Synthesis method of bortezomib intermediate
Through the optimized multi-step reaction process and continuous design, the problems of low reaction yield, low product purity and high pollution in the bortezomi intermediate synthesis process in the prior art are solved, and efficient and low-cost intermediate synthesis is achieved.
Patent Information
- Application Number
- CN202411956230.5
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-28
- Publication Date
- 2025-04-11
AI Technical Summary
In the prior art, the synthesis process of bortezomib intermediate has problems such as low reaction yield, low product purity and high pollution during the process, resulting in higher costs.
An optimized synthesis process route is adopted, including a multi-step reaction process, by controlling the temperature, dropping sequence and using appropriate solvents and catalysts, the bortezomib intermediate is gradually synthesized and a continuous design is adopted in the process to reduce contamination.
The reaction yield and product purity are improved, the pollution in the process is reduced, the production cost is reduced, and the synthesis of bortezomib intermediates is achieved.
Smart Images
Figure CN119798290A_ABST
Abstract
Description
Technical Field
[0001] The invention relates to the technical field of raw material drug synthesis and intermediate synthesis, and in particular to a method for synthesizing a bortezomib intermediate. Background Art
[0002] Bortezomib is a drug for treating hematopoietic malignancies. It is a white or off-white crystalline powder. It is easily soluble in dimethyl sulfoxide and ethanol, but difficult to dissolve in aqueous solution. It is a reversible inhibitor of chymotrypsin-like activity of 26S proteasome in mammalian cells. 26S proteasome is a large protein complex that can degrade ubiquitin. The pan-proteasome channel plays an important role in regulating the intracellular concentration of specific proteins to maintain the stability of the intracellular environment. Proteolysis affects the multi-level signal cascade in cells. This damage to the normal intracellular environment can lead to cell death. Inhibition of 26S proteasome can prevent the hydrolysis of specific proteins. In vitro experiments have shown that bortezomib is cytotoxic to various types of cancer cells. In vivo experiments in preclinical tumor models have shown that bortezomib can delay the growth of tumors including multiple myeloma, and is suitable for the treatment of multiple myeloma patients. Summary of the invention
[0003] The object of the present invention is to provide a method for synthesizing a bortezomib intermediate in view of the above-mentioned problems.
[0004] The present invention provides a method for synthesizing a bortezomib intermediate, comprising the following steps:
[0005] 1) (1S, 2S, 3R, 5S)-(+)-2,3-pinanediol, methyl tert-butyl ether and a water absorbent are added to the reaction system, the temperature is controlled at 0-10° C., and an isobutyl boric acid methyl tert-butyl ether solution is added dropwise until the raw materials react completely, and the intermediate product 1 is obtained after washing, drying and concentration. The intermediate product 1 has the following structural formula:
[0006]
[0007] 2) Compound 1, toluene and dichloromethane are added to the reaction system, replaced with nitrogen, the reaction system is cooled to ≤-80°C, n-butyl lithium reagent is added dropwise, after the addition is completed, the temperature is kept at ≤-80°C for 1h, zinc chloride complex solution is added dropwise, after the addition is completed, the temperature is stirred at ≤-80°C for 1h, and then the temperature is naturally returned to 10°C, quenched, filtered, washed, concentrated, pulped, washed, and dried to obtain intermediate product 2, wherein the intermediate product 2 has the following structure:
[0008]
[0009] 3) Add intermediate product 2, N,N-dimethylformamide and dichloromethane to the reaction system, stir, add potassium carbonate and potassium phthalimide, stir, heat to 60-65°C, control the temperature at 60-65°C, stir for 1.5h, until the raw materials react, concentrate, wash, dry, and concentrate to obtain intermediate product 3, which has the following structure:
[0010]
[0011] 4) Add the intermediate product 3 and anhydrous ethanol to the reaction system, stir, add 85% hydrazine hydrate, stir, control the temperature at 25±2°C, stir and react for 2h until the raw materials react, filter, concentrate, filter, pulp, filter, and concentrate to obtain the intermediate product 4, which has the following structure:
[0012]
[0013] 5) Add the intermediate product 4 and isopropyl ether to the reaction system, control the internal temperature at 20-30°C, stir for 1 h, control the internal temperature at -10--5°C, add a solution of trifluoroacetic acid in isopropyl ether dropwise, control the temperature at -10--5°C and stir for 2 h, filter, and dry to obtain the target product, bortezomib intermediate.
[0014] In some embodiments, the water absorbing agent is one of anhydrous magnesium sulfate or anhydrous sodium sulfate.
[0015] In some embodiments, the hydrogen withdrawal reagent is one of n-butyllithium reagent and LDA reagent.
[0016] In some embodiments, the protective agent is potassium phthalimide.
[0017] Compared with the prior art, the beneficial effects of the present invention are:
[0018] The invention provides an optimized process route for synthesizing a bortezomib intermediate, which greatly improves the reaction yield and product purity, and adopts a continuous design in the process, thereby reducing pollution, improving the yield and reducing the cost. BRIEF DESCRIPTION OF THE DRAWINGS
[0019] Figure 1 The present invention provides a synthetic purification route for the synthetic method of the bortezomib intermediate.
[0020] Figure 2 1 is a liquid chromatogram of the bortezomib intermediate of an embodiment of the present invention. DETAILED DESCRIPTION
[0021] The present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and are not intended to limit the scope of the present invention. In addition, it should be understood that after reading the content taught by the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms fall within the scope limited by the appended claims of the application equally.
[0022] Embodiment 1, as Figure 1 As shown:
[0023] 1) Add 18.9g of methyl tert-butyl ether to a four-necked glass bottle, start stirring, then add 10g of (1S, 2S, 3R, 5S)-(+)-2,3-pinanediol to the four-necked glass bottle, stir until the system in the bottle is dissolved, then add 14.1g of anhydrous magnesium sulfate to the four-necked glass bottle. Add 23.1g of methyl tert-butyl ether to a single-necked glass bottle, start stirring, then add 6.5g of isobutyl boronic acid to the single-necked glass bottle, stir until the system in the bottle is dissolved and set aside. Add isobutyl boronic acid solution dropwise at a temperature of 0-10℃, keep warm for 1h after dropping, filter, wash the filtrate twice with 25g of 5% sodium carbonate solution, then wash three times with 12.5g of purified water, and concentrate to obtain intermediate product 1.
[0024] 2) 10 g of intermediate product 1, 19.2 g of dichloromethane and 69.2 g of toluene were added to a three-necked flask in sequence, stirring was started and the temperature was lowered to ≤-80°C, 25 ml of n-butyl lithium solution was slowly added dropwise, and the temperature was kept at ≤-80°C. Zinc chloride tetrahydrofuran complex solution was added dropwise, and the temperature was kept at ≤-80°C. After the addition was completed, the temperature was kept at 1 h, and then the temperature was naturally returned to 10°C. The mixture was quenched and filtered with 100 ml of 5% ammonium chloride solution, the aqueous phase was separated and discarded, the organic phase was washed 3 times with 50 g of purified water, and then concentrated until no droplets were generated, 60 g of methyl tert-butyl ether and 45 g of water were added, the aqueous phase was separated and discarded, and the organic phase was washed with 45 g of 10% sodium chloride solution, and the organic phase was washed twice with 50 g of purified water. The organic phase was dried with 8.8 g of anhydrous sodium sulfate for 2 h, filtered and concentrated to obtain intermediate product 2.
[0025] 3) Add 10 g of intermediate product 2 and 23.6 g of N,N-dimethylformamide to a four-necked glass bottle, start stirring, then add 0.1 g of potassium carbonate and 7.16 g of potassium phthalimide, raise the temperature to 60-65°C, control the temperature at 60-65°C, stir for 1.5 hours, and then concentrate under reduced pressure until no droplets are generated, then add 54 g of ethyl acetate and 200 g of purified water, stir and separate the liquids, wash the organic phase with saturated sodium chloride solution, dry it with 15 g of anhydrous sodium sulfate for 1 hour, filter, concentrate the filtrate until no droplets are generated, add 30 g of n-heptane for slurrying for 1 hour, filter and concentrate to obtain intermediate product 3.
[0026] 4) Add 10 g of intermediate product 3 and 160 g of anhydrous ethanol to a four-necked glass bottle, stir to dissolve, then add 3.3 g of 85% hydrazine hydrate, control the temperature at 25±2°C, stir to react for 2 h, filter and concentrate, filter and concentrate the precipitated solid, slurry with isopropanol, filter, and concentrate until there is no droplet to obtain intermediate product 4.
[0027] 5) Add 10g of intermediate product 4 and 133g of isopropyl ether to a four-necked glass bottle, control the internal temperature at 20-30°C, and stir for 1h. Add 6.5g of trifluoroacetic acid to a single-necked glass bottle, then add 15g of isopropyl ether, start stirring, control the internal temperature at -10--5°C, dropwise add the isopropyl ether solution of trifluoroacetic acid, control the temperature at -10--5°C, stir for 2h, filter and dry to obtain the target product, bortezomib intermediate, such as Figure 2 As shown, based on (1S,2S,3R,5S)-(+)-2,3-pinanediol, the product yield was 70%.
[0028] The embodiment of the present invention provides an optimized process route for synthesizing a bortezomib intermediate, which greatly improves the reaction yield and product purity, and adopts a continuous design in the process, thereby reducing pollution, improving the yield and reducing the cost.
[0029] Finally, it should be noted that: technicians in this industry should understand that the present invention is not limited to the above-mentioned implementation cases. The above-mentioned embodiments and descriptions are only for explaining the principles of the present invention. Without departing from the spirit and scope of the present invention, the present invention may have various changes and improvements, which shall fall within the scope of the present invention to be protected. The scope of protection of the present invention is defined by the attached claims and their equivalents.
Claims
1. A method for synthesizing a bortezomib intermediate, characterized in that: The following steps are involved: 1) (1S, 2S, 3R, 5S)-(+)-2,3-pinanediol, methyl tert-butyl ether and a water absorbent are added to the reaction system, the temperature is controlled at 0-10° C., and an isobutyl boric acid methyl tert-butyl ether solution is added dropwise until the raw materials react completely, and the intermediate product 1 is obtained after washing, drying and concentration. The intermediate product 1 has the following structural formula: 2) Compound 1, toluene and dichloromethane are added to the reaction system, replaced with nitrogen, the reaction system is cooled to ≤-80°C, n-butyl lithium reagent is added dropwise, after the addition is completed, the temperature is kept at ≤-80°C for 1h, zinc chloride complex solution is added dropwise, after the addition is completed, the temperature is stirred at ≤-80°C for 1h, and then the temperature is naturally returned to 10°C, quenched, filtered, washed, concentrated, pulped, washed, and dried to obtain intermediate product 2, wherein the intermediate product 2 has the following structure: 3) Add intermediate product 2, N,N-dimethylformamide and dichloromethane to the reaction system, stir, add potassium carbonate and potassium phthalimide, stir, heat to 60-65°C, control the temperature at 60-65°C, stir for 1.5h, until the raw materials react, concentrate, wash, dry, and concentrate to obtain intermediate product 3, which has the following structure: 4) Add the intermediate product 3 and anhydrous ethanol to the reaction system, stir, add 85% hydrazine hydrate, stir, control the temperature at 25±2°C, stir and react for 2h until the raw materials react, filter, concentrate, filter, pulp, filter, and concentrate to obtain the intermediate product 4, which has the following structure: 5) Add the intermediate product 4 and isopropyl ether to the reaction system, control the internal temperature at 20-30°C, stir for 1 h, control the internal temperature at -10--5°C, add a solution of trifluoroacetic acid in isopropyl ether dropwise, control the temperature at -10--5°C and stir for 2 h, filter, and dry to obtain the target product, bortezomib intermediate.
2. The synthesis method according to claim 1, characterized in that The water absorbing agent is one of anhydrous magnesium sulfate or anhydrous sodium sulfate.
3. The synthesis method according to claim 1, characterized in that The hydrogen extraction reagent is a n-butyl lithium reagent, one of the LDA reagents.
4. The synthesis method according to claim 1, characterized in that The protective agent is potassium phthalimide.