Large-scale preparation method of empagliflozin intermediate with ultralow water content
Through specific reaction steps and washing processes, the problems of low purity and high moisture content in engaliflozine synthesis were solved, and the preparation of high purity and low moisture 2,3,4,6-tetra-0-(trimethylsilyl)-D-gluconic acid lactone was achieved, improving the stability of the product.
Patent Information
- Application Number
- CN202411981594.9
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-31
- Publication Date
- 2025-03-28
AI Technical Summary
In the existing engagliflozin synthesis methods, the product has low purity and high moisture content, which leads to the product being prone to degradation and deterioration.
Tetrahydrofuran, N-methylmorpholine, gluconate-δ-lactone and 4-dimethylaminopyridine are used as raw materials. Through specific reaction steps and washing processes, 2,3,4,6-tetra-0-(trimethylsilyl)-D-gluconate lactone is prepared, and the temperature and stirring time of the material are controlled to ensure high purity and low moisture of the product.
The purity of 2,3,4,6-tetra-0-(trimethylsilyl)-D-gluconic acid lactone in large-scale factory production has reached more than 98%, and the moisture content is less than 0.05%, effectively avoiding hydrolysis and improving the quality stability of the product.
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Figure CN119708045A_ABST
Abstract
Description
Technical Field
[0001] The invention relates to a large-scale preparation method of empagliflozin with ultra-low water content, and belongs to the field of pharmaceutical chemical synthesis. Background Art
[0002] Empagliflozin (chemical name: (2S,3R,4R,5S,6R)-2-[4-chloro-3-[4-[(S)-tetrahydrofuran-3-yloxy]benzyl]phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol) is used to improve blood sugar control in adult patients with type 2 diabetes. Empagliflozin belongs to the emerging sodium-glucose cotransporter-2 (SGLT-2) inhibitor class of hypoglycemic drugs, which can block the reabsorption of glucose in the kidneys and excrete excess glucose to the body to achieve the effect of lowering blood sugar, and this hypoglycemic effect is independent of β-cell function and insulin resistance. The drug is currently the SGLT2 inhibitor with the most comprehensive indications approved in China. It can be used alone, in combination with metformin, or in combination with metformin and sulfonylurea drugs, which provides a powerful weapon for endocrinologists to better manage the cardiovascular risks of diabetic patients. 2,3,4,6-Tetra-O-(trimethylsilyl)-D-gluconolactone is an important intermediate of empagliflozin API. 2,3,4,6-Tetra-O-trimethylsilyl-D-gluconolactone (TMS-D-gluconolactone for short) has a certain degree of water sensitivity. The compound may undergo chemical changes when exposed to moisture, affecting its stability and expected chemical properties. Specifically, TMS-D-gluconolactone is easily hygroscopic in a humid environment, which may cause the trimethylsilyl (TMS) protecting group in its structure to be hydrolyzed and lose its protective effect. Therefore, during storage and handling, measures need to be taken to avoid exposure to air or contact with moisture. It is generally recommended to store it at 2-8°C under an inert gas environment (such as nitrogen or argon).
[0003] The methods reported in existing literature are mostly laboratory-level preparation methods. The purity of 2,3,4,6-tetra-0-(trimethylsilyl)-D-gluconolactone obtained by expanding production using existing methods is only about 90%, and the water content is high, and the product is easily degraded and deteriorated. Summary of the invention
[0004] The present invention provides a large-scale preparation method of empagliflozin with ultra-low water content, which solves the problems of low product purity, especially high water content, and easy degradation and deterioration of the product in the existing synthesis method.
[0005] In order to solve the above technical problems, the technical solution adopted by the present invention is: A large-scale preparation method of empagliflozin with ultra-low water content comprises the following steps: (1) Using tetrahydrofuran, N-methylmorpholine, glucono-δ-lactone and 4-dimethylaminopyridine as raw materials, 2,3,4,6-tetra-0-(trimethylsilyl)-D-glucono-lactone was prepared by reaction; (2) After the reaction in step (1) is completed, the feed liquid temperature is lowered to 0-10°C, the temperature is controlled at 0-10°C, a toluene / purified water mixture is added, the feed liquid temperature is controlled at 0-10°C, stirred for 30 minutes, allowed to stand for 30 minutes, stratification begins, and the aqueous phase is discarded; (3) Control the temperature at 0-10°C and wash the organic phase once with sodium dihydrogen phosphate solution; (4) Control the temperature at 5-15°C and wash the organic phase twice with sodium dihydrogen phosphate solution; (5) Control the temperature at 10-20°C and wash the organic phase twice with purified water; (6) The organic phase is concentrated under reduced pressure to obtain 2,3,4,6-tetra-0-(trimethylsilyl)-D-gluconolactone.
[0006] Furthermore, preferably, the toluene / purified water mixture is a solution of toluene and purified water mixed in a volume ratio of 1:1.
[0007] Further, preferably: the concentration of the sodium dihydrogen phosphate solution is 0.36-0.38 mol / L.
[0008] Further, preferably: the organic phase is concentrated under reduced pressure by: at 45-55°C, vacuum degree <-0.08MPA, and concentrated under reduced pressure until there is no fraction.
[0009] Furthermore, preferably, the stirring speed in step (2) is 60-80 r / min.
[0010] Further, preferably: the step (1) is specifically: 1) Tetrahydrofuran, N-methylmorpholine, glucono-δ-lactone and 4-dimethylaminopyridine were added to the reaction kettle in sequence, and the reaction kettle was evacuated and replaced with nitrogen three times, and the temperature was lowered to 0-5°C under nitrogen protection; 2) Control the temperature at 0-10°C, add trimethylchlorosilane, and after the addition is complete, control the temperature at 0-10°C and stir for 15 minutes; 3) Raise the temperature, control the temperature at 20-30°C, and stir the reaction for 18-20 hours; 4) Monitor the reaction by HPLC until the concentration of glucono-δ-lactone is ≤2.0%. If the concentration of glucono-δ-lactone is >2.0%, take samples every hour for monitoring.
[0011] Furthermore, preferably: the vacuum degree of the vacuum extraction in step 1) is ≤-0.060 MPa.
[0012] Furthermore, preferably, the stirring speed in steps 2) and 3) is 60-80 r / min.
[0013] Beneficial effects of the present invention: By adopting the method of the present invention, the purity of 2,3,4,6-tetra-0-(trimethylsilyl)-D-gluconolactone prepared in large-scale factory is above 98%, and the water content is less than 0.05%, which can effectively avoid the hydrolysis of 2,3,4,6-tetra-0-(trimethylsilyl)-D-gluconolactone and improve the stability of its quality. BRIEF DESCRIPTION OF THE DRAWINGS
[0014] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.
[0015] Figure 1 The HPLC chart of 2,3,4,6-tetra-0-(trimethylsilyl)-D-gluconolactone prepared by the present invention. DETAILED DESCRIPTION
[0016] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.
[0017] Example 1 A large-scale preparation method of empagliflozin with ultra-low water content comprises the following steps: (1) Add 174 kg of tetrahydrofuran, 159 kg of N-methylmorpholine, 28.0 kg of glucono-δ-lactone, and 0.98 kg of 4-dimethylaminopyridine to the reactor in sequence, evacuate and replace with nitrogen three times; cool down and control the feed liquid temperature to 0-5°C. Add 137 kg of trimethylchlorosilane in a stream, and control the feed liquid temperature to 0-10°C during the stream addition. After the stream addition is completed, control the feed liquid temperature to 0-10°C, stir for 15 minutes, increase the temperature, control the feed liquid temperature to 20-30°C, stir and react for 18-20 hours, and monitor the reaction by HPLC until glucono-δ-lactone ≤ 2.0%. If glucono-δ-lactone is > 2.0%, sample and monitor every hour; (2) The temperature of the feed liquid was lowered to 0-10°C, and the temperature was controlled at 0-10°C. The reaction system was added dropwise to a mixture of toluene (280 L) and purified water (280 L). After the addition was completed, the temperature of the feed liquid was controlled at 0-10°C, stirred (70 r / min) for 30 minutes, and allowed to stand for 30 minutes. The layers began to separate, and the aqueous phase was discarded. (3) Control the temperature at 0-10°C and wash the organic phase once with sodium dihydrogen phosphate solution (0.375 mol / L); (4) Control the temperature at 5-15°C and wash the organic phase twice with sodium dihydrogen phosphate solution (0.375 mol / L); (5) Control the temperature at 10-20°C and wash the organic phase twice with purified water; (6) The organic phase was concentrated under reduced pressure at 45-55°C and vacuum degree <-0.08 MPA until there was no fraction. After concentration, 71.28 kg of 2,3,4,6-tetra-0-(trimethylsilyl)-D-gluconolactone was obtained with a yield of 91.6% and a water content of 0.003%. The HPLC results of the product were as follows: Figure 1 As shown, the purity is 98%.
[0018] Example 2 A large-scale preparation method of empagliflozin with ultra-low water content comprises the following steps: (1) Add 174 kg of tetrahydrofuran, 159 kg of N-methylmorpholine, 28.0 kg of glucono-δ-lactone, and 0.98 kg of 4-dimethylaminopyridine to the reactor in sequence, evacuate and replace with nitrogen three times; cool down and control the feed liquid temperature to 0-5°C. Add 137 kg of trimethylchlorosilane in a stream, and control the feed liquid temperature to 0-10°C during the stream addition. After the stream addition is completed, control the feed liquid temperature to 0-10°C, stir for 15 minutes, increase the temperature, control the feed liquid temperature to 20-30°C, stir and react for 18-20 hours, and monitor the reaction by HPLC until glucono-δ-lactone ≤ 2.0%. If glucono-δ-lactone is > 2.0%, sample and monitor every hour; (2) The temperature of the feed liquid was lowered to 0-10°C, and the temperature was controlled at 0-10°C. The reaction system was added dropwise to a mixture of toluene (280 L) and purified water (280 L). After the addition was completed, the temperature of the feed liquid was controlled at 0-10°C, stirred (60 r / min) for 30 minutes, and allowed to stand for 30 minutes. The layers began to separate, and the aqueous phase was discarded. (3) Control the temperature at 0-10°C and wash the organic phase once with sodium dihydrogen phosphate solution (0.370 mol / L); (4) Control the temperature at 5-15°C and wash the organic phase twice with sodium dihydrogen phosphate solution (0.370 mol / L); (5) Control the temperature at 10-20°C and wash the organic phase twice with purified water; (6) The organic phase was concentrated under reduced pressure at 45-55°C and a vacuum degree of <-0.08 MPA until there was no fraction. After concentration, 72.16 kg of 2,3,4,6-tetra-0-(trimethylsilyl)-D-gluconolactone was obtained with a yield of 91.7%, a water content of 0.002%, and a purity of 97%.
[0019] Example 3 A large-scale preparation method of empagliflozin with ultra-low water content comprises the following steps: (1) Add 174 kg of tetrahydrofuran, 159 kg of N-methylmorpholine, 28.0 kg of glucono-δ-lactone, and 0.98 kg of 4-dimethylaminopyridine to the reactor in sequence, evacuate and replace with nitrogen three times; cool down and control the feed liquid temperature to 0-5°C. Add 137 kg of trimethylchlorosilane in a stream, and control the feed liquid temperature to 0-10°C during the stream addition. After the stream addition is completed, control the feed liquid temperature to 0-10°C, stir for 15 minutes, increase the temperature, control the feed liquid temperature to 20-30°C, stir and react for 18-20 hours, and monitor the reaction by HPLC until glucono-δ-lactone ≤ 2.0%. If glucono-δ-lactone is > 2.0%, sample and monitor every hour; (2) The temperature of the feed liquid was lowered to 0-10°C, and the temperature was controlled at 0-10°C. The reaction system was added dropwise to a mixture of toluene (280 L) and purified water (280 L). After the addition was completed, the temperature of the feed liquid was controlled at 0-10°C, stirred (80 r / min) for 30 minutes, and allowed to stand for 30 minutes. The layers began to separate, and the aqueous phase was discarded. (3) Control the temperature at 0-10°C and wash the organic phase once with sodium dihydrogen phosphate solution (0.380 mol / L); (4) Control the temperature at 5-15°C and wash the organic phase twice with sodium dihydrogen phosphate solution (0.380 mol / L); (5) Control the temperature at 10-20°C and wash the organic phase twice with purified water; (6) The organic phase was concentrated under reduced pressure at 45-55°C and a vacuum degree of <-0.08 MPA until there was no fraction. After concentration, 73.06 kg of 2,3,4,6-tetra-0-(trimethylsilyl)-D-gluconolactone was obtained with a yield of 93.9%, a water content of 0.004%, and a purity of 98%.
[0020] Comparative Example 1 Synthesis reaction: Add 310-SM3 (11.0 kg), NMM (75.0 kg), DMAP (0.385 kg), and THF (68.5 kg) into a 200 L reactor and replace the mixture with nitrogen three times. Cool down to 5 ± 5 °C, control the temperature at 5 ± 5 °C, and add TMSCl (53.7 kg) dropwise. After the addition, control the temperature at 5 ± 5 °C and stir for 15 minutes. Heat to 25 ± 5 °C and stir for 16 h-20 h.
[0021] Post-processing: Add water (78 kg) and n-heptane (52.7 kg) into a 500 L reactor, stir and cool to 5 ± 10 °C; The reaction system was cooled to 10 ± 5 °C, and the reaction system was slowly pressurized into a 500L reactor, and the temperature was controlled at 10 ± 5 °C. After the addition was completed, the reaction system was stirred for 1 hour, and the mixture was allowed to stand for 0.5 hour for extraction and separation, and the organic phase was collected; 3. At 10 ± 5 ℃, add 1 mol / L sodium dihydrogen phosphate aqueous solution (78 kg) to the organic phase and stir for 1 hour. Let it stand for 0.5 hour to extract and separate the liquids. Wash the organic phase once with water (78 kg) and then wash it once with 20% sodium chloride solution (78 kg).
[0022] Drying and concentration: The organic phase was dried with 11.0 kg of anhydrous sodium sulfate and concentrated to no fraction to obtain 7.54 kg of 2,3,4,6-tetra-0-(trimethylsilyl)-D-gluconolactone with a yield of 26.2%, 0.08% water (distilled twice with tetrahydrofuran), and a purity of 90%.
[0023] Comparative Example 2 Synthesis reaction: Add 310-SM3 (11.0kg), NMM (75.0kg), DMAP (0.385kg), and THF (68.5kg) into a 200L reactor and replace with nitrogen three times. Cool down to 5±5℃, control the temperature at 5±5℃, add TMSCl (53.7kg) dropwise, control the temperature at 5±5℃, stir for 15 minutes, raise the temperature to 25±5℃, and stir for 16h-20h.
[0024] Post-processing: Add water (78 kg) and n-heptane (52.7 kg) into a 500 L reactor, stir and cool to 5 ± 10 °C; The reaction system was cooled to 10 ± 5 °C, and the reaction system was slowly pressurized into a 500L reactor, and the temperature was controlled at 10 ± 5 °C. After the addition was completed, the reaction system was stirred for 1 hour, and the mixture was allowed to stand for 0.5 hour for extraction and separation, and the organic phase was collected; 3. At 10 ± 5 ℃, add 1 mol / L sodium dihydrogen phosphate aqueous solution (78 kg) to the organic phase and stir for 1 hour. Let it stand for 0.5 hour to extract and separate the liquids. Wash the organic phase once with water (78 kg) and then wash it once with 20% sodium chloride solution (78 kg).
[0025] Drying and concentration: The organic phase was dried with 11.0 kg of anhydrous sodium sulfate and concentrated to no fraction to obtain 14.8 kg of 2,3,4,6-tetra-0-(trimethylsilyl)-D-gluconolactone with a yield of 51.3%, 0.07% water (distilled three times with tetrahydrofuran), and a purity of 92%.
[0026] Comparative Example 3 Synthesis reaction: Add 310-SM3 (11.0kg), NMM (75.0kg), DMAP (0.385kg), and THF (68.5kg) into a 200L reactor and replace with nitrogen three times. Cool down to 5±5℃, control the temperature at 5±5℃, add TMSCl (53.7kg) dropwise, control the temperature at 5±5℃, stir for 15 minutes, raise the temperature to 25±5℃, and stir for 16h-20h.
[0027] Post-processing: Add water (78 kg) and n-heptane (52.7 kg) into a 500 L reactor, stir and cool to 5 ± 10 °C; The reaction system was cooled to 10 ± 5 °C, and the reaction system was slowly pressurized into a 500L reactor, and the temperature was controlled at 10 ± 5 °C. After the addition was completed, the reaction system was stirred for 1 hour, and the mixture was allowed to stand for 0.5 hour for extraction and separation, and the organic phase was collected; 3. At 10 ± 5 ℃, add 1 mol / L sodium dihydrogen phosphate aqueous solution (78 kg) to the organic phase and stir for 1 hour. Let it stand for 0.5 hour to extract and separate the liquids. Wash the organic phase once with water (78 kg) and then wash it once with 20% sodium chloride solution (78 kg).
[0028] Drying and concentration: The organic phase was dried with 11.0 kg of anhydrous sodium sulfate and concentrated to no fraction to obtain 22.4 kg of 2,3,4,6-tetra-0-(trimethylsilyl)-D-gluconolactone with a yield of 77.7%, a moisture content of 0.08% (distilled twice with tetrahydrofuran), and a purity of 91%.
[0029] From the above comparative examples, it can be seen that the yield of 2,3,4,6-tetra-0-(trimethylsilyl)-D-gluconolactone prepared by the present invention is high, above 91.6%, and the moisture content is low, not higher than 0.004%. The moisture content (0.07-0.08%) of 2,3,4,6-tetra-0-(trimethylsilyl)-D-gluconolactone prepared by comparative examples 1-3 is 17.5-40 times that of the product prepared by the present invention. It can be seen that the moisture content of 2,3,4,6-tetra-0-(trimethylsilyl)-D-gluconolactone prepared by the present invention is much lower than the moisture content of the comparative example. Low moisture content can effectively avoid hydrolysis of 2,3,4,6-tetra-0-(trimethylsilyl)-D-gluconolactone and improve its quality stability.
[0030] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims
1. A large-scale method for preparing an empagliflozin intermediate with ultra-low water content, characterized in that: The following steps are involved: (1) Using tetrahydrofuran, N-methylmorpholine, glucono-δ-lactone and 4-dimethylaminopyridine as raw materials, 2,3,4,6-tetra-0-(trimethylsilyl)-D-glucono-lactone was prepared by reaction; (2) After the reaction in step (1) is completed, the feed liquid temperature is lowered to 0-10°C, the temperature is controlled at 0-10°C, a toluene / purified water mixture is added, the feed liquid temperature is controlled at 0-10°C, stirred for 30 minutes, allowed to stand for 30 minutes, stratification begins, and the aqueous phase is discarded; (3) Control the temperature at 0-10°C and wash the organic phase once with sodium dihydrogen phosphate solution; (4) Control the temperature at 5-15°C and wash the organic phase twice with sodium dihydrogen phosphate solution; (5) Control the temperature at 10-20°C and wash the organic phase twice with purified water; (6) The organic phase is concentrated under reduced pressure to obtain 2,3,4,6-tetra-0-(trimethylsilyl)-D-gluconolactone.
2. The preparation method according to claim 1, characterized in that: The toluene / purified water mixed solution is a solution formed by mixing toluene and purified water in a volume ratio of 1:
1.
3. The preparation method according to claim 1, characterized in that: The concentration of the sodium dihydrogen phosphate solution is 0.36-0.38 mol / L.
4. The preparation method according to claim 1, characterized in that: The organic phase is concentrated under reduced pressure specifically as follows: at 45-55°C, with a vacuum degree of less than -0.08 MPA, and concentrated under reduced pressure until there is no fraction.
5. The preparation method according to claim 1, characterized in that: The stirring speed in step (2) is 60-80 r / min.
6. The preparation method according to any one of claims 1 to 5, characterized in that: The step (1) is specifically as follows: 1) Tetrahydrofuran, N-methylmorpholine, glucono-δ-lactone and 4-dimethylaminopyridine were added to the reaction kettle in sequence, and the reaction kettle was evacuated and replaced with nitrogen three times, and the temperature was lowered to 0-5°C under nitrogen protection; 2) Control the temperature at 0-10°C, add trimethylchlorosilane, and after the addition is complete, control the temperature at 0-10°C and stir for 15 minutes; 3) Raise the temperature, control the temperature at 20-30°C, and stir the reaction for 18-20 hours; 4) Monitor the reaction by HPLC until the concentration of glucono-δ-lactone is ≤2.0%. If the concentration of glucono-δ-lactone is >2.0%, take samples every hour for monitoring.
7. The preparation method according to claim 6, characterized in that: The vacuum degree of the step 1) is ≤-0.060MPa.
8. The preparation method according to claim 6, characterized in that: The stirring speed in steps 2) and 3) is 60-80 r / min.