Amorphous substance of empagliflozin intermediate and preparation method thereof
Through a specific synthesis route and reaction conditions, a high-purity and high-stability amorphous intermediate of empagliflozin was prepared, which solved the problems of insufficient purity and stability in the existing technology and met the needs of industrial production.
Patent Information
- Application Number
- CN202511067560.3
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-07-31
- Publication Date
- 2025-10-17
AI Technical Summary
In the existing technology, the purity and stability of empagliflozin intermediates are insufficient to meet the requirements of industrial production.
A specific synthetic route and reaction conditions are adopted, including using toluene and tetrahydrofuran as solvents, adding n-butyl lithium and compound IV for reaction, followed by quenching, extraction and crystallization steps to finally obtain a high-purity empagliflozin intermediate amorphous substance.
The prepared empagliflozin intermediate amorphous material has high purity, good stability, is easy to store, and is suitable for industrial production.
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Figure CN120795044A_ABST
Abstract
Description
TECHNICAL FIELD
[0001] The application belongs to the field of medicine and chemical industry, and particularly relates to an amorphous substance of an empagliflozin intermediate and a preparation method thereof. BACKGROUND
[0002] Empagliflozin, English name: Empagliflozin, chemical name: (1S)-1,5-dideoxy-1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-furanyl]oxy]phenyl]methyl]phenyl]-D-glucitol, is a selective oral SGLT-2 inhibitor jointly developed by Boehringer Ingelheim and Eli Lilly. It is a drug that can directly reduce blood glucose by selectively inhibiting the reabsorption of filtered glucose in the proximal tubule of the glomerulus, making excess glucose excreted from urine, and is used for treating type II diabetes. Recent clinical research results show that the drug has significant efficacy, good safety and tolerability, and has broad market prospects.
[0003] Methyl 1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-furanyl]oxy]phenyl]methyl]phenyl]-ALPHA-D-glucopyranoside (compound I) is an important intermediate for preparing empagliflozin, and its chemical structural formula is as follows:
[0004]
[0005] The research team of the inventors found the amorphous substance of the empagliflozin intermediate (compound I) in the research process. The amorphous substance is a powder-like substance, easy to store, and has high purity and good stability. SUMMARY
[0006] The purpose of the present application is to provide an amorphous substance of an empagliflozin intermediate with high purity and excellent stability and a preparation method thereof.
[0007] To achieve the above-mentioned purpose, the present application provides the following technical scheme:
[0008] An amorphous substance of an empagliflozin intermediate, wherein the intermediate is methyl 1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-furanyl]oxy]phenyl]methyl]phenyl]-ALPHA-D-glucopyranoside.
[0009] The powder X-ray diffraction is obtained by using CuKa rays, and the overall peak shape is as shown in the following figure: Figure 1
[0010] The present application also discloses a preparation method of the amorphous substance of the empagliflozin intermediate, comprising the following steps:
[0011] (1) Compound II was added with toluene and tetrahydrofuran, stirred to dissolve, replaced with nitrogen, protected, controlled the temperature, injected with n-butyl lithium, and kept warm for reaction. The reaction of the raw materials was completed after testing;
[0012] (2) controlling the temperature, adding the toluene solution of compound IV to the reaction solution obtained in step (1), and maintaining the temperature for reaction;
[0013] (3) The reaction solution obtained in step (2) was slowly poured into water for quenching, the liquid was separated, the aqueous phase was back-extracted with toluene, the organic phases were combined, and the mixture was dried in a water bath to obtain a light yellow oil;
[0014] (4) controlling the temperature, adding methanol to the reaction system obtained in step (3) to dissolve the mixture, then adding methanesulfonic acid, and maintaining the temperature for reaction;
[0015] (5) slowly pouring the reaction system obtained in step (4) into saturated sodium bicarbonate to quench, evaporating the organic solvent in a water bath, adding dichloromethane to separate the liquids, back-extracting the aqueous phase with dichloromethane, combining the organic phases, washing with water, separating the liquids, and drying the organic phase in a water bath to obtain an oily substance;
[0016] (6) Ethyl acetate was added to the oil obtained in step (5), and the mixture was heated until it became clear. Then, n-heptane was added to precipitate a solid. The mixture was cooled and crystallized, filtered, and dried to obtain the target product, Compound I. The synthetic route is as follows:
[0017]
[0018] Furthermore, in the step (1), the molar ratio of compound II to n-butyl lithium is 1:1-3.
[0019] Furthermore, in step (2), the molar ratio of compound II to compound IV is 1:1-3.
[0020] Furthermore, in step (4), the molar ratio of compound II to methanesulfonic acid is 1:0.2-2.
[0021] Furthermore, in steps (1) and (2), the reaction temperature is -100 to -50°C.
[0022] Furthermore, in the step (4), the reaction temperature is 5 to 40°C.
[0023] Furthermore, in the step (6), the mass volume ratio of the oil obtained in the step (5) to ethyl acetate is 1:1 to 10.
[0024] Furthermore, in step (6), the mass volume ratio of the oil obtained in step (5) to n-heptane is 1:5 to 20.
[0025] Compared with the prior art, the present invention has the following beneficial effects:
[0026] The amorphous substance of the empagliflozin intermediate obtained by the application has high purity, good stability and easy preservation, the preparation method is simple in operation and suitable for industrial production. BRIEF DESCRIPTION OF DRAWINGS
[0027] Figure 1 The XRPD pattern of the target product in Example 1 of the application. DETAILED DESCRIPTION
[0028] The technical solutions in the examples of the application will be described clearly and completely below. Obviously, the described examples are only a part of the examples of the application, rather than all the examples. Based on the examples in the application, all the other examples obtained by those skilled in the art without creative labor fall within the protection scope of the application.
[0029] Example 1
[0030]
[0031] A preparation method of an amorphous substance of an empagliflozin intermediate, and the specific steps are as follows:
[0032] (1) Take compound II (20 g, 54.4 mmol), add 120 mL of toluene and 60 mL of tetrahydrofuran, stir to dissolve, replace with nitrogen, control the temperature to-80℃, inject n-butyl lithium (4.9 g, 76.2 mmol), and keep the reaction, and detect that the raw material is completely reacted;
[0033] (2) Control the temperature to-80℃, add a toluene (100 mL) solution of compound IV (38.1 g, 81.6 mmol) to the reaction liquid obtained in step (1), and keep the reaction;
[0034] (3) Slowly pour the reaction liquid obtained in step (2) into 100 mL of water to quench, separate the liquid, use 20 mL of toluene to back-extract the water phase, combine the organic phases, and dry in a water bath to obtain a light yellow oil;
[0035] (4) Control the temperature to 20℃, add 80 mL of methanol to the reaction system obtained in step (3), dissolve, then add methane sulfonic acid (6.3 g, 65.3 mmol), and keep the reaction;
[0036] (5) Slowly pour the reaction system obtained in step (4) into saturated sodium bicarbonate to quench, remove the organic solvent by water bath rotary evaporation, separate the liquid, back-extract the water phase with dichloromethane, combine the organic phases, wash with water, separate the liquid, dry the organic phase in a water bath to obtain an oil;
[0037] (6) To the oil obtained in step (5), add ethyl acetate (mass volume ratio of oil and ethyl acetate is 1:3), heat to dissolve, then add n-heptane (mass volume ratio of oil and n-heptane is 1:10), and solid precipitates; cool to crystallize, filter, and dry to obtain the target product compound I, with a yield of 96.4% and a purity of 99.7%. The XRPD pattern of compound I is shown in Figure 1
[0038] Example 2
[0039]
[0040] A preparation method of an amorphous substance of an empagliflozin intermediate, and the specific steps are as follows:
[0041] (1) Take compound II (20 g, 54.4 mmol), add 120 mL of toluene and 60 mL of tetrahydrofuran, stir to dissolve, replace with nitrogen, control the temperature to-60°C, inject n-butyllithium (7 g, 108.8 mmol), and incubate to react. After detection, it is determined that the raw material has completely reacted.
[0042] (2) Control the temperature to-60°C, add a toluene (100 mL) solution of compound IV (55.9 g, 119.7 mmol) to the reaction solution obtained in step (1), and incubate to react.
[0043] (3) Slowly pour the reaction solution obtained in step (2) into 100 mL of water to quench, separate the liquid, use 20 mL of toluene to back-extract the aqueous phase, combine the organic phases, and dry on a water bath to obtain a light yellow oil;
[0044] (4) Control the temperature to 30°C, add 80 mL of methanol to the reaction system obtained in step (3), dissolve, then add methane sulfonic acid (3.1 g, 32.6 mmol), and incubate to react.
[0045] (5) Slowly pour the reaction system obtained in step (4) into saturated sodium bicarbonate to quench, remove the organic solvent on a water bath, separate the liquid, back-extract the aqueous phase with dichloromethane, combine the organic phases, wash with water, separate the liquid, dry the organic phase on a water bath, and obtain an oil;
[0046] (6) To the oil obtained in step (5), add ethyl acetate (mass volume ratio of oil and ethyl acetate is 1:1.5), heat to dissolve, then add n-heptane (mass volume ratio of oil and n-heptane is 1:8), and solid precipitates; cool to crystallize, filter, and dry to obtain the target product compound I, with a yield of 96.4% and a purity of 99.7%. The XRPD pattern of compound I is shown in
[0047] Example 3
[0048]
[0049] A preparation method of an amorphous substance of an empagliflozin intermediate, the specific steps are as follows:
[0050] (1) Take compound II (20 g, 54.4 mmol), add 120 mL of toluene and 60 mL of tetrahydrofuran, stir to dissolve, replace with nitrogen, control the temperature to-90℃, inject n-butyl lithium (4.2 g, 65.3 mmol), and keep the reaction, and after detection, the raw material is completely reacted;
[0051] (2) Control the temperature to-90℃, add a toluene (100 mL) solution of compound IV (33 g, 70.7 mmol) to the reaction liquid obtained in step (1), and keep the reaction;
[0052] (3) Slowly pour the reaction liquid obtained in step (2) into 100 mL of water to quench, separate the liquid, use 20 mL of toluene to back-extract the aqueous phase, combine the organic phases, and dry in a water bath to obtain a light yellow oil;
[0053] (4) Control the temperature to 10℃, add 80 mL of methanol to the reaction system obtained in step (3), dissolve, then add methane sulfonic acid (7.8 g, 81.6 mmol), and keep the reaction;
[0054] (5) Slowly pour the reaction system obtained in step (4) into saturated sodium bicarbonate to quench, remove the organic solvent by water bath rotary evaporation, separate the liquid, back-extract the aqueous phase with dichloromethane, combine the organic phases, wash with water, separate the liquid, dry the organic phase in a water bath to obtain an oil;
[0055] (6) Add ethyl acetate (the mass and volume ratio of the oil and ethyl acetate is 1:5) to the oil obtained in step (5), heat to dissolve, then add n-heptane (the mass and volume ratio of the oil and n-heptane is 1:14), and solid is precipitated; cool to precipitate crystals, filter, and dry to obtain the target product compound I, with a yield of 93.4% and a purity of 99.6%.
[0056] Although the embodiments of the present application have been shown and described, it can be understood by those skilled in the art that various changes, modifications, replacements and variations can be made to the embodiments without departing from the principles and spirits of the present application, and the scope of the present application is defined by the appended claims and their equivalents.
Claims
1. An amorphous intermediate of empagliflozin, characterized in that: The intermediate is methyl 1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-furanyl]oxy]phenyl]methyl]phenyl]-ALPHA-D-glucopyranoside.
2. The amorphous intermediate of empagliflozin according to claim 1, characterized in that: The powder X-ray diffraction spectrum is obtained using CuKa radiation, and its overall peak shape is shown in FIG1 .
3. A method for preparing the amorphous product of the empagliflozin intermediate according to claim 1 or 2, characterized in that: The following steps are involved: (1) Compound II was added with toluene and tetrahydrofuran, stirred to dissolve, replaced with nitrogen, protected, controlled the temperature, injected with n-butyl lithium, and kept warm for reaction. The reaction of the raw materials was completed after testing; (2) controlling the temperature, adding the toluene solution of compound IV to the reaction solution obtained in step (1), and maintaining the temperature for reaction; (3) The reaction solution obtained in step (2) was slowly poured into water for quenching, the liquid was separated, the aqueous phase was back-extracted with toluene, the organic phases were combined, and the mixture was dried in a water bath to obtain a light yellow oil; (4) controlling the temperature, adding methanol to the reaction system obtained in step (3) to dissolve the mixture, then adding methanesulfonic acid, and maintaining the temperature for reaction; (5) slowly pouring the reaction system obtained in step (4) into saturated sodium bicarbonate to quench, evaporating the organic solvent in a water bath, adding dichloromethane to separate the liquids, back-extracting the aqueous phase with dichloromethane, combining the organic phases, washing with water, separating the liquids, and drying the organic phase in a water bath to obtain an oily substance; (6) Ethyl acetate was added to the oil obtained in step (5), and the mixture was heated until it became clear. Then, n-heptane was added to precipitate a solid. The mixture was cooled and crystallized, filtered, and dried to obtain the target product, Compound I. Its synthetic route is as follows:
4. The method for preparing the amorphous product of the empagliflozin intermediate according to claim 3, wherein: In the step (1), the molar ratio of compound II to n-butyl lithium is 1:1-3.
5. The method for preparing the amorphous product of the empagliflozin intermediate according to claim 3, characterized in that: In the step (2), the molar ratio of compound II to compound IV is 1:1-3.
6. The method for preparing the amorphous form of the empagliflozin intermediate according to claim 3, wherein: In the step (4), the molar ratio of compound II to methanesulfonic acid is 1:0.2-2.
7. The method for preparing the amorphous form of the empagliflozin intermediate according to claim 3, wherein: In the steps (1) and (2), the reaction temperature is -100 to -50°C.
8. The method for preparing the amorphous form of the empagliflozin intermediate according to claim 3, wherein: In the step (4), the reaction temperature is 5 to 40°C.
9. The method for preparing the amorphous product of the empagliflozin intermediate according to claim 3, wherein: In the step (6), the mass volume ratio of the oily substance obtained in the step (5) to ethyl acetate is 1:1 to 10.
10. The method for preparing the amorphous product of the empagliflozin intermediate according to claim 3, characterized in that: In the step (6), the mass volume ratio of the oily substance obtained in the step (5) to n-heptane is 1:5 to 20.