Method for preparing miindoprine by adopting phase transfer catalysis method
By using phase transfer catalysis, tetrabutylammonium bromide catalyst, and a specific solvent system, and controlling the reaction conditions, the problems of low yield and low purity in the synthesis of midostaurin were solved, and efficient and high-purity midostaurin preparation was achieved.
Patent Information
- Application Number
- CN202511575688.0
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-10-31
- Publication Date
- 2026-01-23
AI Technical Summary
Existing methods for synthesizing midostaurin suffer from problems such as low yield, numerous byproducts, and complex purification, making it difficult to achieve efficient preparation.
The phase transfer catalysis method was adopted, using tetrabutylammonium bromide as the phase transfer catalyst. The temperature and pH were controlled, and the reaction was carried out in a mixed solvent of ethyl acetate and dichloromethane. The post-treatment included extraction and low-temperature recrystallization.
High yield and high purity of midostaurin were achieved, making it suitable for large-scale production.
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Abstract
Description
TECHNICAL FIELD
[0001] The application relates to a method for preparing midostaurin by using a phase transfer catalysis method, and belongs to the technical field of drug synthesis. BACKGROUND
[0002] Midostaurin, a semi-synthetic modified product of staurosporine, is a multi-target kinase inhibitor of Flt3, and is used for treating acute myeloid leukemia. There are three existing synthesis methods, the first method is to directly add benzoyl chloride for reaction by taking chloroform or N, N-dimethylformamide as a solvent, N, N-diisopropyl ethylamine as an alkali, but the reaction yield is not high, and acetylated staurosporine is easily generated as a byproduct, and subsequent purification is relatively complex; the second method is to react staurosporine and benzoic anhydride in a mixed solvent system composed of ethanol and water at high temperature, and it is difficult for staurosporine to be completely converted in the system; and the third method is to condense staurosporine and benzoic acid by using O-benzotriazole-tetramethyl urea hexafluorophosphate (HBTU), and the same problems of low yield and expensive reagent exist. Therefore, the method for preparing midostaurin needs to be further optimized. SUMMARY
[0003] The application aims to provide a method for preparing midostaurin by using a phase transfer catalysis method, and the method has the advantages of high yield, high purity and easy scale-up production.
[0004] The technical scheme of the application is as follows:
[0005] A method for preparing midostaurin by using a phase transfer catalysis method, the method comprises the following steps:
[0006] Staurosporine, an organic solvent, ammonia water and a phase transfer catalyst are added into a reaction container, benzoyl chloride is added dropwise under temperature control, ammonia water is added dropwise to control pH, and after the reaction is completed, midostaurin is obtained through extraction, concentration and recrystallization.
[0007] The molar ratio of the staurosporine to the benzoyl chloride is 1:1.0-1.5.
[0008] The organic solvent is a mixed solvent of ethyl acetate and dichloromethane, and the volume ratio is 1:1.0-2.0.
[0009] The phase transfer catalyst is tetrabutylammonium bromide, and the amount is 0.5-1.0 times that of the staurosporine.
[0010] The reaction temperature is 0-5 DEG C.
[0011] The pH range is 6.5-7.5.
[0012] The reaction time is 10-60 minutes.
[0013] The post-treatment and recrystallization method is as follows: after the reaction, the reaction mixture is concentrated, extracted, and crystallized at low temperature with an organic solvent to obtain high-purity midostaurin.
[0014] The reaction formula is as follows:
[0015] BRIEF DESCRIPTION OF DRAWINGS
[0017] Figure 1 HPLC spectrum of midostaurin. 1 H-NMR spectrum.
[0018] Figure 2 HPLC spectrum of midostaurin. DETAILED DESCRIPTION
[0019] The present application will be further described below through specific examples, but the scope of protection of the present application is not limited to this.
[0020] Example 1:
[0021] 106 g of streptomycin (purity greater than 98%) was placed in a mixed solvent of ethyl acetate: dichloromethane = 75 mL: 150 mL, 60 mL (0.65 eq) of 9% ammonia water solution was added until the system was clear, and 73.3 g (1 equivalent) of tetrabutylammonium bromide was added as a phase transfer catalyst. 32 mL (1.2 equivalents) of benzoyl chloride was added at 0°C, and the pH value of the reaction system was adjusted to 7.0 by adding ammonia water. After 10 minutes of reaction, the solvent was removed by reduced pressure distillation, and the concentrate was dissolved in 500 mL of dichloromethane and washed with water 6 times, each time with 500 mL. After re-concentration, it was dissolved in ethyl acetate: dichloromethane = 500 mL: 1500 mL. Then the solution was slowly cooled to -20°C, and in this process, crystallization gradually occurred. After drying the crystals, 102 g of midostaurin was obtained, and the product was detected by HPLC to have a purity of 99.9% and a yield of 87%.
[0022] Example 2:
[0023] 106 grams of streptimidazole (purity >98%) was dissolved in ethyl acetate: dichloromethane = 150 mL: 150 mL mixed solvent, 9% ammonia solution 60 mL (0.65 eq) was added until the system was clear, and 36.6g of tetrabutylammonium bromide (0.5 eq) was added as a phase transfer catalyst. 26.6 mL of benzoyl chloride (1 eq) was added at 5°C, and the pH of the reaction system was adjusted to 6.5 by adding ammonia water. After 20 minutes of reaction, the solvent was removed by reduced pressure distillation, and the concentrate was dissolved in 500 mL of dichloromethane and washed with water 6 times, each time with 500 mL. After re-concentration, it was dissolved in ethyl acetate: dichloromethane = 500 mL: 1500 mL. Then the solution was slowly cooled to -20°C, and during this process, the crystals gradually precipitated. After drying the crystals, 97 grams of midostaurin was obtained, with a purity of 98.6% detected by HPLC, and a yield of 83%.
[0024] Example 3:
[0025] 106 grams of streptimidazole (purity >98%) was dissolved in ethyl acetate: dichloromethane = 100 mL: 150 mL mixed solvent, 9% ammonia solution 60 mL (0.65 eq) was added until the system was clear, and 58.6g of tetrabutylammonium bromide (0.8 eq) was added as a phase transfer catalyst. 39.9 mL of benzoyl chloride (1.5 eq) was added at 0°C, and the pH of the reaction system was adjusted to 7.5 by adding ammonia water. After 60 minutes of reaction, the solvent was removed by reduced pressure distillation, and the concentrate was dissolved in 500 mL of dichloromethane and washed with water 6 times, each time with 500 mL. After re-concentration, it was dissolved in ethyl acetate: dichloromethane = 500 mL: 1500 mL. Then the solution was slowly cooled to -20°C, and during this process, the crystals gradually precipitated. After drying the crystals, 91 grams of midostaurin was obtained, with a purity of 96.8% detected by HPLC, and a yield of 77%.
[0026] The structure characterization and purity detection results of midostaurin are as follows Figure 1 and Figure 2 :
[0027] 1 H NMR (600 MHz, DMSO- d 6) delta 9.32 (d, J= 7.5 Hz, 1H, ArH), 8.64 (s,1H, NH), 8.04-8.08 (m, 2H, ArH), 7.30-7.68 (m, 10H, ArH),7.10 / 6.85 (brs, 1H),5.03 (m, 2H), 5.11 / 4.51 / 4.34 / 4.20 (m, 2H), 2.73-2.89 (m, 6H), 2.33-2.47 (m,4H), 1.92-1.99 (m, 1H).
[0028] While the application has been described with reference to numerous exemplary embodiments, it will be understood that various other modifications can be made within the scope of the application as disclosed herein.
Claims
1. A method of synthesizing midostaurin, characterized by, The process comprises the following steps: Streptolydigin, organic solvent, ammonia and phase transfer catalyst are added into a reaction vessel, benzoyl chloride is added dropwise under temperature control, ammonia is added dropwise to control pH, after the reaction is completed, extraction, concentration and recrystallization are carried out to obtain midostaurin.
2. The method of claim 1, wherein, The molar ratio of streptolydigin to benzoyl chloride is 1:1.0-1.
5.
3. The method of claim 1, wherein, The organic solvent is a mixed solvent of ethyl acetate and dichloromethane, and the volume ratio is 1:1.0-2.
0.
4. The method of claim 1, wherein, The phase transfer catalyst is tetrabutylammonium bromide, and the amount is 0.5-1.0 times that of streptolydigin.
5. The method of claim 1, wherein, The reaction temperature is 0-5℃.
6. The method of claim 1, wherein, The pH range is 6.5-7.
5.
7. The method of claim 1, wherein, The reaction time is 10-60 minutes.
8. The method of claim 1, wherein, The recrystallization solvent is a mixed solvent of ethyl acetate and dichloromethane, and the volume ratio is 1:1.0-3.0.