Preparation method for continuously synthesizing empagliflozin intermediate by using microchannel reactor
By using microchannel reactors for continuous synthesis in empagliflozin production, the problems of slow heat transfer and difficulty in temperature regulation in traditional kettle-type stirred reactors are solved, and efficient and safe preparation of empagliflozin intermediates are achieved. , significantly improve product yield and purity.
Patent Information
- Application Number
- CN202411324869.1
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-09-23
- Publication Date
- 2025-01-03
AI Technical Summary
In the production of empagliflozin, traditional kettle stirring reactors have problems such as slow heat transfer, difficulty in temperature regulation, and frequent by-product generation, resulting in low production efficiency and safety hazards.
The microchannel reactor is used to continuously synthesize the empagliflozin intermediate. By controlling and reacting in the coil reactor and microchannel reactor, reacting with a high-pressure constant flow infusion pump and catalyst to ensure the constant reaction temperature. Reduce by-product generation.
It significantly improves mass transfer and heat transfer efficiency, shortens reaction time, enhances production safety and product quality, reduces by-product generation, and improves reaction efficiency.
Smart Images
Figure CN119241518A_ABST
Abstract
Description
Technical Field
[0001] The invention relates to a preparation method for continuously synthesizing an empagliflozin intermediate by utilizing a microchannel reactor, and belongs to the field of drug intermediate preparation. Background Art
[0002] Empagliflozin, an innovative product of Boehringer Ingelheim, is a selective SGLT-2 inhibitor that has been launched in Europe, the United States, Japan since 2014 and in China in 2017, leading a new era of oral hypoglycemic drugs. Its unique mechanism acts precisely on the renal tubules, promotes urinary sugar excretion, and effectively regulates blood sugar levels. It is designed specifically for patients with type 2 diabetes. Clinical verification shows that Empagliflozin not only has excellent efficacy, but also has excellent safety and tolerability, bringing good news to diabetic patients.
[0003] At present, the production of empagliflozin still relies on traditional kettle-type stirred reactors, which have slow heat transfer and strict temperature control requirements to prevent temperature fluctuations, limiting production efficiency. The core synthesis step, para-glucosylation of benzene ring chlorine, requires precise control at extremely low temperatures. The slightest carelessness can lead to uncontrolled temperature rise, explosion risk or a surge in by-products. The traditional stirring mode makes it difficult to ensure uniform mixing of materials, thereby reducing the conversion rate of raw materials and increasing the proportion of by-products, becoming a key bottleneck restricting process optimization. Summary of the invention
[0004] In view of the defects existing in the above prior art, the present invention provides a preparation method for continuously synthesizing empagliflozin intermediates using a microchannel reactor, and the problem solved is how to achieve a preparation method that increases product yield and reduces the generation of by-products.
[0005] The object of the present invention is achieved by the following technical scheme: a method for preparing an empagliflozin intermediate by continuous synthesis using a microchannel reactor, the method comprising the following steps: S1: mixing the compound of formula IV (3S)-3-[4-[(2-chloro-5-iodophenyl)methyl]phenoxy]tetrahydrofuran with a solvent to obtain a solution a; S2: mixing the compound of formula III, bis-pinacol diboron, with a solvent to obtain a solution b; S3: mixing the compound of formula II, acetyl glucosyl bromide, and a solvent to obtain a solution c; S4: adjust the flow rate of the double-plunger high-pressure constant-flow infusion pump; S5: Cooling down the coil reactor of the continuous flow device; S6: feeding the pre-cooled solution a and solution b into the coil reactor simultaneously, and performing a coupling reaction to obtain solution d; S7: Solution c and solution d are mixed and fed into a microchannel reactor for reaction. After the reaction, the intermediate of empagliflozin compound of formula I is obtained by quenching, extraction and purification.
[0006] The synthetic route of the compound of formula 1 is: Furthermore, in the steps S1 to S3, the solvent is selected from one of a single organic solvent such as tetrahydrofuran, dioxane and toluene and an aqueous solution thereof.
[0007] Preferably, in step S1 and step S3, toluene aqueous solution is used as the solvent, and in step S2, dioxane is used as the solvent.
[0008] Furthermore, in the steps S6 and S7, the reaction is carried out under the catalysis of a base and a catalyst, the base is an organic base or an inorganic base, and the catalyst is a palladium or nickel catalyst.
[0009] Preferably, the organic base includes but is not limited to triethylamine, sodium (potassium) ethoxide, sodium (potassium) tert-butoxide, sodium (potassium) acetate; the inorganic base includes but is not limited to sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide; potassium carbonate is preferred; Preferably, the nickel compound catalyst may be nickel chloride, nickel bromide, (1,1'-bis(diphenylphosphino)ferrocene) nickel dichloride, bis(triphenylphosphine) nickel chloride, etc., preferably (1,1'-bis(diphenylphosphino)ferrocene) nickel dichloride; Preferably, the palladium compound catalyst may be palladium chloride, palladium acetate, tetrakis(triphenylphosphine)palladium, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, bistriphenylphosphine palladium dichloride, etc., preferably [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride.
[0010] Furthermore, in step S6, the molar ratio of the base to the compound of formula IV is 1.5-4:1.
[0011] Preferably, the amount of the base used is 2.5 eq relative to the compound of formula IV.
[0012] Furthermore, in step S6, the molar ratio of the catalyst to the compound of formula IV is 0.01-0.05:1.
[0013] Preferably, the amount of the catalyst used is 0.03 eq relative to the compound of formula IV.
[0014] Furthermore, in step S7, the molar ratio of the base to the compound of formula II is 1.2-4:1.
[0015] Preferably, the amount of the base used is 2 eq relative to the compound of formula II.
[0016] Furthermore, in step S7, the molar ratio of the catalyst to the compound of formula II is 0.01-0.03:1.
[0017] Preferably, the amount of the catalyst used is 0.02 eq relative to the compound of formula II.
[0018] Furthermore, in step S6, the feeding rates of solution a and solution b are 1:1 to 5 mL / min.
[0019] Furthermore, in step S7, the feeding rates of solution d and solution c are 1:0.5-3 mL / min.
[0020] In summary, compared with the prior art, the present invention has the following advantages: In the present invention, the innovative use of microchannel reactor technology significantly improves the mass transfer and heat transfer efficiency of empagliflozin preparation, ensures that the reaction temperature is constant and does not fluctuate, completely avoids the risk of temperature runaway, effectively inhibits the generation of by-products, and greatly enhances production safety. The excellent mass transfer performance in the microchannel ensures the comprehensive and uniform mixing of the liquid-solid heterogeneous reaction liquid, accelerates the reaction process, and greatly shortens the traditional reaction time of several hours to tens of seconds to a few minutes, significantly shortening the production cycle. In addition, the stable reaction environment further reduces the by-product problems caused by temperature fluctuations or excessive time consumption, comprehensively improves the reaction efficiency and product quality, and opens up a new efficient and safe path for the industrial production of empagliflozin. BRIEF DESCRIPTION OF THE DRAWINGS
[0021] Figure 1 This is the overall synthetic route of the present invention. DETAILED DESCRIPTION
[0022] The technical solution of the present invention is further specifically described below through specific embodiments, but the present invention is not limited to these embodiments.
[0023] 36.6 g of the compound of formula IV and 150 ml of toluene aqueous solution were mixed to obtain solution a; 30.5 g of the compound of formula III and 150 ml of dioxane solution were mixed to obtain solution b; 45.1 g of the compound of formula II and 200 ml of toluene aqueous solution were mixed to obtain solution c.
[0024] Adjust the flow rates of double-plunger high-pressure constant-flow infusion pumps A, B, and C, wherein the flow rates of plunger pumps A, B, and C are 1.0 ml / min, 1.3 ml / min, and 0.4 ml / min; cool the coil reactor of the continuous flow equipment to -5°C to 0°C, and then inject solutions a and b into the coil reactor simultaneously using plunger pumps A and B, respectively; dissolve 34.5 g of potassium carbonate and 2.2 g of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride in 100 ml of tetrahydrofuran solution, and inject them into the coil reactor using plunger pump C; after the reaction liquid flows out, drip it into the reaction bottle and collect and store it as solution d.
[0025] Under the protection of inert gas, solution c is input into the preheating zone 1 of the microchannel reactor through metering pump 1, and solution d is input into the preheating zone 2 of the device through metering pump 2. The preheating temperature and reaction temperature are set to 30°C. After the two materials are preheated for 20 minutes respectively, they enter the reaction zone 1 for mixed reaction.
[0026] After the mixed reaction is completed, solution d is transported to preheating zone 3 through metering pump 3, and 46.7g potassium phosphate and 2.54g tetrakis(triphenylphosphine)palladium are dissolved in toluene solution and input into preheating zone 4 of the device through metering pump 4. The preheating temperature is set to 30°C, the reaction temperature is set to 55°C, and the reaction pressure and reaction residence time remain unchanged. After 20 minutes of preheating, the materials in preheating zone 3 and preheating zone 4 are transported to reaction zone 2 for mixed reaction.
[0027] The product was collected from the outlet, extracted with tetrahydrofuran, recrystallized at 25°C for 1 h, filtered at 10 mbar for 1 h, and dried at 70°C for 4 h to obtain 48.13 g of empagliflozin intermediate, with a product yield of 78.1% and a product purity of 98.6%.
[0028] This is a comparative example of Example 1. The amount of the base in step S6 is adjusted to 4 eq relative to the compound of formula IV, and the amount of the catalyst in step S6 is adjusted to 0.05 eq relative to the compound of formula IV. The final product yield is 78.5% and the product purity is 98.2%.
[0029] This is a comparative example of Example 1. The amount of the base in step S6 is adjusted to 1.5 eq relative to the compound of formula IV, and the amount of the catalyst in step S6 is adjusted to 0.01 eq relative to the compound of formula IV. The final product yield is 76.4% and the product purity is 97%.
[0030] This is a comparative example of Example 1. The amount of the base in step S7 is adjusted to 4 eq relative to the compound of formula IV, and the amount of the catalyst in step S7 is adjusted to 0.03 eq relative to the compound of formula IV. The final product yield is 78.2% and the product purity is 99%.
[0031] This is a comparative example of Example 1. The amount of the base in step S7 is adjusted to 1.2 eq relative to the compound of formula IV, and the amount of the catalyst in step S7 is adjusted to 0.01 eq relative to the compound of formula IV. The final product yield is 77% and the product purity is 96.4%.
[0032] The implementation of the present invention is not limited to the above-mentioned embodiments. Without departing from the spirit and scope of the present invention, ordinary technicians in this field can make various changes and improvements to the present invention in form and detail, and these are considered to fall within the protection scope of the present invention.
Claims
1. A method for preparing an empagliflozin intermediate by continuously synthesizing the empagliflozin intermediate using a microchannel reactor, characterized in that: The preparation method comprises: S1: mixing the compound of formula IV (3S)-3-[4-[(2-chloro-5-iodophenyl)methyl]phenoxy]tetrahydrofuran with a solvent to obtain a solution a; S2: mixing the compound of formula III, bis-pinacol diboron, with a solvent to obtain a solution b; S3: mixing the compound of formula II, acetyl glucosyl bromide, and a solvent to obtain a solution c; S4: adjust the flow rate of the double-plunger high-pressure constant-flow infusion pump; S5: Cooling down the coil reactor of the continuous flow device; S6: feeding the pre-cooled solution a and solution b into the coil reactor simultaneously, and performing a coupling reaction to obtain solution d; S7: Solution c and solution d are mixed and fed into a microchannel reactor for reaction. After the reaction, the intermediate of empagliflozin compound of formula I is obtained by quenching, extraction and purification.
2. The method for preparing an empagliflozin intermediate by continuously synthesizing the empagliflozin intermediate using a microchannel reactor according to claim 1, characterized in that: In the steps S1 to S3, the solvent is selected from a single organic solvent such as tetrahydrofuran, dioxane and toluene and an aqueous solution thereof.
3. The method for preparing an empagliflozin intermediate by continuously synthesizing the empagliflozin intermediate using a microchannel reactor according to claim 2, characterized in that: In the steps S6 and S7, the reaction is carried out under the catalysis of a base and a catalyst, the base is an organic base or an inorganic base, and the catalyst is a palladium or nickel catalyst.
4. The method for preparing an empagliflozin intermediate by continuously synthesizing the empagliflozin intermediate using a microchannel reactor according to claim 3, characterized in that: In the step S6, the molar ratio of the base to the compound of formula IV is 1.5-4:
1.
5. The method for preparing an empagliflozin intermediate by continuously synthesizing the empagliflozin intermediate using a microchannel reactor according to claim 4, characterized in that: In step S6, the molar ratio of the catalyst to the compound of formula IV is 0.01-0.05:
1.
6. The method for preparing an empagliflozin intermediate by continuously synthesizing the empagliflozin intermediate using a microchannel reactor according to claim 5, characterized in that: In the step S7, the molar ratio of the base to the compound of formula II is 1.2-4:
1.
7. The method for preparing an empagliflozin intermediate by continuously synthesizing the empagliflozin intermediate using a microchannel reactor according to claim 6, characterized in that: In step S7, the molar ratio of the catalyst to the compound of formula II is 0.01-0.03:
1.
8. The method for preparing an empagliflozin intermediate by continuously synthesizing the empagliflozin intermediate using a microchannel reactor according to claim 7, characterized in that: In the step S6, the feeding rate of solution a and solution b is 1:1-5 mL / min.
9. The method for preparing an empagliflozin intermediate by continuously synthesizing the empagliflozin intermediate using a microchannel reactor according to claim 8, characterized in that: In step S7, the feeding rates of solution d and solution c are 1:0.5-3 mL / min.