, the organic solvent is acetone.

[0018] Preferably, in step (3), the incubation and stirring are performed at 50-55℃ for 5-6 hours, and then the temperature is reduced to -20-0℃ for stirring crystallization; and preferably, the temperature is reduced to -10℃.

[0019] Preferably, the centrifugation speed in step (3) is 800-1800 revolutions per minute, and preferably, the centrifugation speed is 1500-1800 revolutions per minute.

[0020] Preferably, the purity of the prepared triamcinolone acetonide is greater than 98%, and preferably, the purity is greater than 99.4%.

[0021] Compared with the prior art, the present application has the following beneficial effects:

[0022] The present application has the advantages of high production efficiency, simple and controllable process, and is suitable for industrialized production of triamcinolone acetonide. The present application can effectively improve the purity of triamcinolone acetonide, reduce the use of high-risk solvents and reduce production cost. DETAILED DESCRIPTION

[0023] The technical solutions in the embodiments of the present application will be clearly and completely described below. Obviously, the described embodiments are only a part of the embodiments of the present application, but not all the embodiments. Based on the embodiments in the present application, all the other embodiments obtained by a person of ordinary skill in the art without creative effort belong to the protection scope of the present application.

[0024] Embodiment 1

[0025] The embodiment provides a preparation method of triamcinolone acetonide, which comprises the following steps: 0.23 mol of triamcinolone acetonide, 2000 mL of tetrahydrofuran, 0.23 mol of acetic anhydride, 0.23 mol of triethylamine and 0.046 mol of DMAP are added into a flask, the temperature is increased to 40 DEG C, and the mixture is stirred for 4 hours, and then wet products are obtained through filtration. The wet products are placed into a blast drying oven, and the mixture is dried at 60 DEG C for 12 hours. The dry products and 8V of acetone are added into the flask, the temperature is increased to 50 DEG C, and the mixture is stirred for 5 hours. The temperature is decreased to -10 DEG C, the mixture is stirred to crystallize, the centrifugal speed is 1800 r / min, and triamcinolone acetonide 75.3 g is obtained through drying.

[0026] The fine products are detected by using the HPLC method, the purity of the product is 99.339%, the residual raw material is 0.291%, and the maximum single impurity is 0.280%.

[0027] Embodiment 2

[0028] The embodiment provides a preparation method of triamcinolone acetonide, which comprises the following steps: 0.23 mol of triamcinolone acetonide, 2000 mL of tetrahydrofuran, 0.23 mol of acetic anhydride, 0.23 mol of triethylamine and 0.046 mol of DMAP are added into a flask, the temperature is increased to 40 DEG C, and the mixture is stirred for 4 hours, and then wet products are obtained through filtration. The wet products are placed into a blast drying oven, and the mixture is dried at 60 DEG C for 12 hours. The dry products and 8V of acetone are added into the flask, the temperature is increased to 50 DEG C, and the mixture is stirred for 5 hours. The temperature is decreased to -10 DEG C, the mixture is stirred to crystallize, the centrifugal speed is 1800 r / min, and triamcinolone acetonide 75.3 g is obtained through drying.

[0029] The fine products are detected by using the HPLC method, the purity of the product is 98.130%, the residual raw material is 0.994%, and the maximum single impurity is 0.876%.

[0030] Embodiment 3

[0031] The embodiment provides a preparation method of triamcinolone acetonide, which comprises the following steps: 0.1 mol of triamcinolone acetonide, 872 mL of tetrahydrofuran, 0.1 mol of acetic anhydride, 0.1 mol of triethylamine and 0.02 mol of DMAP are added into a flask, the temperature is increased to 42 DEG C, and the mixture is stirred for 4 hours, and then wet products are obtained through filtration. The wet products are placed into a blast drying oven, and the temperature is increased to 60 DEG C, and the mixture is baked for 12 hours. The dry products and 8V of acetone are added into the flask, the temperature is increased to 50 DEG C, and the mixture is stirred for 5 hours. The temperature is decreased to -10 DEG C, the mixture is stirred to crystallize, the centrifugal speed is 1800 r / min, and triamcinolone acetonide 28.8 g is obtained through baking and drying.

[0032] The fine products are detected by using the HPLC method, the purity of the product is 99.194%, the raw material is 0.314%, and the maximum single impurity is 0.475%.

[0033] Example 4

[0034] The embodiment provides a preparation method of triamcinolone acetonide, which comprises the following steps: 0.1 mol of triamcinolone acetonide, 872 mL of tetrahydrofuran, 0.1 mol of acetic anhydride, 0.1 mol of triethylamine and 0.02 mol of DMAP are added into a flask, the temperature is increased to 42 DEG C, and the mixture is stirred for 4 hours, and then wet products are obtained through filtration. The wet products are placed into a blast drying oven, and the temperature is increased to 60 DEG C, and the mixture is baked for 12 hours. The dry products and 8V of acetone are added into the flask, the temperature is increased to 50 DEG C, and the mixture is stirred for 5 hours. The temperature is decreased to -10 DEG C, the mixture is stirred to crystallize, the centrifugal speed is 1800 r / min, and triamcinolone acetonide 28.8 g is obtained through baking and drying.

[0035] The fine products are detected by using the HPLC method, the purity of the product is 99.194%, the raw material is 0.314%, and the maximum single impurity is 0.475%.

[0036] Example 5

[0037] The embodiment provides a preparation method of triamcinolone acetonide, which comprises the following steps: 0.1 mol of triamcinolone acetonide, 872 mL of tetrahydrofuran, 0.1 mol of acetic anhydride, 0.1 mol of triethylamine and 0.02 mol of DMAP are added into a flask, the temperature is increased to 42 DEG C, and the mixture is stirred for 4 hours, and then wet products are obtained through filtration. The wet products are placed into a blast drying oven, and the temperature is increased to 60 DEG C, and the mixture is baked for 12 hours. The dry products and 8V of acetone are added into the flask, the temperature is increased to 50 DEG C, and the mixture is stirred for 5 hours. The temperature is decreased to -10 DEG C, the mixture is stirred to crystallize, the centrifugal speed is 1800 r / min, and triamcinolone acetonide 28.8 g is obtained through baking and drying.

[0038] The fine products are detected by using the HPLC method, the purity of the product is 99.194%, the raw material is 0.314%, and the maximum single impurity is 0.475%.

[0039] Example 6

[0040] The embodiment provides a preparation method of triamcinolone acetonide, which comprises the following steps: 0.1 mol of triamcinolone acetonide, 872 mL of tetrahydrofuran, 0.1 mol of acetic anhydride, 0.1 mol of triethylamine and 0.02 mol of DMAP are added into a flask, the temperature is increased to 39 DEG C, and the mixture is stirred for 4 hours, and then wet products are obtained through filtration. The wet products are placed into a blast drying oven, and the mixture is baked at 60 DEG C for 12 hours. The dry products and 8V of dichloromethane are added into a flask, the temperature is increased to 50 DEG C, and the mixture is stirred for 5 hours. The temperature is decreased to -10 DEG C, the mixture is stirred to crystallize, the centrifugal speed is 1800 r / min, and triamcinolone acetonide 27.3 g is obtained through drying.

[0041] The fine products are detected by using the HPLC method, the purity of the product is 98.976%, the raw material is 0.681%, and the maximum single impurity is 0.343%.

[0042] Example 7

[0043] The embodiment provides a preparation method of triamcinolone acetonide, which comprises the following steps: 0.1 mol of triamcinolone acetonide, 872 mL of tetrahydrofuran, 0.1 mol of acetic anhydride, 0.1 mol of triethylamine and 0.02 mol of DMAP are added into a flask, the temperature is increased to 39 DEG C, and the mixture is stirred for 4 hours, and then wet products are obtained through filtration. The wet products are placed into a blast drying oven, and the mixture is baked at 60 DEG C for 12 hours. The dry products and 8V of dichloromethane are added into a flask, the temperature is increased to 50 DEG C, and the mixture is stirred for 5 hours. The temperature is decreased to -10 DEG C, the mixture is stirred to crystallize, the centrifugal speed is 1800 r / min, and triamcinolone acetonide 27.3 g is obtained through drying.

[0044] The fine products are detected by using the HPLC method, the purity of the product is 98.976%, the raw material is 0.681%, and the maximum single impurity is 0.343%.

[0045] It can be known from the above embodiment that, compared with the existing synthesis method, the purity of the product prepared by using the method described in the embodiment can reach more than 99.4% and the product has good stability. The triamcinolone acetonide prepared by the method has the advantages of simple process, low cost and high yield, and has a good application prospect.

[0046] The above embodiment only expresses the embodiment of the present application, and the description is relatively specific and detailed, but it cannot be understood as the limitation of the patent scope of the present application. It should be pointed out that, for ordinary skilled persons in the art, some modifications and improvements can be made without departing from the concept of the present application, and these all belong to the protection scope of the present application. Therefore, the protection scope of the patent of the present application should be subject to the appended claims.

Claims

1. A method for preparing triamcinolone acetonide, characterized in that, Includes the following steps: (1) Using triamcinolone acetonide as the starting material, triamcinolone acetonide was dissolved in tetrahydrofuran, and acetic anhydride, organic base and 4-dimethylaminopyridine (DMAP) were added and the mixture was stirred under heat to carry out the reaction. The molar ratio of triamcinolone acetonide, tetrahydrofuran, acetic anhydride, organic base and 4-dimethylaminopyridine was 1:(100~110):1:1:(0.05~0.3). (2) Add purified water to crystallize, filter, and dry; (3) Add organic solvent to the filtered cake, keep it warm and stir, then cool it down and stir to precipitate crystals. After centrifugation and drying, it is then mixed with triamcinolone acetonide.

2. The method for preparing triamcinolone acetonide according to claim 1, characterized in that, In step (1), the molar ratio of triamcinolone acetonide, tetrahydrofuran, acetic anhydride, organic base and DMAP is 1:108:1:1:0.

2.

3. The method for preparing triamcinolone acetonide according to claim 1, characterized in that, In step (1), the reaction temperature is 35-45℃, and the reaction is stirred for 4-6 hours.

4. The method for preparing triamcinolone acetonide according to claim 1, characterized in that, In step (1), the organic base includes pyridine, triethylamine and bicyclic amidine (DBU); preferably triethylamine.

5. The method for preparing triamcinolone acetonide according to claim 1, characterized in that, In step (2), the mixture is stirred and crystallized for 2-3 hours. The filter material is one of polypropylene, titanium microporous membrane, or non-woven filter cloth; non-woven filter cloth is preferred.

6. The method for preparing triamcinolone acetonide according to claim 1, characterized in that, In step (3), the organic solvent includes methanol, acetone, methyl ether, dichloromethane and chloroform; preferably acetone.

7. The method for preparing triamcinolone acetonide according to claim 1, characterized in that, In step (3), the temperature is kept at 50-55℃ and stirred for 5-6 hours, and then the temperature is lowered to -20-0℃ for stirring and crystallization; preferably, the temperature is lowered to -10℃.

8. The method for preparing triamcinolone acetonide according to claim 1, characterized in that, In step (3), the centrifugal speed is 800-1800 rpm, preferably 1500-1800 rpm.

9. The method for preparing triamcinolone acetonide according to claim 1, characterized in that, The purity of the prepared triamcinolone acetonide is greater than 98%, preferably greater than 99.4%.

Images